Construction of 2,3-dihydrofuran cores through the [3+2] cycloaddition of gold α-carbonylcarbenoids with alkenes

Article abstract of DOI:10.1002/chem.201000009

Treatment of 2-epoxy-1-alkynylbenzenes with electron-rich alkenes and a [AuCl(PR₃)]/AgX catalyst in CH₂Cl₂ led to the formation of 2-alkenyl-1-(2,3-dihydrofuran-4-yl)benzenes. This transformation comprises of a gold-catalyzed redox reaction to form a gold α- carbonylcarbenoid initially, which then reacts in situ with an alkene in a [3+2] cycloaddition. A range of alkenes are amenable to this tandem reaction, amongst them α-sub-stituted styrenes, enol ethers, and 2,3dimethylbutadienes. Deuterium-labeling experiments suggest a stepwise mechanism for the α-carbonylcarbenoid/alkene [3+2] cycloaddition. The resulting 2,3-dihydrofuran products allow access to diverse oxacyclic compounds through a stereoselective ene-oxonium reaction initiated by treatment with HOTf (1mol%; Tf= trifluoromethanesulfonyl). A stepwise pathway is proposed for this reaction. The feasibility for direct transformation of 2-alkenyl-1-alkynylbenzenes into the desired 2,3-dihydrofuran products through initial m-chloroperbenzoic acid oxidation, followed by the addition of gold catalyst and alkene, has also been demonstrated.

Full text of DOI:10.1002/chem.201000009

FULL PAPER
DOI: 10.1002/chem.201000009
Construction of 2,3-Dihydrofuran Cores through the [3+2] Cycloaddition
of Gold a-Carbonylcarbenoids with Alkenes
Chia-Wen Li, Guan-You Lin, and Rai-Shung Liu*[a]
Abstract: Treatment of 2-epoxy-1-alky-
nylbenzenes with electron-rich alkenes
stituted styrenes, enol ethers, and 2,3-
dimethylbutadienes. Deuterium-label-
oxonium reaction initiated by treat-
ment with HOTf (1 mol%; Tf=tri-
and
a
[AuCl
(PR3)]/AgX catalyst in
ing experiments suggest
a
stepwise
fluoromethanesulfonyl).
A
stepwise
CH2Cl2 led to the formation of 2-alken-
yl-1-(2,3-dihydrofuran-4-yl)benzenes.
mechanism for the a-carbonylcarbe-
noid/alkene [3+2] cycloaddition. The
resulting 2,3-dihydrofuran products
allow access to diverse oxacyclic com-
pounds through a stereoselective ene–
pathway is proposed for this reaction.
The feasibility for direct transformation
of 2-alkenyl-1-alkynylbenzenes into the
This transformation comprises of
a
gold-catalyzed redox reaction to form a
gold a-carbonylcarbenoid initially,
which then reacts in situ with an
alkene in a [3+2] cycloaddition. A
range of alkenes are amenable to this
tandem reaction, amongst them a-sub-
desired
2,3-dihydrofuran
products
through initial m-chloroperbenzoic acid
oxidation, followed by the addition of
gold catalyst and alkene, has also been
demonstrated.
Keywords: cycloaddition · dihydro-
furans · carbenoids · epoxides · gold
Introduction
One important advent in modern synthetic chemistry is the
generation of a metal carbenoid from an alkyne using AuI
catalysts.[1–5] Among the reported gold carbenoids, the a-car-
bonylcarbenoid is the most easily accessible because of the
availability of various redox reactions for carbenoid genera-
tion.[2–4] However, the use of gold a-carbonylcarbenoid A is
less widespread than that of gold alkenylcarbenoid B,[6–8] in-
dicated by its lack of cycloaddition reactions. Alkenylcarbe-
noid B is also represented by the gold-stabilized allyl cation
B’ to rationalize its highly electrophilic nature[6,7] and versa-
tile [3+n] (n=2, 3, or 4) cycloaddition reactions.[8] In con-
trast, gold a-carbonylcarbenoid A truly reflects a carbenoid
character because the resonance structure A’ is less impor-
tant (Scheme 1).
Scheme 1. Representations for a-carbonylcarbenoid A and alkenylcarbe-
noid B.
with alkenes was documented for copper and rhodium sys-
tems from a-diazocarbonyl precursors, reported examples
are limited strictly to reactions with enol ethers.[9] For gold
alkenylcarbenoids B, reactions with alkenes or enol ethers
gave only cyclopropane products.[10,11]
Cycloaddition of gold a-carbonylcarbenoids with dipolar-
ophiles remains a formidable obstacle to overcome. Al-
though the [3+2] cycloaddition of a-carbonylcarbenoids
Recently, Hashmi et al.[4b] and ourselves[4a] independently
studied the cycloisomerization of 2-epoxy-1-alkynylbenzenes
II (Scheme 2) using different gold catalysts. Notably, the use
of [AuCl
the epoxide/ketone rearrangement of starting substrate II.
With [AuCl(PPh3)]/AgSbF6 (5 and 2 mol%, respectively) we
found that the resulting carbenoids III were stable and effi-
ciently trapped with an external styrene or Ph2SO, as depict-
ed in Scheme 2.[5a] The tethered alkene in III does not affect
the carbenoid electrophilicity and the species retains activity
ACHTUNGTERN(NUNG PPh3)]/AgSbF6 (each at 5 mol% loading) led to
[a] C.-W. Li, Dr. G.-Y. Lin, Prof. Dr. R.-S. Liu
Department of Chemistry, National Tsing-Hua University
Hsinchu, Taiwan (ROC)
AHCTUNGTRENNUNG
Fax : (+86)3-5711082
E-mail: rsliu@mx.nthu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000009.
Chem. Eur. J. 2010, 16, 5803 – 5811
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5803

Table 1. Screening of catalyst activity.
Entry
Catalyst[a]
5% [AuClACTHUNGTRNE(NUG PPh3)]
2% AgSbF6
5% [AuClL][c]
2% AgNTf2
t [h]
Yield of 2a [%][b]
Scheme 2. Reaction pathways in this gold catalysis.
1
2
6
6
64
54
toward external nucleophiles. This pathway is distinct from
that reported by Hashmi and co-workers for carbonyldienyl
gold carbenoids.[5g] The gold carbenoids generated from
sulfur- and nitrogen-based redox reactions inevitably suffer
loss of electrophilicity through heteroatom coordination.
The use of these carbenoids is strictly limited to cyclization
with their tethered functionalities.[2–4] Herein, we report the
[3+2] cycloaddition reactions of gold a-carbonylcarbenoids
III with a range of alkenes. We also report that the resultant
2,3-dihydrofurans IV undergo a subsequent HOTf-catalyzed
(Tf=trifluoromethanesulfonyl) cyclization to give tricyclic
tetrahydrofuran species V and other oxacyclic compounds
with high stereocontrol. We also demonstrate examples for
a one-pot transformation of 2-alkenyl-1-alkynylbenzenes I
and alkenes into 2,3-dihydrofurans IV through gold-cata-
lyzed oxidation with m-chloroperbenzoic acid (m-CPBA).
This direct synthesis uses m-CPBA as a source of oxygen to
generate a-carbonylcarbenoid III (Scheme 2).
5% [AuCl
2% AgNTf2
ACHTUNGERTN(NUNG PPh3)]
3
10
12
[a] [1a]=0.1m, alkene (5 equiv), CH2Cl2. [b] Yields are reported after
silica chromatography. [c] [AuClL]=[AuCl{P(tBu)2(o-biphenyl)}].
AHCTUNGTRENNUNG
along with species 3a (21%). Species 3a’ quickly isomerized
to the more stable isomer 3a after a short reaction catalyzed
by Brønsted acid. Isolation of isomer 3a’ in a pure form was
hampered by its instability during elution on a silica column,
1
but it was identified by H NMR spectroscopy.
The generality of this 2,3-dihydrofuran synthesis using
various alkenes and epoxides was assessed (Table 2). We
used three different catalysts to optimize the yields: [AuCl-
Table 2. Gold-catalyzed [3+2] cycloadditions.
Results and Discussion
Generation of a-carbonylcarbenoid III from epoxide II was
Entry Epoxide
R1
Alkene
R3
Conditions[a] Products[b]
previously performed with
a mixture of [AuClCAHTUNTGNRUEGN(PPh3)]
R2
(t [h])
ACHTUNGTRENNUNG(yield [%])
(5 mol%)/AgSbF6 (2 mol%),[12a] which completely inhibited
the competitive epoxy–ketone rearrangement.[5a] As depict-
ed in Table 1, this catalyst mixture implemented the cycliza-
tion of epoxide species 1a with 4-vinyl-1-methoxybenzene
(5 equiv) in CH2Cl2 (408C, 6 h) to give the desired 2,3-dihy-
drofuran 2a in 64% yield. Modification of the catalyst with
1
2
nBu (1a) Me
nBu (1a) Me
4-MeOC6H4
Ph
B (6)
A (6)
A (6)
A (6)
A (6)
B (3)
B (6)
2b (95)
2c (82)
2d (52)
2e (50)
2 f (78)
2g (88)
2h (78)
2i (51)
2j (81)
2k (68)[c]
2l (61)
2m (56)
2n (65)
3
nBu (1a) nBu Ph
4
5
nBu (1a) Me
nBu (1a) Ph
2-naphthyl
Ph
6
nBu (1a)
H
OEt
OMe
À
7
8
nBu (1a) Me
nBu (1a) Me
[AuCl{P(o-biphenyl)ACHTNUTRGNEUNG(tBu)2}] or AgNTf2 failed to result in
any improvement (Table 1, entries 2 and 3). The selection of
CMe
OEt
N
9
Ph (1b)
Ph (1b)
Ph (1b)
Me (1c)
Me (1c)
H
H
Me
Me
H
B (12)
a suitable catalyst is sensitive to the alkene substrate. The
10
11
12
13
4-MeOC6H4
Ph
Ph
OEt
A (12)
A (12)
A (6)
B (3)
[12b]
combination of [AuCl{P(o-biphenyl)
G
was
superior to [AuClACHTUNGTRENNUNG(PPh3)]/AgSbF6 when an enol ether was
used (see below).[13] Subsequent treatment of compound 2a
with HOTf (1 mol%) in CH2Cl2 (238C, 3 h) led to an intra-
molecular cyclization and gave tricyclic ether 3a in 54%
yield. At 40% conversion in CH2Cl2 (238C, 1 h), we ob-
served that the isomeric product 3a’ (15%) was formed
[a] A: [AuCl
ACHTUNGTRENNUNG
A
(5%), AgSbF6 (2%), [epoxide]=0.1m, CH2Cl2, 408C. [b] Yields are re-
ported after separation on a silica column. [c] Cyclopropanation product
was obtained in 14% yield.[19]
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ACHTUNGTRENNUNG[3+2] Cycloadditions of Gold a-Carbonylcarbenoids
FULL PAPER
A
E
methoxy groups at the same carbon atoms failed to give the
desired 2,3-dihydrofurans in tractable amounts.[14]
[12c]
(B), and [AuClACHTUNGTRENNUNG(IPr)]/AgSbF6
pylphenyl)imidazol-2-ylidene), all with an AuI/AgI ration of
5:2 mol%. These systems were applied to derivatives of styr-
enes, enol ethers, and 2,3-dimethylbutadiene, respectively.
Table 2, entries 1–5, shows the effect of a-substitution on
the styrene. Alkenes with R2 =methyl or phenyl (Table 2,
entries 2 and 5) gave better yields than the R2 =n-butyl ana-
logue (Table 2, entry 3). The alkene in which R3 =2-naph-
thyl is an inferior reaction partner to the analogues in which
R3 =4-methoxyphenyl or phenyl (50% 2e versus 95 and
82% 2b and 2c, respectively). Steric effects clearly affect
the cycloaddition. The suitability of mono- and disubstituted
enol ethers as nucleophiles was within our expectations
(Table 2, entries 6 and 7) and furnished 2,3-dihydrofurans
2g and 2h in 88 and 78% yield, respectively. The cycloaddi-
tion is also successful with 2,3-dimethylbutadiene and gives
2i in 51% yield (Table 2, entry 8). Table 2, entries 9–13,
shows varied alkynyl substitution (R1 =Ph, Me) of the epox-
ide substrates. Compounds 1b and 1c reacted with suitable
styrene derivatives and enol ethers to give the desired [3+2]
cycloadducts 2j–2n in 56–81% yield. Alongside adduct 2k,
we obtained the cyclopropanation product in 14% yield
(Table 2, entry 10).
Table 4 highlights the use of cycloalkenes to access com-
plex oxacyclic molecules with effective control of the stereo-
chemistry. Treatment of epoxides 1a and 1c with 2,3-dihy-
Table 4. Cycloadditions of epoxides 1 with cycloalkenes.
Entry Epoxide
R1
Alkene
Conditions[a] Products
(t [h])
Products
ACHTUNGTRNE(NUNG yield
[%])[b]
1
2
nBu (1a)
Me (1c)
4a (65)
4b (52)
B (3)
B (3)
3
4
nBu (1a)
Me (1c)
4c (72)
4d (70)
Table 3 shows the effect of substitution of epoxy and
phenyl moieties on the gold-catalyzed cycloaddition. For ep-
oxides 1d and 1e the reaction with a-phenylstyrene afford-
5
nBu (1a)
A (6)
4e (82)
Table 3. Effect of epoxide and phenyl substituents on the cycloaddition.
[a] A: [AuCl
(tBu)2(o-biphenyl)}] (5%), AgNTf2 (2%), CH2Cl2, 408C. [b] Isolated
yield.
ACHTNUGTERN(NUGN PPh3)] (5%), AgSbF6 (2%), CH2Cl2, 408C; B: [AuCl{P-
AHCTUNGTRENNUNG
drofuran or 3,4-dihydro-2H-pyran in the presence of
[AuCl{P(o-biphenyl)(tBu)2}] (5 mol%)/AgNTf2 (2 mol%) in
Entry
Epoxide[a]
Products
AHCTUNGTRENNUNG
(yield [%])[b]
AHCTUNGTRENNUNG
hot dichloromethane (conditions B) produced furans 4a and
4b (Table 4, entries 1 and 2) and pyrans 4c and 4d (Table 4,
entries 3 and 4), respectively. For all these products, we ob-
tained a single diastereomer and structural characterization
relied on NOE spectroscopy of 4a and 4d.[15] Cycloaddition
of epoxide 1a with 1-methylene-tetrahydronaphthalene gave
the desired spiroether 4e in 82% yield (Table 4, entry 5).
We performed deuterium-labeling experiments to under-
stand the mechanism of the [3+2] cycloaddition reaction. As
depicted in Scheme 3, treatment of epoxide 1a with cis-deu-
terated 4-vinyl-1-methoxybenzene[16] (X=0.76 D) gave
[D1]2a, 1H NMR spectroscopy of which revealed 65 and
14% deuterium content at the cis- and trans-C(3)-dihydro-
furanyl hydrogen atoms, respectively. We conducted a simi-
lar experiment with the trans-deuterated alkene[17] (Y=
0.95 D). The resultant adduct [D1]2a’ contained 15 and 81%
deuterium content at the corresponding cis- and trans-C(3)-
hydrogen atoms, respectively. In both cases, a small portion
of deuterium was scrambled at the other geminal hydrogen.
1
2
3
4
À
1
2
3
4
5
6
R , R =
(CH2)4-, R =R =H (1d)
2o (41), 1d’ (45)
2p (62, Z/E 1:1.9)
2q (76)
2r (49)
2s (73)
R1 =Me, R2 =Et, R3 =R4 =H (1e)[c]
R1 =R2 =Me, R3 =H, R4 =Cl (1 f)
R1 =R2 =Me, R3 =H, R4 =F (1g)
R1 =R2 =Me, R3 =Cl, R4 =H (1h)
R1 =R2 =Me, R3 =F, R4 =H (1i)
2t (57)
[a] [substrate]=0.1m. [b] Yields are reported after separation on a silica
column. [c] Z/E ratio=1:1.2.
ed the desired 2,3-dihydrofurans 2o and 2p in 41 and 62%
yield, respectively(Table 3, entries 1 and 2). In the former
case, we also obtained aldehyde 1d’ (45%), generated from
epoxide–carbonyl rearrangement.[5a] The catalysis is compat-
ible with the presence of fluoro and chloro groups at the C4
and C5 carbon atoms of the phenyl group of the cyclization
substrate (1 f–i) and 2q–t were obtained in 49–76% yield
(Table 3, entries 3–6). The chloride substituent resulted in
the most productive yield. Epoxides with electron-donating
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R.-S. Liu et al.
A and the contribution of the resonance structure A’ is also
significant (Scheme 1).
Table 5 highlights the use of the [3+2] cycloadducts to
construct complex molecular frameworks through a HOTf-
catalyzed cyclization. A small proportion of HOTf (0.1–
Table 5. HOTf-catalyzed cyclization.
Scheme 3. Deuterium-labeling experiment.
Dihydrofuran[a]
R2 R3
Product
Diastereomeric
Entry
R1
(yield [%])[b] ratio
ACHTUNGTRENNUNG
1
2
3
4
5
6
nBu Me Ph (2c)
nBu nBu Ph (2d)
nBu Me naphthyl (2e)
3c (65)
3d (79)
3e (61)
3 f (87)
3l (83)
9:2
13:1
3:1
Lewis acid catalyzed cycloisomerization of cyclopropyl ke-
tones to 2,3-dihydrofurans is only operable for certain sub-
strates[9a,18] and our control experiment opposes intermedia-
cy of cyclopropyl ketones.[19] For starting species 1a, we also
exclude a concerted [3+2] mechanism because [D1]2a con-
tains deuterium at both geminal methylene positions, but in
unequal proportions. This observation leads us to propose a
cationic intermediate C that undergoes a rapid ring closure
to give species [D1]2a, with the deuterium cis to the neigh-
boring aryl group. A small portion of species C undergoes a
nBu Ph
Ph (2 f)
–
Ph Me Ph (2l)
nBu Me 4-MeOC6H4 (2b) 3b’ (62)
12:1
>20:1
7
nBu Me
3i’ (71)[c]
>20:1
[a] [substrate]=0.1m in CH2Cl2. [b] Yields are reported after purification
on a silica column. [c] 0.1% HOTf was used for entry 7.
1 mol%), which acts a Brønsted acid, induces the formation
of a cyclopentane ring in a stereoselective ene–oxonium re-
action. For substrates 2c–f and 2l, the resulting cyclization
products 3c–f and 3l, which contain a cyclopentylidene ring,
are produced stereoselectively in most cases. Unexpectedly,
we obtained cyclization products 3b’ and 3i’, which bore a
methylvinyl group, from HOTf treatment of 2b and 2i. The
stereochemistry of cyclized products 3c, 3b’, and 3i’ was de-
termined by NOE spectroscopy. Notably, we found that the
stereochemistry at the CR2R3 carbon atom of 3b’ and 3i’
are opposite to those of cyclopentylidene compounds 3a,
3c, and 3l. The X-ray structure of compound 3l was also de-
termined (see Figure 1).
À
slow rotation of the C C bond to give [D1]2a with the deu-
terium trans to the aryl group after ring closure (Scheme 4).
This proposed mechanism provides a rationale for the trans-
fused stereochemistry of products 4c and 4d (Table 4, en-
tries 3 and 4). This stepwise pathway may indicate that the
a-carbonyl carbene is not entirely represented by structure
We also performed HOTf-catalyzed carbocyclization of
2,3-dihydrofurans 2o–t, which bore distinct alkenyl (R1 and
R2) and phenyl (R3 and R4) substituents, and obtained the
desired cyclized products 3o–t in good yields (79–84%,
Table 6). These yields are similar to that obtained for 3 f
(87%) and thus, the reaction does not appear to be sensitive
to these particular substituents.
Scheme 5 depicts a plausible mechanism to rationalize the
generation of 3b’ and 3c from cyclization of 2b and 2c, re-
spectively. The differing stereochemistry at the CH3Ar
carbon for the two resulting products is clearly a crucial
factor. Most likely, protonation proceeds initially on the
face opposite the aryl fragment. We envisage that the oxoni-
um cation D derived from 2b is prone to epimerization to
give species D’’ because the hypothetical cation D’ is stabi-
lized by the 4-methoxyphenyl group. Intermediate D is re-
sponsible for generation of cyclopentylidene 3c, and its
isomer 3c’, through the loss of a proton from tertiary cation
E. For species 2b, we envisage that conformation D’’ is at-
Scheme 4. Proposed mechanism of the [3+2] cycloaddition.
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ACHTUNGTRENNUNG[3+2] Cycloadditions of Gold a-Carbonylcarbenoids
FULL PAPER
Table 6. Effect of epoxide and phenyl substituents on HOTf-catalyzed
cyclization.
Entry
Substrate[a]
Product (Yield [%])[b]
1
2
3
4
5
6
R1 =R2 =-(CH2)4-, R3 =R4 =H (2o)
R1 =Me, R2 =Et, R3 =R4 =H (2p)
R1 =R2 =Me, R3 =H, R4 =Cl (2q)
R1 =R2 =Me, R3 =H, R4 =F (2r)
R1 =R2 =Me, R3 =Cl, R4 =H (2s)
R1 =R2 =Me, R3 =F, R4 =H (2t)
3o (79)
3p (79)
3q (81)
3r (84)
3s (80)
3t (83)
[a] [epoxide]=0.1m. [b] Yields are reported after separation on a silica
column.
ment. The NOE spectra of 7b revealed a fully cis-fused con-
figuration for its tetracyclic framework. The large bicyclic
framework of species 4c and 4d greatly favors the confor-
mation of oxonium species D to give the observed cyclopen-
tylidene products 7a and 7b.
Scheme 6 depicts a plausible mechanism to rationalize the
formation of the complex oxacyclic species 5c from 2n. The
mechanism involves a concerted ene–oxonium reaction via a
species of type D’’ to give intermediate 3n’, which contains
a methylvinyl group. The stereochemistry of species 3n’ is
suitable for a second carbocyclization via formation of oxo-
nium intermediate F to induce a second ene–oxonium reac-
tion to give observed compound 5c.
Figure 1. X-ray structure of 3l.
tainable because the concerted ene–oxonium reaction[20]
occurs on the same side as the smaller methyl group.[20] This
concerted pathway is unlikely for substrate 2c because the
endo-phenyl orientation impedes this concerted process.
The use of this gold catalysis is enhanced by the diversity
of the oxacyclic products for which only one diastereomeric
compound was obtained, as illustrated in Table 7. Treatment
of 2,3-dihydrofuranyl acetals 2g, 2j, and 2n with HOTf
(1 mol%) in CH2Cl2 (238C, 3 h) delivered tricyclic oxacyclic
compounds 5a–5c (Table 7, entries 1–3) in fair to good
yields (52–90%). We elucidated
their structures based on com-
1
parison to the H NMR spectra
of oxacyclic products 3b’ and
3i’, given from
a concerted
ene–oxonium reaction.[17] A di-
agnostic 1H NMR signal for
such a structural assignment is
the observed coupling constant
of J=4.0 Hz between the olefin
and its vicinal protons. This
proposed structure was con-
firmed with the NOE spectra of
5c and its sequential proton de-
coupling. In contrast, reaction
of furan species 4a and 4b ste-
reoselectively delivered oxacy-
clic compounds 6a and 6b
(Table 7, entries 4 and 5). The
stereochemistry of 6b was elu-
cidated with the aid of NOE
spectroscopy. For tetrahydro-
3aH-furoACHTUNGTRENNUNG[2,3-b]pyrans 4c and
4d we obtained oxacyclic com-
pounds 7a and 7b as single dia-
stereomers after HOTf treat- Scheme 5. Proposed mechanism of HOTf-catalyzed cyclization.
Chem. Eur. J. 2010, 16, 5803 – 5811
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R.-S. Liu et al.
Table 7. Diverse oxacyclic products from HOTf-catalyzed cyclization.
Entry
R[a]
Product (Yield [%])[b]
1
2
3
nBu (2g)
Ph (2j)
Me (2n)
5a (89)
5b (52)
5c (90)
Scheme 7. Proposed mechanism for the formation of compound 6b.
4
5
nBu (4a)
Me (4b)
6a (71)
6b (78)
rigid structures, which are not favorable for an initial con-
certed ene–oxonium reaction. These substrates will not pro-
duce complicated cage structures as seen with 5a–c.
Table 8 depicts examples for the direct conversion of
enyne I-1a to various 2,3-dihydrofurans through initial treat-
ment with a mixture of m-CPBA and NaHCO3 in CH2Cl2
(4 h, 258C), followed by the subsequent addition of a suita-
ble alkene (10 equiv) and AuI/AgI catalyst (5 and 2 mol%)
before the temperature was brought to 408C. In this one-pot
operation, we obtained side product 8, from a 1,2-addition
of 3-ClC6H4CO2H to gold a-carbonylcarbenoid III. The
yields of the desired 2,3-dihydrofurans 2 are highly depen-
dent on the nucleophilicity of the alkene partner, although
were satisfactory in most instances. This synthesis used ex-
ternal promoter, m-CPBA as a source of oxygen, to gener-
ate a-carbonylcarbenoid III.
6
7
nBu (4c)
Me (4d)
7a (79)
7b (79)
[a] [substrate]=0.1m. [b] Yields are reported after silica-gel column chro-
matography.
Conclusion
Previously, reactions of gold a-carbonylcarbenoids generat-
ed from redox reactions were restricted to intramolecular
cyclizations.[2–4] We have reported the feasibility for catalytic
[3+2] cycloadditions of gold a-carbonylcarbenoids with al-
kenes, to give 2,3-dihydrofuran products efficiently. The gen-
eration of such carbenoids relies on an intramolecular redox
reaction of alkyne–epoxide functionalities, which avoids the
use of diazocarbonyl precursors. Unlike reported rhodium
and copper catalysis, this cycloaddition is compatible with a
diverse assortment of alkenes, which include a-substituted
styrenes, enol ethers, and 2,3-dimethylbutadienes. Deuteri-
um-labeling experiments indicate a stepwise ionic mecha-
nism for the [3+2] cycloaddition pathway. This pathway sug-
gests that [3+2] cycloaddition is difficult to achieve with
high enantioselectivity. The value of this gold catalysis is
demonstrated by the stereocontrolled formation of various
oxacyclic products through the HOTf treatment of 2,3-dihy-
drofurans. In the ene–oxonium cyclization, we obtained dis-
tinct products 3 and 3’, presumably produced from a step-
wise and concerted mechanisms respectively. Further appli-
Scheme 6. Proposed mechanism for the formation of oxacyclic compound
5c.
Scheme 7 illustrates the mechanism of formation of 6b
from 4b. Protonation at the 2,3-dihydrofuranyl C(3)-carbon
of 4b preferentially proceeds on the face opposite the neigh-
boring oxacyclic ring, which produces oxonium species D
with a 3R*,4R* configuration. We envisage that the cis-2-
oxabicycloACHTUNGTRENNUNG[3.3.0]octane ring of oxonium species D is highly
strained and that this strain is sufficient to cause ring cleav-
age to produce a ketone–oxonium species H. Ultimately,
species H gives compound 6b through an stepwise ene–oxo-
nium reaction. For starting substrates 4a–d, their corre-
sponding intermediates D have sterically congested and
5808
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Chem. Eur. J. 2010, 16, 5803 – 5811

ACHTUNGTRENNUNG[3+2] Cycloadditions of Gold a-Carbonylcarbenoids
FULL PAPER
Table 8. One-pot transformation of enyne I-1a into 2,3-dihydrofurans.
(100 mg, 0.44 mmol) and 4-vinyl-1-me-
thoxybenzene (295 mg, 2.2 mmol) in
dichloromethane (3.4 mL) were added
dropwise to the resulting mixture at
238C and the solution was stirred for
6 h at 408C. The solution was filtered
through a Celite bed, then concentrat-
ed in vacuo, and eluted through
a
silica-gel column (EtOAc/hexane 1:9)
to give compound 2a as a colorless oil
(102 mg, 0.28 mmol, 64%).
Entry Alkene[a]
Conditions
Products [%][b]
8 [%]
Compound 3a: A 1% solution of tri-
fluoromethanesulfonic acid in di-
chloromethane (1.0 mL) was added to
a solution of compound 2a (102 mg,
0.28 mmol)
in
dichloromethane
G
ACHTUNGRTENN(UNG PPh3)] (5%)
(38 mL) and the mixture was stirred at
238C for 3 h. The solution was
quenched with water, the organic layer
was extracted with dichloromethane,
dried over MgSO4, and concentrated
in vacuo. The residue was eluted
1
2
2a, R1 =H, R2 =4-MeOC6H4 (46) 41
E
ACHTUNGTRENNUNG
2c, R1 =Me, R2 =Ph (61)
27
AgSbF6 (2%), 12 h
[AuCl(PPh3)] (5%)
AgSbF6 (2%), 6 h
[AuCl{P(tBu)2(o-biphenyl)}] (5%)
AgNTf2 (2%), 3 h
[AuCl{P(tBu)2(o-biphenyl)}] (5%)
AgNTf2 (2%), 3 h
E
ACHTUNGTRENNUNG
3
4
2 f, R1 =R2 =Ph (66)
14
21
through
a silica column (EtOAc/
hexane 1:10) to give 3a as a colorless
oil (54.0 mg, 0.15 mmol, 54%).
R
ACHTUNGTRENNUNG
2g, R1 =H, R2 =OEt (72)
C
ACHTUNGTRENNUNG
One-pot synthesis of 2,3-dihydrofur-
ans: 1-(Hex-1-ynyl)-2-(2-methylprop-
1-enyl)benzene (120 mg, 0.57 mmol) in
dichloromethane (2.0 mL) was added
5
27
to
0.68 mmol) and NaHCO3 (56 mg,
0.68 mmol) in dichloromethane
(3.0 mL) to give solution A and the
mixture was stirred at room tempera-
ture. The epoxide formation was moni-
a solution of m-CPBA (117 mg,
[a] [I-1a]=0.08m, alkene (10 equiv). [b] Yields are reported after separation on a silica column.
cation of this new catalysis to bioactive molecules is under
current investigation.
tored by TLC. After completion of the epoxide,
a solution of
PPh3AuSbF6 (2 mol%) was prepared by mixing [AuCl(PPh3)] (13.8 mg,
AHCTUNGTRENNUNG
0.03 mmol) and AgSbF6 (4.4 mg, 0.01 mmol) in dichloromethane
(2.0 mL) for 10 min. The appropriate styrene (10 equiv) was then added
to give solution B. Solution B was added to solution A and the mixtures
were stirred for 3–12 h at 408C. The resulting solution was filtered
through a Celite bed, concentrated in vacuo, and eluted through a silica-
gel column to give the product.
Experimental Section
General: Unless otherwise noted, all reactions were carried out under a
nitrogen atmosphere in oven-dried glassware using a standard syringe,
cannula, and septa apparatus. Benzene, diethyl ether, tetrahydrofuran,
and hexane were dried with sodium benzophenone and distilled before
use. Dichloromethane was dried over CaH2 and distilled before use.
NMR spectra were run at 400 (1H) or 100 MHz (13C) in CDCl3.
Spectral data of compounds 1a, I-1a, 2a, 3a, and 3a’ are listed below.
Other spectral data and copies of the 1H and 13C NMR spectra of all
compounds are given in the Supporting Information.
Compound 1a: 1H NMR (400 MHz, CDCl3): d=7.35 (d, J=7.6 Hz, 1H),
7.25–7.22 (m, 2H), 7.20–7.16 (m, 1H), 4.04 (s, 1H), 2.44 (t, J=7.2 Hz,
2H), 1.67–1.54 (m, 2H), 1.52–1.43 (m, 5H), 1.01 (s, 3H), 0.93 ppm (t, J=
7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=138.7, 131.4, 127.3, 126.9,
126.0, 122.3, 95.2, 78.1, 64.2, 61.1, 30.9, 24.6, 22.0, 19.2, 18.2, 13.6 ppm; IR
(neat): n˜ =3085 (m), 2958 (s), 2155 (w), 1605 (m), 1458 cmÀ1 (s); HRMS:
m/z: calcd for C16H20O: 228.1514; found: 228.1511.
Compound I-1a: 1H NMR (400 MHz, CDCl3): d=7.41 (d, J=7.6 Hz,
1H), 7.27–7.21 (m, 2H), 7.15–7.11 (m, 1H), 6.51 (s, 1H), 2.47 (t, J=
6.8 Hz, 2H), 1.96 (s, 3H), 1.84 (s, 3H), 1.65–1.51 (m, 4H), 0.98 ppm (t,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=140.3, 135.9, 132.0,
128.9, 126.9, 125.7, 124.2, 123.4, 94.5, 79.7, 30.9, 26.6, 21.9, 19.5, 19.2,
13.6 ppm; IR (neat): n˜ =3150 (s), 2958 (s), 2200 (w), 1657 (m), 1473 cmÀ1
(s); HRMS: m/z: calcd for C16H20: 212.1565; found: 212.1564.
Compound 2a: 1H NMR (400 MHz, CDCl3): d=7.33 (d, J=8.8 Hz, 2H),
7.18–7.15 (m, 4H), 6.90 (d, J=8.4 Hz, 2H), 6.13 (s, 1H), 5.47 (dd, J=
10.4, 8.0 Hz, 1H), 3.8 (s, 3H), 3.25 (dd, J=14.8, 10.4 Hz, 1H), 2.89 (dd,
J=14.4, 7.6 Hz, 1H), 2.07 (t, J=7.2 Hz, 2H), 1.82 (s, 3H), 1.72 (s, 3H),
1.52–1.45 (m, 2H), 1.30–1.23 (m, 2H), 0.82 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=159.1, 153.5, 137.6, 135.8, 135.3, 134.2,
129.8, 129.6, 127.1 (2ꢁCH), 126.0 (2ꢁ CH), 125.1, 113.9 (2ꢁCH), 107.5,
80.7, 55.3, 43.6, 29.0, 26.5, 26.2, 22.6, 19.2, 13.8 ppm; IR (neat): n˜ =3087
Typical procedure for the synthesis of 1a: nBuLi (2.4 mL, 2.5m,
5.9 mmol) was added to a solution of isopropyltriphenylphosphonium
iodide (2.76 g, 6.4 mmol) in THF (25 mL) at 08C and the mixture was
stirred at 08C for 1 h. 2-(Hex-1-ynyl)benzaldehyde (0.99 g, 4.9 mmol) was
added and the mixture was stirred at 238C for 4 h. The solution was
quenched with water and concentrated in vacuo. The organic layer was
extracted with diethyl ether, dried over MgSO4, and concentrated in
vacuo. The residue was eluted through a silica column (hexane) to give
the olefination product as a colorless oil (0.91 g, 4.3 mmol, 88%). m-
CPBA (1.12 g, 6.5 mmol) was added to the enyne compound (0.91 g,
4.3 mmol) in dichloromethane (30 mL) and the mixture was stirred for
8 h at 08C. The resulting solution was quenched with an aqueous solution
of NaHCO3, extracted with diethyl ether, dried over anhydrous MgSO4,
and concentrated in vacuo. The resulting mass was filtered through a
small basic Al2O3 bed, then concentrated in vacuo, and eluted through a
Et3N-pretreated silica column (EtOAc/hexane 1:9) to afford 1a as a col-
orless oil (0.77 g, 3.4 mmol, 79%).
Compound 2a: A solution of PPh3AuSbF6 (2 mol%) was prepared by
mixing [AuClACHTUNGTRENNUNG(PPh3)] (10.0 mg, 0.02 mmol) and AgSbF6 (3.1 mg,
0.009 mmol) in dichloromethane (1.0 mL) for 10 min. Compound 1a
Chem. Eur. J. 2010, 16, 5803 – 5811
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5809

R.-S. Liu et al.
(m), 2945 (s), 1615 (s), 1604 (m), 1217 (m), 1118 cmÀ1 (s); HRMS: m/z:
calcd for C25H30O2: 362.2246; found: 362.2245.
48, 6152–6155; g) A. S. K. Hashmi, M. Rudolph, H.-U. Siehl, M.
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cation for gold alkenylcarbenoid species, see: a) D. Benitez, N. D.
Shapiro, E. Tkatchouk, Y. Wang, W. A. Goddard, F. D. Toste, Nat.
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Angew. Chem. 2009, 121, 2548–2551; Angew. Chem. Int. Ed. 2009,
48, 2510–2513; c) A. Fꢂrstner, L. Morency, Angew. Chem. 2008,
120, 5108–5111; Angew. Chem. Int. Ed. 2008, 47, 5030–5033;
d) A. S. K. Hashmi, Angew. Chem. 2008, 120, 6856–6858; Angew.
Chem. Int. Ed. 2008, 47, 6754–6756.
Compound 3a: 1H NMR (400 MHz, CDCl3): d=7.52 (d, J=7.6 Hz, 1H),
7.27–7.17 (m, 5H), 6.84 (d, J=8.8 Hz, 2H), 4.62 (t, J=6.8 Hz, 1H), 3.77
(s, 3H), 3.50–3.47 (m, 1H), 2.16 (t, J=10.0 Hz, 2H), 2.11 (s, 6H), 1.96 (t,
J=8.0 Hz, 2H), 1.34–1.24 (m, 4H), 0.85 ppm (t, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=158.9, 146.2, 142.4, 137.6, 134.2, 131.9,
127.4 (2ꢁCH), 126.8, 126.7, 125.0, 124.4, 113.7 (2ꢁCH), 94.6, 78.3, 55.3,
52.2, 44.1, 38.0, 26.4, 23.5, 23.2, 22.9, 14.1 ppm; IR (neat): n˜ =3100 (m),
2951 (s), 1605 (s), 1150 cmÀ1 (s); HRMS: m/z: calcd for C25H30O2:
362.2246; found: 362.2243.
[7] a) G. Lemi›re, V. Gandon, K. Cariou, A. Hours, T. Fukuyama, A.-L.
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R.-S. Liu, J. Am. Chem. Soc. 2008, 130, 16488–16489.
[8] The [3+2] cycloaddition refers to aldehydes rather than alkenes,
see: a) N. D. Shapiro, F. D. Toste, J. Am. Chem. Soc. 2008, 130,
9244–9245; b) N. D. Shapiro, Y. Shi, F. D. Toste, J. Am. Chem. Soc.
2009, 131, 11654–11655; c) G. Zhang, L. Zhang, J. Am. Chem. Soc.
2008, 130, 12598–12599.
Compound 3a’: 1H NMR (400 MHz, CDCl3): d=7.27–7.19 (m, 5H),
7.11–7.09 (m, 1H), 6.82 (d, J=8.8 Hz, 2H), 5.02 (s, 1H), 4.83 (m, 1H),
4.46 (dd, J=11.2, 3.6 Hz, 1H), 3.87 (s, 1H), 3.77 (s, 3H), 3.73 (d, J=
7.6 Hz, 1H), 2.17–2.09 (m, 1H), 2.04–1.97 (m, 1H), 1.87–1.84 (m, 4H),
1.61–1.57 (m, 1H), 1.44–1.37 (m, 4H), 0.96 ppm (t, J=6.4 Hz, 3H); IR
(neat): n˜ =3106 (m), 2954 (s), 1607 (s), 1153 cmÀ1 (s); HRMS: m/z: calcd
for C25H30O2: 362.2246; found: 362.2245.
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[13] Results of catalyst screening of epoxides 1a with enol ether are pro-
vided in the Supporting Information.
Acknowledgements
The authors wish to thank the National Science Council, Taiwan for the
support of this work.
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arrangement. For species 1k, the epoxide is expected to attack at
the alkynyl-C(2) carbon to alter reaction pathway. We obtained a
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epoxides 1j and 1k are provided in the Supporting Information.
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5810
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Chem. Eur. J. 2010, 16, 5803 – 5811

ACHTUNGTRENNUNG[3+2] Cycloadditions of Gold a-Carbonylcarbenoids
FULL PAPER
[15] NOE spectra of key compounds are provided in the Supporting In-
formation; CCDC-759967 (3l) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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[19] We obtained 2k and cyclopropanation product VI-2k in 68 and
14% yields, respectively, in the gold catalysis (Table 2, entry 3).
Treatment of this cyclopropyl ketone with the same [AuClACTHNUTRGNEUNG(PPh3)]/
AgSbF6 catalyst under the same conditions failed to give 2k in a
tractable amount. Spectral data of the cyclopropylketone is provided
in the Supporting Information.
Received: January 4, 2010
Revised: February 23, 2010
Published online: April 8, 2010
[20] A concerted pathway was established for an intramolecular ene–
oxonium reaction, see reference [20a]. For reviews for ene reactions,
Chem. Eur. J. 2010, 16, 5803 – 5811
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www.chemeurj.org
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