Gold-catalyzed intermolecular [4C+3C] cycloaddition reactions

Article abstract of DOI:10.1016/j.tetlet.2010.02.099

In the presence of the N-heterocyclic carbene gold catalyst (NHC-AuIPr, 7), propargyl esters 1a-f and 13 undergo a [4C+3C] cycloaddition reaction with cyclopentadiene and furan under mild conditions. The evidence suggests that the formation of the seven-membered ring occurs by a direct cycloaddition process, rather than a stepwise cyclopropanation/Cope rearrangement sequence.

Full text of DOI:10.1016/j.tetlet.2010.02.099

Tetrahedron Letters 51 (2010) 2251–2253
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold-catalyzed intermolecular [4C+3C] cycloaddition reactions
*
Benjamin W. Gung , Lauren N. Bailey, Josh Wonser
Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of the N-heterocyclic carbene gold catalyst (NHC-AuIPr, 7), propargyl esters 1a–f and 13
undergo a [4C+3C] cycloaddition reaction with cyclopentadiene and furan under mild conditions. The evi-
dence suggests that the formation of the seven-membered ring occurs by a direct cycloaddition process,
rather than a stepwise cyclopropanation/Cope rearrangement sequence.
Received 1 February 2010
Revised 16 February 2010
Accepted 18 February 2010
Available online 23 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The potent antiangiogenesis natural product family of cortista-
tins containa center seven-membered ring flanked by two six-mem-
bered rings.1,2 Our initial attempt to construct the tetracyclic ring
system using a transannular [4C+3C] cycloaddition strategy was
met with mixed results.3,4 At the same time, Mascarenas and co-
workers reported an intramolecular [4C+3C] cycloaddition reaction,
in which an allene functional group was selectively activated by Pt or
Au catalyst.5 Thistypeof allene–dieneintramolecular [4C+3C]cyclo-
addition reactions was further improved to occur under milder con-
ditions.6–8 Otherreportsusingpropargyl estersas reactantsinvolved
stepwise [4+3] cycloaddition reactions to prepare benzonorcaradi-
enes and azepines.9,10 More recently, Harmata and Huang reported
that the treatment of 5-silyloxydioxins with 5 mol % AuCl3/AgSbF6
in the presence of cyclopentadiene or furan resulted in the formation
of [4C+3C]-cycloadducts.11 In this Letter, we disclose an intermolec-
ular version of gold-catalyzed formal [4C+3C] cycloaddition reac-
tions. This discovery expands the employment of propargyl esters
as precursors in the gold-catalyzed [4+3] cycloaddition reactions.12
The likely mechanism for our recently reported gold-catalyzed
transannular [4+3] cycloaddition could involve two possible path-
ways based on known examples in the literature.13–15 The first path-
way involves a gold-stabilized allyl cation and the second involves a
gold carbene intermediate. As shown in Scheme 1, the first pathway
(I–II through A and B) includes (1) a 3,3-rearrangement of the prop-
argyl ester to give an allenyl ester (A),16,17 (2) in situ activation by the
same gold catalyst to generate an allyl cation B,18 and (3) a [4+3]
cycloaddition followed by a 1,2-acetoxy migration and deauration
to produce the tetracyclic ring system II. The second mechanism
through intermediates C and D is depicted on the right side in
Scheme 1. This pathway involves a 1,2-acetoxy migration followed
by a cyclopropanation/Cope rearrangement to produce the same
product. Diazoesters undergo cyclopropanation/Cope rearrange-
ment reactions in the presence of rhodium catalysts and Davies
and co-workers have studied these reactions extensively.19,20
Ohe and co-workers reported cyclopropanation of alkenes using
propargylic carboxylates as vinylcarbene precursors and [RuCl2(-
CO)3]2 as the catalyst.21 More recently, Au(I)-catalyzed cycloprop-
anation of olefins using either propargyl esters or enynes as gold-
(I)-carbene precursors was reported.22,23
Because of their easy preparation, propargyl esters are conve-
nient synthetic precursors. We are interested in expanding the
usage of propargyl esters from transannular to inter- and intramo-
OAc
O
[Au]
[Au]
1,2-shift
1,3-shift
I
[Au]
O
O
H
·
[Au]
OAc
O
O
n
n
A
C
activation
cyclopropanation
OAc
H
O
X
[Au]
O
B
X = OAc
[4+3]
D
AcO
H
Cope
O
II
* Corresponding author. Tel.: +1 513 529 2813; fax: +1 513 529 5715.
E-mail address: gungbw@muohio.edu (B.W. Gung).
Scheme 1. Gold-catalyzed transannular [4+3] cycloaddition reaction: two possible
pathways.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.099

2252
B. W. Gung et al. / Tetrahedron Letters 51 (2010) 2251–2253
Table 1
Au(III)-catalyzed cyclopropanation/Cope rearrangement reactions
O
R
O
1-5 mol % [Au]
O
5 mol % AgSbF6
O
R
O
+
R
O
CH2Cl2, r.t.
2
H
H
+
1a-e
a
( ) R = CH3
(b) t-Bu
3a-e
4a-e
(c) Ph
d
( ) p-Tolyl
110 °C
e
( ) p-NO2Ph
Entry
Gold catalysta
mol %
R
Time (h)
% Yield
Ratio (3:4)
1
2
3
4
5
6
6
6
6
6
7
7
8
9
5
5
5
5
5
5
1
5
5
5
Methyl (a)
t-Butyl (b)
Phenyl (c)
p-Tolyl (d)
p-Nitrophenyl (e)
p-Tolyl (d)
p-Tolyl (d)
p-Tolyl (d)
p-Tolyl (d)
p-Tolyl (d)
24
24
24
24
24
1
23
3
2
57
57
90
92
63
82
92
n/a
n/a
n/a
1:1.6
1:2.8
1:2.1
1:2.1
1:1.3
1:1.2
1:1.6
n/a
6
7
8b
9b
10b
n/a
n/a
10
0.25
a
No silver co-catalyst was used for Au(III) catalyst (6).
Complex mixtures.
b
lecular versions as the substrates in gold-catalyzed [4+3] cycload-
dition reactions. The initial experiments were carried out using
propargyl esters 1a–e and Au(III) catalyst PicAuCl2 6 (Table 1 and
Fig. 1)24 which we have successfully employed in transannular
[4+3] cycloaddition reactions.12 Other gold catalysts screened in-
clude the NHC-AuIPr 7 and the R3PAu(I)Cl 8–10.
The reactions of propargylic carboxylates 1a–e with cyclopenta-
diene were studied in CH2Cl2 at room temperature in the presence
of gold catalysts 6–10. In the presence of the Au(III) catalyst 6, a
cyclopropanation and a formal [4C+3C] cycloaddition reaction oc-
curred smoothly to afford a mixture of products 3 and 4. Although
other Au(I) catalysts (8–10) were not effective (entries 8–10), we
are pleased to find the gold catalyst with an N-heterocyclic carbene
(NHC)25 ligand to be a highly effective catalyst for this transforma-
tion. With only 1% of the NHC-Au(I) catalyst 7, the reaction pro-
ceeded smoothly to give the corresponding products 3d and 4d
(entry 7, Table 1). This reaction is very similar to the report by
Ohe using [RuCl2(CO)3]2 as the catalyst,21 although a higher reac-
tion temperature was required previously.
reported data.21 No vinyl cyclopropane with exo configuration
was observed.
The vinyl cyclopropanes endo-3 can be converted to the corre-
sponding bicyclo[3.2.1]octa-2,6-dienes (4) through a Cope rear-
rangement reaction by heating a solution of endo-3 in toluene at
reflux for 12 h. The structure of the bicyclic enol esters 4 was fur-
ther confirmed by conversion to the known ketone 526 with base-
catalyzed removal of the ester group, Eq. (1).
O
NaOH
4a-e
ð1Þ
THF, MeOH
5
With 5 mol % of the gold catalyst 6, several propargyl esters (
1a–e) with different R group were compared for their reactivity
(Table 1). The benzoate esters gave higher yields than the alkano-
ate esters (comparing entries 3 and 4–1 and 2). However, the low
yields of 4a and 4b were most likely due to the volatility of the
products.
Encouraged by the catalytic efficiency of the NHC-AuIPr catalyst
7, the study was expanded to include furan as a diene substrate. In
the presence of 1% of 7, propargyl ester 1f was allowed to react
with 5 equiv of furan, Scheme 2. Interestingly, the effect of the gold
catalyst 7 parallels the ruthenium catalyst ([RuCl2(CO)3]2)27 and
The reaction of 1a (R = Me) gave the vinyl cyclopropane with
endo stereochemistry, that is, 3a, along with 3-acetoxy-4,4-dim-
ethylbicyclo[3.2.1]-octa-2,6-diene (4a), both compounds are
known from the previously reported study with Ru catalyst.21
The 1H and 13C NMR spectra of 3a and 4a are consistent with the
i
Pr
i
Pr
O
O
O
N
N
O
R
O
N
Cl Au
Cl
7
1 mol %
O
H
+
O
p-MeOPh
O
+
Au
Cl
2 mol %
AgSbF6
solvent
2 h, r.t.
i
Pr
i
Pr
O
R
O
6
(5 eqv.)
PicAuCl2 ( )
NHC-Au-IPr (7)
O
1f
4f
11 R =
p
-MeOPh
4f/11 = 0:100 in CH2Cl2
t
Bu
Bu
t
R
70%
26:74 in pentane
P
Au
Cl
P
R
Au Cl
R
O
K2CO3
MeOH, r.t.
O
4f
9 R = 2,4,6-trimethoxyphenyl
10 R = pentafluorophenyl
8
12
Figure 1. Au(III) catalyst 6 and Au(I) catalysts 7–10 were studied for their catalytic
activity in the formal [4C+3C] cycloaddition reactions.
Scheme 2. Reactions of furan with 1f in the presence of catalyst 7.

B. W. Gung et al. / Tetrahedron Letters 51 (2010) 2251–2253
2253
O
O
We have shown that gold catalyst 7 is capable of initiating an
intermolecular [4+3] cycloaddition reaction. Based on the evi-
dence, the formation of the seven-membered rings occurs by a di-
O
O
5 mol % 7
Ph
+
5 mol % AgSbF6
CH2Cl2, r.t.
rect [4+3] cycloaddition mechanism, rather than
a stepwise
(5 eqv.)
cyclopropanation/Cope rearrangement sequence. Further study
on ligand effects on the product ratio is underway in our
laboratories.
13
95%
14 + minor isomers
K2CO3
O
O
Ph
+
Ph
MeOH, r.t.
Acknowledgment
55%, 15a/15b = 2:1
15a
15b
Financial support from the National Institutes of Health
(GM069441) is gratefully acknowledged.
Scheme 3. Reactions of secondary propargyl ester 13 in the presence of catalyst 7.
Supplementary data
the triene aldehyde 11 was obtained as the exclusive product after
2 h at room temperature in the solvent of CH2Cl2. However, when
the same reaction was conducted in pentane a significant amount
of the formal [4+3] cycloaddition product 4f was also isolated.
The structure of 4f was confirmed by converting to the known
ketone 12.28 The structure of the propargyl ester was examined
by using 13 as a reactant in the presence of catalyst 7, Scheme 3.
To our delight, the reaction proceeded smoothly to afford a mix-
ture in 95% yield with one dominant product. The major product,
tentatively assigned as 14, was isolated along with minor isomers
that have similar polarity and are difficult to separate. To expedite
the isolation and structure identification, this mixture was sub-
jected to the usual base-catalyzed removal of the ester group. This
led to a clean separation of the major product 15a and its diaste-
reomer 15b along with small amount of unidentified isomers.
Product 15a is a known compound which was previously prepared
using a classical oxyallyl cation addition to cyclopentadiene.29,30
Under catalysis of the NHC-AuIPr catalyst 7, the results are dra-
matically different for propargyl esters 1a–f and 13. The former
gave a nearly 1:1 mixture of cyclopropanation product 3 and the
formal [4+3] cycloaddition product 4, while the latter produced
predominantly the [4+3] cycloaddition product 14. It is likely that
compound 14 is produced directly from an intermolecular [4+3]
cycloaddition process. Evidence in support of a direct [4+3] cyclo-
addition lies in the mild conditions of the reaction. High tempera-
ture (refluxing in toluene for 12 h) was required for converting the
cyclopropanation products 3a–e to 4a–e while compound 14 was
obtained at room temperature from an overnight reaction. To fur-
ther explore the pathways for the formation of the [4C+3C] cyclo-
addition products, isolated compound 3d was recommitted to the
reaction conditions with fresh gold catalyst 7 for 2 days at rt, Eq.
(2). No reaction was observed. This strongly suggests that the for-
mation of the products 4a–e came from a direct [4C+3C] cycload-
dition mechanism.
Supplementary data (experimental procedures and NMR spec-
tra) associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2010.02.099.
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ð2Þ
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