Palladium (II/IV) catalyzed cyclopropanation reactions: scope and mechanism

Article abstract of DOI:10.1016/j.tet.2008.10.107

This report describes detailed studies of the scope and mechanism of a new Pd-catalyzed oxidation reaction for the stereospecific conversion of enynes into cyclopropyl ketones. Unlike related Pd^II/0, Au, and Pt-catalyzed cyclopropane-forming reactions, these transformations proceed with net inversion of geometry with respect to the starting alkene. This result, along with other mechanistic data, is consistent with a Pd^II/IV mechanism in which the key cyclopropane-forming step involves nucleophilic attack of a tethered olefin onto a Pd^IV-C bond.

Full text of DOI:10.1016/j.tet.2008.10.107

Tetrahedron 65 (2009) 3211–3221
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium (II/IV) catalyzed cyclopropanation reactions: scope and mechanism
*
Thomas W. Lyons, Melanie S. Sanford
University of Michigan, Department of Chemistry, 930 N. University Ave., Ann Arbor, MI 48109, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This report describes detailed studies of the scope and mechanism of a new Pd-catalyzed oxidation
reaction for the stereospecific conversion of enynes into cyclopropyl ketones. Unlike related PdII/0, Au,
and Pt-catalyzed cyclopropane-forming reactions, these transformations proceed with net inversion of
geometry with respect to the starting alkene. This result, along with other mechanistic data, is consistent
with a PdII/IV mechanism in which the key cyclopropane-forming step involves nucleophilic attack of
a tethered olefin onto a PdIV–C bond.
Received 30 September 2008
Received in revised form 21 October 2008
Accepted 28 October 2008
Available online 19 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
promote the rearrangement of 1,5- or 1,6-enynes to afford bicy-
clo[3.1.0] and [4.1.0] ring systems, respectively.5–7 These trans-
Bicyclo[3.1.0] and [4.1.0] ring systems are important compo-
nents of biologically active molecules and also serve as key in-
termediates in the construction of many functionalized organic
products. For example, the natural products mycorrhizin A1 and
duocarmycin A,2 which exhibit potent antibiotic activity, both
contain bicyclo[3.1.0] hexane moieties. In addition, Martin has
utilized a bicyclo[3.1.0] hexane as a key intermediate in the total
synthesis of cyclopropane-containing natural product ambruticin
S.3 Finally, nucleophilic ring opening of bicyclo[3.1.0] and [4.1.0]
hexanes has been employed to stereoselectively generate highly
functionalized organic molecules, such as alkoxy- and alkyl-
substituted lactones and furans.4
One attractive synthetic route to bicyclo[3.1.0] and [4.1.0] ring
systems involves transition metal-catalyzed transformations of
readily accessible enyne starting materials. As summarized in
Schemes 1 and 2, two mechanistically distinct pathways have been
reported for the metal-catalyzed construction of bicyclo[3.1.0]hex-
anes from enynes. In the first, electrophilic Pt and Au catalysts
formations are believed to proceed via nucleophilic attack of the
alkene on the metal-coordinated alkyne to produce a bicyclic car-
bocation such as 3. This intermediate rearranges to form a metal-
locarbene (4), which can then undergo
a 1,2-hydride shift/
elimination sequence to afford cyclopropane 2. These trans-
formations typically proceed with high levels of stereoselectivity to
afford products where the geometry of the cyclopropane sub-
stituents (cis vs trans) is the same as that in the alkene starting
material.
An alternative approach to this class of products involves PdII/0
-
catalyzed reactions of enynes. As shown in a representative ex-
ample in Scheme 2, the key cyclopropane-forming step of these
transformations proceeds via intramolecular syn olefin insertion,
which transforms the s
-alkyl PdII intermediate 8 into cyclopropane
9. Complex 9 is then captured with RSnBu3 to generate product 7.8
Importantly, these reactions proceed with high levels of stereo-
selectivity with retention of the olefin geometry (cis vs trans) in the
cyclopropane product.8,9
R
R
R
H
R
1 mol % (Ph3P)AuSbF6
H
H
H
H
H
H
R
H
[AuI]
Bn
CH2Cl2, rt
[AuI]
[AuI]
Bn
R = CH2CH2CH3
Bn
2
Bn
4
Bn
5
1
3
Scheme 1. A representative example of AuI-catalyzed cyclization of enynes.
We sought to design a new, mechanistically distinct route from
enynes to cyclopropanes that takes advantage of the PdII/IV couple to
promote cyclopropane ring formation. Two potential mechanisms
* Corresponding author. Tel.: þ1 734 615 0451.
E-mail address: mssanfor@umich.edu (M.S. Sanford).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.107

3212
T.W. Lyons, M.S. Sanford / Tetrahedron 65 (2009) 3211–3221
MeO2CO
Ph
H
Ph
H
R
H
H
H
Ph
[PdII]
H
H
Ph
[PdII]
10 mol % Pd(OAc)2
20 mol % PPh3
H
H
N
N
PG
1.1 equiv RSnBu3
THF, reflux
N
PG
7
N
PG
6
•
PG
8
9
Scheme 2. Representative example of Pd0/II-catalyzed cyclization of enynes.
R2
R1
R2
O
R1
cat. [PdII]
H
H
PhI(OAc)2
O
AcOH
O
11
O
O
10
AcO
[PdIV
R1
H
H
R2
R2
R2
O
[PdII]
R1
R1
]
OAc
OAc
H
PhI(OAc)2
OAc
11
– [PdII]
O
O
O
13
O
14
O
12
Scheme 3. PdII/IV-catalyzed enyne oxidative cyclization via mechanism A.
for this new transformation (Mechanisms A and B) are outlined in
Schemes 3 and 4. Both involve the key intermediate 12, which is
accessed through the well-precedented sequence of alkyne ace-
toxypalladation followed by syn olefin insertion.10 Prior work has
scope, and limitations of these transformations are all described in
detail. In addition, experiments designed to provide insights into
the mechanism of the cyclopropane-forming step are discussed.
These studies implicate Mechanism A as the major pathway in
these transformations.11a
shown that intermediate 12 can be terminated by
b-acetoxy elimi-
nation, -hydride elimination, chlorination, carbonylation, or
b
protonolysis to afford a variety of functionalized heterocyclic prod-
ucts.10 However, based on recent studies from our group,11 we rea-
2. Results and discussion
soned that this s
-alkyl PdII intermediate could also be intercepted
2.1. Reaction development and optimization
with strong oxidants (e.g., PhI(OAc)2) to generate the PdIV complex
13 (Mechanism A). Such PdIV intermediates are highly susceptible to
Our initial efforts focused on the cascade cyclization of enyne 19
in the presence of 1.1 equiv of PhI(OAc)2. As discussed above, we
anticipated that this hypervalent iodine(III) oxidant would serve to
intercept Pd-alkyl intermediate 12, providing either acetoxylated
product 20 or cyclopropane 19a. A key requirement for the pro-
posed reaction sequence is that the oxidative functionalization of
SN2-type nucleophilic attack at the a
-carbon,12 and wereasonedthat
the intramolecular vinyl acetate moiety of 13 could serve as an ef-
fective nucleophile for cyclopropane formation. Notably, related
SN2-type cyclopropane-forming reactions with nucleophilic olefins
are well precedented in the organic literature.2,13
An alternative PdII/IV mechanism (Mechanism B) involving Heck-
type olefin insertion from 12 would also be possible (Scheme 4).
However, these two potential mechanisms should be readily dis-
tinguishable through the use of enynes containing 1,2-disubstituted
olefins. In Mechanism A, the SN2-type reductive elimination would
result in net inversion of olefin geometry in the cyclopropane
product, while syn olefin insertion in Mechanism B would lead to
retention of the alkene geometry in the final cyclopropane.
This paper describes the development of Pd-catalyzed reactions
of enyne substrates with strong oxidants like PhI(OAc)2 to afford
cyclopropane products. The development, optimization, substrate
intermediate 12 must proceed faster than competing b-hydride
elimination. As a result, our initial studies focused on a catalyst
system composed of 5 mol % of Pd(OAc)2 and 6 mol % of 2,20-
bipyridine (bipy), since Lu has shown that this combination can be
important for the cyclization of enynes and can greatly limit com-
peting b
-hydride elimination processes.10d,14 We were delighted to
find that the reaction of enyne 19 with 1.1 equiv of PhI(OAc)2 in the
presence of 5 mol % of Pd(OAc)2, 6 mol % of bipy in AcOH at 80 ꢀC
afforded bicyclic b-ketolactone 19a in 79% yield. Interestingly, <5%
of compound 20 (the product of oxidatively-induced C–OAc bond
formation from proposed intermediate 12) was observed by GC and
R2
R1
R2
R1
[cat. PdII]
PhI(OAc)2
H
H
O
AcOH
O
O
15
O
O
10
OAc
R1
[PdIV
]
OAc
OAc
R2
[PdII]
R1
H
R1
R2
[PdII]
R1
OAc
R2
OAc
R2
OAc
H
PhI(OAc)2
H
H
15
– [PdII]
O
O
O
O
O
18
O
12
O
16
O
17
Scheme 4. Alternative PdII/IV-catalyzed mechanism for oxidative enyne cyclization (Mechanism B).

T.W. Lyons, M.S. Sanford / Tetrahedron 65 (2009) 3211–3221
3213
5 mol % Pd(OAc)2
Ph
Ph
Ph
Ph
Ph
6 mol % bipy
AcO
OAc
OAc
OAc
H
1.1 equiv PhI(OAc)2
O
AcOH, 80 °C
O
O
O
O
O
O
O
O
O
19
O
22
19a
20
21
(79%)
< 5% observed
not observed
Scheme 5. Pd(OAc)2/bipy-catalyzed oxidative cyclization of substrate 19.
1H NMR spectroscopic analysis of the crude reaction mixture. Fur-
ther, alkenes 21 and 22, the products of -hydride elimination/al-
kene dissociation from putative intermediate 12, were also not
observed in the reaction mixture (Scheme 5).
when 6 mol % of bipy was used (9% vs 54% yield). However, with
substrates 23, 24, and 26 (entries 1, 2, and 4), the use of bipy/
Pd(OAc)2 led to a decrease in yield relative to just Pd(OAc)2. The
origin of these effects is not completely understood and remains
under investigation at this time.
b
We next sought to investigate the effect of the reaction condi-
tions on the yield and distribution of organic products in this
transformation. We first examined the influence of ambient water
and air on the reaction. A comparison of reactions run using rig-
orously dried AcOH (Table 1, entry 3) versus those with commercial
solvent taken directly from the bottle (Table 1, entry 1) showed that
the yield is slightly higher in the latter case. Similar results were
also obtained when the reactions were set up under ambient
conditions (under air) versus under a nitrogen atmosphere (entries
1 and 2, respectively). These results demonstrate that rigorous
purification of the reaction solvent and exclusion of air are not
necessary, which enhances the ease of reaction set up and practi-
cality of these transformations.
2.2. Substrate scope
We next investigated the scope of this cyclopropane-forming
reaction with a variety of different enynes (Table 3). In general, we
found that some optimization of the reaction for each substrate
improved the yields substantially. As a result, each was optimized
for: (1) the presence/absence of bipy, (2) the amount of oxidant
(ranging from 1.1 to 4 equiv), (3) the reaction temperature (be-
tween 60 and 80 ꢀC), and (4) the reaction time (between 1 and
16 h). Upon optimization, moderate to good yields of 41–79% were
obtained with all of the substrates in Table 3. These transformations
led to the generation of bicyclo[3.1.0] and [4.1.0] ring systems
containing lactones, tetrahydrofurans, pyrrolidines, and lactams.11a
Both alkyl and aryl substituents were tolerated on the alkyne, and
both electron donating (p-OMe) and electron withdrawing (p-CF3)
groups on the aryl ring were also compatible with the reaction
Table 1
Optimization of the oxidative cyclization of enyne 19
Ph
Ph
5 mol % catalyst,
H
1.1 equiv PhI(OAc)2
O
conditions,
O
O
O
19
O
80 °C
Table 2
Effect of bipyridine on the cyclizations of enynes 23–26a
19a
Entry
Starting
Product
Yield with
Yield without
materiala
6 mol % bipyb (%) 6 mol % bipyb (%)
Entry
Catalyst
Conditions
Yielda (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 with 6 mol % bipy
Pd(OAc)2 with 6 mol % bipy
Pd(OAc)2 with 6 mol % bipy
Pd(OAc)2bipy
Pd(OAc)2
Pd(TFA)2
Pd(Cl)2
Pd(Cl)2(CH3CN)2
Pd(Cl)2(PPh3)2
Pd(Cl)2(PhCN)2
Na2PdCl4
Ambient
N2
88
71
83
80
93
81
72
65
62
60
51
H
Dry AcOH
Ambient
Ambient
Ambient
Ambient
Ambient
Ambient
Ambient
Ambient
O
1
61
71
N
N
Ts
23a
Ts
23
9
10
11
Ph
H
Ph
a
2
3
9
59
Yields determined by GC relative to an internal standard.
O
O
O
24a
O
24
O
We next examined the role of the bipyridine ligand, since it was
initially hypothesized to be critical for achieving the desired re-
action. As summarized in Table 1, entry 4, the use of 5 mol % of the
pre-formed catalyst (bipy)Pd(OAc)2 afforded similar yields to the in
situ combination of 5 mol % of Pd(OAc)2 and 6 mol % of bipy. Further
studies revealed that bipy was not essential for this transformation
and 93% yield could be obtained with just Pd(OAc)2 as catalyst
(entry 5). In addition, other PdII complexes also served as effective
catalysts for this transformation in the absence of bipy, although
the yields were lower than that with Pd(OAc)2 (entries 6–11). Based
on these studies, 5 mol % of Pd(OAc)2 was identified as the optimal
catalyst for cyclization of 19, and these reaction conditions pro-
vided 88% isolated yield of 19a.
Ph
Ph
H
H
O
O
54
9
N
N
O
Me
25a
Me
25
Ph
Ph
O
O
4
29
59
O
26a
O
26
O
In contrast to the results with substrate 19, the presence/ab-
sence of bipy did have a substantial effect on the Pd-catalyzed cy-
clization of other enynes. As summarized in Table 2, entry 3, with
substrate 25, a significant enhancement in yield was observed
a
Reaction conditions: 5 mol % Pd(OAc)2, 0–6 mol % bipy, 1.1–8 equiv PhI(OAc)2,
60–80 ꢀC, 1–16 h.
b
Yields determined by GC relative to an internal standard.

3214
T.W. Lyons, M.S. Sanford / Tetrahedron 65 (2009) 3211–3221
Table 3
Substrate scope of Pd-catalyzed enyne cyclization reactionsa
Entry
Substrate
Product
Ph
Yieldb (%)
Entry
7
Substrate
Ph
Product
Ph
Yieldb (%)
Ph
H
H
H
O
O
1
79
48
O
O
31a
O
19a
O
19
O
O
31
Me
p-C6H4CF3
Me
p-C6H4CF3
O
H
O
2
3
4
55
78
66
8
41
44
71
O
O
27a
O
32a
O
27
O
O
32
Ph
p-C6H4OMe
Ph
p-C6H4OMe
O
Me
Me
Me
H
O
9
O
O
28a
O
33a
O
33
O
28
O
Me
H
Me
O
O
10
N
O
N
O
29a
O
29
O
Ts
23a
Ts
23
Ph
CO2Me
Ph
Ph
Ph
Ph
CO2Me
H
O
O
H
H
5
O
70
55
11
47
N
N
O
O
O
30
O
Me
24a
O
30a
Me
24
Ph
O
6
O
24a
O
O
24
O
a
Reaction conditions: 5 mol % Pd(OAc)2, 0–6 mol % bipy, 1.1–4 equiv PhI(OAc)2, 60–80 ꢀC, 1–16 h.
Isolated yields (average of two runs).
b
conditions. Furthermore, 1,1- and 1,2-disubstituted enynes were
effective substrates. In the latter case, with an ester substituent on
the alkene, the product was formed with >20:1 dr.
investigations focused on replacing PhI(OAc)2 with a variety of al-
ternative stoichiometric oxidants in the Pd-catalyzed cyclization of
substrate 19. As summarized in Table 4, these studies revealed that
the use of both Oxone and K2S2O8 as terminal oxidants resulted in
significant quantities of the cyclopropane product 19a (Table 4,
entries 2 and 3). Importantly, both of these are strong oxidants that
One major limitation of these transformations is that tri-
substituted enynes such as 34, 35, and 36 did not react to form
cyclopropane products under the standard reaction conditions
(Fig. 1). Instead, these substrates underwent addition of AcOH
across the alkyne, presumably via initial acetoxypalladation fol-
lowed by protonolysis of the resulting Pd-vinyl intermediate.10
Literature precedent suggests that this undesired side reaction
takes place because olefin insertion to form the lactone ring is slow
with highly substituted alkene derivatives.15
Table 4
Effect of oxidant on the yield of cyclopropane 19a
5 mol % Pd(OAc)2
Ph
6 mol % bipy
Ph
1.1 equiv oxidant
AcOH, 80 °C
H
O
O
2.3. Reaction mechanism
O
19a
O
19
O
We first sought to gain evidence to support a PdII/IV mechanism
for these transformations. As such, our initial mechanistic
Entry
Oxidant
Yield of 19aa (%)
1
2
3
4
5
6
7
PhI(OAc)2
Oxone
K2S2O8
94
50
27
0
0
0
Ph
Ph
Ph
Ph
CO2Me
CuCl2
Cu(OAc)2
Benzoquinone
Air
O
34
O
O
35
O
O
36
O
0
a
Figure 1. Enyne substrates that did not undergo cyclization.
Yields determined by GC relative to an internal standard.

T.W. Lyons, M.S. Sanford / Tetrahedron 65 (2009) 3211–3221
3215
Ph
CH
3Ph
O
Ph
OAc
OAc
Ph
O
Ph
O
5 mol % Pd(OAc)2
8 equiv PhI(OAc)2
H
AcO
H
H3C
OAc
OAc
O
O
AcOH, 80 °C, 2 h
O
O
37
O
37a
O
37b
O
37c
O
37d
(29%)
(8%)
(11%)
(19%)
Calibrated GC yields
Scheme 6. Mixture of products formed in Pd-catalyzed reaction of 37 with PhI(OAc)2.
OAc
Ph
OAc
1. Oxidation
2. C–O red. elim.
O
O
37c
Ph
[PdII]
Ph
CH
3O
H
OAc
PhI(OAc)2
H
β-Hydride elim.
H3C
OAc
Ph
O
O
37b
O
O
O
37a
O
38
Ph
1. β-Hydride elim.
2. Reinsertion
AcO
OAc
3. Oxidation
4. C–O red. elim.
O
O
37d
Scheme 7. Mechanistic rationale for formation of products 37a–d.
have been previously implicated in PdII/IV catalytic cycles.16 In
contrast, neither CuII-based oxidants nor benzoquinone or air
provided any of the desired product 19a (entries 4–7). With CuCl2,
Cu(OAc)2, and benzoquinone, starting material 19a was completely
consumed and a complex mixture of products was formed. With air
as the oxidant, a significant quantity of 19 (40%) remained at the
end of the reaction, along with a mixture of unidentified products.
The requirement for strong two-electron oxidants in this trans-
formation provides initial evidence to support the possibility of
PdIV intermediates.
A second set of experiments focused on the use of substrates
37 and 26 as mechanistic probes for these reactions. Initial studies
of substrate 37 showed that it reacted with 5 mol % of Pd(OAc)2
and 8 equiv of PhI(OAc)2 in AcOH at 80 ꢀC for 2 h to afford
a mixture of four major organic products (Scheme 6).11a,17 In ad-
dition to the desired cyclopropane product (discussed later in this
section), the three side productsdacetoxylated isomers 37c and
37d along with alkene 37bdprovided significant additional
mechanistic insights into these transformations. As shown in
Scheme 7, we hypothesize that 37a–d are derived from a common
reductive elimination from PdIV would provide acetoxylated
product 37c. Finally, reinsertion of alkene 37b into the Pd–H
would afford a linear isomer of 38, which could then undergo
oxidative functionalization with PhI(OAc)2 to afford 37d. Impor-
tantly, C–O bond-forming reductive elimination at unactivated sp3
carbon centers is well-known at PdIV,11c,12b,18 but has not, to our
knowledge, been reported at PdII.19 As such, the formation of
products 37c and 37d provides additional evidence to support
a PdII/IV catalytic cycle.
We noted the acetoxylated side product 37c was formed in >95%
diastereoselectivity as determined by 1H NMR spectroscopy. How-
ever, the relative stereochemistry of the two adjacent stereocenters
in the molecule could not be determined conclusively using NOE
studies or coupling constant analysis.20 Furthermore, efforts to
obtain X-ray quality crystals of 37c were hampered by the fact that
this compound is an oil at room temperature. In order to prepare
a crystalline product, we replaced the phenyl substituent on the
alkyne with a biphenyl group. We anticipated that this modification
would alter the physical properties of the product without signifi-
cantly perturbing the cyclization reaction. The biphenyl-substituted
enyne 39 underwent Pd-catalyzed reaction with PhI(OAc)2 to afford
acetoxylated product 39c as a single detectable isomer in 7% iso-
lated yield. X-ray crystallographic analysis of 39c definitively
established the stereochemical relationship shown in Figure 2.21
Assuming that alkene insertion to form the lactone proceeds in a syn
fashion, 39c is the product of C–OAc bond formation with inversion
of configuration at carbon (Scheme 8). This result provides strong
evidence in support of an SN2 mechanism for reductive elimination
from the PdIV intermediate in this system. Notably, similar results
Pd-alkyl intermediate 38.
b-Hydride elimination from this in-
termediate followed by alkene dissociation would afford 37b.
Oxidation of 38 with PhI(OAc)2 followed by C–O bond-forming
Biphenyl
OAc
Biphenyl
5 mol % Pd(OAc)2
8 equiv PhI(OAc)2
CH3
H
AcO
AcOH, 80 °C, 2 h
O
O
39
O
O
39c
(7%)
Figure 2. X-ray crystal structure of product 39c.22
Scheme 8. Reaction of biphenyl-substituted enyne 39.

3216
T.W. Lyons, M.S. Sanford / Tetrahedron 65 (2009) 3211–3221
CH3
Ph
H
CH3
O
O
H
H
Mechanism A
Mechanism B
H3C
Ph
Ph
O
O
O
O
O
O
37a
37
26a
Scheme 9. Potential mechanisms for cyclopropane formation.
Ph
Ph
CH
O
CH
CH3
3O
3O
5 mol % Pd(OAc)2
8 equiv PhI(OAc)2
AcOH, 80 °C, 2 h
5 mol % Pd(OAc)2
8 equiv PhI(OAc)2
H
H
H
H
Ph
H3C
Ph
AcOH, 80 °C, 2 h
O
O
O
O
O
O
O
37a
26
37
26a
(25%)
(57%)
Scheme 10. Stereochemical experiments with enynes 37 and 26.
have been obtained in other C–O bond-forming reactions from
PdIV.18,20
In each case, these results correspond to inversion of the starting
olefin geometry, which clearly implicates Mechanism A for this
transformation. Notably, this result is in contrast to Pd0/II mediated
cyclopropanation of enynes, which has been reported to proceed
with net retention of olefin geometry (Scheme 2).8,9 Our findings
are also distinguished from similar AuI/PtII-catalyzed reactions in-
volving metal carbene intermediates, which also proceed with re-
tention of the initial olefin geometry in the cyclopropane product
(Scheme 1).5,6
Based on the data described above, a complete catalytic cycle
can be proposed for this transformation (Scheme 11). The reaction
begins with acetoxypalladation of the alkyne followed by intra-
molecular olefin insertion to afford intermediate 38. Next, bond
rotation followed by oxidation of alkyl palladium complex 38 af-
fords the PdIV intermediate 41. (Note that the order of these two
steps could also be reversed.) Nucleophilic attack at Ca by the
intramolecular vinyl acetate then produces the organic
The stereochemical course of cyclopropane formation from
substrate Z-37 as well as from isomeric E-26 also provided key
insights into the mechanism of these transformations. As outlined
in Scheme 9 for substrate Z-37, cyclopropane ring formation via syn
olefin insertion into the C–Pd bond (Mechanism B, Scheme 4)
would afford cyclopropane 26a. In contrast, cyclopropane forma-
tion via nucleophilic substitution (Mechanism A, Scheme 4) would
afford the cis-cyclopropane 37a with net inversion of the alkene
geometry.
Subjection of E-26 and Z-37 to optimized reaction conditions
(5 mol % of Pd(OAc)2 and 8 equiv of PhI(OAc)2 in AcOH at 80 ꢀC)
resulted in products 26a and 37a, respectively, with >20:1 dr
(Scheme 10). The stereochemistry about the ring in each product
was determined by NOE analysis. In addition, the structure of 26a
was confirmed by X-ray crystallography.11a
Ph
CH
3 Ph
H
H
O
H3C
O
O
37a
O
37
O
PdII
CH
3 Ph
Ph
O
PdII
H
OAc
H3C
OAc
O
O
42
O
40
II Ph
OAc
PdIV
CH3Ph
H
Ph
Pd
Ph
CH3
H
R.E.
OAc
OAc -[Pd-H]
OAc
H
OAc
H3C
AcO
O
O
O
O
O
37c
O
41
O
38
O
37b
CH3Ph
H
PdII
PhI
OAc
PhI(OAc)2
O
O
38
Ph
AcO
OAc
O
O
37d
Scheme 11. Proposed PdII/IV catalytic cycle for cyclopropane formation.

T.W. Lyons, M.S. Sanford / Tetrahedron 65 (2009) 3211–3221
3217
OH
O
two competing reactions. In particular, we reasoned that p-sub-
stitution on the aromatic group conjugated with the alkyne would
significantly influence the electronic nature of the vinyl acetate
moiety, and thereby affect the rate of cyclopropane formation.
However, in contrast, this remote substitution is expected to have
minimal impact at the metal center; therefore, the relative rate of
C–OAc bond formation should remain essentially unchanged.
Based on this analysis, we anticipated that the ratio of cyclopro-
pane (CP) to acetate (RE-1) would increase with more electron
donating substituents (which would make the vinyl acetate more
nucleophilic) and decrease with more electron withdrawing sub-
stituents (which would diminish the nucleophilicity of this
moiety).
To probe this hypothesis, we synthesized a series of electroni-
cally different p-substituted enynes and submitted them to our
optimized conditions (5 mol % of Pd(OAc)2 and 8 equiv of PhI(OAc)2
in AcOH at 80 ꢀC). The reactions were assayed by analytical HPLC
with yields calibrated against an internal standard. Interestingly,
the reaction time for each electronically different substrate varied
substantially from 8 h for 45 (with a p-NO2 substituent) to 10 min
for 48 (with a p-OMe group).23 However, it is important to note that
both the cyclopropanes (Cp) and the acetoxylated products (RE-
1)17 were stable under the reaction conditions over the course of
8 h; therefore, all of the reactions were compared at 8 h for
consistency.24
OMs
MeO
Me
MeO
Me
DBU
93%
N
N
BOC
BOC
OMe
43
OMe
44
Scheme 12. Example of organic cyclopropane-forming reaction with similar
mechanism.
intermediate 42. Importantly, the þ4 oxidation state at the Pd
center renders it an excellent leaving group; as such, this reaction
can be considered analogous to intramolecular organic cyclopro-
pane-forming reactions such as that shown in Scheme 12.13b Fi-
nally, hydrolysis of the highly reactive species 42 would provide the
observed cyclopropane product.
A key intermediate in the proposed reaction mechanism is PdIV
complex 41. As discussed above, this complex is believed to un-
dergo two competing reactions: (1) intramolecular nucleophilic
attack by the vinyl acetate to afford cyclopropane Cp or (2) nu-
cleophilic attack by OAc to afford acetoxylated product RE-1
(Scheme 13). As such, we hypothesized that the ratio of cyclo-
propane to acetate products (18:1 in the case of substrate 26)
should be very sensitive to electronic perturbation of one of these
Gratifyingly, we observed a clear trend in the ratio of Cp/RE-1
(Table 5). For example, with the electron deficient p-NO2-
substituted derivative, a 5:1 ratio of Cp/RE-1 was obtained. In
striking contrast, the electron donating p-OMe substituent resulted
in a >200:1 ratio of these two products. This is consistent with
a faster relative rate of cyclopropanation for the more electron rich
enynes as was hypothesized above. Notably, significant quantities
X
X
O
OAc
PdIV
H
OAc
CH3
O
H
OAc
OAc
O
O
X
O
O
b-hydride elimination product (b
-H)17 and the isomeric ace-
O
of
toxylated product (RE-2)17 were also formed in these reactions,
although no clear trends were observed upon variation of the
substituent X. However, this was not unexpected, as both of these
products are formed by independent pathways that do not involve
competing reactivity of intermediate 41.
RE-1
41 (X = H)
Scheme 13. Proposed competing pathways.
Cp
Table 5
Ratio of Cp/RE-1 as a function of aryl substituent X
X
Yielda (%)
Cp
b-H
RE-1
RE-2
Cp/RE-1
NO2 (45)
CF3 (46)
H (26)
Me (47)
OMe (48)
44
36
55
56
66
ꢁ1
2
<1
2
8
5
3
1
ꢁ1
7
12
5
5:1
7:1
18:1
56:1
>200:1
2
ꢁ1
ꢁ1
a
Yields determined by HPLC relative to an internal standard.

3218
T.W. Lyons, M.S. Sanford / Tetrahedron 65 (2009) 3211–3221
3. Conclusions
ramp 15 ꢀC/min to 240 ꢀC, and hold for 10 min. GC–MS analysis was
performed on a Shimadzu GCMS QP-5000 equipped with a Restek
RtxÒ-5 column (30 m, 0.25 mm ID, 0.25
m df). Control reactions
(in the absence of Pd catalyst) were run for each substrate and
showed no reaction.
We have demonstrated a new Pd-catalyzed reaction for the
stereospecific oxidative cyclization of enynes into bicyclic cyclo-
propanes. This method allows for the construction of cyclic prod-
m
ucts from acyclic starting materials with
a complementary
stereochemical outcome to related Pd0/II, AuI, and PtII-catalyzed
processes. We have shown that the choice of oxidant is crucial to
the construction of these products and that with certain substrates,
bidentate ligands are required for cyclization. This reaction is tol-
erant of a variety of functional groups and proceeds in moderate to
good yield with a broad scope of enynes. The observed stereo-
chemistry as well as detailed electronic studies provide strong
evidence supporting the formation of a PdIV intermediate that
undergoes competing C–C bond formation (to generate the cyclo-
propane product) and C–OAc bond formation (to produce an ace-
toxylated compound). These studies offer insight into a new mode
of reactivity for alkyl-PdIV species and should serve as an orthog-
onal approach to accessing highly functionalized bicyclic
cyclopropanes.
4.3. General procedures
4.3.1. Procedure for synthesis of enynes
The enyne substrates were prepared from the corresponding
acid and alcohol according to a literature procedure.10c–e The car-
boxylic acids were prepared as follows: a solution of aryl acetylene
(1 equiv, 0.14 M) was added to a 2.5 M solution of n-BuLi (0.9 equiv)
in hexanes. The reaction was stirred at 0 ꢀC for 30 min and then CO2
gas was bubbled through the solution for 15 min. The reaction
mixture was then washed with 2 M NaOH, the organic layer was
discarded, the aqueous layer was then reacidified with 6 M HCl, and
extracted with diethyl ether. The organic layer was dried over
MgSO4 and concentrated to a solid. For p-NO2 enyne 45 a slight
modification to the above procedure was made: KHMDS
(0.95 equiv) was used as the base and THF was used as the solvent.
4. Experimental
4.3.2. Procedure for Pd-catalyzed cyclopropanation of enynes
The following procedure was used for isolation of the products
presented in Table 5. In a resealable pressure flask, the enyne
substrate (1 equiv), PhI(OAc)2 (8 equiv), and Pd(OAc)2 (5 mol %)
were combined in AcOH to make a 0.16 M solution with respect to
enyne. The vessel was sealed and the reaction heated at 80 ꢀC for
10 min to 8 h. The resulting mixture was cooled to room temper-
ature, diluted with EtOAc, and the organic layer was extracted with
a saturated solution of NaHCO3. The organic layer was dried over
MgSO4, concentrated, and the resulting residue was purified by
chromatography on silica gel.
4.1. Instrumentation
NMR spectra were obtained on a Varian Inova 500 (499.90 MHz
for 1H; 125.70 MHz for 13C) or a Varian Inova 400 (399.96 MHz for
1H; 100.57 MHz for 13C; 376.34 MHz for 19F) spectrometer. 1H NMR
chemical shifts are reported in parts per million (ppm) relative to
TMS, with the residual solvent peak used as an internal reference.
Multiplicities are reported as follows: singlet (s), doublet (d),
doublet of doublets (dd), doublet of doublets of doublets (ddd),
doublet of triplets (dt), doublet of quartets (dq), doublet of triplets
of doublets (dtd), triplet (t), triplet of triplets (tt), quartet (q),
quintet (quin), multiplet (m), and broad resonance (br). IR spectra
were obtained on a Perkin–Elmer ‘Spectrum BX’ FT-IR spectrome-
ter. Melting points were obtained on a MEL-TEMP 3.0 from Labo-
ratory Devices Inc., USA.
4.4. Characterization data
4.4.1. (E)-But-2-enyl 3-(4-methoxyphenyl)propiolate (48)
Enyne 48 was obtained as a pale yellow oil (Rf¼0.39 in 95%
hexanes/5% EtOAc). 1H NMR (500 MHz, CDCl3):
d
7.51 (d, J¼9.0 Hz,
4.2. Materials and methods
2H), 6.86 (d, J¼9.0 Hz, 2H), 5.85 (dq, J¼15.0, 6.5 Hz, 1H), 5.64 (dt,
J¼15.0, 6.5 Hz, 1H), 4.63 (d, J¼6.5 Hz, 2H), 3.81 (s, 3H), 1.73 (d,
Enyne substrates were prepared according to the literature
procedures.10c–e Spectral data for compounds found in Table 1 as
well as products 26a–d have been reported in a previous commu-
nication.11a PhI(OAc)2 and 2,20-bipyridine were obtained from
Aldrich or Acros and used as received. Pd(OAc)2 was obtained from
Pressure Chemical or Frontier Scientific and used as received. The
GC yields reported for Table 1 (entries 1–11) and Table 4 (entries 1–
7) are corrected GC yields based on calibration curves against an
internal standard (1,3-dinitrobenzene and biphenyl, respectively).
Flash chromatography was performed on EM Science silica gel 60
(0.040–0.063 mm particle size, 230–400 mesh) and thin layer
chromatography was performed on Merck TLC plates pre-coated
with silica gel 60 F254. HPLC separations were performed on a Var-
J¼2.0 Hz, 3H). 13C {1H} NMR (100.6 MHz, CDCl3):
d 161.4, 154.1,
134.9, 132.6, 124.2, 114.2, 111.3, 87.1, 80.0, 66.5, 55.3, 17.7. HRMS (EI):
[M]þ calcd for C14H14O3: 230.0943; found: 230.0952. IR (thin film):
1699 cmꢃ1
.
4.4.2. Pd-catalyzed reaction of 48
Substrate 48 (0.300 g, 1.20 mmol, 1 equiv), PhI(OAc)2 (3.357 g,
10.40 mmol, 8 equiv), and Pd(OAc)2 (14.6 mg, 5 mol %) were com-
bined in AcOH (8.14 mL) and heated at 80 ꢀC for 10 min. After the
workup described in the standard procedure above, products 48a
and 48b were isolated from this reaction as described below.
4.4.3. 1-(4-Methoxybenzoyl)-6-methyl-3-oxabicyclo[3.1.0]hexan-
2-one (48a)
Product 48a was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc) and
isolated as a pale yellow solid (0.1572 g, 49% yield, mp¼85.0–
87.6 ꢀC, Rf¼0.17 in 70% hexanes/30% EtOAc). 1H NMR (500 MHz,
ian ProStar 210 HPLC using Waters
(19ꢂ300 mm) columns. HPLC reaction analysis was carried out
with a Waters
-PorasilÒ 10
m mm silica
-PorasilÒ 10
m
m
m silica (3.9ꢂ300 mm) column with
yields based on calibration curves with an internal standard (1,3-
dinitrobenzene). HPLC analysis of the products reported herein was
carried out using the following method: 97% hexanes/3% ethyl ac-
etate starting eluent, ramp to 50% hexanes/50% EtOAc over 40 min,
ramp to 97% hexanes/3% EtOAc over 5 min and hold for 15 min. Gas
chromatography was performed on a Shimadzu GC-17A equipped
CDCl3):
d
7.86 (d, J¼8.5 Hz, 2H), 6.95 (d, J¼8.5 Hz, 2H), 4.54 (dd,
J¼10.0, 5.5 Hz, 1H), 4.21 (d, J¼10.0 Hz, 1H), 3.83 (s, 3H), 2.83 (dd,
J¼8.0, 5.5 Hz, 1H), 2.09 (dq, J¼8.0, 6.5 Hz, 1H), 1.29 (d, J¼6.5 Hz, 3H).
13C {1H} NMR (125.7 MHz, CDCl3):
d 190.6, 171.4, 163.9, 132.5, 131.8,
with a Restek RtxÒ-5 column (15 m, 0.25 mm ID, 0.25
FID detector. GC analysis of all of the products reported herein was
carried out using the following method: 100 ꢀC start temperature,
mm df) and an
113.6, 64.4, 55.4, 41.5, 29.9, 24.6, 7.7. HRMS electrospray with Naþ
added: [MþNa]þ calcd for C14H14O4: 269.0790; found: 269.0792. IR
(Nujol mull): 1756, 1651 cmꢃ1
.

T.W. Lyons, M.S. Sanford / Tetrahedron 65 (2009) 3211–3221
3219
4.4.4. (Z)-(4-Methoxyphenyl)(2-oxo-4-vinyldihydrofuran-3(2H)-
ylidene)methyl acetate (48b)
4.4.9. (Z)-1-(4-(Acetoxy(p-tolyl)methylene)-5-oxotetrahydrofuran-
3-yl)ethyl acetate (47c)
Product 48b was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc)
and isolated as a yellow oil (34 mg, 9% yield, Rf¼0.23 in 70%
Product 47c was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc)
and isolated as a yellow oil (Rf¼0.20 in 70% hexanes/30% EtOAc).
Analytically pure material was obtained from further purification
hexanes/30% EtOAc). 1H NMR (500 MHz, CDCl3):
d 7.50 (d,
J¼9.0 Hz, 2H), 6.87 (d, J¼9.0 Hz, 2H), 5.84 (ddd, J¼17.0, 10.0,
9.0 Hz, 1H), 5.21 (dd, J¼17.0, 10.0 Hz, 2H), 4.45 (t, J¼9.0 Hz, 1H),
4.04 (dd, J¼9.0, 5.0 Hz, 1H), 3.89 (td, J¼9.0, 5.0 Hz, 1H), 3.82 (s,
by HPLC (85% hexanes/15% EtOAc, 24 mL/min, Waters m-porasil
19.1 mm). The isolated yield was not determined due to loss
during purification. However, HPLC analysis of the crude reaction
mixture showed that 47c was formed in 2% yield. 1H NMR
3H), 2.12 (s, 3H). 13C {1H} NMR (100.7 MHz, CDCl3):
d 168.5, 167.4,
161.4, 158.3, 135.7, 130.7, 124.4, 117.1, 115.3, 113.4, 69.2, 55.3, 44.1,
20.8. HRMS electrospray with Naþ added: [MþNa]þ calcd for
C16H16O6: 311.0895; found: 311.0896. IR (thin film): 1762,
(500 MHz, CDCl3):
d
7.48 (d, J¼8.0 Hz, 2H), 7.21 (d, J¼8.0 Hz, 2H),
5.29 (m, 1H), 4.42 (d, J¼10.0 Hz, 1H), 4.28 (dd, J¼10.0, 7.5 Hz, 1H),
3.64 (m, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.07 (s, 3H), 1.25 (d,
1755 cmꢃ1
.
J¼6.5 Hz, 3H). 13C {1H} NMR (100.6 MHz, CDCl3):
d 168.5, 167.4,
161.4, 158.3, 135.7, 130.7, 124.4, 117.1, 115.3, 113.4, 69.2, 55.3, 53.4,
44.1, 20.8. Note that two peaks in the 13C NMR spectrum co-
incidentally overlap. HRMS electrospray with Naþ added:
[MþNa]þ calcd for C18H20O6: 355.1158; found: 355.1160. IR (thin
4.4.5. (E)-But-2-enyl 3-p-tolylpropiolate (47)
Enyne 47 was obtained as a colorless oil (Rf¼0.36 in 95% hex-
anes/5% EtOAc). 1H NMR (500 MHz, CDCl3) for the E isomer:
d 7.46
(d, J¼8.5 Hz, 2H), 7.15 (d, J¼8.5 Hz, 2H), 5.85 (dq, J¼15.0, 7.0 Hz, 1H),
film): 1760, 1738, 1653 cmꢃ1
.
5.64 (tq, J¼15.0, 7.0 Hz, 1H), 4.63 (d, J¼7.0 Hz, 2H), 2.36 (s, 3H), 1.73
(d, J¼7.0 Hz, 3H). 13C {1H} NMR (100.6 MHz, CDCl3):
d
154.0, 141.2,
4.4.10. (Z)-2-(4-(Acetoxy(p-tolyl)methylene)-5-oxotetrahydro-
furan-3-yl)ethyl acetate (47d)
Product 47d was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc) and
isolated as a yellow oil (Rf¼0.16 in 70% hexanes/30% EtOAc). Ana-
lytically pure material was obtained from further purification by
132.9, 132.7, 129.3, 124.2, 116.5, 86.8, 80.2, 66.6, 21.7, 17.6. HRMS (EI)
[M]þ calcd for C14H14O2: 214.0994; found: 214.0996. IR (thin film):
1707 cmꢃ1
.
4.4.6. Reaction with enyne 47
Substrate 47 (0.700 g, 3.27 mmol, 1 equiv), PhI(OAc)2 (8.418 g,
26.1 mmol, 8 equiv), and Pd(OAc)2 (36.6 mg, 5 mol %) were com-
bined in AcOH (20 mL) and heated at 80 ꢀC for 1.5 h. After the
workup described in the standard procedure above, products 47a,
47b, 47c, and 47d were isolated from this reaction as described
below.
HPLC (80% hexanes/20% EtOAc, 24 mL/min, Waters m-porasil
19.1 mm). The isolated yield was not determined due to loss during
purification. However, HPLC analysis of the crude reaction mixture
showed that 47d was formed in 6% yield. 1H NMR (500 MHz,
CDCl3):
d
7.43 (d, J¼8.0 Hz, 2H), 7.23 (d, J¼8.0 Hz, 2H), 4.38 (dd,
J¼9.0, 7.0 Hz, 1H), 4.14 (dd, J¼9.0, 2.5 Hz, 1H), 4.06–4.01 (m, 1H),
3.96 (dt, J¼11.5, 6.0 Hz, 1H), 3.65–3.61 (m, 1H), 2.38 (s, 3H), 2.30 (s,
3H), 1.95 (s, 3H), 1.83–1.77 (m, 2H). 13C {1H} NMR (100.6 MHz,
4.4.7. 6-Methyl-1-(4-methylbenzoyl)-3-oxabicyclo[3.1.0]hexan-
2-one (47a)
Product 47a was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc) and
isolated as a white solid (345 mg, 46% yield, mp¼112.0–114.0 ꢀC,
Rf¼0.26 in 70% hexanes/30% EtOAc). 1H NMR (500 MHz, CDCl3):
CDCl3):
d 170.6, 168.5, 168.1, 154.0, 141.1, 130.9, 129.5, 127.7, 116.8,
69.7, 61.4, 35.7, 32.0, 21.4, 20.8, 20.7. HRMS electrospray with Naþ
added: [MþNa]þ calcd for C18H20O6: 355.1158; found: 355.1160. IR
(thin film): 1749, 1649 cmꢃ1
.
d
7.81 (d, J¼8.5 Hz, 2H), 7.30 (d, J¼8.5 Hz, 2H), 4.60 (dd, J¼10.0,
4.4.11. (E)-But-2-enyl 3-(4-(trifluoromethyl)phenyl)propiolate (46)
Enyne 46 was obtained as a clear oil (Rf¼0.32 in 95% hexanes/
5.5 Hz, 1H), 4.27 (d, J¼10.0 Hz, 1H), 2.89 (dd, J¼8.0, 5.5 Hz, 1H), 2.44
(s, 3H), 2.20 (dq, J¼8.0, 6.5 Hz, 1H), 1.34 (d, J¼6.5 Hz, 3H). 13C {1H}
5% EtOAc). 1H NMR (500 MHz, CDCl3):
d
7.70 (d, J¼8.5 Hz, 2H),
NMR (100.7 MHz, CDCl3):
d
192.2, 171.3, 144.6, 133.1, 129.5, 129.2,
7.65 (d, J¼8.5 Hz, 2H), 5.90–5.84 (m, 1H), 5.66–5.59 (m, 1H), 4.66
64.5, 41.8, 30.6, 24.9, 21.8, 7.8. HRMS electrospray with Naþ added:
(d, J¼7.0 Hz, 2H), 1.74 (d, J¼7.0 Hz, 3H). 13C {1H} NMR (100.7 MHz,
[MþNa]þ calcd for C14H14O3: 253.0841; found: 253.0849. IR (Nujol
CDCl3):
d
153.4, 133.1, 132.2 (q, JCF¼33.2 Hz), 131.1, 125.5 (q,
2
mull): 1760, 1655 cmꢃ1
.
3JCF¼3.9 Hz), 123.9, 123.5 (q, JCF¼272.4 Hz), 123.0, 83.9, 82.2,
1
66.9, 17.8. 19F NMR (376.3 MHz):
d
ꢃ63.0. HRMS (EI): [M]þ calcd
4.4.8. (Z)-(2-Oxo-4-vinyldihydrofuran-3(2H)-ylidene)-
(p-tolyl)methyl acetate (47b)
for C14H11F3O2: 268.0711; found: 268.0709. IR (thin Film):
1712 cmꢃ1
.
Product 47b was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc) and
isolated as a yellow oil (Rf¼0.31 in 70% hexanes/30% EtOAc). Ana-
lytically pure material was isolated by further purification by HPLC
4.4.12. Reaction with enyne 46
Substrate 46 (1.200 g, 3.47 mmol, 1 equiv), PhI(OAc)2 (11.53 g,
35.8 mmol, 8 equiv), and Pd(OAc)2 (50.2 mg, 5 mol %) were com-
bined in AcOH (28 mL) and heated at 80 ꢀC for 6 h. After the workup
described in the standard procedure above, products 46a, 46b, 46c,
and 46d were isolated from this reaction as described below.
(85% hexanes/15% EtOAc, 24 mL/min, Waters m-porasil 19.1 mm).
Isolated yield was not determined due to difficulties in purification,
but was found to be 7% by calibrated HPLC after 1.5 h. Independent
experiments show this compound decomposes relative to an in-
ternal standard under the optimized reaction conditions. 1H NMR
4.4.13. 6-Methyl-1-(4-(trifluoromethyl)benzoyl)-3-
(400 MHz, CDCl3):
d
7.46 (d, J¼8.0 Hz, 2H), 7.20 (d, J¼8.0 Hz, 2H),
oxabicyclo[3.1.0]hexan-2-one (46a)
5.87 (ddd, J¼17.2, 10.0, 6.0 Hz, 1H), 5.25 (dd, J¼17.2, 10.0 Hz, 2H),
Product 46a was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc) and
isolated as a yellow solid (mp¼78.4–79.0 ꢀC, Rf¼0.25 in 70% hex-
anes/30% EtOAc). Analytically pure material was obtained from
further purification by HPLC (85% hexanes/15% EtOAc, 24 mL/min,
4.36 (dd, J¼9.0, 7.2 Hz, 1H), 4.10 (dd, J¼9.0, 2.8 Hz, 1H), 3.93 (m, 1H),
2.38 (s, 3H), 2.34 (s, 3H). 13C {1H} NMR (100.6 MHz, CDCl3):
d 168.3,
167.4, 158.5, 141.0, 135.6, 129.3, 128.9, 128.6, 117.2, 116.1, 69.2, 43.9,
21.5, 20.8. HRMS electrospray with Naþ added: [MþNa]þ calcd for
C16H16O4: 295.0946; found: 295.0942. IR (thin film): 1765,
Waters
m-porasil 19.1 mm). The isolated yield was not determined
1759 cmꢃ1
.
due to loss during purification. However, HPLC analysis of the crude

3220
T.W. Lyons, M.S. Sanford / Tetrahedron 65 (2009) 3211–3221
reaction mixture showed that 46a was formed in 36% yield. 1H NMR
(400 MHz, CDCl3):
4.4.17. (E)-But-2-enyl 3-(4-nitrophenyl)propiolate (45)
d
7.96 (d, J¼8.0 Hz, 2H), 7.73 (d, J¼8.0 Hz, 2H),
Enyne 45 was obtained as a pale yellow solid (mp¼57.1–
4.58 (dd, J¼10.0, 5.2 Hz, 1H), 4.27 (dd, J¼10.0, 1.2 Hz, 1H), 3.00 (ddd,
J¼8.4, 5.2, 1.2 Hz, 1H), 2.22 (dq, J¼8.4, 6.4 Hz, 1H), 1.36 (d, J¼6.4 Hz,
58.8 ꢀC, Rf¼0.23 in 95% hexanes/5% EtOAc). 1H NMR (500 MHz,
CDCl3):
d
8.23 (d, J¼8.5 Hz, 2H), 7.72 (d, J¼8.5 Hz, 2H), 5.91–5.86
3H).13C {1H} NMR (100.6 MHz, CDCl3):
d
192.5,170.6,138.5,134.8 (q,
(m, 1H), 5.63 (qd, J¼7.0, 1.5 Hz, 1H), 4.67 (d, J¼7.0 Hz, 2H), 1.74 (d,
3
1
2JCF¼32 Hz), 129.7, 125.5 (q, JCF¼4.0 Hz), 123.5 (q, JCF¼271.0 Hz),
J¼7.0 Hz, 3H). 13C {1H} NMR (100.7 MHz, CDCl3):
d 153.1, 133.7,
64.4, 42.1, 31.2, 26.7, 7.9. 19F NMR (376.3 MHz):
d
ꢃ63.3. HRMS
133.4, 126.3, 123.8, 123.7, 122.9, 84.1, 82.9, 67.1, 17.8. HRMS (EI):
electrospray with Naþ added: [MþNa]þ calcd for C14H11F3O3:
[M]þ calcd for C13H11NO4: 245.0688; found: 245.0698. IR (thin
307.0558; found: 307.0547. IR (Nujol mull): 1775, 1680 cmꢃ1
.
film): 1701 cmꢃ1
.
4.4.14. (Z)-(2-Oxo-4-vinyldihydrofuran-3(2H)-ylidene)-
4.4.18. Reaction with enyne 45
(4-(trifluoromethyl)phenyl)methyl acetate (46b)
Substrate 45 (0.452 g, 1.84 mmol, 1 equiv), PhI(OAc)2 (4.749 g,
14.7 mmol, 8 equiv), and Pd(OAc)2 (20.7 mg, 5 mol %) were com-
bined in AcOH (11.6 mL) and heated at 80 ꢀC for 8 h. After the
workup described in the standard procedure above, products 45a
and 45b were isolated from this reaction as described below.
Product 46b was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc) and
isolated as a yellow oil (Rf¼0.38 in 70% hexanes/30% EtOAc). Ana-
lytically pure material was obtained from further purification by
HPLC (90% hexanes/10% EtOAc, 24 mL/min, Waters
m-porasil
19.1 mm). Isolated yield was not determined due to difficulties in
4.4.19. 6-Methyl-1-(4-nitrobenzoyl)-3-oxabicyclo[3.1.0]hexan-2-
one (45a)
purification, but was found to be 2% by calibrated HPLC after 6 h. 1H
NMR (400 MHz, CDCl3):
d
7.63 (s, 4H), 5.83 (ddd, J¼16.8, 10.0,
Product 45a was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc) and
isolated as a clear oil (Rf¼0.16 in 70% hexanes/30% EtOAc). Analyt-
ically pure material was obtained from further purification by HPLC
8.4 Hz, 1H), 5.23 (multiple peaks, 2H), 4.47 (t, J¼8.8 Hz, 1H), 4.06
(dd, J¼8.8, 5.2 Hz, 1H), 3.92 (td, J¼8.4, 5.2 Hz, 1H), 2.11 (s, 3H). 13C
{1H} NMR (100.7 MHz, CDCl3):
d 168.4, 167.5, 152.6, 137.0, 135.4,
2
3
132.2 (q, JCF¼32 Hz), 128.4, 125.5 (q, JCF¼3.9 Hz), 123.6 (q,
1JCF¼272.5 Hz),118.9,117.8, 70.2, 43.0, 20.7. HRMS electrospray with
Naþ added: [MþNa]þ calcd for C16H13F3O4: 349.0664; found:
(85% hexanes/15% EtOAc, 24 mL/min, Waters m-porasil 19.1 mm).
The isolated yield was not determined due to loss during purifi-
cation. However, HPLC analysis of the crude reaction mixture
showed that 45a was formed in 43% yield. 1H NMR (400 MHz,
349.0653. IR (thin film): 1760 cmꢃ1
.
CDCl3):
d
8.33 (d, J¼9.0 Hz, 2H), 8.02 (d, J¼9.0 Hz, 2H), 4.59 (dd,
4.4.15. (Z)-1-(4-(Acetoxy(4-(trifluoromethyl)phenyl)methylene)-5-
oxotetrahydrofuran-3-yl)ethyl acetate (46c)
Product 46c was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc) and
isolated as a yellow oil (Rf¼0.18 in 70% hexanes/30% EtOAc). Ana-
lytically pure material was isolated by further purification by HPLC
J¼10.0, 5.6 Hz, 1H), 4.29 (d, J¼10.0 Hz, 1H), 3.07 (ddd, J¼8.0, 5.2,
1.2 Hz, 1H), 2.27 (dq, J¼8.0, 6.0 Hz, 1H), 1.38 (d, J¼6.0 Hz, 3H). 13C
{1H} NMR (100.7 MHz, CDCl3):
d 192.4, 170.4, 150.3, 140.6, 130.3,
123.6, 64.36, 42.4, 31.6, 27.7, 8.0. HRMS electrospray with Naþ
added: [MþNa]þ calcd for C13H11NO5: 284.0535; found: 284.0542.
IR (Nujol mull): 1766, 1674 cmꢃ1
.
(85% hexanes/15% EtOAc, 24 mL/min, Waters m-porasil 19.1 mm).
The isolated yield was not determined due to loss during purifi-
cation. However, HPLC analysis of the crude reaction mixture
showed that 46c was formed in 5% yield. 1H NMR (400 MHz,
4.4.20. (Z)-1-(4-(Acetoxy(4-nitrophenyl)methylene)-5-
oxotetrahydrofuran-3-yl)ethyl acetate (45c)
Product 45c was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc) and
isolated as a clear oil (Rf¼0.11 in 70% hexanes/30% EtOAc). Analyt-
ically pure material was obtained from further purification by HPLC
CDCl3):
d
7.67 (multiple peaks, 4H), 5.28 (m, 1H), 4.45 (dd, J¼9.6,
2.0 Hz, 1H), 4.31 (dd, J¼9.6, 7.2 Hz, 1H), 3.69 (m, 1H), 2.32 (s, 3H),
2.07 (s, 3H), 1.26 (d, J¼6.4 Hz, 3H). 13C {1H} NMR (100.7 MHz,
2
CDCl3):
d
170.2, 167.9, 167.6, 156.5, 135.1, 132.3 (q, JCF¼32.6 Hz),
(85% hexanes/15% EtOAc, 24 mL/min, Waters m-porasil 19.1 mm).
3
1
129.5, 125.0 (q, JCF¼3.9 Hz), 123.9 (q, JCF¼272.1 Hz), 116.9, 69.3,
The isolated yield was not determined due to loss during purifi-
cation. However, HPLC analysis of the crude reaction mixture
showed that 45c was formed in 8% yield. 1H NMR (400 MHz,
65.5, 42.7, 21.1, 20.7, 14.5. 19F NMR (376.3 MHz):
d
ꢃ63.0. HRMS
electrospray with Naþ added: [MþNa]þ calcd for C18H17F3O6:
409.0875; found: 409.0865. IR (thin film): 1775, 1757, 1730 cmꢃ1
.
CDCl3):
d
8.25 (d, J¼9.2 Hz, 2H), 7.72 (d, J¼9.2 Hz, 2H), 5.27 (dq,
J¼6.8, 4.4 Hz, 1H), 4.47 (dd, J¼10.0, 2.0 Hz, 1H), 4.32 (dd, J¼10.0,
4.4.16. (Z)-2-(4-(Acetoxy(4-(trifluoromethyl)phenyl)methylene)-5-
oxotetrahydrofuran-3-yl)ethyl acetate (46d)
7.2 Hz, 1H), 3.72–3.69 (m, 1H), 2.32 (s, 3H), 2.08 (s, 3H), 1.27 (d,
J¼6.8 Hz, 3H). 13C {1H} NMR (100.7 MHz, CDCl3):
d 170.3, 168.0,
Product 46d was purified by gradient column chromatography
(gradient¼80% hexanes/20% EtOAc to 50% hexanes/50% EtOAc) and
isolated as a white solid (mp¼141.5–142.4 ꢀC, Rf¼0.08 in 70% hex-
anes/30% EtOAc). Analytically pure material was obtained from
further purification by HPLC (85% hexanes/15% EtOAc, 24 mL/min,
167.5, 155.4, 148.7, 137.8, 130.2, 123.2, 118.0, 69.3, 65.7, 42.7, 21.1,
20.7, 14.7. HRMS electrospray with Naþ added: [MþNa]þ calcd for
C17H17NO8: 386.0852; found: 386.0858. IR (thin film): 1760, 1738,
1664 cmꢃ1
.
Waters
m-porasil 19.1 mm). The isolated yield was not determined
4.4.21. (Z)-But-2-enyl 3-(biphenyl-4-yl)propiolate (39)
due to loss during purification. However, HPLC analysis of the crude
Enyne 39 was obtained as a pale yellow oil (Rf¼0.11 in 95%
hexanes/5% EtOAc) along with w10% of an unknown impurity. The
impurity was removed by further purification via HPLC (99.5%
reaction mixture showed that 46d was formed in 7% yield. 1H NMR
(400 MHz, CDCl3):
d
7.71 (d, J¼8.4 Hz, 2H), 7.66 (d, J¼8.4 Hz, 2H),
4.42 (dd, J¼9.2, 6.8 Hz, 1H), 4.17 (dd, J¼9.2, 2.0 Hz, 1H), 4.05–3.98
hexanes/0.5% EtOAc, 60 mL/min, Waters
(500 MHz, CDCl3):
m
-porasil 30 mm). 1H NMR
(m, 1H), 3.96–3.90 (m, 1H), 3.57–3.51 (m, 1H), 2.32 (s, 3H), 1.92 (s,
d
7.63 (d, J¼8.5 Hz, 2H), 7.58 (multiple peaks,
3H), 1.81–1.74 (m, 2H). 13C {1H} NMR (100.7 MHz, CDCl3):
d
170.8,
4H), 7.44 (t, J¼7.5 Hz, 2H), 7.24 (t, J¼7.5 Hz, 1H), 5.85–5.78 (m, 1H),
2
167.8, 167.5, 155.3, 135.4, 132.0 (q, JCF¼32.7 Hz), 129.4, 124.9 (q,
5.67–5.61 (m, 1H), 4.82 (d, J¼7.0 Hz, 2H), 1.75 (d, J¼7.5 Hz, 3H). 13C
1JCF¼3.8 Hz), 120.2, 123.5 (q, JCF¼270.2 Hz), 69.8, 61.6, 36.6, 32.2,
{1H} NMR (125.7 MHz, CDCl3):
d 154.0, 143.3, 139.7, 133.4, 130.7,
1
20.9, 20.8. 19F NMR (376.3 MHz):
d
ꢃ63.0. HRMS electrospray with
128.9, 128.1,127.1, 127.0, 123.2, 118.2, 86.3, 81.1, 61.4,13.1. HRMS (EI):
Naþ added: [MþNa]þ calcd for C18H17F3O6: 409.0875; found:
[M]þ calcd for C19H16O2: 276.1150; found: 276.1157. IR (thin film):
409.0870. IR (Nujol mull): 1763, 1733, 1666 cmꢃ1
.
1707 cmꢃ1
.

T.W. Lyons, M.S. Sanford / Tetrahedron 65 (2009) 3211–3221
3221
9. For examples, see: (a) Meyer, F. E.; Parsons, P. J.; Meijere, A. J. Org. Chem. 1991,
56, 6487; (b) Owczarczyk, Z.; Lamaty, F.; Vawter, E. J.; Negishi, E. J. Am. Chem.
Soc. 1992, 114, 10091; (c) Grigg, R.; Dorrity, M. J.; Malone, J. F. Tetrahedron Lett.
1990, 31, 1343; (d) Brown, A.; Grigg, R.; Ravishankar, R.; Thornton-Pett, M.
Tetrahedron Lett. 1994, 2753; (e) Grigg, R.; Sridharan, V. Tetrahedron Lett. 1992,
33, 7965; (f) Grigg, R.; Rasul, R.; Redpath, J.; Wilson, D. Tetrahedron Lett. 1996,
4.4.22. (Z)-1-(4-(Acetoxy(biphenyl-4-yl)methylene)-5-
oxotetrahydrofuran-3-yl)ethyl acetate (39c)
Substrate 39c (0.790 g, 2.86 mmol, 1 equiv), PhI(OAc)2 (7.362 g,
22.9 mmol, 8 equiv), and Pd(OAc)2 (32.1 mg, 5 mol %) were dis-
solved in AcOH (18 mL) and heated at 80 ꢀC for 2 h. Product 39c was
purified by gradient column chromatography (gradient¼80% hex-
anes/20% EtOAc to 50% hexanes/50% EtOAc) and isolated as a white
solid (mp¼150.0–151.1 ꢀC, Rf¼0.22 in 70% hexanes/30% EtOAc).
Analytically pure material was obtained from further purification
´
`
˜
37, 4609; (g) Marco-Martınez, J.; Lopez-Carrillo, V.; Bunuel, E.; Simancas, R.;
Ca´rdenas, D. J. J. Am. Chem. Soc. 2007, 129, 1874.
10. (a) Lu, X.; Zhu, G.; Wang, Z. Synlett 1998, 115; (b) Wang, Z.; Zhang, Z.; Lu, X.
Organometallics 2000, 19, 775; (c) Zhao, L.; Lu, X.; Xu, W. J. Org. Chem. 2005, 70,
4059; (d) Zhang, Q.; Lu, X.; Han, X. J. Org. Chem. 2001, 66, 7676; (e) Zhang, Q.;
Xu, W.; Lu, X. J. Org. Chem. 2005, 70, 1505.
by HPLC (85% hexanes/15% EtOAc, 24 mL/min, Waters
m-porasil
11. For a preliminary account of this work, see: (a) Welbes, L. L.; Lyons, T. W.;
Cychosz, K. A.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 5836. See also: (b)
Tong, X.; Beller, M.; Tse, M. K. J. Am. Chem. Soc. 2007, 129, 4906; (c) Desai, L.;
Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46, 5737; (d) Kalyani, D.; Sanford, M.
S. J. Am. Chem. Soc. 2008, 130, 2150; (e) Desai, L.; Hull, K. L.; Sanford, M. S. J. Am.
Chem. Soc. 2004, 126, 9542.
12. For examples, see: (a) Mun˜iz, K.; Ho¨velmann, C. H.; Streuff, J. J. Am. Chem. Soc.
2008, 130, 763; (b) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179; (c)
Ba¨ckvall, J. E.; Bjoerkman, E. E. J. Org. Chem. 1980, 45, 2893; (d) Henry, P. M.;
Davies, M.; Gerguson, G.; Phillips, S.; Restivo, R. J. Chem. Soc., Chem. Commun.
1974, 112; (e) Ba¨ckvall, J. E. Tetrahedron Lett. 1978, 19, 163; (f) Ba¨ckvall, J. E. Acc.
Chem. Res. 1983, 16, 335.
19.1 mm). The isolated yield was not determined due to loss during
purification. However, HPLC analysis of the crude reaction mixture
showed that 39c was formed in 8% yield. 1H NMR (500 MHz,
CDCl3):
d
7.67 (d, J¼8.0 Hz, 2H), 7.61 (multiple peaks, 4H), 7.45 (t,
7.0 Hz, 2H), 7.37 (t, 7.0 Hz, 1H), 5.31 (m, 1H), 4.45 (dd, J¼2.0, 9.5 Hz,
1H), 4.31 (dd, J¼8.0, 10.0 Hz, 1H), 3.68 (m, 1H), 2.35 (s, 3H), 2.08 (s,
3H), 1.27 (d, J¼6.5 Hz, 3H). 13C {1H} NMR (100.6 MHz, CDCl3):
d
170.3, 168.2, 143.7, 140.2, 130.5, 129.5, 128.8, 127.9, 127.2, 126.7,
115.1, 69.6, 65.3, 42.9, 21.2, 20.9, 14.5. Two peaks coincidentally
overlap. HRMS (EI): [M]þ calcd for C23H22O6: 394.1416; found:
13. For examples, see: (a) Tichenor, M. S.; Trzupek, J. D.; Kastrinsky, D. B.; Shiga, F.;
Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 15683; (b) Boger, D. L.;
Garbaccio, R. M. J. Org. Chem. 1999, 64, 8350.
394.1417. IR (Nujol mull): 1776, 1758, 1732 cmꢃ1
.
14. Zhang, Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604.
15. (a) Heck, R. F. Org. React. 1982, 27, 345; (b) Larhed, M.; Hallberg, A. In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-In-
terscience: New York, NY, 2002; (c) Soderberg, B. C. In Comprehensive Organ-
ometallic Chemistry II; Hegedus, L. S., Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon: Oxford, 1995; Vol. 12, pp 259–287.
16. For examples, see: (a) Desai, L.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8,
1141; (b) Yang, D. Acc. Chem. Res. 2004, 37, 497; (c) Muehlhofer, M.; Strassner, T.;
Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 124, 3824; (d) Reddy, B. V. S.;
Reddy, L. F.; Corey, E. J. Org. Lett. 2006, 8, 3391; (e) Tang, S.; Peng, P.; Pi, S. F.;
Liang, Y.; Wang, N. X.; Li, J. H. Org. Lett. 2008, 10, 1179; (f) Wang, G. W.; Yuan, T.
T.; Wu, X. L. J. Org. Chem. 2008, 73, 4717.
Acknowledgements
This work was supported by NIH NIGMS (RO1 GM073836). We
also gratefully acknowledge the Camille and Henry Dreyfus Foun-
dation and the Alfred P. Sloan Foundation as well as Abbott, Amgen,
AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly,
GlaxoSmithKline, Merck Research Laboratories, and Roche for
funding. Additionally, we thank Jeff Kampf for X-ray crystallography
and Leilani Welbes for preliminary studies and helpful discussions.
17. The olefin geometry of these side products could not be definitively determined
using NOE analysis.
18. (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690; (b) Li,
Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008, 130, 2962.
19. Dick, A. R.; Kampf, J.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790.
20. Reductive elimination from a similar intermediate has been reported to pro-
ceed with inversion, as determined by coupling constant analysis (see Ref. 11b).
21. The olefin geometry of 39c could not be definitively determined in solution via
NOE analysis; however, interestingly, the X-ray structure shows a geometry
consistent with initial cis-acetoxypalladation of the alkyne. While the literature
suggests that trans-acetoxypalladation should predominate under our standard
reaction conditions, early studies of alkyne halo- and acetoxypalladation have
shown that mixtures of trans and cis products can be formed. For examples,
see: (a) Lu, X.; Zhu, G.; Ma, S. Tetrahedron Lett. 1992, 33, 7205; (b) Zhu, G.; Ma,
S.; Lu, X.; Huang, Q. J. Chem. Soc., Chem. Commun. 1995, 271; (d) Lambert, C.;
Utimoto, K.; Nazaki, H. Tetrahedron Lett. 1984, 25, 5323; (e) Yanagihara, N.;
Lambert, C.; Iritani, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 2753;
(f) Ba¨ckvall, J.-E.; Nilsson, Y. I. M.; Gatti, R. G. P. Organometallics 1995, 14, 4242.
Further investigations are underway to understand the factors controlling cis
versus trans acetoxypalladation as well as the effect that this has on the out-
come of these cyclopropane-forming transformations.
22. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 704193. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: þ44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
23. Kinetics studies have shown that these reactions are zero order in oxidant.
Therefore, the change in rate with electronically differentiated alkenes does not
provide information about the cyclopropane-forming step of this reaction.
References and notes
1. (a) Trofast, J.; Wickberg, B. Tetrahedron 1977, 33, 875; (b) Koft, E. R.; Smith, A. B.,
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Jr.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 12432.
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Clive, D. L. J.; Liu, D. J. Org. Chem. 2008, 73, 3078; (d) Chavan, S. P.; Pasapathy, K.;
Shivasankar, K. Synth. Commun. 2004, 34, 397.
5. (a) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004,126, 8654;
(b) Harrak, Y.; Blaszykowski, C.; Bernard, M.; Cariou, K.; Mainetti, E.; Mour-
ie`sDhimane, A.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2004,126, 8656; (c)
Luzung, M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858.
6. For reviews on cycloisomerizations, see: (a) Zhang, L.; Sun, J.; Kozmin, S. A. Adv.
Synth. Catal. 2006, 348, 2271; (b) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev.
2002, 102, 813; (c) Trost, B. M.; Krische, M. J. Synlett 1998, 1.
7. Intramolecular cyclization of diazo compounds has also frequently been used to
access bicyclo[3.1.0] and [4.1.0] ring systems. For examples, see: (a) Doyle, M. P.;
Pieters, R. J. J. Am. Chem. Soc. 1991, 113, 1423; (b) Doyle, M. P.; Austin, R. E.;
Bailey, A. S.; Dwyer, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. Y.; Liras, S.;
Oalmann, C. J.; Pieters, R. J.; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou,
Q.; Martin, S. F. J. Am. Chem. Soc. 1995, 117, 5763; (c) Doyle, M. P.; Peterson, C. S.;
Parker, D. L., Jr. Angew. Chem., Int. Ed. 1996, 35, 1334.
24. In contrast, significant decomposition of the alkene products (
served under these conditions. Many small peaks were observed in the GC and
HPLC traces of these reactions after 8 h, suggesting that -H decomposes to
b-H) was ob-
b
a mixture of unidentified minor products. We believe that this accounts for the
poor mass balance in many of these reactions.
8. Bo¨hmer, J.; Grigg, R.; Marchbank, J. D. Chem. Commun. 2002, 768.