Comparative studies of palladium and copper-catalysed γ-arylation of silyloxy furans with diaryliodonium salts

Article abstract of DOI:10.1016/j.tet.2019.02.042

The γ-arylation of substituted silyl-activated butenolides has been studied using a broad scope of unsymmetrical hypervalent diaryliodonium salts via a palladium- or copper-catalysed coupling reaction, yielding interesting reactivity trends. The mild catalytic conditions and coupling partner variability provide access to synthetically useful building blocks toward the pursuit of aryl-lactone containing natural products and allows for facile diversification.

Full text of DOI:10.1016/j.tet.2019.02.042

Accepted Manuscript
Comparative studies of palladium and copper-catalyzed γ-arylation of silyloxy furans
with diaryliodonium salts
Taylor S. Alexander, Travis J. Clay, Bryan Maldonado, Johny M. Nguyen, David B.C.
Martin
PII:
S0040-4020(19)30201-7
https://doi.org/10.1016/j.tet.2019.02.042
TET 30165
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 December 2018
Revised Date: 16 February 2019
Accepted Date: 21 February 2019
Please cite this article as: Alexander TS, Clay TJ, Maldonado B, Nguyen JM, Martin DBC, Comparative
studies of palladium and copper-catalyzed γ-arylation of silyloxy furans with diaryliodonium salts,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.02.042.
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Comparative Studies of Palladium and
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Taylor S. Alexandera, Travis J. Claya, Bryan Maldonadoa, Johny M. Nguyena, and David B. C. Martina

1
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Tetrahedron
journal homepage: www.elsevier.com
Comparative studies of palladium and copper-catalyzed γ-arylation of silyloxy furans
with diaryliodonium salts
Taylor S. Alexandera, Travis J. Claya, Bryan Maldonadoa Johny M. Nguyena, and David B. C. Martina*.
,
a
Department of Chemistry, University of California Riverside, Riverside, California 92521, United States.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The γ-arylation of substituted silyl-activated butenolides has been studied using a broad scope of
unsymmetrical hypervalent diaryliodonium salts via a palladium- or copper-catalysed coupling
reaction, yielding interesting reactivity trends. The mild catalytic conditions and coupling
partner variability provide access to synthetically useful building blocks toward the pursuit of
aryl-lactone containing natural products and allows for facile diversification.
Available online
2019 Elsevier Ltd. All rights reserved
.
Keywords:
Palladium catalysis
Copper catalysis
Arylation
Butenolides
Silyloxy furan
Diaryliodonium salts
1. Introduction
Ar
or
Butenolides and other lactones are a common class of
Pd
Cu
O
R
Ar
structural motifs widely distributed in biologically active natural
products (Figure 1), including the terpene lactones mintlactone,
trans-crotonin (nor-clerodane) and fraxinellone (limonoid).[1–4]
These moieties are also found in other terpenoids such as
salvinorin A (neo-clerodane), which exhibits psychotropic
activity.[5] Due to the pervasive occurrence of γ-lactones as a
structural component in valuable naturally occurring and
pharmaceutically relevant compounds, there is a significant
interest in the facile derivatization of butenolides. As a result,
many methods for generating substituted butenolides have been
+
I
Pd(0) or Cu(I)
Catalyzed Arylation
O
R
OSiR3
X
O
Ar
I
I
X
reported,
including
condensations and
cross-coupling
Oxidative
Addition
methods.[6–11] A seminal study performed by Kang and
coworkers presented one example of a γ-phenylation using
palladium catalysis and Buchwald has reported many examples
L
L
L2Cu(I) or
L2Pd(0)
M
Ar
O
O
Catalytic
Cycle
O
O
Reductive
Elimination
Nucleophilic
Attack
O
O
O
O
O
H
H
H
Ar
O
O
H
O
O
O
R
– SiR3
O
Ar
L
L
M
R
O
O
OSiR3
H
O
O
MeO2C
Mintlactone
butenolide
trans-Crotonin
Antiproliferative Neuroprotective
Fraxinellone
Salvinorin A
Psychotropic
OSiR3
R
Scheme 1. Proposed transition metal-catalysed γ-arylation
reaction and catalytic cycle.
Figure 1. Biologically active lactone natural products.

2
Tetrahedron
diphenyliodonium and found that PF6 provided the greatest
ACCEPTED MANUSCRIPT
of arylation with aryl halides under more forcing
conditions.[12,13] More recently, MacMillan and Gaunt
have developed copper catalysed asymmetric α-arylation
reactions between aryl iodonium salts and a variety of
silylated nucleophiles, including one cyclic silylketene
acetal.[14,15] Despite these advances, a general method for
the formation of γ-aryl-lactones under mild conditions has
not been reported.
yield (Figure S1).
During our early optimization studies, we observed that
although there was unreacted iodonium the crude reaction
mixture after 16 h, the silyloxy furan was consumed, in large part
by desilylation under the reaction conditions. Additionally,
palladium nanoparticles were routinely observed to precipitate
from the reaction mixture. An NMR time study revealed that in
Table 1. Ligand evaluation with symmetric iodonium.
Given our interest in the synthesis of terpene natural
products including bioactive lactones, we recognized the
2
I
potential of
a general catalytic arylation to access the
PF6
furanolactone present in many members (Figure 1).[1–4,16] We
therefore sought to develop a transition metal-catalysed γ-
arylation reaction to access a variety of aryl butenolides by
coupling silyloxy furans and diaryliodoniums (Scheme 1,
top).[17–20] One anticipated challenge of this chemistry is the
potential lability of the newly formed methine stereocenter that
bears a mildly acidic hydrogen, which could lead to racemization
or tautomerization, as observed by Kang.[12] Additionally, we
required a method that would only result in monoarylation rather
than giving γ,γ-disubstituted products observed by Buchwald.
The use of diaryliodonium salts and an activated silyloxy furan
nucleophile was anticipated to allow for very mild conditions
without the need for a strong base. Furthermore, we were
inspired by critical advances in the closely related α-arylation of
carbonyl compounds with hypervalent iodonium species that
shares many features with the desired reaction.[20–26] With
these design parameters in mind, we explored two distinct
catalytic systems for the arylation of silyloxy furans to give γ-
aryl butenolides as described below.
O
O
Pd source (5 mol%)
Ligand (5 mol%)
Additive
OTIPS
O
Solvent, rt, 16 h
1 (2 eq)
3a
Entry
Pd Source
Ligand
Solvent
Additive
Yield
1
2
3
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
–
DMA/H2O
DMA/H2O
DMA/H2O
–
–
–
4%
39%
6%
PCy3 (10%)
PCy3 (10%)
4
5
Pd(OAc)2
Pd(OAc)2
DavePhos
dppp
DMA/H2O
DMA/H2O
–
–
20%
9%
6
7
Pd(OAc)2
Pd(OAc)2
dppe
DMA/H2O
DMA/H2O
–
–
21%
41%
dppbz
8
9
Pd(OAc)2
Pd(OAc)2
dppbz
dppbz
THF
DCE
–
–
31%
38%
2. Results and Discussion
10
11
Pd(OAc)2
Pd(OAc)2
dppbz
dppbz
DCM
DCM
–
39%
19%
Early optimization efforts were carried out using
symmetric diphenyliodonium salt
2 as a model substrate by
NaOMe
examining the palladium source, ligands, solvents, additives,
iodonium counterion, and temperature (Table 1). Initial
conditions were adapted from Kang’s singular example,
using ligand-free Pd(OAc)2 and an aqueous solvent system
of DME/H2O (4:1), which unfortunately yielded no
product.[12] Due to the high lability of TMS-ethers, we
explored the use of TBS- and TIPS-ethers. Under modified
12
13
Pd(OAc)2
Pd(OAc)2
dppbz
dppbz
DCM
DCM
AgOAc
LiOAc
19%
21%
14
15
Pd(OAc)2
Pd(OAc)2
dppbz
dppbz
DCM
DCM
NaOAc(0.5 equiv)
NaOAc(0.8 equiv)
55%
80%
*NMR yields determined by dibenzyl ether internal standard.
Reaction conditions: Silyloxy furan (2eq), diphenyliodonium (1eq),
catalyst (5 mol%) and ligand (5 mol% for bidentate, 10 mol% for
monodentate), and additives (0.8eq) in solvent (0.12M)
conditions of DMA/H2O (4:1) and silyloxy furan
1, the
desired product was generated in 4% yield without
isomerization of the alkene to the β, γ -position (Entry 1). A
significant increase in reactivity was achieved using PCy3 as
a ligand in DMA/H2O solvent (39%, Entry 2). We
evaluated different palladium sources such as Pd2(dba)3
(Entry 3, 6%) and Pd(COD)(CH2TMS)2 (6%, not shown) as
reliable precursors of Pd(0); unfortunately, neither source
efficiently catalysed the reaction. Additionally, Pd(II)
sources such as Buchwald 3rd generation precatalysts were
examined with different ligands but offered no
the presence of water, full degradation of silyl enol ether 1
occurred within a couple hours. To address this, the solvent
system was examined in an effort to exclude water as a co-
solvent (Table 1, Entries 8–10). Upon switching to DCM, it was
found that the silyloxy furan no longer degraded, the reaction
time was dramatically decreased, and the precipitation of
palladium was no longer observed. At this point, more than 60
additives were evaluated in an effort to improve the yield (Entries
11–15). It was observed that acetate salts generally out-
performed most other types of additives, including other organic
and inorganic bases. These extensive optimization efforts led to
an 80% yield of butenolide 3a using 0.8 eq NaOAc and
diphenyliodonium hexafluorophosphate as the limiting reagent.
With these optimized conditions in hand for the
advantage.[27]
Next, phosphine ligands of various
electronic and steric characteristics were evaluated,
including mono- and bidentate phosphines. The mono-
phosphine ligands surveyed included commonly used
Buchwald ligands such as DavePhos (20%, Entry 4),
JohnPhos (17%) SPhos (20%), XPhos (15%), however the
best monodentate phosphine ligand was found to be PCy3
(39%, Entry 2). Among bidentate phosphine ligands, dppp
(9%, Entry 5) and dppe (21%, Entry 6) did not offer any
improvement, but dppbz was found to perform slightly
better (41%, Entry 7). Additionally, we evaluated the effect
of using NO3, OTf, and BF4 as the counterion to
symmetric diphenyliodonium 2, we investigated the arylation
using an unsymmetrical iodonium to explore the generality of
this system with other aryl groups.[28] Using (Ph-I-Mes)PF6 (9a),
the phenyl group was selectively coupled, generating aryl
butenolide 3 in 43% yield (Table 2, Entry 3). Unfortunately, the

3
reaction with various silyloxy furans and unsymmetrical
ACCEPTED MANUSCRIPT
diaryliodonium salts. Accessing the three isomeric methyl-
substituted silyloxy furans was performed over 1-2 steps
(Scheme 2). Reduction of citraconic anhydride (5) with NaBH4
gave a separable mixture of α-Me and β-Me butenolides 6 and
8.[29] Silylation with TIPS-OTf provided the desired silyloxy
furans in excellent yield.[30] The γ-substituted silyloxy furan 10
was accessed directly from commercially available α-angelica
lactone (9) in 81% yield. The unsymmetrical diaryliodonium
Table 2. Ligand Evaluation with Unsymmetric Iodonium
4a
I
PF6
O
O
Pd(OAc)2 (5 mol%)
Ligand (5 mol%)
NaOAc (0.8 equiv)
DCM, rt, 16 h
O
OTIPS
3a
1 (2 eq)
Table 3. Synthesis of hypervalent iodonium salts
Entry
Ligand
Yield
e.r.
1
2
3
P(furyl)3
P(o-tolyl)3
dppbz
34%
2%
–
–
HO
1. TFE, rt
Ar
OAc
B
Ar
+
I
I
2. Counterion
exchange
HO
OAc
–
43%
X
11
12
4, 13–20
X = PF6, BF4, OTf, NO3
4
5
dppm
dppe
2%
–
–
–
–
–
51%
34%
8%
O
6
dppp
7
dppb
I
I
I
X
X
PF6
8
BINAP
61%
50%
19%
20%
15%
4a–c
13a–d
14
42% yield
9
(S)-T-BINAP
(R)-SEGPhos
(R,R)-Quinox-P
(S)-Phox
44:56 e.r.
49:51 e.r.
48:52 e.r.
49:51 e.r.
PF6: 51%
BF4: 64%
OTf: 74%
PF6: 90%
BF4: 90%
OTf: 94%
NO3: 78%
10
11
12
CF3
OMe
F
*NMR yields determined by dibenzyl ether internal standard.
Reaction conditions: Silyloxy furan (2eq), diphenyliodonium (1eq),
catalyst (5 mol%) and ligand (5 mol% for bidentate, 10 mol% for
monodentate), and additives (0.8eq) in solvent (0.12M)
I
I
I
CF3
PF6
PF6
PF6
15
79% yield
16
84% yield
17
6% yield
Br
Br
Scheme 2. Silyloxy Furan Substrates
I
I
I
PF6
Br
PF6
PF6
18
19
20
60% yield
50% yield
70% yield
salts were most efficiently synthesized by reacting
iodomesitylene diacetate with the corresponding aryl boronic
acid (Table 3), following the strategy reported by
Widdowson.[31] The use of TFE as the solvent obviates the
need for a strong Lewis acid, according to the work of Kita and
MacMillan, and a variety of aryl boronic acids could be
incorporated including acid- and oxidation-sensitive groups such
as furan (13a–d).[32–34] A wide range of aryl coupling partners
with different counter-anions were prepared in moderate to high
yields, with the exception of bis-CF3 derivative 17 due to the
strong electron-withdrawing effect of the CF3 groups. As shown
in Table 4, the arylation of β- and α-methyl silyloxy furans 1 and
7 was very efficient using symmetrical diphenyliodonium 2 and
dppbz as ligand, at yields of 80% and 90%, respectively. In
contrast, the arylation of γ-methyl 10 to generate 22a with a fully
substituted carbon proceeded in only 13% yield. Using
unsymmetrical diaryliodonium salts, lower yields were obtained.
The arylation of the β-methyl silyloxy furan 1 proceeded in 45–
61% yield for phenyl and bromophenyl derivatives, including the
hindered o-bromophenyl 3b. We observed no loss of the aryl
bromide under the mild reaction conditions. The corresponding
3-furyl product 3d was obtained in only 8% yield due to low
conversion and undesired side reactions. The arylation of the α-
methyl silyloxy furan 7 also suffered from reduced yields with
electron-rich and electron-deficient aryl groups (21b–e, 25–50%
yield was significantly lower than the optimized model system,
therefore reaction conditions were revisited. We evaluated
ligands that were structurally and electronically similar to dppbz,
such as dppe and dppp, where the bite angle of the phosphines
was varied. Further optimization led to a yield of 61% with
BINAP (Entry 8). Next, in pursuit of enantioselectivity, a wider
array of chiral bidentate phosphine ligands including (S)-T-
BINAP, (R,R)-Quinox-P, and (S)-PHOX were evaluated,
however, the observed enantioselectivity was very low (up to
12% ee). The use of rac-BINAP did, however, provide the
highest yield for the unsymmetrical diaryliodonium salt (61%,
Entry 8).
With our new optimized conditions in hand, we sought
to investigate the scope and tolerance of this novel arylation

4
Tetrahedron
of Gaunt and MacMillan, we were pleased to find that Cu(OTf)2
ACCEPTED MANUSCRIPT
complexed with bisoxazoline ligands could also catalyse the
Table 4. Scope of Palladium-Catalysed Arylation
desired arylation reaction (Table 5).[14,15] Using the β-methyl
silyl-butenolide 1 and (Ph-I-Mes)PF6 4a as model substrates, the
copper catalyst system was optimized with respect to solvent,
ligand and other parameters. We re-investigated the counterion
effect of the unsymmetric iodonium (Figure S2) and found that
PF6 (80%) again outperformed BF4 (53%) and OTf (51%).
Additionally, we found that the phenylation proceeded with a
greater yield of 80% with the unsymmetrical (Ph-I-Mes)PF6
compared to the symmetric diphenyliodonium, which gave a
yield of only 63% despite ligand evaluation (Figure S3).
Ultimately, we observed that Cu(OTf)2 and PhBox (5 mol%
each) with the unsymmetric (Ph-I-Mes)PF6 in DCM at room
temperature provided optimal reaction conditions, resulting in an
80% yield, albeit with very low enantioselectivity (Entry 2, Table
5). Other solvents and ligands did not provide any improvement
upon these results (Entries 3–8). The scope of the arylation was
investigated using this copper catalyst system (Table 6).
Interestingly, it was found that when using the copper catalyst
system, reactivity generally improved for the β-methyl silyl-
butenolide 1, as observed by good yields of the arylation using
the phenyl iodonium (80%, Table 5) as well as the m-
bromophenyl and p-bromophenyl derivatives (85% and 68% for
3f and 3c, respectively). This stands in contrast to the palladium
catalyst system which showed better reactivity of the α-methyl
silyl-butenolide 7. Again, no loss of aryl bromide was observed
with the copper catalyst system. Reactivity of the γ-methyl silyl-
butenolide remained quite poor, showing no improvement over
the Pd-catalyst system. Overall, copper appears to be generally
more effective with the sterically hindered β-Me-silyloxy furan
partner, however performs poorly with the α- and γ-Me-silyloxy
Ar
Ar
I
2 or
PF6
O
R
O
R
Pd(OAc)2 (5 mol%)
ligand (5 mol%)
NaOAc (0.8 equiv)
DCM, rt, 16 h
OTIPS
O
2 eq
butenolide
With 2
With (MesIAr)PF6
Br
O
Br
O
O
O
O
O
O
O
O
O
O
3a
3a
3b
3c
3d
80% yield[b,c]
61% yield[d]
46% yield[d]
45% yield[d]
8% yield[d]
Me
OMe
F
O
O
O
O
O
O
O
O
O
O
O
21a
21b
21c
21d
21e
90% yield[b,c]
50% yield[c]
25% yield[c]
34% yield[c] 27% yield[c]
OMe
F
O
furan.
Unfortunately, the variable efficiency of these
transformations did not reveal any notable trends and the low
yields of furyl iodonium derivatives (7% yield for 3d) have
hampered further development of this arylation reaction for the
synthesis of furanolactone natural products.
O
O
O
O
O
O
O
O
O
O
22a
13% yield[b,c]
22a
5% yield[c]
22b
10% yield[d]
22c
8% yield[c]
22d
16% yield[c]
Table 5. Optimization of Copper-Catalysed Arylation[a]
[b]
[a] Isolated yields.
Diphenyliodonium hexafluoro-phosphate used.
[c] Ligands is dppbz. [d]Ligand is BINAP.
I
4a
O
PF6
yield). The 3-furyl group was transferred with modest efficiency
in this case (27%). Further optimization for this particular
diaryliodonium was pursued, including solvent, ligands and
counterions, however the yields of butenolides 3d and 21e could
not be improved. Furans are sensitive to oxidation and may be
incompatible with oxidizing iodonium salts under these reaction
conditions. To the best of our knowledge, the only example of a
metal catalysed arylation using a 3-furyl iodonium is a C–N bond
forming reaction that proceeds in significantly diminished yield
compared to other aryl and vinyl coupling partners (42% vs 70–
90% yield).[35] The arylation of the γ-methyl silyloxy furan 10
proved difficult as well, providing only low yields of the
corresponding butenolide products (22a–22d), likely due to steric
congestion. Notably, α-arylated products were not observed in
any reactions in Table 4. Overall, it was found that greater
reactivity was observed with the less sterically hindered α- and β-
methyl silyloxy furans using the palladium catalyst system. The
poor yields with more challenging substrates, especially the 3-
furyl product 3d, caused us to re-examine our strategy and look
for a more efficient catalyst system.
O
Cu(OTf)2 (5 mol%)
Ligand (5 mol%)
Solvent, rt, 16 h
OTIPS
O
1 (3 eq)
3a
e.r.
Ligand
Solvent
Entry
Yield
1
2
3
4
5
6
7
8
None
PhBox
t-BuBox
i-PrBox
PhBox
PhBox
PhBox
PhBox
DCM
DCM
0%
80%
0%
–
43:57 e.r.
DCM
–
DCM
73%
22%
0%
42:58 e.r.
EtOAc
Dioxane
Hexanes
Toluene
n.d.
–
–
0%
25%
43:57 e.r.
[a] Isolated yields, e.r. determined by HPLC.
In recent years, several innovative arylation methods
have been reported using Cu(I) and Cu(II) precatalysts with
various ligand systems.[14,15,34–37] Inspired by the precedent

5
Table 6. Arylation Scope with Copper-Box Catalyst[a]
active molecules. Further efforts toward the development of a
ACCEPTED MANUSCRIPT
highly enantioselective arylation and the implementation of this
method in natural product synthesis are ongoing and will be
reported in due course.
Ar
Ar
I
PF6
O
4. Experimental
R
R
O
Cu(OTf)2 (5 mol%)
PhBox (5 mol%)
DCM, rt, 16 h
OTIPS
Synthesis of 3-Methyl-2(5H)-furanone (6)
O
3 eq
butenolide
To a flame-dried vial was added citraconic anhydride
(10ml, 110.22 mmol), THF (250ml), and NaBH4 (5.24 g, 126.36
mmol). The reaction was stirred at 0 ◦C for 6 hours. The reaction
mixture was quenched with H2O (30ml), and then acidified with
aqueous 6 M HCl. The reaction mixture was then extracted with
Et2O three times, then the combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
resulting crude yellow oil was purified by flash chromatography
(SiO2) using 4:1 Et2O/hexanes to afford the desired product as a
Br
Br
O
O
O
O
O
O
O
O
O
1
yellow/green oil (1.62 g, 16.53 mmol, 15%). H NMR (CDCl3,
3e
3f
3c
3d
7% yield
400 MHz) δ 7.14 (m, 1H), 4.77 (t, J = 2.0 Hz, 2H), 1.94 (m, 3H);
13C NMR (CDCl3, 100 MHz) δ 10.6, 70.2, 129.8, 144.6, 174.8.
Spectral data matched literature sources.[40]
51% yield[b]
85% yield
68% yield
Br
Br
O
Synthesis of 4-Methyl-2(5H)-furanone (8)
Br
To a flame-dried vial was added citraconic anhydride
(10 ml, 110.22 mmol), THF (250ml), and NaBH4 (5.24 g, 126.36
mmol). The reaction was stirred at 0 ◦C for 6 hours. The reaction
mixture was quenched with H2O (30ml), and then acidified with
aqueous 6M HCl. The reaction mixture was then extracted with
Et2O three times, then the combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
resulting crude yellow oil was purified by flash chromatography
(SiO2) using 4:1 Et2O/hexanes to afford the desired product as a
yellow/green oil (7.35 g, 550.75 mmol, 68%). 1H NMR (CDCl3,
400 MHz) δ 5.86 (s, 1H), 4.72 (s, 2H), 2.14 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 174.21, 166.44, 115.95, 73.83, 13.85.
Spectral data matched literature sources.[29]
O
O
O
O
O
O
O
O
21f
11% yield
21g
21% yield
21e
21h
20% yield
0% yield
Br
O
O
O
O
O
O
O
22a
13% yield
22e
13% yield
22d
7% yield
Synthesis of 2-(triisopropylsiloxy)-3-methyl-furan (7)
To a flame-dried round bottom flask was added the
alpha-methyl butenolide (1.5 g, 15.29 mmol) and DCM (15 ml).
The reaction flask was then cooled to 0 C̊ . Next, Et3N (6.3 ml,
[a] Isolated yields. [b] iPrBox used as ligand.
45 mmol) and TIPSOTf (4.88 ml, 18 mmol) were added to the
reaction flask. The reaction flask was then allowed to warm to
room temperature and stirred for 6 hours. The reaction was
quenched with an aqueous solution of NaHCO3 and extracted
with EtOAc. The combined organic layers were washed with
brine and then dried over anhydrous Na2SO4. The organic layers
were then filtered and concentrated in vacuo. The crude yellow
oil was purified by flash chromatography (SiO2) using 1% Et3N
in 50:1 Et2O/EtOAc to afford the desired product as a yellow oil.
The crude product was further purified by vacuum distillation to
yield the desired product as a colorless oil (3.5g, 13.75 mmol,
90%). 1H NMR (CDCl3, 400 MHz) δ 6.74 (d, J = 2.03 Hz, 1H),
6.09 (d, J = 2.03 Hz, 1H), 1.84 (s, 3H), 1.26 (sep, J = 7.12 Hz,
3H), 1.08 (d, J = 7.12 Hz, 18H); 13C NMR (CDCl3, 100 MHz) δ
153.01, 130.55, 113.74, 91.42, 17.59, 12.38, 8.3. Spectral data
matched literature sources.[41]
3. Conclusion
In summary, we have developed two transition metal-
catalysed arylation method-logies to access aryl butenolides
using a palladium or copper catalytic system, both of which
provide selective arylation at the γ-position.
The main
degradation pathway for the silyloxy furan nucleophile, namely
proto-desilylation, was overcome by the proper selection of
reaction solvent and basic additive. In both cases, these reactions
occur under mild conditions at ambient temperature with low
catalyst loading. The yields under palladium catalysis are
variable with more sterically hindered substrates generally
leading to lower yields, in part due to degradation pathways.
Interestingly, it was found that better yields were observed for
the α-methyl silyl-butenolide when using a palladium catalyst
system, while for the β-methyl silyl-butenolide a copper catalyst
system resulted in better coupling efficiency. The arylation
reaction outlined here allows for a wide range of electronically
and sterically varied aromatic groups to be coupled successfully,
although the yields remain low for many substrates including the
3-furyl coupling partner. The development of this reaction
provides access to a variety of aryl butenolides that are
synthetically interesting due to their incorporation as building
blocks in natural products and other interesting biologically
Synthesis of 2-(triisopropylsiloxy)-4-methyl-furan (1)
To a flame-dried round bottom flask was added the
beta-methyl butenolide (1.5g, 15.29 mmol) and DCM (15ml).
The reaction flask was then cooled to 0 C̊ . Next, Et3N (6.3ml,
45 mmol) and TIPSOTf (4.88ml, 18 mmol) were added to the
reaction flask. The reaction flask was then allowed to warm to

6
Tetrahedron
room temperature and stirred for 6 hours. The reaction was
MHz) δ 145.11, 142.92, 133.12, 132.74, 132.29, 130.74, 118.89,
ACCEPTED MANUSCRIPT
quenched with NaHCO3 and extracted with EtOAc. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The
crude yellow oil was purified by flash chromatography (SiO2)
using 1% Et3N in 50:1 Et2O/EtOAc to afford the desired product
as a yellow oil. The crude product was further purified by
distillation to yield the desired product as a colorless oil (3.73 g,
110.53, 27.18, 21.17.
sources.[15]
Spectral data matched literature
Synthesis of Mesityl(phenyl)iodonium triflate (4c)
Prepared according to General Procedure A. Reaction
run on 2.05 mmol (250mg) scale, yielding a white solid (716.42
mg, 1.5 mmol, 74%). H NMR (CDCl3, 400 MHz) δ 7.69 (m, J =
1
1
14.66 mmol, 96%). H NMR (CDCl3, 400 MHz) δ 6.60 (s, 1H),
7.6 Hz, 2H), 7.57 (m, J = 7.4 Hz, 1H), 7.44 (m, J = 7.6 Hz, 2H),
7.13 (s, 2H), 2.62 (s, 6H), 2.36 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 145.11, 142.92, 133.12, 132.74, 132.29, 130.74, 118.89,
110.53, 27.18, 21.17. Spectral data matched literature
sources.[15]
5.04 (s, 1H), δ 1.96 (s, 3H), 1.26 (sep, J = 7.12 Hz, 3H), 1.08 (d,
J = 7.12 Hz, 18H); 13C NMR (100 MHz, CDCl3) δ 156.79,
128.21, 121.55, 86.31, 17.77, 12.38, 10.6. Spectral data matched
literature sources.[41]
Synthesis of 2-(triisopropylsiloxy)-5-methyl-furan (10)
Synthesis of Mesityl(furyl)iodonium hexafluorophosphate
(13a)
To a flame-dried round bottom flask was added angelica
lactone (1.5g, 15.29 mmol) and DCM (15ml). The reaction flask
Prepared according to General Procedure A. Reaction
was then cooled to 0
C̊ . Next, Et3N (6.3ml, 45 mmol) and
run on 2.2 mmol (250mg) scale, yielding an orange solid
TIPSOTf (4.88ml, 18 mmol) were added to the reaction flask.
The reaction flask was then allowed to warm to room
temperature and stirred for 6 hours. The reaction was quenched
with NaHCO3 and extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The crude yellow oil was
purified by flash chromatography (SiO2) using 1% Et3N in 50:1
Et2O/EtOAc to afford the desired product as a yellow oil. The
crude product was further purified by distillation to yield the
1
(845.21mg, 1.8 mmol, 90%). H NMR (CDCl3, 400 MHz) δ 7.84 (s,
1H), 7.49 (s, 1H), 7.06 (s, 2H), 6.53 (s, 1H), 2.67 (s, 6H), 2.32 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 148.23, 145.64, 143.93, 141.56,
130.15, 129.22, 127.94, 112.74, 27.07, 21.03.[31]
Synthesis of Mesityl(furyl)iodonium tetrafluoroborate
(13b)
Prepared according to General Procedure A. Reaction
1
desired product as a colorless oil (3.15 g, 12.38 mmol, 81%). H
run on 2.2 mmol (250mg) scale, yielding an orange solid
1
NMR (CDCl3, 400 MHz) δ 5.74 (s, 1H), 4.96 (d, J = 2.71 Hz,
1H), 2.16 (s, 3H) 1.26 (m, 3H), 1.08 (d, J = 7.12 Hz, 18H); 13C
NMR (CDCl3, 100 MHz) δ 155.38, 140.98, 106.14, 83.64, 17.64,
13.58, 12.29. Spectral data matched literature sources.[30]
(845.21mg, 1.8 mmol, 90%). H NMR (CDCl3, 400 MHz) δ 7.84 (s,
1H), 7.49 (s, 1H), 7.06 (s, 2H), 6.53 (s, 1H), 2.67 (s, 6H), 2.32 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 148.23, 145.64, 143.93, 141.56,
130.15, 129.22, 127.94, 112.74, 27.07, 21.03.[31]
General Procedure A: Synthesis of Iodonium Salts
Synthesis of Mesityl(furyl)iodonium triflate (13c)
To a flame-dried round bottom flask was charged was
Prepared according to General Procedure A. Reaction
added the aryl boronic acid (1 eq) and trifluoroethanol (0.22 M).
run on 2.2 mmol (250mg) scale, yielding an orange solid
◦
The reaction flask was cooled to 0 C, then iodomesityl was
1
(956.87mg, 2.1 mmol, 94%). H NMR (CDCl3, 400 MHz) δ 7.84
added (1.05 eq) and then the reaction was allowed to warm to
room temperature and stirred for 4 hours. The corresponding
counterion (NH4PF6, NH4BF4, AgOTf, or AgNO3) was added as a
saturated solution and stirred vigorously for an additional 1 hour.
After 1 hour, the reaction mixture was extracted three times with
dichloromethane. The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. If further
purification was necessary, trituration in Et2O was performed.
Procedure adapted from Widdowson et al.[31]
(s, 1H), 7.49 (s, 1H), 7.06 (s, 2H), 6.53 (s, 1H), 2.67 (s, 6H), 2.32
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 148.23, 145.64, 143.93,
141.56, 130.15, 129.22, 127.94, 112.74, 27.07, 21.03.[31]
Synthesis of Mesityl(furyl)iodonium nitrate (13d)
Prepared according to General Procedure A. Reaction
run on 2.2 mmol (250mg) scale, yielding an orange solid (643.77
mg, 1.7 mmol, 78%). 1H NMR (CDCl3, 400 MHz), δ 7.84 (s,
1H), 7.49 (s, 1H), 7.06 (s, 2H), 6.53 (s, 1H), 2.67 (s, 6H), 2.32 (s,
3H); 13C NMR (CDCl3, 100 MHz), δ 148.23, 145.64, 143.93,
141.56, 130.15, 129.22, 127.94, 112.74, 27.07, 21.03.[31]
Synthesis
of
Mesityl(phenyl)iodonium
hexafluorophosphate (4a)
Prepared according to General Procedure A. Reaction
Synthesis
hexafluorophosphate (14)
of
Mesityl(p-tolyl)iodonium
run on 4.10 mmol (500mg) scale, yielding a white solid
1
(985.3mg, 2.10 mmol, 51%). H NMR (CDCl3, 400 MHz) δ 7.69
Prepared according to General Procedure A. Reaction
(m, J = 7.6 Hz, 2H), 7.57 (m, J = 7.4 Hz, 1H), 7.44 (m, J = 7.6
Hz, 2H), 7.13 (s, 2H), 2.62 (s, 6H), 2.36 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 145.11, 142.92, 133.12, 132.74, 132.29,
130.74, 118.89, 110.53, 27.18, 21.17. Spectral data matched
literature sources.[15]
run on 1.0 mmol (136mg) scale, yielding a white solid (202.8mg,
1
0.4 mmol, 42%). H NMR (CDCl3, 400 MHz) δ 7.62 (m, J = 8.5
Hz, 2H), 7.27 (m, J = 8.5 Hz, 2H), 7.13 (s, 2H), 2.64 (s, 6H),
2.39 (s, 3H), 2.36 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ
145.23, 143.85, 142.85, 133.73, 133.56, 130.87, 119.04, 106.47,
27.24, 21.37, 21.18.
sources.[37]
Spectral data matched literature
Synthesis of Mesityl(phenyl)iodonium tetrafluoroborate
(4b)
Prepared according to General Procedure A. Reaction
Synthesis
hexafluorophosphate (15)
of
Mesityl(4-fluorophenyl)iodonium
run on 2.05 mmol (250mg) scale, yielding a white solid (537.91
1
mg, 1.3 mmol, 64%). H NMR (CDCl3, 400 MHz) δ 7.69 (m, J =
Prepared according to General Procedure A. Reaction
run on 1.0 mmol (140mg) scale, yielding a tan solid (367mg, 0.8
7.6 Hz, 2H), 7.57 (m, J = 7.4 Hz, 1H), 7.44 (m, J = 7.6 Hz, 2H),
7.13 (s, 2H), 2.62 (s, 6H), 2.36 (s, 3H); 13C NMR (CDCl3, 100

7
mmol, 79%). 1H NMR (CDCl3, 400 MHz) δ 7.75 (m, 2H), 7.25
General Procedure B: Synthesis of Aryl-butenolides Using
Palladium
ACCEPTED MANUSCRIPT
(m, 2H), 7.15 (s, 2H), 2.64 (s, 6H), 2.34 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 164.77 (d, JC-F = 256.4 Hz), 145.11, 142.66,
136.06, 130.77, 120.31, 120.08, 104.35, 27.18, 21.18. Spectral
data matched literature sources.[37]
To a flame dried vial was added palladium acetate (5
mol%) and 1,2-bis(diphenylphosphino)benzene (5 mol%),
followed by the iodonium salt (1 eq) and sodium acetate (0.8 eq).
The reaction vial was then pump and backfilled with nitrogen
three times. Once under a nitrogen atmosphere, dichloromethane
(0.052 M) was added, followed by the silyl enol ether (2 eq).
The reaction was stirred for 16 hours at room temperature under
nitrogen atmosphere. After 16 hours, the reaction mixture was
extracted three times with diethyl ether. The combined organic
layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography (SiO2) using a 50:50 diethyl ether/hexanes to
afford the desired product as a colorless or yellow oil.
Synthesis
hexafluorophosphate (16)
Prepared according to General Procedure A. Reaction
of
Mesityl(4-methoxyphenyl)iodonium
run on 1.0 mmol (152mg) scale, yielding a tan solid (416.3mg,
1
0.8 mmol, 84%). H NMR (400 MHz, CDCl3) δ 7.69 (m, J = 9.2 Hz,
2H), 7.09 (s, 2H) 6.96 (m, J = 9.2 Hz, 2H), 3.80 (s, 3H), 2.63 (s,
6H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.96, 144.86,
142.48, 136.07, 130.68, 127.96, 120.09, 118.52, 55.83, 27.05,
21.05. Spectral data matched literature sources.[15]
General Procedure C: Synthesis of Aryl-butenolides Using
Copper
Synthesis
of
Mesityl(3,5-
To a flame dried vial in a glovebox was added
copper(II) triflate (5 mol%) and (S,S)-2,2’-isopropylidenebis(4-
phenyl-2-oxazoline) (5 mol%). The vial was then placed under a
nitrogen atmosphere followed by the addition of dichloromethane
(0.5 ml). Next, the iodonium (1 eq) was added to a separate vial
and then pump and backfilled three times with nitrogen before
the addition of dichloromethane (1 ml). The catalyst complex
solution was then allowed to stir under nitrogen atmosphere for
10 minutes before being transferred to the iodonium solution.
After the catalyst and iodonium solution were combined, the silyl
enol ether (3 eq) was added to the reaction vial. The reaction was
allowed to stir at room temperature for 24 hours under a nitrogen
atmosphere. The reaction mixture was quenched with aqueous
sodium bicarbonate and extracted three times with
dichloromethane. The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography (SiO2) using
a 50:50 diethyl ether/hexanes to afford the desired product as a
colorless or yellow oil.
bis(trifluoromethyl)phenyliodonium hexafluorophosphate
(17)
Prepared according to General Procedure A. Reaction
run on 3.94 mmol (1.0g) scale, yielding a white solid (131.4mg,
1
0.2 mmol, 6%). H NMR (400 MHz, CDCl3) δ 8.19 (s, 2H), 7.94
(s, 1H) 7.10 (s, 2H), 2.60 (s, 6H), 2.34 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 144.92, 142.97, 134.47 (q, JC-F = 34.7 Hz),
133.16, 130.42, 125.18, 124.58 (d, JC-F = 273.7 Hz), 120.02,
112.09, 26.97, 21.13.
sources.[42]
Spectral data matched literature
Synthesis
hexafluorophosphate (18)
Prepared according to General Procedure A. Reaction
of
Mesityl(2-bromophenyl)iodonium
run on 1.25 mmol (250mg) scale, yielding a white solid (404mg,
1
0.7 mmol, 60%). H NMR (400 MHz, CDCl3) δ 7.77 (m, J = 8.0
Hz, 1H), 7.52 (m, J = 7.3 Hz, 1H), 7.40 (m, J = 7.3 Hz, 1H), 7.24
(s, 2H) 6.93 (m, J = 8.0 Hz, 1H), 2.60 (s, 6H), 2.42 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 146.21, 143.28, 134.76, 133.71,
131.63, 131.30, 124.39, 119.76, 114.87, 27.12, 21.26. Spectral
data matched literature sources.[43]
4-Methyl-5-phenylfuran-2(5H)-one (3a)
Prepared according to General Procedure B using
diphenyliodonium-hexafluorophosphate with 5 mol % Pd(OAc)2
and 5 mol % dppbz for 16 hours. Reaction was run on 0.165
mmol (70.3 mg) scale. The crude material was purified using
silica gel with a solvent system of 50:50 Hexanes/Diethyl Ether
to afford 3a as a clear oil. (22.9 mg, 0.13 mmol, 80% yield)
3a: Prepared according to General Procedure B using (Mesityl-I-
Phenyl)PF6 with 5 mol % Pd(OAc)2 and 5 mol % BINAP for 16
hours. Reaction was run on 0.165 mmol (77.2 mg) scale. The
crude material was purified using silica gel with a solvent system
of 50:50 Hexanes/Diethyl Ether to afford 3a as a clear oil. (17.5
mg, 0.10 mmol, 61% yield)
Synthesis
hexafluorophosphate (19)
Prepared according to General Procedure A. Reaction
of
Mesityl(3-bromophenyl)iodonium
run on 1.25 mmol (250mg) scale, yielding a white solid (340mg,
1
0.6 mmol, 50%). H NMR (400 MHz, CDCl3) δ 7.73 (m, J = 7.8
Hz, 2H), 7.62 (m, J = 8.4 Hz, 1H), 7.30 (m, J = 8.1 Hz, 1H), 7.11
(s, 2H), 2.60 (s, 6H), 2.35 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ 145.01, 142.99, 135.18, 134.78, 133.45, 131.96, 130.66,
125.13, 119.40, 111.00, 27.22, 21.23. Spectral data matched
literature sources.[15]
3a: Prepared according to General Procedure C using (Mesityl-I-
Phenyl)PF6 with 5 mol % Cu(OTf)2 and 5 mol % PhBox for 16
hours. Reaction was run on 0.165 mmol (77.2 mg) scale. The
crude material was purified using silica gel with a solvent system
of 50:50 Hexanes/Diethyl Ether to afford 3a as a clear oil. (22.9
Synthesis
hexafluorophosphate (20)
of
Mesityl(4-bromophenyl)iodonium
Prepared according to General Procedure A. Reaction run
on 2.05 mmol (250mg) scale, yielding a white solid (474mg, 0.9
mmol, 70%). H NMR (400 MHz, DMSO-d6) δ 7.86 (m, J = 8.7
Hz, 2H), 7.71 (m, J = 8.7 Hz, 2H), 7.22 (m, 2H), 2.68 (s, 6H),
2.30 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 143.24, 141.57,
136.26, 134.66, 129.83, 125.76, 122.82, 113.15, 26.28, 20.53.
Spectral data matched literature sources.[43]
1
mg, 0.13 mmol, 80% yield) H NMR (400 MHz, CDCl3) δ 7.39
1
(m, 3H), 7.24 (m, 2H), 5.93 (s, 1H), 5.71 (s, 1H), 1.92 (s, 3H) 13
C
NMR (100 MHz, CDCl3) δ 173.48, 168.60, 134.31, 129.49,
129.10, 126.82, 116.35, 86.60, 14.10. Spectral data matched
literature sources.[44]
5-(2-Bromophenyl)-4-methylfuran-2(5H)-one (3b)
Prepared according to General Procedure B using with
5 mol % Pd(OAc)2 and 5 mol % BINAP for 16 hours. Reaction

8
Tetrahedron
1
was run on 0.165 mmol (70.3 mg) scale. The crude material
yield). H NMR (400 MHz, CDCl3) δ 7.18 (m, J = 8.7 Hz, 2H),
7.10 (s, 1H), 6.92 (m, J = 8.7 Hz, 2H), 5.83 (s, 1H), 3.82 (s, 3H),
2.01 (s, 3H) 13C NMR (100 MHz, CDCl3) δ 160.27, 148.26,
129.69, 128.16, 126.98, 114.32, 82.03, 55.37, 29.71, 10.66.
Spectral data matched literature sources.[47]
ACCEPTED MANUSCRIPT
was purified using silica gel with a solvent system of 50:50
Hexanes/Diethyl Ether to afford 3b as a clear oil. (19.2 mg, 0.08
mmol, 46% yield) 1H NMR (400 MHz, CDCl3) δ 7.62 (s, J = 8.0
Hz, 1H), 7.35 (s, J = 7.6 Hz, 1H), 7.25 (m, J = 7.6 Hz, 1H), 7.11
(m, J = 8.0 Hz, 1H), 6.36 (s, 1H), 5.95 (s, 1H), 2.00 (s, 3H) 13C
NMR (100 MHz, CDCl3) δ 173.34, 168.96, 133.91, 133.34,
130.80, 128.32, 127.56, 123.49, 116.62, 84.62, 14.28. HRMS
(ESI) calculated for C11H10BrO2 [M + H]+ 252.9859, found
252.9852.
5-(4-Fluorophenyl)-3-methylfuran-2(5H)-one (21d)
Prepared according to General Procedure B with 5 mol
% Pd(OAc)2 and 5 mol % dppbz for 16 hours. Reaction was run
on 0.165 mmol (77.2 mg) scale. The crude material was purified
using silica gel with a solvent system of 50:50 Hexanes/Diethyl
Ether to afford 21d as a clear oil. (10.7 mg, 0.06 mmol, 34%
5-(4-Bromophenyl)-4-methylfuran-2(5H)-one (3c)
Prepared according to General Procedure B using with
5 mol % Pd(OAc)2 and 5 mol % BINAP for 16 hours. Reaction
was run on 0.165 mmol (70.3 mg) scale. The crude material was
purified using silica gel with a solvent system of 50:50
Hexanes/Diethyl Ether to afford 3c as a clear oil. (18.8 mg, 0.07
mmol, 45 % yield)
1
yield) H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.11 (m, 4H),
5.86 (s, 1H), 2.01 (s, 3H) 13C NMR (100 MHz, CDCl3) δ 148.05,
130.00, 128.50, 116.17, 115.96, 81.51, 29.79, 20.27, 10.74.
Spectral data matched literature sources.[45]
5-Methyl-5-phenylfuran-2(5H)-one (22a)
Prepared according to General Procedure B using
diphenyliodonium-hexafluorophosphate with 5 mol % Pd(OAc)2
and 5 mol % dppbz for 16 hours. Reaction was run on 0.165
mmol (70.3 mg) scale. The crude material was purified using
silica gel with a solvent system of 50:50 Hexanes/Diethyl Ether
to afford 22a as a clear oil. (3.7 mg, 0.02 mmol, 13% yield)
22a: Prepared according to General Procedure B using (Mesityl-
I-Phenyl)PF6 with 5 mol % Pd(OAc)2 and 5 mol % dppbz for 16
hours. Reaction was run on 0.165 mmol (77.2 mg) scale. The
crude material was purified using silica gel with a solvent system
of 50:50 Hexanes/Diethyl Ether to afford 22a as a clear oil. (1.4
mg, 0.01 mmol, 5% yield)
3c: Prepared according to General Procedure C with 5 mol %
Cu(OTf)2 and 5 mol % PhBox for 16 hours. Reaction was run on
0.165 mmol (77.2 mg) scale. The crude material was purified
using silica gel with a solvent system of 50:50 Hexanes/Diethyl
Ether to afford 3c as a clear oil. (28.4 mg, 0.11 mmol, 68 %
1
yield) H NMR (400 MHz, CDCl3) δ 7.53 (m, J = 8.4 Hz, 2H),
7.13 (m, J = 8.4 Hz, 2H), 5.94 (s, 1H), 5.67 (s, 1H) 1.92 (s, 3H)
13C NMR (100 MHz, CDCl3) δ 173.04, 168.00, 133.47, 132.37,
128.48, 123.65, 116.65, 85.74, 14.07. HRMS (ESI) calculated
for C12H12O2 [M + H]+ 252.9859, found 252.9856.
3-Methyl-5-phenyl-2(5H)-furanone (21a)
22a: Prepared according to General Procedure C using (Mesityl-
I-Phenyl)PF6 with 5 mol % Cu(OTf)2 and 5 mol % PhBox for 16
hours. Reaction was run on 0.165 mmol (77.2 mg) scale. The
crude material was purified using silica gel with a solvent system
of 50:50 Hexanes/Diethyl Ether to afford 22a as a clear oil. (3.7
Prepared according to General Procedure B using
diphenyliodonium-hexafluorophosphate with 5 mol % Pd(OAc)2
and 5 mol % dppbz for 16 hours. Reaction was run on 0.165
mmol (70.3 mg) scale. The crude material was purified using
silica gel with a solvent system of 50:50 Hexanes/Diethyl Ether
to afford 21a as a clear oil. (25.8 mg, 0.14 mmol, 90% yield)
1
mg, 0.02 mmol, 13% yield) H NMR (400 MHz, CDCl3) δ 7.65
(d, J = 5.6 Hz, 1H), 7.63 (m, 2H), 7.50 (m, 1H), 7.40 (m, 2H),
6.08 (d, J = 5.6 Hz, 1H), 1.84 (s, 3H) 13C NMR (100 MHz,
CDCl3) δ 172.41, 160.42, 139.15, 128.87, 128.38, 124.78,
21a: Prepared according to General Procedure B using (Mesityl-
I-Phenyl)PF6 with 5 mol % Pd(OAc)2 and 5 mol % dppbz for 16
hours. Reaction was run on 0.165 mmol (77.2 mg) scale. The
crude material was purified using silica gel with a solvent system
of 50:50 Hexanes/Diethyl Ether to afford 21a as a clear oil. (2.9
119.37, 88.95, 26.36.
sources.[48]
Spectral data matched literature
5-Methyl-5-(4-methoxyphenyl)furan-2(5H)-one (22b)
Prepared according to General Procedure B using
(Mesityl-I-4-methoxyphenyl)PF6 with 5 mol % Pd(OAc)2 and 5
mol % dppbz for 16 hours. Reaction was run on 0.165 mmol
(82.2 mg) scale. The crude material was purified using silica gel
with a solvent system of 50:50 Hexanes/Diethyl Ether to
1
mg, 0.02 mmol, 10% yield) H NMR (400 MHz, CDCl3) δ 7.38
(m, 5H), 7.13 (s, 1H), 5.88 (s, 1H), 2.01 (s, 3H) 13C NMR (100
MHz, CDCl3) δ 148.36, 129.11, 128.96, 126.45, 82.13, 17.95,
11.91, 10.65. Spectral data matched literature sources.[45]
5-(4-Methylphenyl)-3-methylfuran-2(5H)-one (21b)
Prepared according to General Procedure B with 5 mol
% Pd(OAc)2 and 5 mol % dppbz for 16 hours. Reaction was run
on 0.165 mmol (77.2 mg) scale. The crude material was purified
using silica gel with a solvent system of 50:50 Hexanes/Diethyl
Ether to afford 21b as a clear oil. (15.6 mg, 0.08 mmol, 50%
yield) 1H NMR (400 MHz, CDCl3) δ 7.16 (m, 4H), 7.11 (m, 1H),
5.85 (m, 1H), 2.36 (s, 3H), 2.00 (s, 3H) 13C NMR (100 MHz,
CDCl3) δ 148.43, 139.11, 137.19, 132.10, 130.55, 129.61,
126.50, 82.13, 18.15, 13.41. Spectral data matched literature
sources.[46]
afford 22b as a clear oil. (3.3 mg, 0.01 mmol, 10%
yield). Spectral data matched literature sources.[49]
5-Methyl-5-(4-fluorophenyl)furan-2(5H)-one (22c)
Prepared according to General Procedure B using
(Mesityl-I-4-fluorophenyl)PF6 with 5 mol % Pd(OAc)2 and 5
mol % dppbz for 16 hours. Reaction was run on 0.165 mmol
(80.1 mg) scale. The crude material was purified using silica gel
with a solvent system of 50:50 Hexanes/Diethyl Ether to
afford 22c as
a
clear oil. (2.5 mg, 0.01 mmol, 8%
yield). Spectral data matched literature sources.
Spectral data matched literature sources.[49]
5-(4-Methoxyphenyl)-3-methylfuran-2(5H)-one (21c)
Prepared according to General Procedure B with 5 mol
5-(4-Methylphenyl)-4-methylfuran-2(5H)-one (3e)
% Pd(OAc)2 and 5 mol % dppbz for 16 hours. Reaction was run
on 0.165 mmol (77.2 mg) scale. The crude material was purified
using silica gel with a solvent system of 50:50 Hexanes/Diethyl
Ether to afford 21c as a clear oil. (8.4 mg, 0.04 mmol, 25%
Prepared according to General Procedure C with 5 mol
% Cu(OTf)2 and 5 mol % iPrBox for 16 hours. Reaction was run
on 0.165 mmol (77.2 mg) scale. The crude material was purified
using silica gel with a solvent system of 50:50 Hexanes/Diethyl

9
Ether to afford 3e as a clear oil. (15.7 mg, 0.08 mmol, 51 %
yield) H NMR (400 MHz, CDCl3) δ 7.20 (m, J = 8.0 Hz, 2H),
funding from the NSF (CHE-0541848). D.B.C.M is a member of
the UC Riverside Center for Catalysis.
ACCEPTED MANUSCRIPT
1
7.13 (m, J = 8.4 Hz, 2H), 5.93 (s, 1H), 5.68 (s, 1H), 3.12 (s, 3H),
1.91 (s, 3H) 13C NMR (100 MHz, CDCl3) δ 173.44, 168.53,
139.46, 131.25, 129.74, 126.79, 116.34, 86.53, 21.25, 14.08.
HRMS (ESI) calculated for C12H12O2 [M + H]+ 189.091, found
189.0899.
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Acknowledgements
The University of California, Riverside is gratefully
acknowledged for financial support. NMR instrumentation for
this research was supported by funding from the NSF (CHE-
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