Controlling olefin isomerization in the heck reaction with neopentyl phosphine ligands

Article abstract of DOI:10.1021/jo501840u

The use of neopentyl phosphine ligands was examined in the coupling of aryl bromides with alkenes. Di-tert-butylneopentylphosphine (DTBNpP) was found to promote Heck couplings with aryl bromides at ambient temperature. In the Heck coupling of cyclic alkenes, the degree of alkene isomerization was found to be controlled by the choice of ligand with DTBNpP promoting isomerization to a much greater extent than trineopentylphosphine (TNpP). Under optimal conditions, DTBNpP provides high selectivity for 2-aryl-2,3-dihydrofuran in the arylation of 2,3-dihydrofuran, whereas TNpP provided high selectivity for the isomeric 2-aryl-2,5-dihydrofuran. A similar complementary product selectivity is seen in the Heck coupling of cyclopentene. Heck coupling of 2-bromophenols or 2-bromoanilides with 2,3-dihydrofurans affords 2,5-epoxybenzoxepin and 2,5-epoxybenzazepins, respectively.

Full text of DOI:10.1021/jo501840u

Article
pubs.acs.org/joc
Controlling Olefin Isomerization in the Heck Reaction with Neopentyl
Phosphine Ligands
Matthew G. Lauer, Mallory K. Thompson, and Kevin H. Shaughnessy*
Department of Chemistry, The University of Alabama, P.O. Box 870336, Tuscaloosa, Alabama 35487-0336, United States
S
* Supporting Information
ABSTRACT: The use of neopentyl phosphine ligands was examined
in the coupling of aryl bromides with alkenes. Di-tert-butylneopentyl-
phosphine (DTBNpP) was found to promote Heck couplings with
aryl bromides at ambient temperature. In the Heck coupling of cyclic
alkenes, the degree of alkene isomerization was found to be
controlled by the choice of ligand with DTBNpP promoting
isomerization to a much greater extent than trineopentylphosphine
(TNpP). Under optimal conditions, DTBNpP provides high
selectivity for 2-aryl-2,3-dihydrofuran in the arylation of 2,3-
dihydrofuran, whereas TNpP provided high selectivity for the
isomeric 2-aryl-2,5-dihydrofuran. A similar complementary product
selectivity is seen in the Heck coupling of cyclopentene. Heck coupling of 2-bromophenols or 2-bromoanilides with 2,3-
dihydrofurans affords 2,5-epoxybenzoxepin and 2,5-epoxybenzazepins, respectively.
Santelli and co-workers found that a number of reaction
conditions including base, solvent, and temperature affect the
selectivity in the coupling of aryl bromides with linear and
branched 1-alkenes when utilizing a tetraphosphine palladium
catalyst.4 Often isomerization can be suppressed with the
addition of stoichiometric Ag(I) or Tl(I) salts.5
INTRODUCTION
■
Since the seminal reports in the early 1970s by Mizoroki1 and
Heck2 of the palladium-catalyzed reactions of organic halides
with olefins, the Heck reaction has become one of the most
used metal-catalyzed carbon−carbon bond forming methods.3
Heck reactions with styrene and acrylate ester olefin coupling
partners produce a single vinyl arene product. However,
reactions with alkyl olefins bearing allylic protons result in
product mixtures due to varying degrees of migration of the
newly formed carbon−carbon double bond (Figure 1).
Cyclic olefins have the added complication of the
thermodynamically favored 1-arylcycloalkene product being
inaccessible via syn β-hydride elimination after the initial
migratory insertion of the olefin into the Pd−Ar bond (Figure
1).6 Under a large number of conditions, double bond
migration is believed to occur via a “chain-walking” mechanism
in which the hydridopalladium species does not undergo olefin
exchange.7 As a result, a mixture of allylic and homoallylic
products is generally formed with only minor amounts of the
vinylic product. Beller and co-workers reported conditions
(Pd2(dba)3·dba, PCy3, Na2CO3, DMA, 140 °C) for the Heck
reaction of aryl bromides and cyclopentene where the double
bond isomerization is a result of base-catalyzed isomerization
and not the resulting hydridopalladium complexes.8 As a result,
sodium acetate gives the allylic olefin as the major product,
whereas the more basic sodium carbonate provides the
conjugated vinyl olefin as the major product.
Zhou and co-workers recently reported conditions for
achieving excellent vinyl selectivity in the Heck coupling of
cyclic olefins in which the resulting hydridopalladium complex
is responsible for the isomerization.6,9 In order to access the
vinyl arene product, the hydridopalladium intermediate must be
able to undergo olefin exchange of the initial allylic olefin
Received: August 8, 2014
Figure 1. Product selectivity in the Heck reaction.
© XXXX American Chemical Society
A
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product. Zhou proposes that stabilization of the hydrido-
palladium complex by the solvent (veratrole, DMPU) allows for
the hydridopalladium complex to switch faces in order to
undergo syn β-hydride elimination to give the thermodynami-
cally most stable vinyl arene product.6 Chelating ligands have
been used to control the selectivity in the Heck reaction of
cyclic olefins. The trend that stronger σ-donating ligands on
palladium promote isomerization was observed.10 Trans-
chelating ligands also can affect the selectivity.11
Table 1. Optimization of Room-Temperature Heck Reaction
a
a
entry
solvent
% conv.
entry
solvent
% conv.
Although a plethora of reaction conditions are reported for
use in the Heck reaction, bulky, electron rich phosphines afford
some of the most active catalysts.12 Neopentylphosphines have
received attention as bulky, electron rich phosphines (Figure
2). Catalysts derived from di-tert-butylneopentylphosphine
1
2
3
4
5
DMF
98
77
76
72
60
6
7
toluene
MeOH
DMF
26
25
98
3
MeCN
acetone
DMSO
dioxane
b
8
c
9
DMF
a
% conversion determined by relative GC areas of 4-bromoanisole and
b
c
1a. N,N-Dicyclohexylmethylamine (1.5 equiv) used as base. TNpP
(2 mol %) used as ligand.
styrene (Table 2). 2-Bromoacetanilide could be successfully
coupled with styrene to produce 1f in an 83% yield using
Figure 2. Neopentyl phosphine ligands.
a b c d e
, , , ,
Table 2. Heck Reactions of Acrylates and Styrenes
(DTBNpP) have a reactivity similar to those derived from
tri-tert-butylphosphine (TTBP), catalyzing the Suzuki, Sonoga-
shira, and Buchwald−Hartwig couplings at room temper-
ature.13 tert-Butyldineopentylphosphine (TBDNpP) and
trineopentylphosphine (TNpP) generally proved to be less
reactive at ambient temperature, presumably due to their
weaker electron donating ability.13a Recently, however, TNpP
in combination with Pd2(dba)3 was found to be an extremely
active catalyst in the Buchwald−Hartwig couplings of amines
and enolates with sterically hindered aryl bromides and
chlorides at temperatures from 80 to 100 °C.13d,14 The
surprising success of TNpP with sterically hindered substrates is
believed to come from the added conformational flexibility of
the neopentyl groups relative to the more static tert-butyl
groups.
Herein, we report ligand controlled olefin isomerization in
the Heck reaction of cyclic olefins utilizing DTBNpP and
TNpP. DTBNpP was found to promote isomerization of the
resulting olefins, whereas TNpP results in minimal isomer-
ization under otherwise identical conditions. The catalyst
derived from DTBNpP affords epoxybenzoxepins and epox-
ybenzazepins from 2,3-dihydrofuran (2,3-DHF) and 2-
bromophenols or 2-bromoaniline derivatives.
a
Yields are an average of two 1 mmol reactions. Reaction conditions:
ArBr (1 mmol), alkene (1.4 equiv), Pd(dba)2 (2 mol %), DTBNpP (2
RESULTS AND DISCUSSION
■
The Heck reaction of aryl bromides with acrylates and styrene
utilizing DTBNpP as a ligand was first explored in an attempt
to find mild reaction conditions. Our group previously reported
that elevated temperatures (80−100 °C) were required for the
coupling of aryl bromides with styrene in dioxane when
DTBNpP was utilized as a ligand for palladium.13b A brief
solvent screen revealed that the coupling of 4-bromoanisole
with tert-butyl acrylate proceeded at room temperature in a
number of polar aprotic solvents with DMF, providing the best
conversion (Table 1, entries 1−7). Both N,N-diisopropyl-
ethylamine (DIPEA) and N,N-dicyclohexylmethylamine gave
similar conversions to 1a (entries 1 and 8). Very low
conversion was obtained when TNpP was used as the ligand
under these conditions (entry 9).
b
mol %), DIPEA (1.5 equiv), DMF, 24 °C. Reaction performed at 80
°C with Pd(dba)2 (2 mol %) and DTBNpP (2 mol %). Reaction
c
performed at 80 °C with Pd(dba)2 (2 mol %) and TNpP (4 mol %).
d
e
Determined by GC analysis. Reaction performed at 160 °C with
Pd(dba)2 (5 mol %) and TNpP (10 mol %).
DTBNpP at 80 °C; however 2-bromotoluene gave <5%
conversion to 1g under identical conditions. TNpP was
previously shown to outperform DTBNpP with sterically
hindered substrates in both the Buchwald−Hartwig and the
Suzuki couplings, so the use of TNpP with 2-bromotoluene and
other hindered ortho-substituted aryl bromides was examined.14
Although TNpP gave low conversions at ambient temper-
ature for nonhindered substrates (Table 1, entry 9) it gave a
good yield (85%) of 1g at 80 °C. Di-ortho-substituted products
1h and 1i could also be formed in good yield utilizing TNpP,
Electron rich and poor aryl bromides both gave high yields of
the desired coupled products (1) with acrylate esters and
B
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a
although a higher temperature (160 °C) and catalyst loading (5
mol % Pd(dba)2) were required.
Table 5. Optimization of Heck Reaction with 2,3-DHF
3-Buten-2-ol also reacted with a number of aryl bromides
under the standard reaction conditions to give the correspond-
ing methyl ketone as the major product (Table 3). The
a b
,
Table 3. Heck Reactions with 3-Buten-2-ol
a
a
entry
solvent
base
ligand
3a:4a
yield (%)
1
2
MeCN
MeCN
MeCN
MeCN
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
MeOH
MeCN
MeOH
MeOH
MeOH
DIPEA
DIPEA
KOAc
KOAc
DIPEA
DIPEA
KOAc
KOAc
KOAc
DIPEA
KOAc
DIPEA
KOAc
KOAc
KOAc
DTBNpP
TNpP
88:12
29:71
66:34
15:85
72:28
17:83
60:40
8:92
79
79
86
92
3
DTBNpP
TNpP
4
b
5
DTBNpP
TNpP
20
6
83
82
95
98
72
68
7
DTBNpP
TNpP
8
c
9
TNpP
4:96
10
11
12
13
TTBP
TTBP
PCy3
89:11
90:10
6:94
a
b
Yields are an average of two 1 mmol reactions. Reaction performed
b
32
with Pd(dba)2 (5 mol %), TNpP (10 mol %), 160 °C.
b
PCy3
1:99
37
d
b
14
d
PCy3
1:99
52
reactions producing products 2a and 2b from the electron rich
aryl bromides were remarkably fast, reaching completion within
2 h at 24 °C. 3-Buten-2-ol could be coupled with the sterically
hindered aryl bromide, 2-bromo-1,3-dimethylbenzene, utilizing
TNpP as the ligand to produce 2d in a yield of 76%.
Next, Heck reactions were examined utilizing 2,3-DHF as the
olefin coupling partner (Table 4). The conditions optimized for
15
TNpP
1:99
98
a
Product ratios and yields were determined by GC using an internal
standard on a 0.25 mmol scale; yield refers to the total yield of both
product isomers (3a and 4a). Reaction did not reach completion. 6
b
c
d
mol % of TNpP was used in the reaction. Reaction conducted at 80
°C for 17 h.
a
were then optimized with TNpP for the 2,5-DHF product (4).
Methanol and potassium acetate proved to be the best solvent
and base combination with TNpP to give the highest selectivity
for the 2,5-DHF product (4) (entries 8 and 9). Under a series
of different conditions, DTBNpP consistently gave selectivity
for the 2,3-DHF product (3) (entries 1, 3, 5, and 7), whereas
TNpP gave selectivity for the 2,5-DHF product (4) (entries 2,
4, 6, and 8). Although the choice of base and solvent affects the
product selectivity, ligand choice seems to be the most
important factor in controlling double bond isomerization.
TTBP gave excellent selectivity for the 2,3-DHF product (3)
under both sets of optimized conditions (entries 10 and 11),
although in lower yields than achieved with DTBNpP.
Tricyclohexylphosphine (PCy3) produced 2,5-DHF product 4
with good selectivity, but the reactions failed to reach
completion under the two sets of optimized conditions (entries
12 and 13). The reaction utilizing PCy3 still failed to reach
completion at 80 °C for 17 h, whereas TNpP still gave excellent
yield and selectivity for product 4 at 80 °C (entries 14 and 15).
The substrate scope was examined after optimized conditions
were found (Table 6). The DTBNpP conditions gave good
yields and selectivity for a number of 2,3-DHF products (3)
derived from electron rich and deficient aryl bromides. The
conditions with TNpP worked well, producing excellent
selectivity for the 2,5-DHF products 4a, 4b, and 4f. However,
the products 4c, 4d, and 4e derived from electron deficient aryl
bromides gave lower selectivity for 2,5-DHF product (4), while
requiring higher temperatures and reaction times. Not
surprisingly, the DTBNpP-derived catalyst gave low con-
versions with the more hindered 2-bromotoluene, affording
only a 35% yield of ortho-substituted 3g, although with high
selectivity for the 2,3-DHF product. The conditions to produce
2,5-DHF (4) utilizing the more conformationally flexible TNpP
Table 4. Heck Reactions with 2,3-DHF
a
Isolated yields of 3 are an average of two 1 mmol scale reactions.
Ratios in parentheses (3:4) are of the crude reaction mixture and were
determined by GC peak area.
acrylates and styrene gave high selectivity for 2,3-DHF products
(3) within 2 h at ambient temperature. Both electron rich and
poor aryl bromides produced good yields and selectivity for the
2,3-DHF product (3).
Once again, TNpP failed to give a high conversion at
ambient temperature. When utilizing DTBNpP at 60 °C, a
number of different solvents produced good yields of the 2,3-
DHF product (3), so the use of TNpP was explored at 60 °C.
Surprisingly, TNpP produced the opposite selectivity to that
seen with DTBNpP, producing the 2,5-DHF product (4),
under otherwise identical conditions (Table 5). Conditions
C
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a b c
, ,
produced a good yield (70%) and excellent selectivity (98%)
for 4g. The heterocyclic compound 3-bromothiophene
produced good yield and selectivity for products 3h and 4h.
However, 2-bromopyridine failed to react under optimized
conditions. 1-Bromo-4-chlorobenzene and 2,3-DHF selectively
coupled at the carbon containing the bromine to give 4-
chlorophenyl products 3i and 4i in good yield and selectivity. 4-
Chlorotoluene failed to react with 2,3-DHF under both sets of
optimized conditions. The activated aryl chloride 4-chloroace-
tophenone produced 76% conversion to product in 17 h with
the DTBNpP-derived catalyst at 80 °C with excellent selectivity
for the 2,3-DHF product 3c (98:2). 4-Chloroacetophenone
failed to react with 2,3-DHF with the catalyst system derived
from TNpP.
Table 6. Heck Reaction with 2,3-DHF
When the conditions optimized for the 2,3-DHF products
(3) were applied to 2-bromophenol, a mixture of DHF
products 3 and 4 were formed along with a small amount of
2,3,4,5-tetrahydro-2,5-epoxy-1-benzoxepin (5a) (Table 7, entry
2). A structure similar to that of 5a is found in the core of the
spiroxins, a family of marine-derived antitumor antibiotics.15
A
catalytic amount of 2-propanol was found to promote
formation of 5a, although its role is not clear at this time
(entry 4). It was found that lowering the equivalents of DIPEA
from 1.5 to 1.0 resulted in the formation of 5a without
contamination by the 2,3-DHF product (3) (entries 5−7). This
effect is presumably due to slower reductive elimination of the
hydridopalladium species with the lower base concentration. As
a result, there is ample time for the palladium−hydride bond to
reinsert across the 2,3-DHF product (3) to allow reductive
elimination of the carbon−oxygen bond (Scheme 1, path A).
The cyclization could also occur via the formation of a
carbocation intermediate that is then trapped by the pendant
alcohol (path B).16 Acetone and MeCN were both found to be
viable solvents for the cyclization reaction. Holzapfel and co-
workers previously reported the formation of 5a via a Heck
reaction between 2-hydroxyarylmercuric salts and 2,3-DHF
with 1 equiv of Pd(OAc)2 in THF.17
The 2-bromophenol substrates were shown to tolerate both
electron donating and withdrawing groups para to the OH
(Table 8). Next, 2-bromoaniline was examined to see if it
would give epoxybenzazepins similar to the structure found at
the core of the recently reported pyrroloiminoquinone alkaloid,
atkamine.18 Unfortunately 2-bromoaniline failed to react with
2,3-DHF to give product 5e. However, cyclization proceeded
with the addition of an acetyl or tosyl protecting group to the
a
Conditions: A: 2,3-DHF (5 equiv), Pd2(dba)3 (1.5 mol %), DTBNpP
(3 mol %), DIPEA (1.5 equiv), MeCN, 60 °C, 2 h. B: 2,3-DHF (2.5
equiv), Pd2(dba)3 (1.5 mol %), TNpP (6 mol %), KOAc (1.5 equiv),
MeOH, 60 °C, 2−5 h. C: 2,3-DHF (5 equiv), Pd2(dba)3 (1.5 mol %),
b
TNpP (6 mol %), KOAc (1.5 equiv), MeOH, 80 °C, 5−17 h. Ratios
are based on GC peak areas of reaction mixture. Isolated yields of
major isomer.
c
Table 7. Optimization for the Formation of 5a
a
entry
solvent
T (°C)
DIPEA (equiv)
additive
yield (%)
1
2
3
4
5
6
7
DMF
24
80
80
80
80
80
80
1
0
5
MeCN
acetone
acetone
MeCN
acetone
acetone
1.5
1.5
1.5
1
8
iPrOH (0.5 equiv)
iPrOH (0.5 equiv)
26
54
55
61
1
1
a
1
Yield determined by H NMR analysis of the reaction mixture with an internal standard.
D
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a b c
, ,
Scheme 1. Plausible Mechanisms for Formation of 5a
Table 9. Heck Reaction of Cyclopentene
Table 8. Heck Reaction of 2-Bromo-Phenols and Anilines
a
with 2,3-DHF Producing 5
a
Conditions: A: cyclopentene (4 equiv), Pd(dba)2 (5 mol %),
DTBNpP·HBF4 (5 mol %), DIPEA (1.5 equiv), acetone, 80 °C, 24 h.
B: cyclopentene (4 equiv), Pd(dba)2 (5 mol %), TNpP (10 mol %),
KOAc (1.5 equiv), MeOH, 80 °C, 24 h. C: cyclopentene (4 equiv),
Pd(dba)2 (5 mol %), DTBNpP·HBF4 (10 mol %), DIPEA (1 equiv),
b
2-propanol (0.5 equiv), acetone, 80 °C, 17 h. Ratios are based on GC
c
peak areas of reaction mixture. Isolated yields, 6 and 7 were isolated
as a mixture and individual yields are based on ratios obtained via
NMR spectroscopy of the isolated mixture. Ratios for 6 and 7 matched
( 2%) when determined from the reaction mixture via GC or from
the isolated mixture after column chromatography via 1H NMR
spectroscopy.
the trisubstituted olefin, which does not allow for reinsertion of
the hydridopalladium complex to allow for reductive
elimination of the carbon oxygen bond. Alternatively, decreased
stability of the potential carbocation intermediate necessary for
cyclization may disfavor formation of the bicyclic ether product.
When the cyclization conditions (C) were applied with other
aryl halide coupling partners, the vinyl product was still
obtained with excellent selectivity and good yields. The
cyclization conditions apparently allow for more efficient olefin
exchange of the hydridopalladium intermediates so that syn β-
hydride elimination may occur to form the most stable
conjugated vinylic product (8).
To help verify that the double bond isomerization is due to
the hydridopalladium species generated during the reaction, a
mixture of Heck products 6a and 7a was subjected to a
hydridopalladium species generated from isobutyryl chloride
(Scheme 2).19 Subjecting 6a and 7a to the in situ generated
palladium(II) hydride catalyst resulted in isomerization of the
olefin to give 8a as the major component. Heating Heck
products 6a and 7a to 80 °C in the presence of DIPEA for 24 h
resulted in no observable isomerization by GC analysis. As a
result, it appears migration of the olefin under the reaction
conditions is due to hydridopalladium species generated during
the reaction and not the base, unlike the system reported by
Beller and co-workers for the Heck reaction with cyclic olefins.8
The results with 2,3-DHF and cyclopentene show a common
pattern. The catalyst derived from DTBNpP favors formation
a
Yields are an average of two 1 mmol reactions.
aniline starting material to produce 5f and 5g, with the tosyl
group providing a higher yield.
Cyclopentene was next explored as a coupling partner in the
Heck reaction (Table 9). The conditions optimized for
DTBNpP at 80 °C gave allylic olefin product 6 as the major
product, albeit with poor selectivity (Table 9, conditions A).
When conditions optimized for TNpP at 80 °C were used, 6
was once again formed as the major product, but with much
better selectivity (Table 9, conditions B). When utilizing TNpP
as the ligand, there was minimal isomerization producing only
traces of the vinylic product 8 (2−3%). Both sets of conditions
(A and B) produced measurable amounts of the homoallylic
product 7 that could not be isolated from allylic product 6 via
column chromatography. The TNpP conditions (B) produced
less of the homoallylic product 7 compared to the DTBNpP
conditions (A).
When the cyclization conditions (Table 9, conditions C) for
the formation of 5 where applied to the coupling of 2-
bromophenol and cyclopentene, no cyclized product was
observed. However, the vinylic product 8d was formed in
excellent selectivity (>99%) and in high yield (90%).
Cyclization may not occur due to the increased stability of
E
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the relative electron donating abilities of the phosphine ligands.
The more electron rich palladium centers containing TTBP or
DTBNpP as a ligand bind to the olefin product more tightly
due to stronger π-backbonding. The strong bonding allows for
the hydridopalladium species to undergo reversible insertion/
elimination to give the thermodynamically more stable product
3 or 8, while preventing reductive elimination of HBr. In
contrast, the tricyclohexylphosphine and TNpP hydridopalla-
dium species dissociate from the olefin faster due to the weaker
π-backbonding, allowing for reductive elimination of HBr
before reinsertion of the hydridopalladium species and
isomerization can occur (Scheme 3). The same trend holds
with the use of chelating ligands in the coupling of cyclic
olefins.10
Scheme 2. Source of Double Bond Migration
of products resulting from isomerization to form the most
stable alkene product (3 or 8, Scheme 3). In contrast, the
The electronic nature of the aryl halide also affects the
product selectivity in Heck couplings of 2,3-DHF. Electron
deficient aryl halides decreased the selectivity for product 4
when using TNpP (4c, 4d, 4e, Table 6), but had little effect on
the selectivity with the DTBNpP-derived catalyst. In contrast,
lower selectivity was observed with the electron rich 4-
bromoanisole using DTBNpP (3a, Table 6). These observa-
tions may support our hypothesis. The more electron deficient
2-aryl-DHF products may act as better backbonding acceptors,
which results in increased isomerization with the TNpP-derived
catalyst. In contrast, the more electron rich product formed
from 4-bromoanisole, may bind less tightly because it is a
poorer back-bonding acceptor. This decreases the amount of
isomerization, decreasing the selectivity for product 3.
With the cyclopentene couplings, the base concentration also
plays a crucial role, as the hydridopalladium must switch faces
of the alkene to allow for syn β-hydride elimination to form the
vinylic product 8. With a lower concentration of base, the
hydridopalladium species survives long enough after dissocia-
tion from the olefin to switch faces of the cycloalkane, thus
allowing syn β-hydride elimination to the conjugated product.
At higher base concentrations, the elimination of HBr occurs
too readily after dissociation of the hydridopalladium species to
allow isomerization to vinylic product 8. As seen in Table 9,
only a 37% selectivity of 8a was produced with 1.5 equiv of
DIPEA compared to 99% selectivity for 8a with 1.0 equiv of
DIPEA.
Scheme 3. Isomerization of DHF Products through
Reversible Insertion/Elimination Steps
TNpP-derived catalyst forms the less stable nonconjugated
product in each case (4 or 6/7). These products result from the
initial β-hydride elimination, without further isomerization to
the more stable products. It is possible that the DTBNpP-
derived palladium-hydride is more stable than the TNpP
analogue, resulting in more extensive isomerization. Alter-
natively, the alkene product may coordinate more strongly to
the DTBNpP complex than the TNpP complex, which again
would allow for more extensive isomerization.
Fu and co-workers reported that ligand steric hindrance plays
a critical role in the reductive elimination of HCl from
(R3P)2PdHCl.20 The reductive elimination of HCl from
(TTBP)2PdHCl occurs at 20 °C in the presence of 35 equiv
of N,N-dicyclohexylmethylamine, whereas reductive elimina-
tion of HCl with the less sterically hindered tricyclohexyl-
phosphine complex does not occur under identical conditions.
Using hydroxide as the base, elimination of HBr from
(Cy3P)2PdHBr was achieved at 75 °C.21 Given that TTBP
promotes more alkene isomerization in the Heck coupling of
2,3-DHF compared to PCy3, the rate of HX elimination from
the L2PdHBr complexes does not appear to be the determining
factor in the product selectivity. DTBNpP has similar steric
demand to TTBP based on calculated steric parameters and
reactivity profiles.13a The flexible TNpP ligand is able to adopt
less sterically demanding conformations that may be more
comparable to PCy3.14 Therefore, it would appear that the
steric effect on palladium-hydride stability is not the primary
factor in determining the product selectivity.
CONCLUSIONS
■
DTBNpP in combination with Pd(dba)2 was shown to catalyze
the Heck reaction of aryl bromides at ambient temperature.
Although the TNpP-derived catalyst showed minimal activity at
ambient temperature, it showed increased reactivity with
sterically hindered substrates at elevated temperatures.
DTBNpP and TNpP were found to promote different degrees
of isomerization in the coupling of cyclic olefins, allowing
selective production of arylated cycloalkene isomers. DTBNpP
promoted isomerization of the initial olefin product, whereas
TNpP did not. A catalytic method for the formation of 2,3,4,5-
tetrahydro-2,5-epoxy-1-benzoxepins (5) having a structure
similar to that found at the core of a number of biologically
active natural products was found. We propose that the greater
electron donating ability of DTBNpP relative to TNpP allows
for stronger coordination of the olefin products to the electron
rich palladium center. This, in turn, promotes isomerization
while preventing reductive elimination of HBr, giving ample
time to form the thermodynamically more stable products
through reversible migratory insertion/β-hydride elimination
steps. The findings reported should aid in ligand selection for
As a result, we hypothesize that the selectivity in the
isomerization of the resulting Heck products is primarily due to
F
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The Journal of Organic Chemistry
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°C. The crude product was purified by flash chromatography on silica
gel using a solvent gradient (0−2% EtOAc/hexanes) to give 1d (202
mg, 0.96 mmol, 96%) as a white solid. 1H NMR (CDCl3, 500 MHz): δ
7.47 (d, J = 7.4 Hz, 2H), 7.43 (m, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.22
(t, J = 7.3 Hz, 2H), 7.05 (d, J = 16.3 Hz, 1H), 6.96 (d, J = 16.3 Hz,
1H), 6.88 (m, 2H), 3.79 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ
159.5, 137.9, 130.5, 128.8, 128.4, 127.9, 127.4, 126.8, 126.5, 114.3,
55.5.
future palladium-catalyzed reactions involving olefin isomer-
ization due to hydridopalladium species.
EXPERIMENTAL SECTION
■
General Experimental Methods. DTBNpP, TNpP, and TTBP
were obtained from FMC, Lithium Division. 2-Bromoacetanilide,22 N-
(2-bromophenyl)-4-methylbenzenesulfonamide,23 and Pd(dba)2
24
(E)-4-Styrylbenzonitrile (1e).30 General Procedure A was followed
using 4-bromobenzonitrile (182 mg, 1.00 mmol), Pd(dba)2 (2 mol %,
11.5 mg, 0.02 mmol), DTBNpP·HBF4 (2 mol %, 6.1 mg; 0.02 mmol),
and styrene (0.16 mL, 1.4 mmol) while stirring for 48 h at 24 °C. The
crude product was purified by flash chromatography on silica gel using
a solvent gradient (0−3% EtOAc/hexanes) to give 1e (177 mg, 0.86
mmol, 86%) as a white solid. 1H NMR (CDCl3, 500 MHz): δ 7.59 (d,
J = 8.4 Hz, 2H), 7.55−7.50 (m, 4H), 7.37 (t, J = 7.3 Hz, 2H), 7.31 (m,
1H), 7.18 (d, J = 16.3 Hz, 1H), 7.06 (d, J = 16.3 Hz, 1H); 13C NMR
(CDCl3, 125 MHz): δ 141.9, 136.4, 132.6, 132.5, 129.0, 128.9, 127.1,
127.0, 126.8, 119.2, 110.7.
were prepared from known literature procedures. Anhydrous DMF
was stored in a nitrogen-filled glovebox. MeCN was distilled over
CaH2 under nitrogen gas. Acetone and methanol were vigorously
bubbled with nitrogen gas for at least 15 min immediately prior to use.
All other reagents were obtained from commercial sources and used as
received. Reaction temperatures refer to previously equilibrated oil
bath temperatures. Pd(dba)2 and Pd2(dba)3 gave similar results in the
coupling reactions involving 2,3-DHF; the use of Pd2(dba)3 was not
tested in the other Heck couplings.25 HRMS was obtained on a
magnetic sector mass spectrometer using EI ionization and operating
in the positive ion mode.
General Procedure A - Heck Reaction of Acrylate Esters and
Styrene (Table 2). To a 4 mL borosilicate glass vial were added
Pd(dba)2 (2 or 5 mol %), phosphine (2, 4, or 10 mol %), and DMF (1
mL) inside a glovebox. The vial was fitted with a septa screw cap and
removed from the glovebox. To the vial were added aryl bromide (1
mmol, if a solid, the aryl bromide was added prior to adding DMF in
the glovebox), olefin (1.4 equiv), and DIPEA (1.5 equiv, 0.26 mL; 1.5
mmol). The vial was then stirred at 24−160 °C (reactions heated to
160 °C were performed in a pressure tube with adequate shielding) for
24−48 h. After cooling to ambient temperature, the reaction mixture
was subjected directly to flash chromatography on silica gel.
(E)-N-(2-Styrylphenyl)acetamide (1f).31 General Procedure A was
followed using 2′-bromoacetanilide35 (214 mg, 1.00 mmol), Pd(dba)2
(2 mol %, 11.5 mg, 0.02 mmol), DTBNpP·HBF4 (2 mol %, 6.1 mg;
0.02 mmol), and styrene (0.16 mL, 1.4 mmol) while stirring for 24 h at
80 °C. The crude product was purified by flash chromatography on
silica gel using a solvent gradient (0−3% EtOAc/hexanes) to give 1f
1
(194 mg, 0.82 mmol, 82%) as a white solid. H NMR (CDCl3, 500
MHz): δ 7.75 (br s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.47−7.43 (m, 3H),
7.32 (t, J = 7.4 Hz, 2H), 7.26−7.24 (m, 1H), 7.16 (t, J = 7.2 Hz, 1H),
7.11−7.07 (m, 2H), 6.89 (d, J = 16.2 Hz, 1H), 2.06 (s, 3H); 13C NMR
(CDCl3, 125 MHz): δ 169.3, 137.3, 134.8, 131.2, 130.9, 128.8, 128.2,
128.1, 126.8, 126.5, 125.8, 125.1, 123.8, 24.0.
tert-Butyl (E)-3-(4-Methoxyphenyl)acrylate (1a).26 General Proce-
dure A was followed using 4-bromoanisole (0.125 mL, 1.00 mmol),
Pd(dba)2 (2 mol %, 11.5 mg, 0.02 mmol), DTBNpP·HBF4 (2 mol %,
6.1 mg; 0.02 mmol), and tert-butyl acrylate (0.20 mL, 1.4 mmol) while
stirring for 24 h at 24 °C. The crude product was purified by flash
chromatography on silica gel using a solvent gradient (0−2.5%
EtOAc/hexanes) to give 1a (228 mg, 0.97 mmol, 97%) as a clear, light
yellow oil. 1H NMR (CDCl3, 500 MHz): δ 7.54 (d, J = 15.9 Hz, 1H),
7.44 (m, 2H), 6.87 (m, 2H), 6.24 (d, J = 16.0 Hz, 1H), 3.81 (s, 3 H),
1.53 (s, 9H); 13C NMR (CDCl3, 125 MHz): δ 165.5, 141.2, 139.1,
132.7, 128.4, 124.0, 118.5, 113.2, 81.3, 28.2.
(E)-1-Methyl-2-styrylbenzene (1g).30 General Procedure A was
followed using 2-bromotoluene (0.120 mL, 1.00 mmol), Pd(dba)2 (2
mol %, 11.5 mg, 0.02 mmol), TNpP (4 mol %, 9.8 mg; 0.04 mmol),
and styrene (0.16 mL, 1.4 mmol) while stirring for 24 h at 80 °C. The
crude product was purified by flash chromatography on silica gel using
hexanes to give 1g (165 mg, 0.85 mmol, 85%) as a clear colorless oil.
1H NMR (CDCl3, 500 MHz): δ 7.57 (d, J = 7.2 Hz, 1H), 7.50 (m,
2H), 7.35−7.30 (m, 3H), 7.26−7.22 (m, 1H), 7.20−7.15 (m, 3H),
6.98 (d, J = 16.1 Hz, 1H), 2.40 (s, 3H); 13C NMR (CDCl3, 125 MHz):
δ 137.9, 136.6, 136.0, 130.6, 130.2, 128.9, 127.8, 127.7, 126.8, 126.4,
125.6, 20.1.
tert-Butyl (E)-3-(4-Cyanophenyl)acrylate (1b).27 General Proce-
dure A was followed using 4-bromobenzonitrile (182 mg, 1.00 mmol),
Pd(dba)2 (2 mol %, 11.5 mg, 0.02 mmol), DTBNpP·HBF4 (2 mol %,
6.1 mg; 0.02 mmol), and tert-butyl acrylate (0.20 mL, 1.4 mmol) while
stirring for 24 h at 24 °C. The crude product was purified by flash
chromatography on silica gel using a solvent gradient (0−4% EtOAc/
(E)-1,3-Dimethyl-2-styrylbenzene (1h).32 General Procedure A was
followed using 2-bromo-1,3-dimethylbenzene (0.133 mL, 1.00 mmol),
Pd(dba)2 (5 mol %, 28.8 mg, 0.05 mmol), TNpP (10 mol %, 24.4 mg;
0.10 mmol), and styrene (0.16 mL, 1.4 mmol) while stirring for 24 h at
160 °C. The crude product was purified by flash chromatography on
silica gel using hexanes to give 1h (172 mg, 0.83 mmol, 83%) as a clear
colorless oil. 1H NMR (CDCl3, 500 MHz): δ 7.46 (d, J = 7.3 Hz, 2H),
7.32 (m, 2H), 7.23 (m, 1H), 7.08 (d, J = 16.6 Hz, 1H), 7.05−7.04 (m,
3H), 6.57 (d, J = 16.6 Hz, 1H), 2.34 (s, 6H); 13C NMR (CDCl3, 125
MHz): δ 137.8, 137.1, 136.4, 134.2, 128.8, 128.1, 127.7, 127.1, 126.9,
126.5, 21.2.
1
hexanes) to give 1b (214 mg, 0.93 mmol, 93%) as a white solid. H
NMR (CDCl3, 500 MHz): δ 7.67 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4
Hz, 2H), 7.56 (d, J = 16.0 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H), 1.54 (s,
9H); 13C NMR (CDCl3, 125 MHz): δ 166.8, 161.3, 143.3, 129.7,
127.6, 117.9, 114.4, 80.3, 55.5, 28.4.
Butyl (E)-3-(3-Methoxyphenyl)acrylate (1c).28 General Procedure
A was followed using 3-bromoanisole (0.127 mL, 1.00 mmol),
Pd(dba)2 (2 mol %, 11.5 mg, 0.02 mmol), DTBNpP·HBF4 (2 mol %,
6.1 mg; 0.02 mmol), and n-butyl acrylate (0.20 mL, 1.4 mmol) while
stirring for 24 h at 24 °C. The crude product was purified by flash
chromatography on silica gel using a solvent gradient (0−2.5%
EtOAc/hexanes) to give 1c (227 mg, 0.98 mmol, 98%) as a clear,
(E)-1,3,5-Triisopropyl-2-styrylbenzene (1i).32 General Procedure A
was followed using 1-bromo-1,3,5-triisopropylbenzene (0.260 mL,
1.00 mmol), Pd(dba)2 (5 mol %, 28.8 mg, 0.05 mmol), TNpP (10 mol
%, 24.4 mg; 0.10 mmol), and styrene (0.16 mL, 1.4 mmol) while
stirring for 24 h at 160 °C. The crude product was purified by flash
chromatography on silica gel using hexanes to give 1i (234 mg, 0.83
mmol, 76%) as a clear colorless solid. 1H NMR (CDCl3, 500 MHz): δ
7.49 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.27−7.24 (m, 1H),
7.19 (d, J = 16.6 Hz, 1H), 7.03 (s, 2H), 6.49 (d, J = 16.6 Hz, 1H), 3.82
(sept, J = 6.8 Hz, 2H), 2.90 (sept, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz,
6H), 1.21 (d, J = 6.9 Hz, 12H); 13C NMR (CDCl3, 125 MHz): δ
147.9, 146.9, 137.9, 134.1, 133.2, 128.9, 127.7, 127.2, 126.5, 120.8,
34.5, 30.4, 24.3, 24.2.
1
colorless oil. H NMR (CDCl3, 500 MHz): δ 7.64 (d, J = 16.0 Hz,
1H), 7.27 (t, J = 7.9 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 7.03 (m, 1H),
6.91 (dd, J = 8.1, 2.3 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 4.20 (t, J =
6.7 Hz, 2H), 3.80 (s, 3H), 1.71−1.65 (m, 2H), 1.43 (sex, J = 7.5 Hz,
2H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz): δ 167.0,
160.1, 144.5, 136.0, 129.9, 120.8, 118.7, 116.2, 113.0, 64.5, 55.3, 30.9,
19.3, 13.8.
(E)-1-Methoxy-4-styrylbenzene (1d).29 General Procedure A was
followed using 4-bromoanisole (0.125 mL, 1.00 mmol), Pd(dba)2 (2
mol %, 11.5 mg, 0.02 mmol), DTBNpP·HBF4 (2 mol %, 6.1 mg; 0.02
mmol), and styrene (0.16 mL, 1.4 mmol) while stirring for 48 h at 24
General Procedure B - Heck Reaction of 3-Buten-2-ol (Table
3). To a 4 mL borosilicate glass vial were added Pd(dba)2 (2 or 5 mol
%), phosphine (2 or 10 mol %), and DMF (1 mL) inside a glovebox.
The vial was fitted with a septa screw cap and removed from the
G
dx.doi.org/10.1021/jo501840u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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glovebox. To the vial were added aryl bromide (1 mmol, if a solid, the
aryl bromide was added prior to adding DMF in the glovebox), 3-
buten-2-ol (1.3 equiv, 0.115 mL, 1.3 mmol), and DIPEA (1.5 equiv,
0.26 mL; 1.5 mmol). The vial was then stirred at 24−160 °C
(reactions heated to 160 °C were performed in a pressure tube behind
a blast shield) for 2−24 h. After cooling to ambient temperature, the
reaction mixture was subjected directly to flash chromatography on
silica gel.
2-(3-Methoxyphenyl)-2,3-dihydrofuran (3b).37 General Procedure
C was followed using 3-bromoanisole (0.127 mL, 1.00 mmol). The
crude product was purified by flash chromatography on silica gel using
a solvent gradient (0−2% EtOAc/hexanes) to give 3b (141 mg, 0.80
1
mmol, 80%) as a clear, colorless oil. H NMR (CDCl3, 500 MHz): δ
7.26 (m, 1H), 6.92 (m, 2H), 6.82 (m, 1H),6.44 (m, 1H), 5.48 (dd, J =
10.5, 8.5 Hz, 1H), 4.94 (m, 1H), 3.80 (s, 3H), 3.06 (ddt, J = 15.2, 10.8,
2.3 Hz, 1H), 2.59 (ddt, J = 15.2, 8.4, 2.3 Hz, 1H); 13C NMR (CDCl3,
125 MHz): δ 160.0, 145.5, 144.9, 129.8, 118.0, 113.3, 111.3, 99.2 82.4,
55.4, 38.0.
4-(4-Methoxyphenyl)butan-2-one (2a).33 General Procedure B
was followed using 4-bromoanisole (0.125 mL, 1.00 mmol), Pd(dba)2
(2 mol %, 11.5 mg, 0.02 mmol), and DTBNpP·HBF4 (2 mol %, 6.1
mg; 0.02 mmol) while stirring for 1 h at 24 °C. The crude product was
purified by flash chromatography on silica gel using a solvent gradient
(8% EtOAc/hexanes) to give 2a (134 mg, 0.75 mmol, 75%) as a clear,
1-(4-(2,3-Dihydrofuran-2-yl)phenyl)ethanone (3c).38 General Pro-
cedure C was followed using 4-bromoacetophenone (199 mg, 1.00
mmol). The crude product was purified by flash chromatography on
silica gel using a solvent gradient (0−5% EtOAc/hexanes) to give 3c
(164 mg, 0.87 mmol, 87%) as a clear, colorless oil. 1H NMR (CDCl3,
500 MHz): δ 7.96 (m, 2H), 7.44 (m, 2H), 6.47 (dt, J = 2.6, 2.4 Hz,
1H), 5.57 (dd, J = 10.8, 8.2 Hz, 1H), 4.97 (dt, J = 2.6, 2.6 Hz, 1H),
3.13 (ddt, J = 15.2, 8.5, 2.4 Hz, 1H), 2.60 (s, 3H), 2.57 (ddt, J = 15.2,
8.2, 2.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δ 197.7, 148.5, 145.4,
136.5, 128.7, 125.6, 99.1, 81.6, 37.9, 26.6.
1
colorless oil. H NMR (CDCl3, 500 MHz): δ 7.08 (m, 2H), 6.81 (m,
2H), 3.76 (s, 3H), 2.83 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H),
2.11 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 208.1, 158.1, 133.1,
129.3, 114.0, 55.3, 45.5, 30.2, 29.0.
4-(4-(Dimethylamino)phenyl)butan-2-one (2b).34 The above
general procedure was followed using 4-bromo-N,N-dimethylaniline
(200 mg, 1.00 mmol), Pd(dba)2 (2 mol %, 11.5 mg, 0.02 mmol), and
DTBNpP·HBF4 (2 mol %, 6.1 mg; 0.02 mmol) while stirring for 2 h at
24 °C. The crude product was purified by flash chromatography on
silica gel using a solvent gradient (3−4% EtOAc/hexanes) to give 2b
2-((4-Trifluoromethyl)phenyl)-2,3-dihydrofuran (3d).38 General
Procedure C was followed using 4-bromobenzotrifluoride (0.140
mL, 1.00 mmol). The crude product was purified by flash
chromatography on silica gel using a solvent gradient (0−0.5%
EtOAc/hexanes) to give 3d (124 mg, 0.58 mmol, 58%) as a clear,
1
(138 mg, 0.72 mmol, 72%) as a yellow solid. H NMR (CDCl3, 500
1
MHz): δ 7.04 (m, 2H), 6.67 (m, 2H), 2.89 (s, 6H), 2.80 (m, 2H), 2.70
(m, 2H), 2.11 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 208.5, 149.3,
129.1, 129.0, 113.1, 45.7, 40.9, 30.2, 29.0.
colorless oil. H NMR (CDCl3, 500 MHz): δ 7.63 (m, 2H), 7.48 (m,
2H), 6.47 (dt, J = 5.0, 2.4 Hz, 1H), 5.57 (dd, J = 10.8, 8.2 Hz, 1H),
4.97 (dt, J = 2.6, 2.5 Hz, 1H), 3.14 (ddt, J = 15.2, 10.8, 2.4 Hz, 1H),
2.57 (ddt, J = 15.2, 8.0, 2.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δ
147.4, 145.5, 130 (q, J = 32.4 Hz), 126.0, 125.7 (q, J = 3.9 Hz), 124.4
(q, J = 270 Hz), 99.2, 81.6, 38.1.
General Procedure D - Synthesis of 2,3-Dihydrofurans (3)
(Table 6, Conditions A). To a 4 mL borosilicate glass vial were
added Pd2(dba)3 (1.5 mol %, 13.7 mg, 0.015 mmol) and DTBNpP
(2.9 mol %, 6.3 mg; 0.029 mmol) inside a glovebox. The vial was fitted
with a septa screw cap and removed from the glovebox. To the vial
were added MeCN (1 mL), aryl bromide (1 mmol, if a solid, the aryl
bromide was added prior to removing from glovebox), 2,3-
dihydrofuran (5.3 equiv, 0.40 mL, 5.3 mmol), and DIPEA (1.5
equiv, 0.26 mL; 1.5 mmol). The vial was then placed in an oil bath
preheated to 60 °C for 2 h. After cooling to ambient temperature, the
reaction mixture was concentrated under reduced pressure and
subjected to flash chromatography on silica gel.
4-(4-Acetylphenyl)butan-2-one (2c).35 General Procedure B was
followed using 4-bromoacetophenone (199 mg, 1.00 mmol), Pd(dba)2
(2 mol %, 11.5 mg, 0.02 mmol), and DTBNpP·HBF4 (2 mol %, 6.1
mg; 0.02 mmol) while stirring for 17 h at 24 °C. The crude product
was purified by flash chromatography on silica gel using a solvent
gradient (5−8% EtOAc/hexanes) to give 2c (162 mg, 0.85 mmol,
1
85%) as a yellow oil. H NMR (CDCl3, 500 MHz): δ 7.88 (m, 2H),
7.28 (m, 2H), 2.95 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.57
(m, 3H), 2.15 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 207.3, 197.8,
147.0, 135.4, 128.8, 128.7, 44.6, 30.2, 29.7, 26.7.
4-(2,6-Dimethylphenyl)butan-2-one (2d). General Procedure B
was followed using 2-bromo-1,3-dimethylbenzene (0.133 mL, 1.00
mmol), Pd(dba)2 (5 mol %, 28.8 mg, 0.05 mmol), and PNp3 (10 mol
%, 24.4 mg; 0.10 mmol) while stirring for 17 h at 160 °C. The crude
product was purified by flash chromatography on silica gel using a
solvent gradient (5−8% EtOAc/hexanes) to give 2d (135 mg, 0.77
2-(4-Methoxyphenyl)-2,3-dihydrofuran (3a).36 General Procedure
D was followed using 4-bromoanisole (0.125 mL, 1.00 mmol). The
crude product was purified by flash chromatography on silica gel using
a solvent gradient (0−3% EtOAc/hexanes) to give 3a (118 mg, 0.67
mmol, 67%) as a clear, light yellow oil. 1H NMR (CDCl3, 500 MHz):
δ 7.32 (m, 2H), 6.92 (m, 2H), 6.45 (dt, J = 2.6, 2.4 Hz, 1H), 5.49 (dd,
J = 10.6, 8.6 Hz, 1H), 4.97 (dt, J = 2.6, 2.5 Hz, 1H), 3.82 (s, 3H), 3.05
(ddt, J = 15.2, 10.6, 2.4 Hz, 1H), 2.63 (ddt, J = 15.2, 8.5, 2.3 Hz, 1H);
13C NMR (CDCl3, 125 MHz): δ 159.3, 145.4, 135.2, 127.2, 114.1,
1
mmol, 77%) as a light yellow oil. H NMR (CDCl3, 500 MHz): δ
7.03−6.98 (m, 3H), 7.91−2.88 (m, 2H), 2.59−2.56 (m, 2H), 2.30 (s,
6H), 2.17 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 208.3, 137.8,
136.2, 128.4, 126.2, 42.8, 30.0, 23.8, 19.9; HRMS: m/z calcd for
C12H16O (M+) 176.1201, found 176.1204.
General Procedure C − Heck Reaction of 2,3-Dihydrofuran
at 24 °C (Table 4). To a 4 mL borosilicate glass vial were added
Pd(dba)2 (2 mol %, 11.5 mg, 0.02 mmol), DTBNpP·HBF4 (2 mol %,
6.1 mg; 0.02 mmol), and DMF (1 mL) inside a glovebox. The vial was
fitted with a septa screw cap and removed from the glovebox. To the
vial were added aryl bromide (1 mmol, if a solid, the aryl bromide was
added prior to adding DMF in the glovebox), 2,3-DHF (4 equiv, 0.30
mL, 4.0 mmol), and DIPEA (1.0 equiv, 0.175 mL; 1.0 mmol). The vial
was then stirred at 24 °C for 2 h. After cooling to ambient
temperature, the reaction mixture was subjected directly to flash
chromatography on silica gel.
99.2, 82.4, 55.4, 37.8.
2-(3-Methoxyphenyl)-2,3-dihydrofuran (3b).37 General Procedure
D was followed using 3-bromoanisole (0.127 mL, 1.00 mmol). The
crude product was purified by flash chromatography on silica gel using
a solvent gradient (0−2% EtOAc/hexanes) to give 3b (145 mg, 0.82
1
mmol, 82%) as a clear, colorless oil. H NMR (CDCl3, 500 MHz): δ
7.26 (m, 1H), 6.92 (m, 2H), 6.82 (m, 1H),6.44 (m, 1H), 5.48 (dd, J =
10.5, 8.5 Hz, 1H), 4.94 (m, 1H), 3.80 (s, 3H), 3.06 (ddt, J = 15.2, 10.8,
2.3 Hz, 1H), 2.59 (ddt, J = 15.2, 8.4, 2.3 Hz, 1H); 13C NMR (CDCl3,
125 MHz): δ 160.0, 145.5, 144.9, 129.8, 118.0, 113.3, 111.3, 99.2 82.4,
55.4, 38.0.
2-(4-Methoxyphenyl)-2,3-dihydrofuran (3a).36 General Procedure
C was followed using 4-bromoanisole (0.125 mL, 1.00 mmol). The
crude product was purified by flash chromatography on silica gel using
a solvent gradient (0−3% EtOAc/hexanes) to give 3a (130 mg, 0.74
mmol, 74%) as a clear, light yellow oil. 1H NMR (CDCl3, 500 MHz):
δ 7.32 (m, 2H), 6.92 (m, 2H), 6.45 (dt, J = 2.6, 2.4 Hz, 1H), 5.49 (dd,
J = 10.6, 8.6 Hz, 1H), 4.97 (dt, J = 2.6, 2.5 Hz, 1H), 3.82 (s, 3H), 3.05
(ddt, J = 15.2, 10.6, 2.4 Hz, 1H), 2.63 (ddt, J = 15.2, 8.5, 2.3 Hz, 1H);
13C NMR (CDCl3, 125 MHz): δ 159.3, 145.4, 135.2, 127.2, 114.1,
1-(4-(2,3-Dihydrofuran-2-yl)phenyl)ethanone (3c).38 General Pro-
cedure D was followed using 4-bromoacetophenone (0.199 g, 1.00
mmol). The crude product was purified by flash chromatography on
silica gel using a solvent gradient (0−5% EtOAc/hexanes) to give 3c
(162 mg, 0.86 mmol, 86%) as a clear, colorless oil. 1H NMR (CDCl3,
500 MHz): δ 7.96 (m, 2H), 7.44 (m, 2H), 6.47 (dt, J = 2.6, 2.4 Hz,
1H), 5.57 (dd, J = 10.8, 8.2 Hz, 1H), 4.97 (dt, J = 2.6, 2.6 Hz, 1H),
99.2, 82.4, 55.4, 37.8.
H
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3.13 (ddt, J = 15.2, 8.5, 2.4 Hz, 1H), 2.60 (s, 3H), 2.57 (ddt, J = 15.2,
8.2, 2.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δ 197.7, 148.5, 145.4,
136.5, 128.7, 125.6, 99.1, 81.6, 37.9, 26.6.
cap and removed from the glovebox. To the vial were added methanol
(1 mL), aryl bromide (1 mmol, if a solid, the aryl bromide was added
prior to removing from glovebox), and 2,3-dihydrofuran (2.5−5.3
equiv). The vial was then placed in an oil bath preheated to 60−80 °C
for 2−12 h. After cooling to ambient temperature, the reaction mixture
was concentrated under reduced pressure and subjected to flash
chromatography on silica gel.
2-((4-Trifluoromethyl)phenyl)-2,3-dihydrofuran (3d).38 General
Procedure D was followed using 4-bromobenzotrifluoride (0.140
mL, 1.00 mmol). The crude product was purified by flash
chromatography on silica gel using a solvent gradient (0−0.5%
EtOAc/hexanes) to give 3d (125 mg, 0.58 mmol, 58%) as a clear,
2-(4-Methoxyphenyl)-2,5-dihydrofuran (4a).41 General Procedure
E was followed using 4-bromoanisole (0.125 mL, 1.00 mmol) and 2,3-
dihydrofuran (0.19 mL, 2.5 mmol). The reaction mixture was heated
to 60 °C for 2 h. The crude product was purified by flash
chromatography on silica gel using a solvent gradient (0−4%
EtOAc/hexanes) to give 4a (140 mg, 0.80 mmol, 80%) as a clear,
1
colorless oil. H NMR (CDCl3, 500 MHz): δ 7.63 (m, 2H), 7.48 (m,
2H), 6.47 (dt, J = 5.0, 2.4 Hz, 1H), 5.57 (dd, J = 10.8, 8.2 Hz, 1H),
4.97 (dt, J = 2.6, 2.5 Hz, 1H), 3.14 (ddt, J = 15.2, 10.8, 2.4 Hz, 1H),
2.57 (ddt, J = 15.2, 8.0, 2.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δ
147.4, 145.5, 130 (q, J = 32.4 Hz), 126.0, 125.7 (q, J = 3.9 Hz), 124.4
(q, J = 270 Hz), 99.2, 81.6, 38.1.
1
colorless oil. H NMR (CDCl3, 500 MHz): δ 7.22 (m, 2H), 6.88 (m,
4-(2,3-Dihydrofuran-2-yl)benzonitrile (3e). General Procedure D
was followed using 4-bromobenzonitrile (0.183 g, 1.00 mmol). The
crude product was purified by flash chromatography on silica gel using
a solvent gradient (0−3% EtOAc/hexanes) to give 3e (125 mg, 0.73
mmol, 73%) as a clear, light yellow oil. 1H NMR (CDCl3, 500 MHz):
δ 7.65 (m, 2H), 7.45 (m, 2H), 6.46 (dt, J = 2.6, 2.4 Hz, 1H), 5.56 (dd,
J = 10.9, 8.0 Hz, 1H), 4.97 (dt, J = 2.6, 2.5 Hz, 1H), 3.15 (ddt, J = 15.2,
11.0, 2.4 Hz, 1H), 2.53 (ddt, J = 15.2, 7.9, 2.4 Hz, 1H); 13C NMR
(CDCl3, 125 MHz): δ 148.7, 145.5, 132.6, 126.3, 119.0, 99.2, 81.4,
38.1; HRMS: m/z calcd for C11H9NO (M+) 171.0684, found
171.0680.
2H), 6.04 (m, 1H), 5.86 (m, 1H), 5.74 (m, 1H), 4.87−4.82 (m, 1H),
4.75−4.71 (m, 1H), 3.80 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ
159.6, 134.3, 130.2, 128.1, 126.9, 114.1, 87.7, 75.7, 55.5.
2-(3-Methoxyphenyl)-2,5-dihydrofuran (4b). General Procedure E
was followed using 3-bromoanisole (0.127 mL, 1.00 mmol) and 2,3-
dihydrofuran (0.19 mL, 2.5 mmol). The reaction mixture was heated
to 60 °C for 5 h. The crude product was purified by flash
chromatography on silica gel using a solvent gradient (0−4%
EtOAc/hexanes) to give 4b (132 mg, 0.74 mmol, 74%) as a clear,
colorless oil. 1H NMR (CDCl3, 500 MHz): δ 7.25 (dd, J = 7.8, 7.8 Hz,
1H), 6.89 (m, 1H), 6.86 (m, 1H), 6.80 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H),
6.01 (m, 1H), 5.88 (m, 1H), 5.76 (m, 1H), 4.88−4.84 (m, 1H), 4.78−
4.74 (m, 1H), 3.79 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 160.0,
143.9, 130.1, 129.7, 126.8, 118.8, 113.4, 112.0, 87.9, 76.0, 55.4; HRMS:
m/z calcd for C11H11O2 (M+) 175.0759, found 175.0753.
2-(3,5-Dimethylphenyl)-2,3-dihydrofuran (3f). General Procedure
D was followed using 1-bromo-3,5-dimethylbenzene (0.136 mL, 1.00
mmol). The crude product was purified by flash chromatography on
silica gel using a solvent gradient (0−1% EtOAc/hexanes) to give 3f
(108 mg, 0.62 mmol, 62%) as a clear, colorless oil. 1H NMR (CDCl3,
500 MHz): δ 6.99 (s, 2H), 6.94 (s, 1H), 6.45 (dt, J = 2.6, 2.4 Hz, 1H),
5.45 (dd, J = 10.6, 8.6 Hz, 1H), 4.96 (dt, J = 2.6, 2.5 Hz, 1H), 3.05
(ddt, J = 15.2, 10.7, 2.4 Hz, 1H), 2.61 (ddt, J = 15.2, 8.6, 2.3 Hz, 1H);
13C NMR (CDCl3, 125 MHz): δ 145.5, 143.1, 138.3, 129.5, 123.6,
99.3, 82.7, 38.0, 21.5; HRMS: m/z calcd for C12H14O (M+) 174.1045,
found 174.1052.
1-(4-(2,5-Dihydrofuran-2-yl)phenyl)ethanone (4c). General Pro-
cedure E was followed using 4-bromoacetophenone (0.199 g, 1.00
mmol) and 2,3-dihydrofuran (0.40 mL, 5.3 mmol). The reaction
mixture was heated to 80 °C for 5 h. The crude product was purified
by flash chromatography on silica gel using a solvent gradient (0−5%
EtOAc/hexanes) to give 4c (150 mg, 0.80 mmol, 80%) as a light
1
yellow solid. H NMR (CDCl3, 500 MHz): δ 7.92 (m, 2H), 6.38 (m,
2-(o-Tolyl)-2,3-dihydrofuran (3g).39 A slight modification of
General Procedure D was followed using 2-bromotoluene (0.183 g,
1.00 mmol). The reaction was performed at 80 °C for 5 h. The crude
product was purified by flash chromatography on silica gel using a
solvent gradient (0−1% EtOAc/hexanes) to give 3g (57 mg, 0.35
2H), 6.04 (m, 1H), 5.87 (m, 1H), 5.82 (m, 1H), 4.90−4.86 (m, 1H),
4.80−4.76 (m, 1H), 2.57 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ
197.8, 147.5, 136.6, 129.4, 128.7, 127.1, 126.3, 87.3, 76.1, 26.6; HRMS:
m/z calcd for C12H12O2 (M+) 188.0837, found 188.0841.
2-((4-Trifluoromethyl)phenyl)-2,5-dihydrofuran (4d). General
Procedure E was followed using 4-bromobenzotrifluoride (0.140 mL,
1.00 mmol) and 2,3-dihydrofuran (0.40 mL, 5.3 mmol). The reaction
mixture was heated to 80 °C for 7 h. The crude product was purified
by flash chromatography on silica gel using a solvent gradient (0−1%
EtOAc/hexanes) to give 4d (141 mg, 0.66 mmol, 66%) as a clear, light
1
mmol, 35%) as a clear, colorless oil. H NMR (CDCl3, 500 MHz): δ
7.40 (m, 1H), 7.22−7.14 (m, 3H), 6.48 (dt, J = 2.6, 2.4 Hz, 1H), 5.68
(dd, J = 10.8, 8.6 Hz, 1H), 4.93 (dt, J = 2.6, 2.5 Hz, 1H), 3.10 (ddt, J =
15.0, 10.8, 2.4 Hz, 1H), 2.45 (ddt, J = 15.0, 8.5, 2.3 Hz, 1H), 2.31 (s,
3H); 13C NMR (CDCl3, 125 MHz): δ 145.5, 141.3, 134.2, 130.6,
127.5, 126.3, 124.9, 99.0, 80.2, 37.1, 19.4.
1
yellow oil. H NMR (CDCl3, 500 MHz): δ 7.60 (m, 2H), 7.42 (m,
2H), 6.06 (m, 1H), 5.88 (m, 1H), 5.84 (m, 1H), 4.89 (m, 1H), 4.80
(m, 1H); 13C NMR (CDCl3, 125 MHz): δ 146.4, 130.2 (q, J = 32.4
Hz), 129.6, 127.4, 126.7, 125.7 (q, J = 3.8 Hz), 124.4 (q, J = 270 Hz),
87.4, 76.3; HRMS: m/z calcd for C11H9OF3 (M+) 214.0605, found
214.0602.
2-(Thiophen-3-yl)-2,3-dihydrofuran (3h). General Procedure D
was followed using 3-bromothiophene (0.094 mL, 1.00 mmol). The
crude product was purified by flash chromatography on silica gel using
hexanes to give 3h (101 mg, 0.67 mmol, 67%) as a clear, colorless oil.
1H NMR (CDCl3, 500 MHz): δ 7.30 (dd, J = 5.0, 3.0 Hz, 1H), 7.22
4-(2,5-Dihydrofuran-2-yl)benzonitrile (4e). General Procedure E
was followed using 4-bromobenzonitrile (0.183 g, 1.00 mmol) and 2,3-
dihydrofuran (0.40 mL, 5.3 mmol). The reaction mixture was heated
to 80 °C for 12 h. The crude product was purified by flash
chromatography on silica gel using a solvent gradient (3−6% EtOAc/
hexanes) to give 4e (103 mg, 0.60 mmol, 60%) as a clear, colorless oil,
(m, 1H), 7.09 (dd, J = 5.0, 1.2 Hz, 1H), 6.39 (m, 1H), 5.57 (dd, J =
10.5, 8.1 Hz, 1H), 4.95 (m, 1H), 3.01 (ddt, J = 15.1, 10.5, 2.4 Hz, 1H),
2.64 (ddt, J = 15.1, 8.1, 2.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δ
145.2, 143.9, 126.5, 125.7, 121.2, 99.2, 78.8, 36.9; HRMS: m/z calcd
for C8H8OS (M+) 152.0296, found 152.0297.
2-(4-Chlorophenyl)-2,3-dihydrofuran (3i).40 General Procedure D
was followed using 1-bromo-4-chlorobenzene (0.116 g, 1.00 mmol).
The crude product was purified by flash chromatography on silica gel
using hexanes to give 3i (116 mg, 0.64 mmol, 64%) as a clear, colorless
oil. 1H NMR (CDCl3, 500 MHz): δ 7.32−7.27 (m, 4H), 6.42 (m, 1H),
5.47 (dd, J = 10.7, 8.2 Hz, 1H), 4.94 (m, 1H), 3.06 (ddt, J = 15.2, 10.8,
2.4 Hz, 1H), 2.54 (ddt, J = 15.2, 8.2, 2.4 Hz, 1H); 13C NMR (CDCl3,
125 MHz): δ 145.4, 141.7, 133.4, 128.8, 127.1, 99.1, 81.7, 38.0.
General Procedure E - Synthesis of 2,5-Dihydrofurans (4)
(Table 6, Conditions B and C). To a 4 mL borosilicate glass vial
were added Pd2(dba)3 (1.5 mol %, 13.7 mg, 0.015 mmol), TNpP (6
mol %, 14.7 mg; 0.06 mmol), and potassium acetate (1.5 equiv, 0.150
g; 1.5 mmol) inside a glovebox. The vial was fitted with a septa screw
1
which solidified to a white solid upon sitting. H NMR (CDCl3, 500
MHz): δ 7.63 (m, 2H), 7.41 (m, 2H), 6.10 (m, 1H), 5.88−5.82 (m,
2H), 4.89 (m, 1H), 4.82 (m, 1H); 13C NMR (CDCl3, 125 MHz): δ
147.7, 132.6, 129.2, 127.7, 127.0, 119.0, 111.7, 87.3, 76.4; HRMS: m/z
calcd for C11H9NO (M+) 171.0684, found 171.0680.
2-(3,5-Dimethylphenyl)-2,5-dihydrofuran (4f). General Procedure
E was followed using 1-bromo-3,5-dimethylbenzene (0.136 mL, 1.00
mmol) and 2,3-dihydrofuran (0.19 mL, 2.5 mmol). The reaction
mixture was heated to 60 °C for 2 h. The crude product was purified
by flash chromatography on silica gel using a solvent gradient (0−3%
EtOAc/hexanes) to give 4f (125 mg, 0.72 mmol, 72%) as a clear, light
1
yellow oil. H NMR (CDCl3, 500 MHz): δ 6.91 (m, 3H), 6.00 (m,
I
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1H), 5.86 (m, 1H), 5.72 (m, 1H), 4.88−4.83 (m, 1H), 4.76−4.72 (m,
1H), 2.30 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ 142.1, 138.2,
130.2, 129.6, 126.6, 124.3, 88.1, 75.9, 21.4; HRMS: m/z calcd for
C12H14O (M+) 174.1045, found 174.1049.
chromatography on silica gel using a solvent gradient (0−0.5%
EtOAc/hexanes) to give 5c (126 mg, 0.64 mmol, 64%) as a clear, light
yellow oil, which solidified to a white solid upon sitting. H NMR
1
(CDCl3, 500 MHz): δ 7.08 (dd, J = 8.6, 2.5 Hz, 1H), 6.92 (d, J = 2.5
Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 5.92 (m, 1H), 5.07 (m, 1H), 2.26−
2.15 (m, 4H); 13C NMR (CDCl3, 125 MHz): δ 148.9, 128.8, 128.7,
124.9, 124.5, 117.7, 100.7, 77.0, 35.7, 33.5; HRMS: m/z calcd for
C10H9O2Cl (M+) 196.0291, found 196.0295.
7-Fluoro-2,3,4,5-tetrahydro-2,5-epoxybenzo[b]oxepine (5d).
General Procedure F was followed using 2-bromo-4-fluorophenol
(191 mg, 1.00 mmol). The crude product was purified by flash
chromatography on silica gel eluted with 25% CH2Cl2/hexanes to give
5d (106 mg, 0.59 mmol, 59%) as a clear, colorless oil, which solidified
to a white solid upon sitting. 1H NMR (CDCl3, 500 MHz): δ 6.83 (dt,
J = 8.7, 3.0 Hz, 1H), 6.70−6.66 (m, 2H), 5.92 (m, 1H), 5.07 (m, 1H),
2.26−2.16 (m, 4H); 13C NMR (CDCl3, 125 MHz): δ 156.6 (d, J =
237.6 Hz), 146.1 (d, J = 1.6 Hz), 128.2 (d, J = 6.8 Hz), 117.2 (d, J =
7.9 Hz), 115.3 (d, J = 22.9 Hz), 111.2 (d, J = 23.6 Hz), 100.5, 77.0,
35.8, 33.3; HRMS: m/z calcd for C10H9FO2 (M+) 180.0594, found
180.0585.
1-(2,3,4,5-Tetrahydro-1H-2,5-epoxybenzo[b]azepin-1-yl)ethan-1-
one (5f). General Procedure F was followed using 2′-bromo-
acetanilide35 (214 mg, 1.00 mmol). The crude product was purified
by flash chromatography on silica gel eluted with CH2Cl2 to give 5f
(58 mg, 0.28 mmol, 28%) as a cloudy white oil. 1H NMR (CDCl3, 500
MHz): δ 8.04 (br s, 1H), 7.22(ddd, J = 8.4, 6.8, 2.2 Hz, 1H) 7.05−7.00
(m, 2H), 6.28 (br s, 1H), 5.13 (d, J = 6.2 Hz, 1H), 2.40−2.34 (m, 4H),
2.26−2.16 (m, 1H), 2.11−2.05 (m, 2H); 13C NMR (CDCl3, 125
MHz): δ 169.2, 134.7, 130.7, 127.9, 124.4, 123.9, 122.7, 86.4, 78.7,
36.1, 32.2, 24.7; HRMS: m/z calcd for C12H13NO2 (M+) 203.0946,
found 203.0946.
1-Tosyl-2,3,4,5-tetrahydro-1H-2,5-epoxybenzo[b]azepine (5g).
General Procedure F was followed using N-(2-bromophenyl)-4-
methylbenzenesulfonamide36 (326 mg, 1.00 mmol). The crude
product was purified by flash chromatography on silica gel eluted
with 50% CH2Cl2/hexanes to give 5g (169 mg, 0.53 mmol, 53%) as a
white solid. 1H NMR (CDCl3, 500 MHz): δ 7.86 (d, J = 8.4 Hz, 1H),
7.58 (m, 2H) 7.20 (m, 1H), 7.14 (m, 2H), 7.03 (ddd, J = 7.5, 7.4, 1.0
Hz, 1H), 6.87 (dd, J = 7.5, 1.4 Hz, 1H), 6.47 (m, 1H), 4.87 (m, 1H),
2.43−2.35 (m, 1H), 2.33 (s, 3H), 2.13−1.97 (m, 3H); 13C NMR
(CDCl3, 125 MHz): δ 143.9, 135.7, 133.3, 131.0, 129.4, 128.1, 127.9,
124.9, 124.7, 123.2, 87.8, 77.7, 36.9, 31.4, 21.7; HRMS: m/z calcd for
C17H17NO3S (M+) 315.0929, found 315.0922.
2-(o-Tolyl)-2,5-dihydrofuran (4g).42 General Procedure E was
followed using 2-bromotoluene (0.120 mL, 1.00 mmol) and 2,3-
dihydrofuran (0.40 mL, 5.3 mmol). The reaction mixture was heated
to 80 °C for 5 h. The crude product was purified by flash
chromatography on silica gel using a solvent gradient (0−2%
EtOAc/hexanes) to give 4g (112 mg, 0.70 mmol, 70%) as a clear,
light yellow oil. 1H NMR (CDCl3, 500 MHz): δ 7.29 (m, 1H), 7.19−
7.12 (m, 3H), 6.03−5.98 (m, 2H), 5.90 (m, 1H), 4.87−4.83 (m, 1H),
4.78−4.74 (m, 1H), 2.38 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ
140.1, 135.2, 130.5,129.2, 127.7, 126.9, 126.33, 126.30, 85.2, 75.7, 19.1.
2-(Thiophen-3-yl)-2,5-dihydrofuran (4h). General Procedure E was
followed using 3-bromothiophene (0.094 mL, 1.00 mmol) and 2,3-
dihydrofuran (0.40 mL, 5.3 mmol). The reaction mixture was heated
to 80 °C for 17 h. The crude product was purified by flash
chromatography on silica gel using a solvent gradient (20−40%
CH2Cl2/hexanes) to give 4h (97 mg, 0.63 mmol, 63%) as a clear, light
1
yellow oil. H NMR (CDCl3, 500 MHz): δ 7.29 (dd, J = 5.0, 3.0 Hz,
1H), 7.20 (m, 1H), 7.02 (dd, J = 5.0, 1.2 Hz, 1H), 6.04 (m, 1H), 5.91
(m, 1H), 5.88 (m, 1H), 4.82 (m, 1H), 4.72 (m, 1H); 13C NMR
(CDCl3, 125 MHz): δ 143.5, 129.3, 127.1, 126.3, 126.2, 121.8, 83.6,
75.4; HRMS: m/z calcd for C8H8OS (M+) 152.0296, found 152.0291.
2-(4-Chlorophenyl)-2,3-dihydrofuran (4i).10b General Procedure E
was followed using 1-bromo-4-chlorobenzene (0.116 g, 1.00 mmol)
and 2,3-dihydrofuran (0.40 mL, 5.3 mmol). The reaction mixture was
heated to 80 °C for 17 h. The crude product was purified by flash
chromatography on silica gel using a solvent gradient (0−1% EtOAc/
hexanes) to give 4i (165 mg, 0.91 mmol, 91%) as a clear, light yellow
1
oil. H NMR (CDCl3, 500 MHz): δ 7.31−7.29 (m, 2H), 7.25−7.22
(m, 2H), 6.03 (m, 1H), 5.83 (m, 1H), 5.75 (m, 1H), 4.87−4.82 (m,
1H), 4.77−4.73 (m, 1H); 13C NMR (CDCl3, 125 MHz): δ 140.7,
133.6, 129.7, 128.7, 127.9, 127.1, 87.2, 75.9.
General Procedure F - The Synthesis of Product 5 (Table 8).
To a 4 mL borosilicate glass vial were added Pd(dba)2 (2 mol %, 11.5
mg, 0.02 mmol) and DTBNpP·HBF4 (4 mol %, 12.2 mg; 0.04 mmol)
inside a glovebox. The vial was fitted with a septa screw cap and
removed from the glovebox. To the vial were added acetone (1 mL),
aryl bromide (1 mmol, if a solid, the aryl bromide was added prior to
removing from the glovebox), 2,3-DHF (2.6 equiv, 0.20 mL, 2.6
mmol), 2-propanol (0.5 equiv, 0.038 mL, 0.5 mmol), and DIPEA (1.0
equiv, 0.175 mL; 1.0 mmol). The vial was then stirred at 80 °C for 24
h. After cooling to ambient temperature, the reaction mixture was
concentrated under reduced pressure and subjected to flash
chromatography on silica gel.
General Procedure G - Heck Reaction with Cyclopentene To
Produce 6 (Table 9, Conditions B). To a pressure tube were added
Pd(dba)2 (5 mol %, 28.8 mg, 0.05 mmol), TNpP (10 mol %, 24.4 mg;
0.10 mmol), and potassium acetate (1.5 equiv, 0.15 g, 1.5 mmol)
inside a glovebox. The tube was fitted with a Teflon screw cap and
removed from the glovebox. To the tube were added methanol (1
mL), aryl bromide (1 mmol, if a solid, the aryl bromide was added
prior to removing from the glovebox), and cyclopentene (4 equiv, 0.36
mL, 4 mmol) under a positive pressure of N2. The reaction mixture
was then stirred at 80 °C for 24 h. After cooling to ambient
temperature, the reaction mixture was concentrated under reduced
pressure and subjected to flash chromatography on silica gel.
1-(Cyclopent-2-en-1-yl)-4-methoxybenzene (6a).16 General Pro-
cedure G was followed using 4-bromoanisole (0.125 mL, 1.00 mmol).
The crude product was purified by flash chromatography on silica gel
eluted with hexanes to give 6a and 7a as a (68:10) mixture: (135 mg,
2,3,4,5-Tetrahydro-2,5-epoxybenzo[b]oxepine (5a).43 General
Procedure F was followed using 2-bromophenol (0.116 mL, 1.00
mmol). The crude product was purified by flash chromatography on
silica gel using a solvent gradient (20−30% CH2Cl2/hexanes) to give
1
5a (97 mg, 0.60 mmol, 60%) as a clear, light yellow oil. H NMR
(CDCl3, 500 MHz): δ 7.15 (dt, J = 8.0, 1.6 Hz, 1H), 6.95 (dd, J = 7.4,
1.5 Hz, 1H), 6.84 (dd, J = 7.4, 1.0 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H),
5.94 (m, 1H), 5.13 (m, 1H), 2.31−2.17 (m, 4H); 13C NMR (CDCl3,
125 MHz): δ 150.2, 128.9, 127.5, 124.6, 120.2, 116.3, 100.6, 77.4, 35.9,
33.6.
7-Methoxy-2,3,4,5-tetrahydro-2,5-epoxybenzo[b]oxepine (5b).
General Procedure F was followed using 2-bromo-4-methoxyphenol
(203 mg, 1.00 mmol). The crude product was purified by flash
chromatography on silica gel using a solvent gradient (0−1% EtOAc/
hexanes) to give 5b (97 mg, 0.60 mmol, 60%) as a clear, light yellow
1
0.78 mmol, 78%) as a clear, colorless oil. 6a: H NMR (CDCl3, 500
MHz): δ 7.08 (m, 2H), 6.82 (m, 2H) 5.90 (m, 1H), 5.74 (m, 1H),
3.83 (m, 1H), 3.75 (s, 3H), 2.50−2.43 (m, 1H), 2.40−2.33 (m, 2H),
1.67 (m, 1H); 13C NMR (CDCl3, 125 MHz): δ 158.0, 138.7, 134.7,
131.6, 128.1, 113.9, 55.3, 50.6, 34.0, 32.5.
1
oil. H NMR (CDCl3, 500 MHz): δ 6.71−6.67 (m, 2H), 6.51 (d, J =
2.6 Hz, 1H), 5.91 (m, 1H), 5.06 (m, 1H), 3.73 (s, 3H), 2.25−2.16 (m,
4H); 13C NMR (CDCl3, 125 MHz): δ 153.3, 143.9, 127.9, 116.9,
114.2, 110.2, 100.5, 77.3, 55.9, 35.9, 33.2; HRMS: m/z calcd for
C11H12O3 (M+) 192.0786, found 192.0789.
1-(4-(Cyclopent-2-en-1-yl)phenyl)ethan-1-one (6b).16 General
Procedure G was followed using 4-bromoacetophenone (199 mg,
1.00 mmol). The crude product was purified by flash chromatography
on silica gel using a solvent gradient (0−2% EtOAc/hexanes) to give
6b and 7b as a (83:8) mixture: (169 mg, 0.91 mmol, 91%) as a yellow
7-Chloro-2,3,4,5-tetrahydro-2,5-epoxybenzo[b]oxepine (5c).
General Procedure F was followed using 2-bromo-4-chlorophenol
(208 mg, 1.00 mmol). The crude product was purified by flash
1
oil. 6b: H NMR (CDCl3, 500 MHz): δ 7.88 (m, 2H), 7.26 (m, 2H)
J
dx.doi.org/10.1021/jo501840u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
5.97 (m, 1H), 5.75 (m, 1H), 3.94 (m, 1H), 2.56 (s, 3H), 2.51−2.40
(m, 3H), 1.74−1.68 (m, 1H); 13C NMR (CDCl3, 125 MHz): δ 197.8,
152.3, 135.4, 133.5, 132.8, 128.7, 127.5, 51.4, 33.7, 32.6, 26.6.
4-(Cyclopent-2-en-1-yl)benzonitrile (6c).44 General Procedure G
was followed using 4-bromobenzonitrile (182 mg, 1.00 mmol). The
crude product was purified by flash chromatography on silica gel using
a solvent gradient (0−2% EtOAc/hexanes) to give 6c and 7c as a
(83:8) mixture: (169 mg, 0.91 mmol, 91%) as a light yellow oil. 6c: 1H
NMR (CDCl3, 500 MHz): δ 7.56 (m, 2H), 7.29 (m, 2H) 6.01 (m,
1H), 5.73 (m, 1H), 3.94 (m, 1H), 2.54−2.40 (m, 3H), 1.72−1.66 (m,
1H); 13C NMR (CDCl3, 125 MHz): δ 152.3, 133.5, 133.0, 132.4,
128.2, 119.3, 110.0, 51.6, 33.7, 32.6.
(CDCl3, 125 MHz): δ 141.32, 141.26, 132.2, 130.8, 126.1, 119.3,
110.0, 33.7, 33.0, 23.3.
2-(Cyclopent-1-en-1-yl)phenol (8d).45 General Procedure H was
followed using 2-bromophenol (0.116 mL, 1.00 mmol). The crude
product was purified by flash chromatography on silica gel using a
solvent gradient (0−2% EtOAc/hexanes) and a second column eluted
with CH2Cl2 to give 8d: (146 mg, 0.91 mmol, 91%) as a light brown
1
solid. H NMR (CDCl3, 500 MHz): δ 7.20 (dd, J = 3.8, 1.5 Hz, 1H),
7.15 (m, 1H) 6.94−6.91 (m, 2H), 6.15 (m, 1H), 5.68 (s, 1H), 2.75 (m,
2H), 2.62 (m, 2H), 2.03 (pent, J = 7.7 Hz, 2H); 13C NMR (CDCl3,
125 MHz): δ 153.1, 140.2, 129.3, 128.3, 128.1, 124.2, 120.5, 115.7,
36.3, 34.1, 23.1.
N-(2-(Cyclopent-1-en-1-yl)phenyl)acetamide (8e).46 General Pro-
cedure H was followed using 2′-bromoacetanilide35 (214 mg, 1.00
mmol). The crude product was purified by flash chromatography on
silica gel using a solvent gradient (10−20% EtOAc/hexanes to give 8e:
2-(Cyclopent-2-en-1-yl)phenol (6d).45 General Procedure G was
followed using 2-bromophenol (116 mL, 1.00 mmol). The crude
product was purified by flash chromatography on silica gel using a
solvent gradient (0−1% EtOAc/hexanes) to give 6d and 7d as a
(67:4) mixture: (114 mg, 0.71 mmol, 71%) as a clear colorless oil. 6d:
1H NMR (CDCl3, 500 MHz): δ 7.56 (m, 2H), 7.15−7.11 (m, 2H)
1
(116 mg, 0.57 mmol, 57%) as a white solid. H NMR (CDCl3, 500
MHz): δ 8.18 (d, J = 8.2 Hz, 1H), 7.57 (br s, 1H) 7.22 (t, J = 7.3 Hz,
1H), 7.18 (d, J = 7.4 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 5.90 (m, 1H),
2.67 (m, 2H), 2.58 (m, 2H), 2.14 (s, 3H), 2.02 (m, 2H); 13C NMR
(CDCl3, 125 MHz): δ 168.2, 141.0, 134.8, 130.4, 128.6, 127.9, 127.8,
124.1, 121.5, 36.9, 34.0, 24.9, 23.5.
6.89 (dt, J = 7.5, 1.0 Hz, 1H), 6.82 (dd, J = 7.9, 0.6 Hz, 1H), 6.10 (m,
1H), 5.92 (m, 1H), 5.31 (br s, 1H), 4.11−4.06 (m, 1H), 2.63−2.55
(m, 1H), 2.53−2.43 (m, 2H), 1.86−1.78 (m, 1H); 13C NMR (CDCl3,
125 MHz): δ 154.3, 134.4, 133.5, 130.9, 129.0, 127.7, 120.8, 116.2,
47.2, 32.9, 31.7.
ASSOCIATED CONTENT
N-(2-(Cyclopent-2-en-1-yl)phenyl)acetamide (6e).46 General Pro-
cedure G was followed using 2′-bromoacetanilide35 (214 mg, 1.00
mmol). The crude product was purified by flash chromatography on
silica gel using a solvent gradient (15−25% EtOAc/hexanes) to give 6e
and 7e as a (73:18) mixture: (183 mg, 0.91 mmol, 91%) as a white
solid. 6e: 1H NMR (CDCl3, 500 MHz): δ 7.77 (br s, 1H), 7.65 (d, J =
7.6 Hz, 1H) 7.17−7.13 (m, 2H), 7.08 (m, 1H), 6.00 (m, 1H), 5.76 (m,
1H), 4.00 (m, 1H), 2.53−2.34 (m, 3H), 2.08 (s, 3H), 2.08 (s,3H),
1.71−1.64 (m, 1H); 13C NMR (CDCl3, 125 MHz): δ 168.8, 137.4,
135.3, 133.6, 133.0, 128.3, 126.9, 125.6, 124.8, 47.6, 32.7, 31.7, 24.1.
General Procedure H - Heck Reaction with Cyclopentene To
Produce 8 (Table 9, Conditions C). To a pressure tube were added
Pd(dba)2 (5 mol %, 28.8 mg, 0.05 mmol) and DTBNpP·HBF4 (10
mol %, 30.4 mg; 0.10 mmol) inside a glovebox. The vial was fitted with
a septa screw cap and removed from the glovebox. To the vial were
added acetone (1 mL), aryl bromide (1 mmol, if a solid, the aryl
bromide was added prior to removing from the glovebox),
cyclopentene (4 equiv, 0.36 mL, 4 mmol), and DIPEA (1.0 equiv,
0.18 mL, 1.0 mmol). The vial was then stirred at 80 °C for 17 h. After
cooling to ambient temperature, the reaction mixture was concen-
trated under reduced pressure and subjected to flash chromatography
on silica gel.
■
S
* Supporting Information
1H and 13C NMR spectra for all products in Tables 2, 3, 4, 6, 8,
and 9. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kshaughn@ua.edu (K.H.S.).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1058984)
for financial support of this work, FMC, Lithium Division for
donation of DTBNpP and TNpP, and Johnson-Matthey for
donation of palladium compounds.
REFERENCES
■
(1) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 45,
581.
1-(Cyclopent-1-en-1-yl)-4-methoxybenzene (8a).47 General Pro-
cedure H was followed using 4-bromoanisole (0.125 mL, 1.00 mmol).
The crude product was purified by flash chromatography on silica gel
eluted with hexanes to give 8a: (163 mg, 0.93 mmol, 93%) as a white
(2) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320−2322.
(3) (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146−151.
(b) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009−
3066. (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4442−4489. (d) Magano, J.; Dunetz, J. Chem. Rev. 2011,
111, 2177−2250. (e) Ruan, J.; Xiao, J. Acc. Chem. Res. 2011, 44, 614−
626.
(4) Fall, Y.; Berthiol, F.; Doucet, H.; Santelli, M. Synthesis 2007,
1683−1686.
(5) (a) Abelman, M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52,
4130−4133. (b) Grigg, R.; Loganathan, V.; Santhakumar, V.;
Sridharan, V.; Teasdale, A. Tetrahedron Lett. 1991, 32, 687−690.
(6) Wu, X.; Lu, Y.; Hirao, H.; Zhou, J. Chem.Eur. J. 2013, 19,
6014−6020.
1
solid. H NMR (CDCl3, 500 MHz): δ 7.35 (m, 2H), 6.83 (m, 2H)
6.03 (m, 1H), 3.77 (s, 3H), 2.66 (m, 2H), 2.49 (m, 2H), 1.99 (m,
2H); 13C NMR (CDCl3, 125 MHz): δ 158.8, 142.0, 129.9, 126.9,
124.0, 113.8, 55.4, 33.50, 33.48, 23.6.
1-(4-(Cyclopent-1-en-1-yl)phenyl)ethan-1-one (8b).48 General
Procedure H was followed using 4-bromoacetophenone (199 mg,
1.00 mmol). The crude product was purified by flash chromatography
on silica gel using a solvent gradient (0−1% EtOAc/hexanes) to give
8b: (178 mg, 0.95 mmol, 95%) as a white solid. 1H NMR (CDCl3, 500
MHz): δ 7.90 (m, 2H), 7.49 (m, 2H) 6.34 (m, 1H), 2.72 (m, 2H),
2.58 (s, 3H), 2.56 (m, 2H), 2.04 (m, 2H); 13C NMR (CDCl3, 125
MHz): δ 197.7, 142.0, 141.6, 135.6, 129.8, 128.7, 125.8, 33.8, 33.2,
26.7, 23.5.
(7) (a) Wheatley, B. M. M.; Keay, B. A. J. Org. Chem. 2007, 72,
7253−7259. (b) Kochi, T.; Hamasaki, T.; Aoyama, Y.; Kawasaki, J.;
Kakiuchi, F. J. Am. Chem. Soc. 2012, 134, 16544−16547. (c) Mei, T.-
S.; Patel, H. H.; Sigman, M. S. Nature 2014, 508, 340−344.
4-(Cyclopent-1-en-1-yl)benzonitrile (8c).44 General Procedure H
was followed using 4-bromobenzonitrile (182 mg, 1.00 mmol). The
crude product was purified by flash chromatography on silica gel using
a solvent gradient (0−1% EtOAc/hexanes) and a second column
eluted with CH2Cl2 to give 8c: (139 mg, 0.82 mmol, 82%) as a white
(8) Hartung, C. G.; Kohler, K.; Beller, M. Org. Lett. 1999, 1, 709−
̈
711.
(9) Wu, X.; Zhou, J. Chem. Commun. 2013, 49, 4794−4796.
(10) (a) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc.
Chem. Res. 2003, 36, 659−667. (b) Hu, J.; Lu, Y.; Li, Y.; Zhou, J.
1
solid. H NMR (CDCl3, 500 MHz): δ 7.56 (m, 2H), 7.47 (m, 2H)
6.35 (m, 1H), 2.69 (m, 2H), 2.56 (m, 2H), 2.04 (m, 2H); 13C NMR
K
dx.doi.org/10.1021/jo501840u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Chem. Commun. 2013, 49, 9425−9427. (c) Rubina, M.; Sherrill, W.
M.; Barkov, A. Y.; Rubin, M. Beilstein J. Org. Chem. 2014, 10, 1536−
1548.
Vishwakarma, R. A.; Sivaramakrishnan, H. Bioorg. Med. Chem. Lett.
2011, 21, 3784−3787.
(35) Rahaim, R. J., Jr.; Maleczka, R. E., Jr. Org. Lett. 2011, 13, 584−
587.
(11) Kaganovsky, L.; Cho, K.-B.; Gelman, D. Organometallics 2008,
(36) Schmidt, B.; Geißler, D. Eur. J. Org. Chem. 2011, 4814−4822.
(37) Schmidt, B. J. Org. Chem. 2004, 69, 7672−7687.
(38) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989−7000.
(39) Penn, L.; Shpruhman, A.; Gelman, D. J. Org. Chem. 2007, 72,
3875−3879.
27, 5139−5145.
(12) (a) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44,
366−374. (b) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555−1565.
(c) Fleckenstein, C. A.; Plenio, H. Chem. Soc. Rev. 2010, 39, 694−711.
(d) Li, H.; Johansson Seechurn, C. C. C.; Colacot, T. J. ACS Catal.
2012, 2, 1147−1164.
(40) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113,
1417−1419.
(13) (a) Hill, L. L.; Moore, L. R.; Huang, R.; Craciun, R.; Vincent, A.
J.; Dixon, D. A.; Chou, J.; Woltermann, C. J.; Shaughnessy, K. H. J.
Org. Chem. 2006, 71, 5117−5125. (b) Hill, L. L.; Smith, J. M.; Brown,
W. S.; Moore, L. R.; Guevara, P.; Pair, E. S.; Porter, J.; Chou, J.;
Woltermann, C. J.; Craciun, R.; Dixon, D. A.; Shaughnessy, K. H.
Tetrahedron 2008, 64, 6920−6934. (c) Hill, L. L.; Crowell, J. L.;
Tutwiler, S. L.; Massie, N. L.; Hines, C. C.; Griffin, S. T.; Rogers, R.
D.; Shaughnessy, K. H.; Grasa, G. A.; Johansson Seechurn, C. C. C.;
Li, H.; Colacot, T. J.; Chou, J.; Woltermann, C. J. J. Org. Chem. 2010,
75, 6477−6488. (d) Raders, S. M.; Jones, J. M.; Kelley, S. P.; Rogers,
R. D.; Shaughnessy, K. H. Eur. J. Org. Chem. 2014, DOI: 10.1002/
ejoc.201402474.
(41) Machado, A. H. L.; de Sousa, M. A.; Patto, D. C. S.; Azevedo, L.
F. S.; Bombonato, F. I.; Correia, C. R. D. Tetrahedron Lett. 2009, 50,
1222−1225.
(42) Wang, Y.; Zheng, K.; Hong, R. J. Am. Chem. Soc. 2014, 134,
4096−4099.
(43) Crich, D.; Patel, M. Org. Lett. 2005, 7, 3625−3628.
(44) Zhu, M.-K.; Zhao, J.-F.; Loh, T.-P. Org. Lett. 2011, 13, 6308−
6311.
(45) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell, W. L.;
̌
́
Kocovsky, P. J. Org. Chem. 1999, 64, 2751−2764.
(46) Gataullin, R. R.; Nasyrov, M. F.; D’yachenko, D. I.; Fatykhov, A.
A.; Shitikova, O. V.; Spirikhin, L. V.; Abdrakhmanov, I. B. Russ. Chem.
Bull. 2002, 51, 124−127.
(14) Raders, S. M.; Moore, J. N.; Parks, J. K.; Miller, A. D.; Leißing,
T. M.; Kelley, S. P.; Rogers, R. D.; Shaughnessy, K. H. J. Org. Chem.
2013, 78, 4649−4664.
(47) Han, X.; Zhang, Y.; Wu, J. J. Am. Chem. Soc. 2010, 132, 4104−
4106.
(15) (a) McDonald, L. A.; Abbanat, D. R.; Barbieri, L. R.; Bernan, V.
S.; Discafani, C. M.; Greenstein, M.; Janota, K.; Korshalla, J. D.;
Lassota, P.; Tischler, M.; Carter, G. T. Tetrahedron Lett. 1999, 40,
2489−2492. (b) Wang, T.; Shirota, O.; Nakanishi, K.; Berova, N.;
McDonald, L. A.; Barbieri, L. R.; Carter, G. T. Can. J. Chem. 2001, 79,
1786−1791.
(48) Djakovitch, L.; Wagner, M.; Hartung, C. G.; Beller, M.; Koehler,
K. J. Mol. Catal. A: Chem. 2004, 219, 121−130.
́
(16) Kerti, G.; Kurtan, T.; Antus, S. ARKIVOC 2009, (vi), 103−110.
(17) Holzapfel, C. W.; Williams, D. B. G. Synth. Commun. 1994, 24,
2139−2146.
(18) Zou, Y.; Hamann, M. T. Org. Lett. 2013, 15, 1516−1519.
(19) Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.;
Skrydstrup, T. J. Am. Chem. Soc. 2010, 132, 7998−8009.
(20) Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 13178−
13179.
(21) Li, H.; Grasa, G. A.; Colacot, T. J. Org. Lett. 2010, 12, 3332−
3335.
́
(22) Cho, G. Y.; Remy, P.; Jansson, J.; Moessner, C.; Bolm, C. Org.
Lett. 2004, 6, 3293−3296.
(23) Krolski, M. E.; Renaldo, A. F.; Rudisill, D. E.; Stille, J. K. J. Org.
Chem. 1988, 53, 1170−1176.
(24) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnett, J. J.; Ibers, J. A. J.
Organomet. Chem. 1974, 65, 253−266.
(25) Cong, M.; Fan, Y.; Raimundo, J.-M.; Tang, J.; Peng, L. Org. Lett.
2014, 16, 4074−4077.
(26) Lipshutz, B. H.; Ghorai, S.; Leong, W. W. Y.; Taft, B. R.;
Krogstad, D. V. J. Org. Chem. 2011, 76, 5061−5073.
(27) Claridge, T. D. W.; Davies, S. G.; Lee, J. A.; Nicholson, R. L.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Toms, S. M. Org. Lett.
2008, 10, 5437−5440.
(28) Yan, H.; Sun, P.; Qu, X.; Lu, L.; Zhu, Y.; Yang, H.; Mao, J. Synth.
Commun. 2013, 43, 2773−2783.
(29) Schabel, T.; Belger, C.; Plietker, B. Org. Lett. 2013, 13, 2858−
2861.
(30) Moncomble, A.; Le Floch, P.; Lledos, A.; Gosmimi, C. J. Org.
Chem. 2012, 77, 5056−5062.
(31) Patureau, F.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9982−
9983.
(32) Yang, F.-L.; Ma, X.-T.; Tian, S.-K. Chem.Eur. J. 2012, 18,
1582−1585.
(33) Penafiel, I.; Pastor, I. M.; Yus, M.; Esteruelas, M. A.; Olivan
́
, M.
̃
Organometallics 2012, 31, 6154−6161.
(34) Dhuru, S.; Bhedi, D.; Gophane, D.; Hirbhagat, K.; Nadar, V.;
More, D.; Parikh, S.; Dalal, R.; Fonseca, L. C.; Kharas, F.; Vadnal, P.;
L
dx.doi.org/10.1021/jo501840u | J. Org. Chem. XXXX, XXX, XXX−XXX