Preparation of tetrasubstituted olefins using mono or double aerobic direct C-H functionalization strategies: Importance of steric effects

Article abstract of DOI:10.1021/acs.joc.5b00148

A novel protocol for the synthesis of tetrasubstituted olefins through a biomimetic approach has been explored. Both mono- and diarylations were performed under ambient oxygen pressure, giving a range of highly hindered tetrasubstituted alkenes. For diarylation of disubstituted substrates, it was demonstrated that the second arylation is the rate-limiting step of the overall transformation.

Full text of DOI:10.1021/acs.joc.5b00148

Article
pubs.acs.org/joc
Preparation of Tetrasubstituted Olefins Using Mono or Double
Aerobic Direct C−H Functionalization Strategies: Importance of
Steric Effects
Nicolas Gigant,* Franco
,
†,‡
is Quintin, and Jan-E. Bac
̈
kvall*,†
†
̧
†
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
‡Equipe de Chimie des Substances Naturelles, Universite
Paris-Sud, UMR CNRS 8076 BioCIS, LabEx LERMIT, Faculte
Pharmacie, 5, rue Jean-Baptiste Clement, 92296 Chatenay-Malabry, France
S Supporting Information
́
́
de
́
̂
*
ABSTRACT: A novel protocol for the synthesis of tetrasub-
stituted olefins through a biomimetic approach has been
explored. Both mono- and diarylations were performed under
ambient oxygen pressure, giving a range of highly hindered
tetrasubstituted alkenes. For diarylation of disubstituted
substrates, it was demonstrated that the second arylation is
the rate-limiting step of the overall transformation.
INTRODUCTION
tetrasubstituted alkenes via the dehydrogenative Heck reaction
approach.
■
Tetrasubstituted olefins constitute an important class of
compounds since many of these olefins show significant
biological activities (Figure 1). For example, (Z)-Tamoxifen
displays effects against breast cancer while Rofecoxib is a
powerful nonsteroidal anti-inflammatory drug. Dibenzoxapin
In the past few years, we have been involved in the
development of new sustainable C−C couplings via C−H
10
1
activations using a biomimetic approach. Following this
2
concept, the high kinetic barrier preventing the catalyst
regeneration is circumvented by the use of catalytic amounts of
and related compounds have been evaluated as nuclear hormone
11
electron-transfer mediators (ETMs). In this way, the reduced
3
receptor modulators, and finally, tetrasubstituted isocombre-
catalyst can be reoxidized by O at atmospheric pressure,
2
tastatins A-4 have been recently identified as new tubulin
producing water as the sole byproduct of the reaction. On the
basis of this strategy, we have previously established protocols for
the dehydrogenative Heck reaction that have the following
advantages: (i) relative low palladium and arene loadings, (ii)
4
inhibitors.
Reported efficient methods for accessing such unsaturated
structures are mainly based on the use of transition-metal
5
catalysis via carbofunctionalization of alkynes, olefin meta-
utilization of O under ambient pressure as the oxidant, and (iii)
6
7
2
thesis, or cross-coupling reactions. Among the latter, the
oxidative Heck coupling has been frequently employed for the
extension of the scope to nonbiased olefins and heterocycles.
Our continued interest in this field prompted us to explore the
preparation of tetrasubstituted olefins via a biomimetic approach,
and our contribution is reported herein.
8
preparation of disubstituted alkenes. However, only a few
examples of successful Heck arylation have been reported
regarding the synthesis of tri- or tetrasubstituted olefins.
7b−e
There are several problems associated with the oxidative Heck
coupling between aromatic heterocycles and trisubstituted
olefins to give tetrasubstituted olefins. The problems with the
latter reaction can be rationalized by the low reactivity of the
trisubstituted substrates. Due to steric hindrance around the
unsaturated core, the latter alkenes are not reactive enough to
undergo the required carbopalladation. Another problem is
associated with the regeneration of the active catalyst. In general,
the use of strong oxidants or additivessuch as TEMPO
RESULTS AND DISCUSSION
■
We first planned to prepare a trisubstituted olefin via a
dehydrogenative Heck reaction that could be used as starting
material for the synthesis of tetrasubstituted olefins. In our
previously reported arylation of nonbiased olefins, we showed
that acridine as a ligand dramatically enhances the reaction rate
and totally controls the site selectivity in the coupling with
veratrole. We initiated our studies with a 1:10 ratio of alkene 1a
and veratrole (2a) using Pd(OAc) (5 mol %) as catalyst,
acridine (5 mol %) as ligand, and benzoquinone (BQ) (10 mol
) and iron phthalocyanine Fe(Pc) (2.5 mol %) as electron-
transfer mediators in a mixture of acetic acid:dioxane (1:1, v:v)
10a
7e
(
2,2,6,6-tetramethylpiperidine-N-oxyl radical) derivatives and/
2
7c,d
or inorganic salts is required, thus reducing the applicability
and sustainability of the reaction. In addition, in the dehydrogen-
ative version of the Heck reactionthe Fujiwara−Moritani
%
9
reaction the challenging metal insertion into the aromatic C−
H bond makes the synthetic task even more difficult. Therefore,
Received: January 20, 2015
there is a demand for improvements of the synthesis of
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00148
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 1. Representative drugs containing tetrasubstituted olefins.
a
Table 1. Optimization of the Synthesis of Tetrasubstituted Olefins
conditions
b
b
entry
T (°C)
arene (equiv)
variations from standard conditions (concerning solvent and catalysts)
3aa (%)
4aa (%)
1
2
3
4
5
6
7
8
9
90
90
10
10
10
10
10
10
10
10
15
15
15
15
15
15
none
AcOH as solvent
66
59
36
42
30
57
28
24
trace
56
33
18
51
27
17
35
3
100
110
100
100
100
100
100
100
100
100
100
100
none
none
BQ (20 mol %) and Fe(Pc) (5 mol %)
AcOH:dioxane (75:25) as solvent
AcOH:dioxane (25:75) as solvent
39
29
9
Pd(OAc) (7.5 mol %)
66
66
9
2
c
none
1
1
1
1
1
0
1
2
3
4
AcOH:CH CN (8:2) as solvent
3
PivOH:dioxane (1:1) as solvent
7
C H COOH:dioxane (1:1) as solvent
6
2
5
1,4-diOMeBQ (10 mol %) instead of BQ
Cu(Pc) (2.5 mol %) instead of Fe(Pc)
37
37
49
a
b
Reaction conditions: 1a (0.30 mmol), 2a (10 or 15 equiv) in the appropriate catalytic system for 24 h under O (balloon). NMR yield using an
2
c
internal standard. Yield after flash chromatography.
for 24 h at 90 °C under ambient oxygen pressure (Table 1, entry
improved the yield of 4aa up to 66%. Considering the
importance of the choice of solvent in the Fujiwara−Moritani
reaction, we also evaluated the role of a range of cosolvents such
1). Interestingly, we found that formation of the trisubstituted
alkene 3aa was accompanied by the tetrasubstituted alkene 4aa.
This reaction shows that the biomimetic approach is a viable
strategy for providing access to tetrasubstituted olefins. Taking
into account that there are not many examples in the literature
13
as acetonitrile instead of dioxane, or pivalic acid or propionic
acid instead of acetic acid, but none of these changes increased
the yield of 4aa (entries 10−12). We chose to conclude our
optimization studies with an additional screening of ETMs, but
these alternative catalytic systems were not more efficient than
those used in the standard conditions (entries 13−14).
10f,12
for the diarylation of alkenes,
it was highly interesting to
develop a one-pot double arylation of 1a.
Attempts to increase the rate of the reaction by the use of pure
acetic acid as the solvent were unsuccessful and led to only 17%
yield of 4aa (Table 1, entry 2). An increase of the reaction
temperature to 100 °C under the standard conditions resulted in
an improvement and gave olefin 4aa in a 35% yield, (Table 1,
entry 3). However, a further increase of the reaction temperature
to 110 °C decreased the amount of 4aa to 3% (entry 4). The
dramatic decrease of 4aa may be due to decomposition at 110 °C
under the acidic conditions. An increase of the catalytic amount
of ETMs did not significantly affect the yield of the coupling, and
modifications of the solvent ratio led to decreased yields (entries
The double dehydrogenative sequence for the conversion of
disubstituted alkene 1a into trisubstituted alkene 3aa and
1
tetrasubstituted alkene 4aa was monitored by H NMR
spectroscopy (Figure 2). The reaction profile indicates that
olefin 1a is almost totally consumed after only 2 h, mostly giving
3
3
aa with only trace amounts of 4aa. Then, the concentration of
aa is decreasing slowly with concomitant formation of 4aa,
demonstrating that the rate-limitating step of the sequence is the
formation of the desired tetrasubstituted product. The steric
hindrance around the double bond certainly slows down the
carbopalladation.
5
−7). We were pleased to find that the use of a higher catalyst
loading (entry 8) or an increase of the arene loading (entry 9)
B
DOI: 10.1021/acs.joc.5b00148
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Article
reactive sites, generating complicated mixtures of isomers after a
double cross-coupling. Usually, the site selectivity is controlled
by (i) electronic factors with a preference for the most electron-
rich carbon, (ii) steric factors with a preference for the less-
hindered carbon. First, the influence of the substituents in 1,1-
disubstituted alkene substrates was examined by reaction with
veratrole 2a as the aromatic coupling partner. We were pleased to
find that a range of esters smoothly underwent the diarylation,
giving 4aa−4ca in good yields. An acetate and a ketone are both
tolerated in the double dehydrogenative cross-coupling, albeit in
lower yields (4da and 4ea). An olefin substrate containing an
isatin moiety underwent a smooth reaction, resulting in the
formation of 4fa in 55% yield. To our satisfaction, the site
selectivity of the reaction with 1,2-diethoxybenzene and o-xylene
was complete, leading to two highly substituted scaffolds 4ab and
Figure 2. Reaction profile of the biomimetic double dehydrogenative
sequence between alkene 1a and arene 2a using the reaction conditions
of entry 9, Table 1.
4ac. However, no diarylated product was observed when 1,4-
dimethoxybenzene 2d was employed as coupling partner, the
reaction yielding only the trisubstituted olefin 3ad in an 83%
yield. The second arylation is apparently suppressed due to steric
reasons. The lack of reactivity due to steric effects was confirmed
by using 1,3-dimethoxybenzene 2e as coupling partner. Indeed, a
63:37 mixture in favor of the ortho-isomer 3ae-α (the most
reactive site) was isolated, accompanied by roughly 5% of a
diarylated scaffold. In this example, due to its steric hindrance,
We chose to continue our studies with a range of one-pot
diarylations using the optimum conditions (Scheme 1). In most
cases, the introduction of directing groupssuch as acyl
groupscan only be employed to partially control the regio-
7
d,14
and the stereoselectivity of tetrasubstituted alkenes.
Indeed,
simple arenes can potentially undergo metalation at several
, , , ,
a b c d e
Scheme 1. Synthesis of Tetrasubstituted Olefins via a Double Aerobic Direct C−H Activation
a
b
c
d
For reaction conditions, see Table 1. Pd(OAc) (5 mol %), acridine (5 mol %). Pd(OAc) (7.5 mol %), acridine (7.5 mol %). Reaction
2
2
e
performed at 90 °C. Ratio of isomers (α:β) determined by NMR spectroscopy of isolated product.
C
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The Journal of Organic Chemistry
Article
, , , ,
a b c d e
Scheme 2. Synthesis of Tetrasubstituted Olefins via a Mono Aerobic Direct C−H Activation
a
b
c
d
For reaction conditions, see Table 1. Pd(OAc) (5 mol %), acridine (5 mol %). Pd(OAc) (7.5 mol %), acridine (7.5 mol %). Ratio of isomers
2
2
e
(α:β or o:m:p) determined by NMR spectroscopy of isolated product. Ratio of regioisomers, which could not be assigned and are thus given in no
particular order (determined by NMR of isolated product).
3
2
ae-α is already too crowded to perform a second arylation with
e. In addition, 3ae-β can only react with the β position of 2e,
further explore the scope of this transformation, the coupling
reaction with 1g (or 1h) was conducted with difunctionalized
arenes such as veratrole, naphtalene, or o-xylene, which furnished
a range of densely substituted alkenes 5ga, 5gj, 5gc, and 5ha with
which is unfortunately the less reactive carbon of the arene.
We also confirmed the influence of steric hindrance starting
from trisubstituted alkenes 1g and 1h (Scheme 2). Reaction of 1g
with arene 2d did not deliver the desired product 5gd, the
starting materials being mostly recovered and no identifiable
byproduct being detected. Furthermore, with arene 2e, only one
isomer 5ge was obtained in a 16% yield, whereas 57% of olefin 1g
remained intact. These systematic studies on these sterically
hindered substrates led to some instructive results: ortho-C−H
functionalization of simple arenes is very slow with trisubstituted
olefins, illustrating the influence of steric effects on the rate. The
reaction was also conducted with 1,3-benzodioxole (1f) as
coupling partner, and surprisingly, the selectivity of the coupling
was not complete. The desired alkenes 5gf were isolated as a
mixture of isomers in a 18:82 ratio in favor of the β-alkenylated
scaffold. In light of these results, it was of interest to establish the
selectivity of anisole as coupling partner. Anisole is known to
mainly undergo palladium insertion at (i) para, (ii) ortho, (iii)
15
synthetically useful yields and complete selectivity.
CONCLUSION
■
In summary, we have developed an operationally simple protocol
for the synthesis of tetrasubstituted olefins via mono or double
aerobic dehydrogenative Heck couplings through a biomimetic
approach. It was shown that the steric hindrance around the
unsaturated core plays a key role in the selectivity of the reaction,
and a range of highly substituted alkenes were isolated with
complete chemoselectivity around the double bond and with
partial to complete regioselectivity depending on the arene.
Remarkably, the reaction involves readily available nonfunction-
alized reagents and proceeds at ambient oxygen pressure.
EXPERIMENTAL SECTION
■
General Information. Reactions were monitored by thin-layer
chromatography (TLC) analysis using silica gel (60 F254) plates.
Compounds were visualized by UV irradiation and/or spraying with a
solution of potassium permanganate, followed by charring at 150 °C.
Flash column chromatography was performed on silica gel 60 (230−400
1
0a−c,13
meta positions.
As expected, no coupling occurred at the
ortho position of anisole, and 5gg was isolated as a mixture of
isomers in a 0:46:54 (o:m:p) ratio. Similarly, toluene and
chlorobenzene were also successfully employed and only two
regioisomers were detected in each case (5gh and 5gi). To
1
13
mesh, 0.040−0.063 mm). H and C NMR spectra were recorded on a
13
spectrometer at 400 MHz ( C, 100 MHz). Chemical shifts are given in
D
DOI: 10.1021/acs.joc.5b00148
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Article
parts per million from tetramethylsilane (TMS) as internal standard.
The following abbreviations are used for the proton spectra multi-
plicities: s: singulet, d: doublet, t: triplet, q: quartet, qu: quintuplet,
sex:sextet, m: multiplet. Coupling constants (J) are reported in hertz
5.56 (t, J = 1.7, 0.4 Hz, 1H), 4.56 (t, J = 1.5 Hz, 2H), 4.18 (t, J = 6.7 Hz,
2H), 1.69−1.62 (m, 2H), 1.44−1.34 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).
13
C NMR (CDCl , 100 MHz): δ 167.8, 165.5, 134.8, 134.3, 132.1, 125.9,
3
123.6, 65.1, 38.4, 30.7, 19.3, 13.8.
(
Hz). HRMS were recorded using ESI-TOF techniques. Dry solvents
Methyl 2-(Acetoxymethyl)acrylate (1d). Compound 1d was
22
1
were obtained from a VAC solvent purifier. All reagents were obtained
from commercial suppliers unless otherwise stated.
Protecting alkenes 1 were prepared following a two-step sequence
Baylis−Hillman reaction (giving products 6)/Mitsunobu reaction as
described below.
prepared according to a literature procedure. H NMR (CDCl , 400
3
MHz): δ 6.34 (q, J = 1.3 Hz, 1H), 5.83 (q, J = 1.3 Hz, 1H), 4.79 (t, J = 1.5
13
Hz, 2H), 3.77 (s, 3H), 2.08 (s, 3H). C NMR (CDCl , 100 MHz): δ
3
1
70.4, 165.7, 135.3, 127.6, 62.5, 52.1, 20.9.
-(2-Methylene-3-oxobutyl)isoindoline-1,3-dione (1e). Com-
2
tert-Butyl 2-(Hydroxymethyl)acrylate (6b). The title compound
pound 1e was prepared via a Mitsunobu reaction according to a
was prepared via Baylis−Hillman reaction according to a literature
20
literature procedure. Experimental data were in accordance with those
16
procedure. Experimental data were in accordance with those reported
1
reported in the previous literature. H NMR (CDCl , 400 MHz): δ 7.87
1
6
1
3
in the previous literature. H NMR (CDCl , 400 MHz): δ 6.15 (m,
3
(dd, J = 5.6, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 6.13 (m, 1H),
13
1
H), 5.74 (m, 1H), 4.28 (m, 2H), 1.51 (s, 9H). C NMR (CDCl , 100
13
3
5.70 (m, 1H), 4.54 (t, J = 1.5 Hz, 2H), 2.37 (s, 3H). C NMR (CDCl3,
MHz): δ 165.8, 140.9, 125.0, 81.5, 63.0, 28.2.
tert-Butyl 2-(Hydroxymethyl)acrylate (6c). The title compound
1
00 MHz): δ 198.2, 168.0, 142.6, 134.4, 134.3, 123.7, 123.6, 37.7, 26.0.
Methyl 2-((2,3-Dioxoindolin-1-yl)methyl)acrylate (1f). To a
was prepared via Baylis−Hillman reaction according to a literature
solution of (hydroxymethyl)acrylate 6d (600 mg, 5.17 mmol, 1 equiv) in
diethyl ether (25 mL) was added dropwise phosphorus tribromide (535
μL, 5.68 mmol, 1.1 equiv) at 0 °C under argon. After 1 h at 25 °C,
16
procedure. Experimental data were in accordance with those reported
17
1
in the previous literature. H NMR (CDCl , 400 MHz): δ 6.25 (q, J =
3
1
2
.3 Hz, 1H), 5.82 (q, J = 1.4 Hz, 1H), 4.33 (m, 2H), 4.20 (t, J = 6.6 Hz,
H), 1.67 (qu, J = 7.4 Hz, 2H), 1.40 (sex, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4
NaHCO was added and the reaction mixture was extracted with diethyl
3
ether (3 × 30 mL). The combined organic layers were washed with brine
13
Hz, 3H). C NMR (CDCl , 100 MHz): δ 166.5, 139.6, 125.7, 64.9,
3
(
50 mL) and dried over MgSO , filtered, and concentrated under
4
6
2.8, 30.7, 19.2, 13.8.
Methyl 2-(Hydroxymethyl)acrylate (6d). The title compound
reduced pressure. The resulting allylic bromide (270 mg, 1.51 mmol,
equiv) was dissolved in acetonitrile (15 mL) in the presence of indoline-
was prepared via Baylis−Hillman reaction according to a literature
16
2,3-dione (260 mg, 1.81 mol, 1.2 equiv) and K
CO (250 mg, 1.81
2 3
procedure. Experimental data were in accordance with those reported
16
1
mmol, 1.2 equiv). The resulting solution was stirred for 20 h at 25 °C.
in the previous literature. H NMR (CDCl , 400 MHz): δ 6.23 (q, J =
3
13
H
×
2
O was then added, and the mixture was extracted with ethyl acetate (3
30 mL). The organic phase was washed with brine, dried over MgSO4,
0
.9 Hz, 1H), 5.83 (q, J = 1.3 Hz, 1H), 4.36 (m, 2H), 3.80 (s, 3H).
C
NMR (CDCl , 100 MHz): δ 166.8, 139.4, 125.9, 62.4, 52.0.
3
filtered, and concentrated under reduced pressure. The desired product
f was purified by flash chromatography (petroleum ether/ethyl acetate
3-(Hydroxymethyl)but-3-en-2-one (6e). The title compound
1
was prepared via a Baylis−Hillman reaction according to a literature
18
= 6:4 to 5:5) and isolated as an orange solid in 26% yield over two steps
procedure. Experimental data were in accordance with those reported
1
1
8
1
(327 mg). H NMR (CDCl , 400 MHz): δ 7.58 (ddd, J = 7.5, 1.3, 0.6 Hz,
3
in the previous literature. H NMR (CDCl , 400 MHz): δ 6.11 (s,
3
13
1H), 7.54 (dd, J = 7.8, 1.4 Hz, 1H), 7.11 (td, J = 7.5, 0.7 Hz, 1H), 6.89 (d,
1
H), 6.03 (t, J = 1.4 Hz, 1H), 4.29 (q, J = 0.8 Hz, 2H), 2.35 (s, 3H).
C
J = 7.9 Hz, 1H), 6.35 (t, J = 1.3 Hz, 1H), 5.73 (t, J = 1.5 Hz, 1H), 4.58 (s,
NMR (CDCl , 100 MHz): δ 200.5, 147.3, 126.2, 62.3, 26.0.
3
13
2
H), 3.79 (s, 3H). C NMR (CDCl , 100 MHz): δ 182.9, 165.9, 158.3,
Methyl 2-(Hydroxy(phenyl)methyl)acrylate (6g). The title
compound was prepared via Baylis−Hillman reaction according to a
3
1
50.5, 138.6, 133.1, 127.5, 125.5, 124.1, 117.7, 111.1, 52.4, 40.7. HRMS
+
19
(ESI) m/z: [M + Na] calcd for C H NNaO 268.0586, found
literature procedure. Experimental data were in accordance with those
13 11
4
19
1
268.0589.
reported in the previous literature. H NMR (CDCl , 400 MHz): δ
3
(
E)-Methyl 2-((1,3-Dioxoisoindolin-2-yl)methyl)-3-phenyl
7
5
1
.39−7.28 (m, 5H), 6.34 (q, J = 0.8 Hz, 1H), 5.83 (t, J = 1.2 Hz, 1H),
13
Acrylate (1g). Compound 1g was prepared via a Mitsunobu reaction
.57 (s, 1H), 3.73 (s, 3H). C NMR (CDCl , 100 MHz): δ 166.9, 142.1,
3
20
according to a literature procedure. Experimental data were in
accordance with those reported in the previous literature. Exper-
41.4, 128.6, 128.0, 126.7, 126.3, 73.4, 52.1.
Methyl 2-((4-Chlorophenyl)(hydroxy)methyl)acrylate (6h).
21
imental data were in accordance with those reported in the previous
The title compound was prepared via Baylis−Hillman reaction
1
19
literature. H NMR (CDCl , 400 MHz): δ 7.95 (s, 1H), 7.78 (dd, J = 5.5,
according to a literature procedure. Experimental data were in
3
1
9
1
3.1 Hz, 2H), 7.67 (dd, J = 5.5, 3.0 Hz, 2H), 7.46 (d, J = 7.7 Hz, 2H), 7.35
accordance with those reported in the previous literature. H NMR
(
t, J = 7.5 Hz, 2H), 7.27 (t, J = 7.5 Hz, 1H), 4.75 (s, 2H), 3.75 (s, 3H).
(
1
CDCl , 400 MHz): δ 7.30 (m, 4H), 6.33 (t, J = 0.8 Hz, 1H), 5.83 (t, J =
3
1
3
13
C NMR (CDCl , 100 MHz): δ 168.0, 167.1, 143.4, 134.8, 133.9, 132.1,
.2 Hz, 1H), 5.51 (m, 1H), 3.70 (s, 3H). C NMR (CDCl , 100 MHz):
3
3
δ 166.7, 141.7, 139.9, 133.6, 128.6, 128.1, 126.4, 72.7, 52.1.
Ethyl 2-((1,3-Dioxoisoindolin-2-yl)methyl)acrylate (1a). Com-
129.1, 128.8, 128.6, 126.5, 123.5, 52.1, 35.9.
(E)-Methyl 3-(4-Chlorophenyl)-2-((1,3-dioxoisoindolin-2-yl)-
methyl)acrylate (1h). Compound 1h was prepared via a Mitsunobu
pound 1a was prepared via a Mitsunobu reaction according to a
2
0
20
reaction according to a literature procedure. Experimental data were in
literature procedure. Experimental data were in accordance with those
21
1
21
1
accordance with those reported in the previous literature. H NMR
(CDCl , 400 MHz): δ 7.90 (s, 1H) 7.81 (dd, J = 5.6, 3.1 Hz, 2H), 7.71
(dd, J = 5.5, 3.0 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.0 Hz,
reported in the previous literature. H NMR (CDCl , 400 MHz): δ
3
7
1
7
1
.88 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.6, 3.1 Hz, 2H), 6.33 (t, J =
3
.4 Hz, 1H), 5.57 (t, J = 3.3 Hz, 1H), 4.57 (t, J = 3.1 Hz, 2H), 4.25 (q, J =
.1 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). 1 C NMR (CDCl , 100 MHz): δ
3
13
2H), 4.74 (d, J = 1.1 Hz, 2H), 3.78 (s, 3H). C NMR (CDCl , 100
3
3
67.8, 165.4, 134.7, 134.2, 132.1, 125.9, 123.5, 61.2, 38.4, 14.2.
tert-Butyl 2-((1,3-Dioxoisoindolin-2-yl)methyl)acrylate (1b).
MHz): δ 168.0, 166.9, 142.0, 134.1, 133.2, 132.0, 130.4, 128.9, 127.1,
123.7, 123.3, 52.4, 35.8.
Compound 1b was prepared via a Mitsunobu reaction according to a
General Procedure for the Synthesis of Functionalized
20
Olefins 3, 4, or 5. Pd(OAc) (5 mol %), acridine (5 mol %), p-
literature procedure. Experimental data were in accordance with those
2
20
1
reported in the previous literature. H NMR (CDCl , 400 MHz): δ
benzoquinone (10 mol %), iron phtalocyanine (2.5 mol %), olefin 1 (1
equiv), arene 2 (15 equiv), and AcOH:dioxane (1:1, 1.0 mL) were
charged in a Schlenk tube. The resulting mixture was degassed three
times under reduced pressure before introducing oxygen gas with a
balloon. After vigorous stirring at 100 °C for 24 h, the reaction mixture
was cooled to room temperature, diluted with AcOEt, filtered through
Celite, rinsed with AcOEt, and concentrated under vacuum. Products
were purified by flash chromatography with hexane/ethyl acetate to
yield the desired functionalized olefins 3, 4, or 5.
3
7
1
1
1
.88 (dd, J = 5.6, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.0 Hz, 2H), 6.21 (td, J =
.4, 0.5 Hz, 1H), 5.44 (t, J = 1.7, 0.5 Hz, 1H), 4.52 (t, J = 1.6 Hz, 2H),
13
.50 (s, 9H). C NMR (CDCl , 100 MHz): δ 167.9, 164.6, 136.1, 134.2,
3
32.1, 124.6, 123.6, 81.6, 38.5, 28.2.
Butyl 2-((1,3-Dioxoisoindolin-2-yl)methyl)acrylate (1c). Com-
pound 1c was prepared via a Mitsunobu reaction according to a
20
1
literature procedure. H NMR (CDCl , 400 MHz): δ 7.87 (dd, J = 5.6,
3
3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.0 Hz, 2H), 6.31 (td, J = 1.4, 0.4 Hz, 1H),
E
DOI: 10.1021/acs.joc.5b00148
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Ethyl 3,3-Bis(3,4-dimethoxyphenyl)-2-((1,3-dioxoisoindolin-
1H), 6.60 (d, J = 2.0 Hz, 1H), 4.66 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H),
13
2
-yl)methyl)acrylate (4aa). Prepared following the general proce-
3.80 (s, 3H), 3.76 (s, 3H), 1.77 (s, 3H). C NMR (CDCl , 100 MHz): δ
3
dure. Compound 4aa was obtained as a red solid in 62% yield (66 mg)
205.3, 168.2, 150.1, 149.1, 149.0, 148.9, 148.8, 134.4, 134.1, 134.0, 132.9,
132.1, 123.5, 123.3, 122.7, 112.9, 112.8, 111.0, 110.8, 56.1, 56.1, 56.0,
after flash chromatography (SiO , petroleum ether/ethyl acetate, 7:3 to
2
1
+
5
(
6
2
:5). H NMR (CDCl , 400 MHz): δ 7.79 (dd, J = 5.6, 3.0 Hz, 2H), 7.67
3
56.0, 40.4, 30.6. HRMS (ESI) m/z: [M + Na] calcd for C H NNaO
2
9
27
7
dd, J = 5.6, 3.0 Hz, 2H), 7.04 (d, J = 1.8 Hz, 1H), 6.87−6.80 (m, 2H),
5
24.1680, found 524.1682 (−0.5 ppm).
.73 (d, J = 0.9 Hz, 2H), 6.67 (s, 1H), 4.68 (s, 2H), 3.88 (q, J = 7.2 Hz,
Methyl 3,3-Bis(3,4-dimethoxyphenyl)-2-((2,3-dioxoindolin-
13
H), 3.85 (s, 6H), 3.84 (s, 3H), 3.75 (s, 3H), 0.85 (t, J = 7.1 Hz, 3H). C
1-yl)methyl)acrylate (4fa). Prepared following the general procedure,
NMR (CDCl , 100 MHz): δ 169.2, 167.9, 149.1, 149.0, 148.9, 148.7,
except that Pd(OAc) (7.5 mol %) and acridine (7.5 mol %) were used.
3
2
1
1
[
48.4, 134.6, 133.9, 132.5, 132.1, 125.5, 123.2, 122.4, 121.7, 112.8, 112.1,
Compound 4fa was obtained as a red solid in 55% yield (57 mg) after
10.9, 110.5, 60.8, 56.1, 55.9, 55.9, 55.9, 39.4, 13.7. HRMS (ESI) m/z:
flash chromatography (SiO , petroleum ether/ethyl acetate, 6:4 to 4:6).
2
+
1
M + Na] calcd for C H NNaO 554.1785, found 554.1782 (0.6
30
29
8
H NMR (CDCl , 400 MHz): δ 7.53−7.49 (m, 2H), 7.06 (td, J = 7.5, 0.8
Hz, 1H), 6.92 (m, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H),
3
ppm).
(
E)-Ethyl 3-(3,4-Dimethoxyphenyl)-2-((1,3-dioxoisoindolin-2-
6
3
1
1
1
.70−6.76 (m, 3H), 6.55 (d, J = 2.0 Hz, 1H), 4.74 (s, 2H), 3.88 (s, 3H),
1
yl)methyl)acrylate (3aa). H NMR (CDCl , 400 MHz): δ 7.88 (s,
13
3
.85 (s, 3H), 3.75 (s, 3H), 3.73 (s, 3H), 3.44 (s, 3H). C NMR (CDCl ,
3
1
(
H), 7.77 (dd, J = 5.6, 3.1 Hz, 2H), 7.66 (dd, J = 5.5, 3.2 Hz, 2H), 7.14
d, J = 1.9 Hz, 1H), 7.06 (ddd, J = 8.3, 2.0, 0.7 Hz, 1H), 7.14 (d, J = 8.4
00 MHz): δ 183.0, 170.2, 157.9, 150.8, 150.8, 149.6, 149.5, 148.9,
48.6, 137.9. 134.2, 131.7, 125.1, 123.6, 123.1, 122.2, 121.7, 117.9, 112.3,
Hz, 1H), 4.79 (d, J = 1.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H),
12.0, 111.3, 111.2, 110.5, 56.1, 56.1, 55.9, 55.9, 52.3, 41.2. HRMS (ESI)
3
1
1
.84 (s, 3H), 1.23 (t, J = 7.0 Hz, 3H). 13C NMR (CDCl , 100 MHz): δ
+
3
m/z: [M + Na] calcd for C H NNaO 540.1629, found 540.1637
29
27
8
68.0, 166.9, 149.6, 148.9, 143.0, 133.9, 132.1, 127.5, 125.2, 123.2, 122.7,
(
−1.5 ppm).
+
12.4, 111.0, 61.1, 56.0, 55.9, 36.0, 14.2. HRMS (ESI) m/z: [M + Na]
Ethyl 3,3-Bis(3,4-diethoxyphenyl)-2-((1,3-dioxoisoindolin-2-
calcd for C H NNaO 418.1261, found 418.1241 (4.8 ppm).
22
21
6
yl)methyl)acrylate (4ab). Prepared following the general procedure.
Compound 4ab was obtained as a yellow solid in 42% yield (49 mg)
tert-Butyl 3,3-Bis(3,4-dimethoxyphenyl)-2-((1,3-dioxoiso-
indolin-2-yl)methyl)acrylate (4ba). Prepared following the general
procedure. Compound 4ba was obtained as a red solid in 53% yield (59
after flash chromatography (SiO , petroleum ether/ethyl acetate, 7:3 to
2
1
5
:5). H NMR (CDCl , 400 MHz): δ 7.80 (dd, J = 5.5, 3.1 Hz, 2H), 7.67
3
mg) after flash chromatography (SiO , petroleum ether/ethyl acetate,
2
1
(dd, J = 5.4, 3.1 Hz, 2H), 6.96 (d, J = 1.7 Hz, 1H), 6.83 (m, 2H), 6.71 (m,
H), 6.65 (d, J = 1.8 Hz, 1H), 4.67 (s, 2H), 4.10−4.01 (m, 6H), 3.94 (q, J
7.0 Hz, 2H), 3.85 (q, J = 7.1 Hz, 2H), 1.45−1.34 (m, 12H), 0.83 (t, J =
7
2
8
2
:3 to 6:4). H NMR (CDCl , 400 MHz): δ 7.82 (dd, J = 5.5, 3.0 Hz,
3
2
H), 7.70 (dd, J = 5.5, 3.1 Hz, 2H), 7.11 (d, J = 1.9 Hz, 1H), 6.89 (dd, J =
.2, 2.0 Hz, 1H), 6.84−6.75 (m, 3H), 6.70 (d, J = 1.8 Hz, 1H), 4.68 (s,
H), 3.89 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.79 (s, 3H), 1.09 (s, 9H).
=
13
7
.1 Hz, 3H). C NMR (CDCl , 100 MHz): δ 169.4, 168.0, 149.5, 148.8,
3
1
3
148.7, 148.3, 148.1, 134.8, 133.9, 132.6, 132.2, 125.0, 123.3, 122.6, 121.9,
C NMR (CDCl , 100 MHz): δ 167.9, 167.8, 148.8, 148.6, 148.6, 148.3,
3
1
1
14.9, 114.3, 112.8, 112.5, 64.6, 64.6, 64.5, 64.5, 60.8, 39.5, 14.9, 14.9,
1
1
[
47.0, 134.8, 133.9, 132.6, 132.1, 127.3, 123.1, 122.2, 121.7, 112.6, 112.2,
+
4.9, 14.8, 13.7. HRMS (ESI) m/z: [M + Na] calcd for C H NNaO
3
4
37
8
01.8, 110.4, 81.1, 56.0, 55.9, 55.8, 55.8, 39.3, 27.4. HRMS (ESI) m/z:
+
610.2411, found 610.2438 (−4.4 ppm).
M + Na] calcd for C H NNaO 582.2098, found 582.2122 (−4.0
32
33
8
Ethyl 3,3-Bis(3,4-dimethylphenyl)-2-((1,3-dioxoisoindolin-2-
ppm).
yl)methyl)acrylate (4ac). Prepared following the general procedure,
Butyl 3,3-Bis(3,4-dimethoxyphenyl)-2-((1,3-dioxoisoindolin-
-yl)methyl)acrylate (4ca). Prepared following the general proce-
except that Pd(OAc) (7.5 mol %) and acridine (7.5 mol %) were used.
2
2
Compound 4ac was obtained as a yellow solid in 56% yield (52 mg) after
dure, except that Pd(OAc) (7.5 mol %) and acridine (7.5 mol %) were
2
1
flash chromatography (SiO , petroleum ether/ethyl acetate, 6:4). H
2
used. Compound 4ca was obtained as a red solid in 60% yield (67 mg)
NMR (CDCl , 400 MHz): δ 7.80 (dd, J = 5.5, 3.0 Hz, 2H), 7.66 (dd, J =
3
after flash chromatography (SiO , petroleum ether/ethyl acetate, 7:3 to
2
1
5.5, 3.0 Hz, 2H), 7.07 (m, 3H), 6.99 (d, J = 7.8 Hz, 1H), 6.96 (s, 1H),
5
(
:5). H NMR (CDCl , 400 MHz): δ 7.80 (dd, J = 5.6, 3.1 Hz, 2H), 7.68
3
6
.88 (dd, J = 7.7, 1.9 Hz, 1H), 4.64 (s, 2H), 3.87 (q, J = 7.1 Hz, 2H), 2.21
dd, J = 5.5, 3.0 Hz, 2H), 7.03 (d, J = 1.8 Hz, 1H), 6.86 (dd, J = 8.2, 1.9
Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.74 (m, 2H), 6.67 (s, 1H), 4.68 (s,
1
3
(s, 6H), 2.20 (s, 3H), 2.17 (s, 3H), 0.81 (t, J = 7.2 Hz, 3H). C NMR
(
CDCl , 100 MHz): δ 169.1, 167.9, 150.6, 139.6, 137.6, 136.6, 136.5,
2
3
H), 3.86 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.81 (t, J = 6.6 Hz, 2H),
3
.76 (s, 3H), 1.19 (m, 2H), 0.96 (m, 2H), 0.67 (t, J = 7.3 Hz, 3H). 13
136.4, 136.0, 133.9, 132.3, 130.5, 129.8, 129.6, 129.3, 126.9, 126.2, 125.3,
23.2, 60.7, 39.1, 19.8, 19.8, 19.7, 19.6, 13.5. HRMS (ESI) m/z: [M +
C
1
NMR (CDCl , 100 MHz): δ 169.5, 167.9, 149.1, 149.0, 148.9, 148.7,
3
+
Na] calcd for C H NNaO 490.1989, found 490.1994 (−1.0 ppm).
1
1
(
5
48.5, 134.7, 134.0, 132.5, 132.2, 125.5, 123.3, 122.5, 121.8, 112.8, 112.1,
30 29
4
(E)-Ethyl 3-(2,5-Dimethoxyphenyl)-2-((1,3-dioxoisoindolin-2-
10.9, 110.5, 64.9, 56.1, 55.9, 55.9, 55.9, 39.5, 30.3, 18.9, 13.6. HRMS
+
yl)methyl)acrylate (3ad). Prepared following the general procedure.
Compound 3ad was obtained as a brown solid in 83% yield (66 mg)
ESI) m/z: [M + Na] calcd for C H NNaO 582.2098, found
32
33
8
82.2093 (0.8 ppm).
Methyl 2-(Acetoxymethyl)-3,3-bis(3,4-dimethoxyphenyl)-
acrylate (4da). Prepared following the general procedure, except that
after flash chromatography (SiO , petroleum ether/ethyl acetate, 7:3 to
2
1
6
:4). H NMR (CDCl , 400 MHz): δ 7.95 (s, 1H), 7.75 (dd, J = 5.5, 3.0
3
Hz, 2H), 7.65 (dd, J = 5.5, 3.2 Hz, 2H), 7.15 (m, 1H), 6.76 (m, 2H), 4.69
(d, J = 1.2 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.74 (s, 3H),
Pd(OAc) (7.5 mol %) and acridine (7.5 mol %) at 90 °C were used.
2
Compound 4da was obtained as a red solid in 27% yield (23 mg) after
1.22 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl
, 100 MHz): δ 167.9, 166.5,
153.3, 151.6, 139.5, 133.8, 132.2, 127.3, 124.5, 123.2, 115.4, 115.3, 111.9,
flash chromatography (SiO , petroleum ether/ethyl acetate, 6:4 to 4:6).
3
2
1
H NMR (CDCl , 400 MHz): δ 6.83−6.71 (m, 5H), 6.63 (d, J = 2.0 Hz,
3
+
6
1.1, 56.2, 55.9, 36.1, 14.2. HRMS (ESI) m/z: [M + Na] calcd for
1
3
1
1
H), 4.85 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H),
13
C H NNaO 418.1261, found 418.1254 (1.7 ppm).
.54 (s, 3H), 2.09 (s, 3H). C NMR (CDCl , 100 MHz): δ 170.7, 170.3,
22 21
6
3
(E)-Ethyl 3-(3,5-Dimethoxyphenyl)-2-((1,3-dioxoisoindolin-2-
53.4, 150.0, 150.0, 148.6, 148.6, 134.2, 132.3, 125.0, 123.0, 122.1, 113.1,
yl)methyl)acrylate (3ae-β). Prepared following the general proce-
dure. Compounds 3ae-α and 3ae-β were obtained and separated as
12.3, 110.8, 110.5, 60.0, 56.0, 56.0, 56.0, 55.9, 52.0, 21.1. HRMS (ESI)
+
m/z: [M + Na] calcd for C H NaO 453.1520, found 453.1524 (−0.9
23
26
8
brown solids in 82% yield (66 mg, α:β = 63:37) after flash
ppm).
1
chromatography (SiO , petroleum ether/ethyl acetate, 7:3 to 6:4). H
2
-(2-(Bis(3,4-dimethoxyphenyl)methylene)-3-oxobutyl)-
2
isoindoline-1,3-dione (4ea). Prepared following the general
NMR (CDCl , 400 MHz): δ 7.87 (s, 1H), 7.76 (dd, J = 5.7, 3.0 Hz, 2H),
3
procedure, except that Pd(OAc) (7.5 mol %) and acridine (7.5 mol
7.66 (dd, J = 5.4, 3.0 Hz, 2H), 6.59 (dd, J = 2.3, 0.7 Hz, 2H), 6.28 (d, J =
2.2 Hz, 1H), 4.74 (d, J = 1.3 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.75 (s,
2
%
) at 90 °C were used. Compound 4ea was obtained as a brown solid in
6H), 1.23 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl
, 100 MHz): δ 167.9,
41% yield (41 mg) after flash chromatography (SiO , petroleum ether/
3
2
1
ethyl acetate, 5:5 to 4:6). H NMR (CDCl , 400 MHz): δ 7.77 (dd, J =
166.5, 160.8, 142.8, 136.7, 134.4, 133.9, 132.1, 127.3, 123.7, 123.1, 106.6,
3
+
5.5, 3.1 Hz, 2H), 7.67 (dd, J = 5.5, 2.9 Hz, 2H), 7.01 (d, J = 2.0 Hz, 1H),
100.8, 62.2, 55.5, 55.5, 36.0, 14.2. HRMS (ESI) m/z: [M + Na] calcd
6.84 (dd, J = 8.2, 2.0 Hz, 1H), 6.78 (m, 2H), 6.73 (dd, J = 8.2, 2.0 Hz,
for C H NNaO 418.1261, found 418.1256 (1.1 ppm).
22
21
6
F
DOI: 10.1021/acs.joc.5b00148
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
E)-Ethyl 3-(2,4-Dimethoxyphenyl)-2-((1,3-dioxoisoindolin-2-
(E)-Methyl 3-(3-Chlorophenyl)-2-((1,3-dioxoisoindolin-2-yl)-
methyl)-3-phenyl Acrylate and (E)-Methyl 3-(4-Chlorophenyl)-
2-((1,3-dioxoisoindolin-2-yl)methyl)-3-phenyl Acrylate (5gi).
1
yl)methyl)acrylate (3ae-α). H NMR (CDCl , 400 MHz): δ 7.98 (s,
1
(
3
H), 7.77 (dd, J = 5.6, 3.1 Hz, 2H), 7.65 (dd, J = 5.5, 2.9 Hz, 2H), 7.48
dd, J = 8.4, 0.6 Hz, 1H), 6.46 (dd, J = 8.4, 2.4 Hz, 1H), 6.42 (d, J = 2.5
Hz, 1H), 4.70 (d, J = 1.1 Hz, 2H), (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.78
s, 3H), 1.20 (t, J = 7.1 Hz, 3H). C NMR (CDCl , 100 MHz): δ 168.0,
66.9, 161.8, 158.9, 139.4, 133.8, 132.2, 131.1, 125.2, 123.1, 116.7, 104.5,
Prepared following the general procedure, except that Pd(OAc) (7.5
2
mol %) and acridine (7.5 mol %) were used. Compounds 5gi were
obtained as an inseparable mixture of isomers as a yellow solid in 36%
yield (31 mg, ratio which could not be assigned and is thus given in no
13
(
1
9
3
+
8.5, 60.9, 55.6, 55.5, 36.3, 14.2. HRMS (ESI) m/z: [M + Na] calcd for
particular order = 0:63:37) after flash chromatography (SiO
2
, petroleum
, 400 MHz): δ
7.81 (m, 3.16H), 7.69 (m, 3.16H), 7.35−7.11 (m, 14.22H), 4.61 (s, 2H),
4.60 (s, 1.16H), 3.39 (s, 1.74 H), 3.38 (s, 3H). 13C NMR (CDCl
, 100
1
C H NNaO 418.1261, found 418.1281 (−4.7 ppm).
ether/ethyl acetate/toluene, 5:3:2). H NMR (CDCl
3
2
2
(
21
6
E)-Methyl 3-(3,5-Dimethoxyphenyl)-2-((1,3-dioxoisoindolin-
2
-yl)methyl)-3-phenyl Acrylate (5ge). Prepared following the
3
general procedure. Compound 5ge was obtained as an orange solid in
6% yield (15 mg) after flash chromatography (SiO , petroleum ether/
MHz): δ 168.9, 168.8, 167.8, 167.8, 148.9, 148.5, 141.4, 141.2, 140.9,
138.1, 134.5, 134.4, 134.1, 134.1, 132.1, 132.1, 130.8, 129.9, 129.3, 128.8,
128.5, 128.5, 128.4, 128.4, 128.3, 128.3, 128.2, 127.5, 127.2, 126.7, 123.4,
1
2
1
ethyl acetate/toluene, 5:3:2). H NMR (CDCl , 400 MHz): δ 7.80 (dd,
3
+
J = 5.6, 3.1 Hz, 2H), 7.68 (dd, J = 5.5, 3.0 Hz, 2H), 7.25 (m, 3H), 7.18
123.4, 52.0, 52.0, 39.0, 39.0. HRMS (ESI) m/z: [M + Na] calcd for
(
m, 2H), 6.52 (d, J = 2.3 Hz, 2H), 6.34 (t, J = 2.3 Hz, 1H), 4.66 (s, 2H),
C
25
H
18ClNNaO
(E)-Methyl 3-(3,4-Dimethoxyphenyl)-2-((1,3-dioxoisoindolin-
-yl)methyl)-3-phenyl Acrylate (5ga). Prepared following the
4
454.0817, found 454.0827 (−2.2 ppm).
13
3
1
1
.74 (s, 6H), 3.39 (s, 3H). C NMR (CDCl , 100 MHz): δ 169.1, 167.8,
3
2
60.8, 149.8, 141.5, 141.2, 134.4, 134.0, 132.1, 128.3, 128.1, 123.7, 123.3,
+
general procedure. Compound 5ga was obtained as a red solid in 55%
07.2, 100.3, 55.5, 51.9, 39.2. HRMS (ESI) m/z: [M + Na] calcd for
yield (50 mg) after flash chromatography (SiO , petroleum ether/ethyl
C H NNaO 480.1418, found 480.1430 (−2.6 ppm).
2
27
23
6
1
acetate, 7:3). H NMR (CDCl , 400 MHz): δ 7.80 (dd, J = 5.5, 3.1 Hz,
(
E)-Methyl 3-(Benzo[d][1,3]dioxol-4-yl)-2-((1,3-dioxoiso-
3
indolin-2-yl)methyl)-3-phenyl Acrylate (5gf-α) and (E)-Methyl
2H), 7.68 (dd, J = 5.5, 3.0 Hz, 2H), 7.25 (m, 3H), 7.15 (m, 2H), 6.99 (d,
J = 1.7 Hz, 1H), 6.82 (m, 2H), 4.69 (s, 2H), 3.84 (s, 3H), 3.84 (s, 3H),
3
-(3,4-Dimethoxyphenyl)-2-((1,3-dioxoisoindolin-2-yl)methyl)-
-phenyl Acrylate (5gf-β). Prepared following the general procedure.
13
3
3.37 (s, 3H). C NMR (CDCl , 100 MHz): δ 169.3, 167.9, 150.2, 149.0,
3
Compounds 5gf-α and 5gf-β were obtained as an inseparable mixture of
148.7, 141.9, 134.0, 132.4, 132.1, 128.6, 128.1, 128.1, 125.8, 123.3, 122.2,
+
isomers as a red solid in 59% yield (52 mg, α:β = 18:82) after flash
112.7, 110.9, 56.1, 55.9, 51.8, 39.4. HRMS (ESI) m/z: [M + Na] calcd
1
chromatography (SiO , petroleum ether/ethyl acetate, 75:25 to 6:4). H
for C H NNaO 480.1418, found 480.1433 (−3.3 ppm).
2
27 23
6
NMR (CDCl , 400 MHz): δ 7.82 (m, 2.44H), 7.69 (m, 2.44H), 7.26 (m,
(E)-Methyl 2-((1,3-Dioxoisoindolin-2-yl)methyl)-3-(naph-
thalen-2-yl)-3-phenyl Acrylate (5gj). Prepared following the general
3
3
6
0
.66H), 7.14 (m, 2.44H), 6.86 (dd, J = 7.8, 2.0 Hz, 1H), 6.79 (m, 2H),
.74 (m, 0.44H), 6.65 (dd, J = 5.4, 3.7 Hz, 0.22H), 5.93 (s, 2H), 5.89 (s,
procedure, except that Pd(OAc) (7.5 mol %) and acridine (7.5 mol %)
2
.44H), 4.67 (s, 2H), 4.62 (s, 0.44H), 3.41 (s, 0.66H), 3.36 (s, 3H). 13
C
were used. Compound 5gj was obtained as a brown solid in 83% yield
NMR (CDCl , 100 MHz): δ 169.2, 169.2, 167.9, 167.8, 150.2, 147.8,
(74 mg) after flash chromatography (SiO , petroleum ether/ethyl
3
2
1
1
1
1
47.7, 147.6, 141.7, 140.5, 134.0, 133.9, 133.5, 132.2, 132.1, 129.2, 128.6,
28.4, 128.2, 128.2, 128.1, 128.1, 127.8, 123.9, 123.4, 123.4, 123.3, 122.6,
21.9, 121.2, 110.0, 109.8, 108.5, 108.3, 101.3, 101.2, 52.0, 51.8, 39.2,
acetate/toluene, 7:3:2). H NMR (CDCl
3
, 400 MHz): δ 7.91 (d, J = 1.1
Hz, 1H), 7.85−7.76 (m, 5H), 7.64 (dd, J = 5.5, 3.1 Hz, 2H), 7.48 (m,
2H), 7.39 (dd, J = 8.5, 1.7 Hz, 1H), 7.28−7.16 (m, 5H), 4.70 (s, 2H),
+
13
3
8.7. HRMS (ESI) m/z: [M + Na] calcd for C H NNaO 464.1105,
3.43 (s, 3H). C NMR (CDCl
3
, 100 MHz): δ 169.2, 167.9, 150.2, 141.6,
26
19
6
found 464.1102 (0.5 ppm).
137.1, 134.0, 133.1, 133.0, 132.1, 128.7, 128.7, 128.4, 128.3, 128.2, 128.2,
(
E)-Methyl 2-((1,3-Dioxoisoindolin-2-yl)methyl)-3-(3-
127.8, 127.1, 126.6, 126.6, 126.5, 123.2, 51.9, 39.2. HRMS (ESI) m/z:
+
methoxyphenyl)-3-phenyl Acrylate (5gg-m) and (E)-Methyl 2-
[M + Na] calcd for C H NNaO 470.1363, found 470.1343 (4.2
29
21
4
(
(1,3-Dioxoisoindolin-2-yl)methyl)-3-(4-methoxyphenyl)-3-
phenyl Acrylate (5gg-p). Prepared following the general procedure,
ppm).
(E)-Methyl 3-(3,4-Dimethylphenyl)-2-((1,3-dioxoisoindolin-2-
except that Pd(OAc) (7.5 mol %) and acridine (7.5 mol %) were used.
yl)methyl)-3-phenyl Acrylate (5gc). Prepared following the general
2
Compounds 5gg-m and 5gg-p were obtained as an inseparable mixture
of isomers as a yellow solid in 51% yield (44 mg, o:m:p = 0:46:54) after
procedure, except that Pd(OAc) (7.5 mol %) and acridine (7.5 mol %)
2
were used. Compound 5gc was obtained as a yellow solid in 60% yield
1
flash chromatography (SiO , petroleum ether/ethyl acetate, 75:25). H
(51 mg) after flash chromatography (SiO , petroleum ether/ethyl
2
2
1
NMR (CDCl , 400 MHz): δ 7.82 (m, 3.70H), 7.68 (m, 3.70H), 7.28−
acetate/toluene, 7:3:2). H NMR (CDCl , 400 MHz): δ 7.80 (dd, J =
3
3
7
6
.13 (m, 12.45H), 6.98 (dd, J = 2.6, 1.5 Hz, 0.85H), 6.90 (m, 2.85H),
.81 (ddd, J = 8.3, 2.6, 1.0 Hz, 0.85H), 4.67 (s, 2H), 4.64 (s, 1.7H), 3.79
5.5, 3.0 Hz, 2H), 7.68 (dd, J = 5.5, 3.2 Hz, 2H), 7.25 (m, 3H), 7.16 (m,
2H), 7.10−7.04 (m, 3H), 4.67 (s, 2H), 3.89 (s, 3H), 2.22 (s, 3H), 2.20
13
13
(
(
s, 3H), 3.78 (s, 2.55H), 3.39 (s, 2.55H), 3.36 (s, 3H). C NMR
(s, 3H). C NMR (CDCl , 100 MHz): δ 169.4, 167.8, 150.8, 142.0,
3
CDCl , 100 MHz): δ 169.4, 169.1, 168.0, 167.8, 159.7, 159.6, 150.6,
137.2, 136.8, 136.6, 133.9, 132.2, 130.4, 129.7, 128.5, 128.0, 127.9, 126.8,
3
+
1
1
1
50.0, 142.1, 141.4, 141.0, 134.0, 134.0, 132.2, 132.2, 132.2, 131.0, 129.6,
29.1, 128.7, 128.4, 128.1, 128.1, 128.1, 128.1, 126.4, 125.4, 123.3, 121.6,
125.5, 123.2, 51.7, 39.2, 19.8, 19.8. HRMS (ESI) m/z: [M + Na] calcd
for C H NNaO 448.1519, found 448.1537 (−4.0 ppm).
27
23
4
14.6, 114.0, 113.9, 55.4, 55.3, 51.9, 51.8, 39.3, 39.2. HRMS (ESI) m/z:
(Z)-Methyl 3-(4-Chlorophenyl)-3-(3,4-dimethoxyphenyl)-2-
((1,3-dioxoisoindolin-2-yl)methyl)acrylate (5ha). Prepared fol-
lowing the general procedure. Compound 5ha was obtained as a red
+
[
M + Na] calcd for C H NNaO 450.1312, found 450.1331 (−4.9
26
21
5
ppm).
(
E)-Methyl 2-((1,3-Dioxoisoindolin-2-yl)methyl)-3-phenyl-3-
m-tolyl)acrylate and (E)-Methyl 2-((1,3-Dioxoisoindolin-2-yl)-
methyl)-3-phenyl-3-(p-tolyl)acrylate (5gh). Prepared following the
solid in 55% yield (54 mg) after flash chromatography (SiO , petroleum
2
1
(
ether/ethyl acetate, 7:3). H NMR (CDCl , 400 MHz): δ 7.80 (dd, J =
3
5
.4, 2.9 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H),
7.09 (d, J = 8.7 Hz, 2H), 6.95 (m, 1H), 6.80 (m, 2H), 4.68 (s, 2H), 3.85
s, 3H), 3.84 (s, 3H), 3.41 (s, 3H). 13C NMR (CDCl , 100 MHz): δ
general procedure, except that Pd(OAc) (7.5 mol %) and acridine (7.5
2
mol %) were used. Compounds 5gh were obtained as an inseparable
mixture of isomers as a yellow solid in 57% yield (47 mg, ratio that could
not be assigned and is thus given in no particular order = 0:40:60) after
flash chromatography (SiO , petroleum ether/ethyl acetate/toluene,
:3:2). H NMR (CDCl , 400 MHz): δ 7.80 (m, 3.4H), 7.68 (m, 3.4H),
(
3
169.0, 167.9, 149.2, 149.0, 148.9, 140.4, 134.2, 134.1, 132.1, 132.0, 130.0,
128.4, 126.3, 123.3, 122.3, 112.6, 111.0, 56.1, 56.0, 52.0, 39.4. HRMS
(ESI) m/z: [M + Na] calcd for C H ClNNaO 514.1028, found
+
2
27 22
6
1
5
7
2
1
1
1
5
514.1021 (1.3 ppm).
3
.27−7.07 (m, 14.3H), 4.65 (s, 1.4H), 4.63 (s, 2H), 3.39 (s, 3H), 3.38 (s,
.1H), 2.33 (s, 2.1H), 2.30 (s, 3H). 13C NMR (CDCl , 100 MHz): δ
3
ASSOCIATED CONTENT
■
69.3, 169.3, 167.9, 167.8, 150.7, 150.7, 141.9, 141.7, 139.7, 138.2, 138.2,
36.9, 134.0, 132.2, 132.2, 129.8, 129.4, 129.2, 129.1, 129.0, 128.6, 128.5,
28.4, 128.3, 128.1, 128.1, 126.3, 126.0, 125.7, 125.4, 123.3, 123.3, 51.9,
1.9, 39.2, 39.1, 21.5, 21.4. HRMS (ESI) m/z: [M + Na] calcd for
C H NNaO 434.1363, found 434.1372 (−2.2 ppm).
6
*
S
Supporting Information
1
13
Copies of H and C NMR spectra of alkenes 1f, 3, 4, and 5. This
material is available free of charge via the Internet at http://pubs.
acs.org.
+
2
21
4
G
DOI: 10.1021/acs.joc.5b00148
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
3
(
1
11) A review: Piera, J.; Bac
506−3523.
12) (a) Harada, S.; Yano, H.; Obora, Y. ChemCatChem 2013, 5, 121−
25. (b) Pankajakshan, S.; Xu, Y.-H.; Cheng, J. K.; Low, M. T.; Loh, T.-
̈
kvall, J.-E. Angew. Chem., Int. Ed. 2008, 47,
AUTHOR INFORMATION
Corresponding Authors
E-mail: jeb@organ.su.se (J.-E.B.).
E-mail: nicolas.gigant@u-psud.fr (N.G.).
■
*
*
P. Angew. Chem., Int. Ed. 2012, 51, 5701−5705. (c) Yamada, T.;
Notes
Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2005, 70, 5471−5474.
(
13) Acetonitrile can compete with BQ as a ligand, and this may lower
The authors declare no competing financial interest.
the rate: Jones, R. C.; Galezowski, M.; O’Shea, D. F. J. Org. Chem. 2013,
7
8, 8044−8053.
ACKNOWLEDGMENTS
■
(14) Pan, D.; Chen, A.; Su, Y.; Zhou, W.; Li, S.; Jia, W.; Xiao, J.; Liu, Q.;
Financial support from the European Research Council (ERC
AdG 247014), The Swedish Research Council, and The Knut
and Alice Wallenberg Foundation is gratefully acknowledged.
Zhang, L.; Jioa, N. Angew. Chem., Int. Ed. 2008, 47, 4729−4732.
(15) The stereochemistry of 5ga was determined by 2D NOE
experiment, which is in correlation with a typical syn β-H elimination.
(
̂
16) Pautigny, C.; Jeulin, S.; Ayad, T.; Zhang, Z.; Genet, J.-P.;
Ratovelomanana-Vidal, V. Adv. Synth. Catal. 2008, 350, 2525−2532.
(
(
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DOI: 10.1021/acs.joc.5b00148
J. Org. Chem. XXXX, XXX, XXX−XXX