Stereoretentive suzuki-miyaura and kumada-Tamao-corriu cross-couplings for preparing (E)-and (Z)-stereodefined, fully substituted α,β-unsaturated esters: Application for a pharmacophore synthesis

Article abstract of DOI:10.1055/s-0037-1610652

Substrate-general stereocomplementary Suzuki-Miyaura (SM) cross-coupling and relevant Kumada-Tamao-Corriu (KTC) crosscoupling reactions for preparing (E)-and (Z)-stereodefined, fully substituted α,β-unsaturated esters are described. The SM cross-coupling

Full text of DOI:10.1055/s-0037-1610652

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
paper
A
en
Y. Sato et al.
Paper
Synthesis
Stereoretentive Suzuki–Miyaura and Kumada–Tamao–Corriu
Cross-Couplings for Preparing (E)- and (Z)-Stereodefined, Fully
Substituted α,β-Unsaturated Esters: Application for a Pharmaco-
phore Synthesis
ArB(OH)2 [SM]
or RMgBr
[KTC]
Yuka Sato
(E)-Enol
tosylations
OTs
Ar (or R)
R2
Yuichiro Ashida
Daisuke Yoshitake
Mayuko Hoshino
Taichi Takemoto
Yoo Tanabe*
R2
R1
R1
cat. Pd(OAc)2,
cat. SPhos
O
CO2Me
CO2Me
CO2Me
R1
R2
OTs
Ar (or R)
CO2Me
CO2Me
R1
R1
(Z)-Enol
tosylations
Department of Chemistry, School of Science and Technology,
Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337,
R2
R2
Japan
C6H4(m-OBn)
C6H4(m-OBn)
CO2Me
tanabe@kwansei.ac.jp
Me
Application
Dedicated to Professor Teruaki Mukaiyama on the celebration of
his 90th birthday (Sotuju)
CO2Me
Me
Received: 05.06.2018
Accepted after revision: 12.07.2018
Published online: 23.08.2018
cost-effectiveness and sufficient reactivity, as well as their
desirable stability.2 Relevant methods using phosphonates3
and carbamates4 were recently disclosed. Fully substituted
(E)- and (Z)-α,β-unsaturated esters, obtained by these
methods, are distinctive scaffolds for the construction of in-
accessible stereodefined olefins.
DOI: 10.1055/s-0037-1610652; Art ID: ss-2018-f0388-op
Abstract Substrate-general stereocomplementary Suzuki–Miyaura
(SM) cross-coupling and relevant Kumada–Tamao–Corriu (KTC) cross-
coupling reactions for preparing (E)- and (Z)-stereodefined, fully substi-
tuted α,β-unsaturated esters are described. The SM cross-coupling re-
actions were performed under Pd(OAc)2/SPhos/iPr2NEt catalysis (24 ex-
amples, 66–99% yield). The KTC cross-coupling reactions were also
performed under similar Pd(OAc)2/SPhos conditions (11 examples, 50–
98% yield). Application to a useful pharmacophore containing a cyclo-
propane structure was investigated, wherein distinctive (E)- and (Z)-ste-
reochemical difference between XPhos and SPhos was observed. A
plausible mechanism for the stereoretention and stereoinversion cross-
coupling reactions is proposed.
Consistent with our long-standing studies on (E)- and
(Z)-stereocomplementary synthetic approaches, we have
reported stereoretentive Suzuki–Miyaura (SM),2e,5 Negishi,6
Sonogashira,2d and iron-catalyzed cross-coupling7 reactions
starting from (E)- and (Z)-stereodefined enol tosylates. Ap-
plications to the (E)- and (Z)-parallel concise syntheses of
zimelidine (use of the SM reaction)5 and tamoxifen (use of
the Negishi reaction),6 representative probes for multisub-
stituted stereodefined olefins, were recently accomplished.
The SM cross-coupling reaction is the most privileged
tool among various cross-coupling reactions. One represen-
tative SM cross-coupling reaction using (Z)-enol tosylates
derived from methyl acetoacetate is the subject of a recent
article in Organic Syntheses.8 Our previous method using
the SM cross-coupling reaction, however, did not deal with
substrate-general, fully substituted α,β-unsaturated esters
but rather with specific β,β-diaryl- and α,β-diaryl-α,β-un-
saturated esters.5 We report herein SM cross-coupling reac-
tions and relevant Kumada–Tamao–Corriu (KTC) cross-cou-
pling reactions to prepare more general α,α,β-fully substi-
tuted α,β-unsaturated esters (E)-1 and (Z)-1 (Figure 1). Both
methods (SM and KTC) are conducted under similar cata-
lytic systems (Scheme 1).
Key words Suzuki–Miyaura cross-coupling, Kumada–Tamao–Corriu
cross-coupling, fully substituted α,β-unsaturated esters, pharmaco-
phore, stereoretention, XPhos, SPhos
Both (E)- and (Z)-stereodefined olefins are widely dis-
tributed as basic frameworks of natural products, pharma-
ceuticals, supramolecules, and so forth. The development of
stereoselective preparative methods for these stereodefined
olefins is, therefore, a valuable subject in synthetic chemis-
try. A comprehensive review and several books have ad-
dressed the distinctive progress in this area.1 Especially, due
to the structural complexity compared with di- or trisubsti-
tuted derivatives, the stereocontrolled syntheses of fully (all
carbon) substituted olefins is attracting considerable atten-
tion as a challenging topic.1a
In addition, the present SM cross-coupling method can
be successfully applied for a robust (E)- and (Z)-stereo-
retentive method as exemplified in a key pharmacophore 5,
which was recently developed by a Merck group (Scheme
Among a variety of synthetic methods, stereocontrolled
cross-coupling reactions using enol sulfonates derived from
readily available β-keto esters are superb in view of their
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
Y. Sato et al.
Paper
Synthesis
This work
Reported syntheses
Ar1
Ar1
Ar
Ar
R2
CO2Me
CO2Me
Ar2
Ar2
R1
R1
SM
cross-coupling
R2
(Z)-1
CO2Me
CO2Me
(E)-1
R
1 = alkyl, Ph
2 = alkyl, Ph, OMe
Ar2
Ar2
R
Ar1
R (or Ph)
CO2Me
CO2Me
R (or Ph)
Me
Me
R2
KTC
cross-coupling
Ar1
R1
R1
CO2Me
R2
CO2Me
SM
cross-coupling
(E)-1
(Z)-1
Figure 1 Our objective for the preparation of fully substituted α,β-unsaturated esters
2).9 Notably, Merck’s method resulted in (E)- to (Z)-inver-
sion using enol tosylate (E)-3, whereas the present method
proceeded with retention (i.e., in an (E)- and (Z)-stereocom-
plementary manner).
Our initial attempt to perform this SM cross-coupling
reaction was intentionally guided using stereocongested
enol tosylates (E)- and (Z)-2a2f derived from methyl 2-bu-
tyl-3-oxooctanoate10 as a much less reactive substrate
probe (Table 1). Catalysis system screening revealed that
the combination of Pd(OAc)2/SPhos/iPr2NEt afforded the
best (E/Z)-stereoretention.11 In all cases examined, except
that using p-ClC6H4B(OH)2 reagent (entries 7, 8), the reac-
tion proceeded smoothly to afford the desired products (E)-
and (Z)-1a-1–1a-6 in excellent yield with good to excellent
(E)-Enol
tosylations
ArB(OH)2 [SM] or
OTs
Ar (or R)
R2
RMgBr [KMC]
R2
R1
R1
cat. Pd(OAc)2,
cat. SPhos
O
CO2Me
(E)-2
CO2Me
CO2Me
(E)-1
R1
OTs
Ar (or R)
R2
R2
CO2Me
CO2Me
R1
R1
(Z)-Enol
tosylations
R2
Table 1 Suzuki–Miyaura Cross-Coupling Reaction of (E)-2a and (Z)-2a
(Z)-1
(Z)-2
Scheme 1 (E)- and (Z)-stereocomplementary synthesis of fully substi-
tuted (E)- and (Z)-α,β-unsaturated esters
ArB(OH)2 (1.5 equiv), iPr2NEt (3.0 equiv)
OTs
Ar
Pd(OAc)2 (5 mol%), SPhos (10 mol%)
nBu
nBu
nPen
nPen
nPen
toluene/H2O (1:5), 80–85 °C, 2 h
CO2Me
CO2Me
(E)-2a
(E)-1a
OBn
OTs
Ar
OTs
CO2Me
retention
CO2Me
nPen
Me
CO2Me
Me
nBu
nBu
CO2Me
(E)-3
(Z)-2a
(Z)-1a
(E)-4
OBn
E/Za
inversion
Entry
Substrate Ar
Product
Yield (%)
OTs
1
2
(E)-2a
(Z)-2a
(E)-2a
(Z)-2a
(E)-2a
(Z)-2a
(E)-2a
(Z)-2a
(E)-2a
(Z)-2a
(E)-2a
(Z)-2a
Ph
(E)-1a-1
(Z)-1a-1
(E)-1a-2
(Z)-1a-2
(E)-1a-3
(Z)-1a-3
(E)-1a-4
(Z)-1a-4
(E)-1a-5
(Z)-1a-5
(E)-1a-6
(Z)-1a-6
97
92:8
CO2Me
CO2Me
Ph
99
2:>98
91:9
Me
(Z)-3
Me
3
p-MeC6H4
p-MeC6H4
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
p-ClC6H4
3-furyl
96
(Z)-4
4
99
2:>98
89:11
2:>98
92:8
The present protocol:
Merck's protocol:
asymmetric
hydrogenation
5
99
6
95
OBn
7
66
8
68 (11)b
89
2:>98
87:13
2:>98
93:7
CO2Me
9
Me
10
11
12
3-furyl
98
5
3-thienyl
3-thienyl
93
Scheme 2 (E)- and (Z)-stereoretentive synthesis of a pharmacophore
91
2:>98
a Determined by 1H NMR spectroscopy of the crude products.
b Methyl (Z)-2-butyl-3-(4′-chlorobiphenyl-4-yl)oct-2-enoate ((Z)-1a-4′)
was obtained as a major byproduct.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
Y. Sato et al.
Paper
Synthesis
(E)- and (Z)-stereoretention. The heterocyclic 3-furyl- and
3-thienylboronic acid reactants also underwent the reac-
tion successfully to afford the desired products (E)- and (Z)-
1a-5, 1a-6 (entries 9–12). In general, relevant Negishi cross-
coupling reactions cannot be applied for this type of het-
erocyclic reagent.
With the successful outcome in hand, the substrate-
generality of the present SM cross-coupling reaction was
examined (Scheme 3) using a variety of enol tosylates (E)-
and (Z)-2b–2h under the identical conditions as in Table
1.12 The salient features are as follows: (i) Three sets of ali-
phatic substrates underwent the reaction to give the corre-
sponding products (E)- and (Z)-1b–1d in good to excellent
yield with nearly complete (E)- and (Z)-stereoretention. (ii)
A labile 7-chloro-substituted substrate was applicable, to
give (E)- and (Z)-1e. (iii) Two sets of phenyl substrates also
underwent the reaction successfully, affording the corre-
sponding products (E)-1f and (Z)-1f, and (E)-1g in good to
excellent yields with excellent (E)- and (Z)-stereoretention.
(iv) An α-methoxy-substituted substrate was also applied in
the reaction to yield the desired products (E)- and (Z)-1h.
Next, we turned our attention to KTC cross-coupling re-
actions of R3MgBr (R3 = alkyl, Ph) with enol tosylates (E)-
and (Z)-2a, 2i under conditions similar to those applied
when using Pd(OAc)2/SPhos catalysis (Scheme 4). The sa-
lient features are as follows: (i) In most cases good to excel-
lent yield and selectivity were obtained. (ii) MeCN solvent
matched the reaction using (E)-2 substrates, whereas THF
solvent matched that using (Z)-2 substrates. (iii) R3MgBr
where R3 = Me, Et, iPr, and Ph were applicable as the re-
agent. (iv) A side reduction reaction of the TsO group oc-
curred exclusively when the reaction of (E)-2a with EtMgBr
was carried out, possibly due to a plausible β-hydride shift
of the Et group. In contrast, the reaction using (Z)-2a gave
satisfactory results. (v) The reaction using PhMgBr proceed-
OTs
R3
R3MgBr (1.5 equiv),
Pd(OAc)2 (5 mol%), SPhos (10 mol%)
R2
CO2Me
(E)-2
OTs
R2
R1
R1
CO2Me
MeCN, 40–45 °C, 3 h
OTs
(E)-1
R3
Ph
ArB(OH)2 (1.5 equiv), iPr2NEt (3.0 equiv)
Pd(OAc)2 (5 mol%), SPhos (10 mol%)
R2
R2
R1
R1
CO2Me
CO2Me
CO2Me
CO2Me
toluene/H2O (1:5), 80–85 °C, 2 h
R1
R1
THF, 40–45 °C, 3 h
(E)-2
(E)-1
R2
R2
(Z)-1
OTs
Ph
(Z)-2
CO2Me
CO2Me
R1
R1
R2
(Z)-2
R2
a
yield (E/Z)
(Z)-1
Me
Ph
Et
nBu
CO2Me
nBu
yield (E/Z)a
nBu
nPen
nPen
nPen
CO2Me
Ph
Ph
Ph
Ph
CO2Me
nBu
iPr
CO2Me
CO2Me
(Z)-1a-7
96% (3:97)
(E)-1a-1
82% (7:93)
Me
Me
Me
not obtained b
Me
CO2Me
(E)-1b
CO2Me
iPr
(Z)-1c
nBu
(Z)-1b
(E)-1c
80% (>98:2)
Me
Et
Ph
95% (98:2)
93% (2:>98)
92% (2:>98)
CO2Me
CO2Me
CO2Me
nPen
nPen
nPen
nBu
nBu
nBu
Ph
Ph
Ph
Ph
Me
CO2Me
CO2Me
(E)-1a-7
98% (97:3)
(E)-1a-8
74% (>98:2)
(Z)-1a-1
50% (80:20)
Me
nPen
nPen
Cl
Cl
3
3
CO2Me
(E)-1d
Me
(Z)-1d
Me
CO2Me
(Z)-1e
96% (2:>98)
(E)-1e
99% (97:3)
93% (>98:2)
Et
iPr
Ph
96% (2:>98)
Ph
Ph
Ph
Me
Me
Me
C6H4(p-Me)
C6H4(p-Me)
CO2Me
C6H4(p-Me)
CO2Me
CO2Me
CO2Me
Me
Ph
Ph
Ph
Ph
(E)-1i-1
(E)-1i-2
(E)-1i-3
77% (4:96)
71% (2:>98)
91% (19:81)
CO2Me
Me
CO2Me
(E)-1f
99% (95:5)
(Z)-1f
99% (2:>98)
(E)-1g
92% (>98:2)
Et
iPr
Ph
CO2Me
CO2Me
CO2Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
OMe
CO2Me
nPen
nPen
(Z)-1i-1
(Z)-1i-2
(Z)-1i-3
78% (94:6)
51% (96:4)
88% (71:29)
CO2Me
OMe
(Z)-1h
(E)-1h
95% (>98:2)
Scheme 4 Kumada–Tamao–Corriu cross-coupling reaction of (E)-2
and (Z)-2. a Determined by 1H NMR spectroscopy of the crude prod-
ucts. b Instead, methyl (Z)-2-butyloct-2-enoate was obtained as the
main product.
99% (3:97)
Scheme 3 Substrate generality of the Suzuki–Miyaura cross-coupling
reaction of (E)-2 and (Z)-2. a Determined by 1H NMR spectroscopy of
the crude products.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
Y. Sato et al.
Paper
Synthesis
ed smoothly to give the desired product (E)- and (Z)-1a-3 in
excellent yield but slight (E)- to (Z)- and (Z)- to (E)-isomeri-
zation took place.
logue (E)-3b-1 actually gave (Z)-4a and (Z)-4b, respectively,
with apparent stereoinversion (E to Z) (entries 1, 2). (ii) Nov-
el p-O2NC6H4 analogues (E)-3a-2 and (E)-3b-2 similarly un-
derwent the inversion reaction (entries 3, 4). (iii) To our de-
light, the present Method B was consistently stereoretentive
to circumvent (E)- to (Z)-isomerization (entries 5–8). (iv)
The reaction of (Z)-3a-1 using both Methods A and B oc-
curred in a highly (Z)-stereoretentive manner, as expected
(entries 9, 10).
The proposed mechanism for not only (E)-stereoreten-
tion, but also (E)- to (Z)-inversion processes, is depicted in
Scheme 5; a catalytic cycle starting from (E)-3a-1 yields
product (E)-4a or (Z)-4a. ArPdLn (Ln = XPhos or SPhos) inter-
mediate I is initially formed through the privileged pathway
of the SM cross-coupling reaction. Stereoretentive product
(E)-4a is in turn afforded with the regeneration of Pd(0)Ln
(Method B). When the zwitterion intermediate II is trans-
formed to III with single-bond rotation by equilibrium, ste-
reoinversion product (Z)-4a is obtained through ArPdLn in-
termediate IV. Although the concrete reason for the ligand
effect is unclear at present, the present Method B using
SPhos catalysis sufficiently retarded the (E)- to (Z)-stereoin-
version compared with the reported Method A using XPhos
catalysis.13 This tendency coincides with the aforemen-
tioned initial catalysis screening.11
As a distinct application, we investigated the SM cross-
coupling reaction for (E)- and (Z)-stereocomplementary
synthesis of a key pharmacophore (Z)-4a3 together with its
stereoisomer (E)-4a (Table 2). Two sets of enol sulfonate an-
alogues were used as the substrate: (E)-3a-1 and (E)-3b-1
(Ar = Ts), and (E)-3a-2 and (E)-3b-2 (Ar = p-O2NC6H4). Merck
group’s reported conditions (Method A) utilized XPhos ca-
talysis, whereas the present conditions utilized SPhos catal-
ysis (Method B). The salient features are as follows: (i) Re-
examination of Method A using (E)-3a-1 and isopropyl ana-
Table 2 Suzuki–Miyaura Cross-Coupling: Comparison of the Reported
and Present Methods
OBn
OSO2Ar
the present method (B)
Me
Me
R
R
CO2Me
CO2Me
(E)-4a, 4b
reported method
(A)
(E)-3a-1, 2: R =
(E)-3b-1, 2: R =
OBn
reported method (A)
Ar
OTs
OSO2Ar
CO2Me
Me
the present method (B)
CO2Me
R
CO2Me
Me
CO2Me
(E)-3a-1
R
Me
(Z)-3a-1: R =
Me
(Z)-4a
(Z)-4a
Pd(0)Ln
OTs
LnPd
Me
CO2Me
(A) m-(BnO)C6H4B(OH)2 (1.5 equiv), iPr2NEt (3.0 equiv), Pd(OAc)2 (5 mol%),
XPhos (10 mol%), toluene–H2O (1:5), 80–85 °C, 2 h
Ar
ArBH(OH)2
Me
(B) m-(BnO)C6H4B(OH)2 (1.5 equiv), iPr2NEt (3.0 equiv), Pd(OAc)2 (5 mol%),
SPhos (10 mol%), toluene–H2O (1:5), 80–85 °C, 2 h
< Method B >
Ar
CO2Me
(TsO)B(OH)2
Entry Method Ar
Substrate Major
product
Yield
(%)
E/Za
(E)-4a
Ar
PdLn
PdLn
CO2Me
Me
1b
2
A
A
A
A
B
B
B
B
A
B
Ts
(E)-3a-1
(E)-3b-1
(E)-3a-2
(E)-3b-2
(E)-3a-1
(E)-3b-1
(E)-3a-2
(E)-3b-2
(Z)-3a-1
(Z)-3a-1
(Z)-4a
59
61
84
64
88
64
44
76
74d
86
5:95
Me
CO2Me
Ts
(Z)-4b
(Z)-4a
(Z)-4b
(E)-4a
(E)-4b
(E)-4a
(E)-4b
(Z)-4a
(Z)-4a
26:74
4:96
IV
I
3
p-O2NC6H4
Ar
Ar
PdLn
O
PdLn
4
p-O2NC6H4
33:67
86:14
95:5
Me
O
OMe
5
Ts
Me
MeO
6
Ts
< Method A >
III
II
7
p-O2NC6H4
77:23
>98:2
0:100e
2:>98
Ln = XPhos (Method A)
SPhos (Method B)
8
p-O2NC6H4
9c
Ts
Ts
Scheme 5 Plausible reaction mechanism with retention and isomeriza-
10
tion pathways
a Determined by 1H NMR spectroscopy of the crude products.
b Re-examination of the reported method.
c Reported data.
In conclusion, we have developed substrate-general ste-
reoretentive SM cross-coupling and relevant KTC cross-cou-
pling reactions for preparing (E)- and (Z)-stereodefined, ful-
ly substituted α,β-unsaturated esters. A synthetic applica-
d Isolation data.
e The ratio of crude product was not reported.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
Y. Sato et al.
Paper
Synthesis
tion to a useful pharmacophore possessing a cyclopropane
structure was performed, wherein we observed distinctive
(E)- and (Z)-stereochemical difference between XPhos (ste-
reoinversion) and SPhos (stereoretention) catalysis.
HRMS (ESI): m/z [M + Na]+ calcd for C20H30O2Na: 325.2143; found:
325.2129.
Methyl (Z)-2-Butyl-3-(4-methylphenyl)oct-2-enoate ((Z)-1a-2)
Yield: 151 mg (99%, E/Z = 2:>98); colorless oil.
IR (neat): 2920, 1715, 1511, 1431, 1323, 1245, 1200, 1137 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.83 (t, J = 6.5 Hz, 3 H), 0.93 (t, J = 6.9
Hz, 3 H), 1.17–1.50 (m, 10 H), 2.32 (s, 3 H), 2.37–2.47 (m, 4 H), 3.37 (s,
3 H), 6.97–7.04 (m, 2 H), 7.05–7.12 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 13.9, 21.1, 22.4, 22.6, 27.5, 30.0, 31.1,
31.7, 34.0, 51.1, 127.3, 128.6, 131.3, 136.4, 139.6, 146.1, 171.4.
All reactions were carried out in oven-dried glassware under an ar-
gon atmosphere. Flash column chromatography was performed with
Merck silica gel 60 (230–400 mesh ASTM). TLC analysis was per-
formed on Merck 0.25 mm silica gel 60 F254 plates. Melting points
were determined on a hot-stage microscope apparatus (AS ONE,
ATM-01) and are uncorrected. NMR spectra were recorded on a JEOL
DELTA 300 or JEOL RESONANCE ECX-500 spectrometer, operating at
300 MHz or 500 MHz for 1H NMR and 75 MHz or 125 MHz for 13C
NMR acquisitions. Chemical shifts (δ, ppm) in CDCl3 are reported
downfield from TMS (0 ppm) for 1H NMR data. For 13C NMR data,
chemical shifts are reported in the scale relative to CDCl3 (77.00 ppm)
as an internal reference. IR spectra were recorded on a JASCO FT/IR-
5300 spectrophotometer. Mass spectra were measured on a JEOL
JMS-T100LC spectrometer. Enol tosylates (E)-2a, (Z)-2a, (E)-2b, (Z)-
2b, (E)-2c, (Z)-2c, (E)-2d, (Z)-2d, (E)-2e, (Z)-2e, (E)-2f, (Z)-2f, (E)-2g,
(E)-2h, (Z)-2h, (E)-2i, and (Z)-2i are known compounds.2f (E)-3a-1
and (E)-3a-2 are also reported compounds.9 The (E)- and (Z)-stereo-
complementary enol tosylations of parent β-keto esters were carried
out using the TsCl–Me2N(CH2)6NMe2 reagent for (E)-2 and the TsCl–
TMEDA–LiCl reagent for (Z)-2.2f (E)-3a-2 and (E)-3b-2 were prepared
according to a Merck group’s procedure.9 All stereochemistries (E,Z) of
the fully substituted (E)- and (Z)-α,β-unsaturated esters 1 and 4 were
determined by comparison with reported compounds or by deduc-
tion from them.
Methyl (E)-2-Butyl-3-(4-methoxyphenyl)oct-2-enoate ((E)-1a-3)
Yield: 160 mg (99%, E/Z = 89:11); colorless oil.
IR (neat): 2954, 2927, 2859, 1717, 1608, 1509, 1463, 1245 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.76 (t, J = 7.2 Hz, 3 H), 0.82 (t, J = 7.2
Hz, 3 H), 1.08–1.34 (m, 10 H), 2.09 (t, J = 7.2 Hz, 2 H), 2.43 (t, J = 7.2
Hz, 2 H), 3.78 (s, 3 H), 3.82 (s, 3 H), 6.84–6.90 (m, 2 H), 6.99–7.05 (m, 2
H).
13C NMR (75 MHz, CDCl3): δ = 13.8, 14.0, 22.4, 27.7, 30.8, 31.3, 31.7,
36.6, 51.3, 55.2, 113.5, 128.9, 130.6, 133.7, 147.0, 158.4, 170.9.
HRMS (ESI): m/z [M + Na]+ calcd for C20H30O3Na: 341.2093; found:
341.2095.
Methyl (Z)-2-Butyl-3-(4-methoxyphenyl)oct-2-enoate ((Z)-1a-3)
Yield: 151 mg (95%, E/Z = 2:>98); colorless oil.
IR (neat): 2955, 2871, 1710, 1607, 1509, 1462, 1323, 1244 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.83 (t, J = 6.9 Hz, 3 H), 0.93 (t, J = 6.9
Hz, 3 H), 1.17–1.48 (m, 10 H), 2.34–2.47 (m, 4 H), 3.38 (s, 3 H), 3.80 (s,
3 H), 6.77–6.85 (m, 2 H), 7.02–7.09 (m, 2 H).
Suzuki–Miyaura Cross-Couplings; General Procedure (Scheme 3)
13C NMR (75 MHz, CDCl3): δ = 13.8, 22.3, 22.5, 27.5, 30.0, 31.0, 31.5,
33.9, 51.0, 54.9, 113.2, 128.5, 131.2, 134.8, 145.4, 158.5, 171.5.
An enol tosylate (0.50 mmol) was added to a stirred suspension of
ArB(OH)2 (0.75 mmol), iPr2NEt (194 mg, 1.50 mmol), Pd(OAc)2 (6 mg,
0.025 mmol), and SPhos (20 mg, 0.05 mmol) in toluene (0.7 mL)/wa-
ter (3.3 mL) at 80–85 °C under an argon atmosphere, and the mixture
was stirred for 2 h. After cooling, water was added to the mixture,
which was extracted twice with AcOEt. The combined organic phase
was washed with water and brine, dried (Na2SO4), and concentrated.
The obtained crude product was purified by silica gel column chro-
matography (hexane/Et2O, 200:1 to 100:1) to give the desired prod-
uct.
Methyl (E)-2-Butyl-3-(4-chlorophenyl)oct-2-enoate ((E)-1a-4)
Yield: 106 mg (66%, E/Z = 92:8); colorless oil.
IR (neat): 2956, 2929, 2860, 1720, 1489, 1462, 1433, 1204 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.76 (t, J = 7.2 Hz, 3 H), 0.82 (t, J = 7.2
Hz, 3 H), 1.07–1.36 (m, 10 H), 2.05 (t, J = 7.2 Hz, 2 H), 2.42 (t, J = 7.2
Hz, 2 H), 3.79 (s, 3 H), 7.00–7.07 (m, 2 H), 7.29–7.36 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 13.7, 13.9, 22.3, 27.6, 30.8, 31.1, 31.6,
36.3, 51.4, 128.4, 129.2, 131.3, 132.8, 139.8, 145.8, 170.4.
Methyl (E)-2-Butyl-3-phenyloct-2-enoate ((E)-1a-1)3
Yield: 139 mg (97%, E/Z = 92:8); colorless oil.
Methyl (Z)-2-Butyl-3-(4-chlorophenyl)oct-2-enoate ((Z)-1a-4)
Yield: 110 mg (68%, E/Z = 2:>98); colorless oil.
Methyl (Z)-2-Butyl-3-phenyloct-2-enoate ((Z)-1a-1)3
Yield: 152 mg (99%, E/Z = 2:>98); colorless oil.
IR (neat): 2956, 2860, 1715, 1488, 1466, 1432, 1242, 1139 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.83 (t, J = 6.9 Hz, 3 H), 0.93 (t, J = 6.9
Hz, 3 H), 1.18–1.49 (m, 10 H), 2.34–2.47 (m, 4 H), 3.38 (s, 3 H), 7.01–
7.08 (m, 2 H), 7.22–7.29 (m, 2 H).
Methyl (E)-2-Butyl-3-(4-methylphenyl)oct-2-enoate ((E)-1a-2)
Yield: 146 mg (96%, E/Z = 91:9); oil.
IR (neat): 2956, 2927, 2860, 1718, 1509, 1457, 1203, 1136 cm–1
.
13C NMR (75 MHz, CDCl3): δ = 13.9, 22.4, 22.5, 27.4, 29.9, 31.0, 31.6,
1H NMR (300 MHz, CDCl3): δ = 0.76 (t, J = 7.2 Hz, 3 H), 0.82 (t, J = 7.2
Hz, 3 H), 1.09–1.36 (m, 10 H), 2.08 (t, J = 7.2 Hz, 2 H), 2.36 (s, 3 H),
2.44 (t, J = 7.2 Hz, 2 H), 3.79 (s, 3 H), 6.95–7.02 (m, 2 H), 7.11–7.19 (m,
2 H).
34.0, 51.2, 128.1, 128.8, 132.2, 132.7, 141.1, 144.9, 170.8.
HRMS (ESI): m/z [M + Na]+ calcd for C19H27O2ClNa: 345.1597; found:
345.1611.
13C NMR (75 MHz, CDCl3): δ = 13.7, 13.9, 21.1, 22.3, 22.4, 27.7, 30.8,
31.2, 31.6, 36.5, 51.2, 127.6, 128.7, 130.5, 136.4, 138.4, 147.4, 170.7.
Methyl (Z)-2-Butyl-3-(4′-chlorobiphenyl-4-yl)oct-2-enoate ((Z)-
1a-4′)
19 mg (11%); colorless oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

F
Y. Sato et al.
Paper
Synthesis
IR (neat): 2955, 2927, 2859, 1714, 1485, 1457, 1432, 1241 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.76 (t, J = 7.5 Hz, 3 H), 1.15 (sext,
J = 7.5 Hz, 2 H), 1.23–1.32 (m, 2 H), 2.13 (t, J = 8.0 Hz, 2 H), 2.16 (s, 3
H), 3.81 (s, 3 H), 7.11–7.15 (m, 2 H), 7.25–7.29 (m, 1 H), 7.32–7.37 (m,
2 H).
13C NMR (125 MHz, CDCl3): δ = 13.7, 22.3, 23.3, 30.6, 31.2, 51.4, 126.9,
127.1 (2 C), 128.2 (2 C), 130.6, 143.0, 143.5, 170.5.
1H NMR (300 MHz, CDCl3): δ = 0.84 (t, J = 7.2 Hz, 3 H), 0.94 (t, J = 7.2
Hz, 3 H), 1.16–1.51 (m, 10 H), 2.36–2.54 (m, 4 H), 3.36 (s, 3 H), 7.15–
7.23 (m, 2 H), 7.36–7.43 (m, 2 H), 7.44–7.56 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 14.0, 22.4, 22.6, 27.6, 30.0, 31.1, 31.7,
34.1, 51.2, 126.4, 128.0, 128.2, 128.9, 131.9, 133.3, 138.3, 139.2, 142.1,
145.7, 171.2.
Methyl (Z)-2-(1-Phenylethylidene)hexanoate ((Z)-1b)6
Yield: 134 mg (92%, E/Z = 2:>98); colorless oil.
HRMS (ESI): m/z [M + Na]+ calcd for C25H31O2ClNa: 421.1910; found:
421.1897.
IR (neat): 2955, 2871, 1714, 1492, 1433, 1318, 1240, 1139 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.94 (t, J = 7.5 Hz, 3 H), 1.34–1.51 (m, 4
H), 2.10 (s, 3 H), 2.44 (t, J = 8.0 Hz, 2 H), 3.37 (s, 3 H), 7.12–7.16 (m, 2
H), 7.21–7.25 (m, 1 H), 7.27–7.32 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 13.9, 20.8, 22.5, 30.4, 30.7, 51.1, 126.8
(2 C), 126.9, 127.9 (2 C), 131.5, 141.7, 144.0, 171.1.
Methyl (E)-2-Butyl-3-(3-furyl)oct-2-enoate ((E)-1a-5)
Yield: 124 mg (89%, E/Z = 87:13); pale yellow oil.
IR (neat): 2955, 2929, 2860, 1956, 1716, 1458, 1434, 1204 cm–1
1H NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 7.2 Hz, 6 H), 1.18–1.43 (m,
10 H), 2.30 (t, J = 7.2 Hz, 2 H), 2.37 (t, J = 7.2 Hz, 2 H), 3.78 (s, 3 H),
6.31–6.33 (m, 1 H), 7.31–7.33 (m, 1 H), 7.41–7.43 (m, 1 H).
.
HRMS (ESI): m/z [M + Na]+ calcd for C15H20O2Na: 255.1361; found:
255.1360.
13C NMR (75 MHz, CDCl3): δ = 13.8, 13.9, 22.3, 22.4, 28.2, 31.0, 31.0
(x2), 31.6, 35.8, 51.3, 110.9, 124.5, 131.6, 137.6, 139.7, 142.6, 170.6.
HRMS (ESI): m/z [M + Na]+ calcd for C17H26O3Na: 301.1790; found:
301.1796.
Methyl (E)-2-Isopropyl-3-phenylbut-2-enoate ((E)-1c)6
Yield: 87 mg (80%, E/Z = >98:2); colorless oil.
Methyl (Z)-2-Isopropyl-3-phenylbut-2-enoate ((Z)-1c)6
Yield: 102 mg (93%, E/Z = 2:>98); colorless oil.
Methyl (Z)-2-Butyl-3-(3-furyl)oct-2-enoate ((Z)-1a-5)
Yield: 136 mg (98%, E/Z = 2:>98); pale yellow oil.
IR (neat): 2926, 2860, 1718, 1637, 1503, 1461, 1433, 1330 cm–1
.
Methyl (E)-2-Methyl-3-phenyloct-2-enoate ((E)-1d)3
Yield: 115 mg (93%, E/Z = >98:2); colorless oil.
1H NMR (300 MHz, CDCl3): δ = 0.86 (t, J = 6.9 Hz, 3 H), 0.92 (t, J = 6.9
Hz, 3 H), 1.18–1.48 (m, 10 H), 2.27–2.43 (m, 4 H), 3.58 (s, 3 H), 6.27–
6.32 (m, 1 H), 7.30–7.39 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 13.8, 13.8, 22.4, 22.5, 27.9, 30.0, 30.8,
31.6, 32.9, 51.3, 110.2, 125.6, 131.5, 134.1, 139.7, 142.5, 171.8.
Methyl (Z)-2-Methyl-3-phenyloct-2-enoate ((Z)-1d)3
Yield: 118 mg (96%, E/Z = 2:>98); colorless oil.
Methyl (E)-7-Chloro-2-methyl-3-phenylhept-2-enoate ((E)-1e)3
Yield: 143 mg (99%, E/Z = 97:3); colorless oil.
Methyl (E)-2-Butyl-3-(3-thienyl)oct-2-enoate ((E)-1a-6)
Yield: 137 mg (93%, E/Z = 93:7); colorless oil.
IR (neat): 2955, 2927, 2859, 1717, 1457, 1433, 1200, 1132 cm–1
.
Methyl (Z)-7-Chloro-2-methyl-3-phenylhept-2-enoate ((Z)-1e)3
Yield: 128 mg (96%, E/Z = 2:>98); colorless oil.
1H NMR (300 MHz, CDCl3): δ = 0.80 (t, J = 7.2 Hz, 3 H), 0.83 (t, J = 7.2
Hz, 3 H), 1.13–1.37 (m, 10 H), 2.18 (t, J = 7.2 Hz, 2 H), 2.43 (t, J = 7.2
Hz, 2 H), 3.79 (s, 3 H), 6.89–6.94 (m, 1 H), 6.99–7.03 (m, 1 H), 7.28–
7.33 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 13.7, 13.9, 22.3, 28.0, 30.9, 31.3, 31.5,
36.2, 51.3, 121.8, 125.1, 127.7, 131.5, 141.3, 142.2, 170.5.
Methyl (E)-2-Methyl-3-(4-methylphenyl)-3-phenylacrylate ((E)-
1f)6
Yield: 132 mg (99%, E/Z = 95:5); pale yellow oil.
Methyl (Z)-2-Methyl-3-(4-methylphenyl)-3-phenylacrylate ((Z)-
Methyl (Z)-2-Butyl-3-(3-thienyl)oct-2-enoate ((Z)-1a-6)
Yield: 134 mg (91%, E/Z = 2:>98); pale yellow oil.
IR (neat): 2924, 2856, 1713, 1457, 1431, 1312, 1235, 1201 cm–1
1f)6
Yield: 133 mg (99%, E/Z = 2:>98); pale yellow oil.
.
1H NMR (300 MHz, CDCl3): δ = 0.84 (t, J = 6.9 Hz, 3 H), 0.92 (t, J = 6.9
Hz, 3 H), 1.18–1.48 (m, 10 H), 2.35–2.44 (m, 4 H), 3.45 (s, 3 H), 6.91–
6.95 (m, 1 H), 7.01–7.05 (m, 1 H), 7.22–7.26 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 13.8, 22.3, 22.5, 27.7, 29.9, 30.8, 31.5,
33.5, 51.2, 121.5, 124.7, 127.3, 132.0, 139.5, 142.4, 171.6.
Methyl (E)-3-(4-Methylphenyl)-2,3-diphenylacrylate ((E)-1g)
Yield: 144 mg (92%, E/Z = >98:2); colorless crystals; mp 147–148 °C.
IR (neat): 2955, 1717, 1489, 1442, 1430, 1262, 1221, 1145 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.36 (s, 3 H), 3.58 (s, 3 H), 6.97–7.02
(m, 2 H), 7.07–7.19 (m, 12 H).
13C NMR (75 MHz, CDCl3): δ = 21.2, 51.8, 127.2, 127.5, 127.7, 128.1,
128.8, 128.8, 129.7, 130.8, 132.8, 137.5, 137.9, 139.3, 140.6, 146.2,
170.9.
HRMS (ESI): m/z [M + Na]+ calcd for C17H26O2SNa: 317.1551; found:
317.1548.
Methyl (E)-2-(1-Phenylethylidene)hexanoate ((E)-1b)6
Yield: 134 mg (95%, E/Z = 98:2); colorless oil.
HRMS (ESI): m/z [M + Na]+ calcd for C23H20O2Na: 351.1361; found:
351.1350.
IR (neat): 2955, 2860, 1718, 1490, 1434, 1316, 1258, 1136 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

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Y. Sato et al.
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Synthesis
Methyl (E)-2-Methoxy-3-phenyloct-2-enoate ((E)-1h)6
Yield: 125 mg (95%, E/Z = >98:2); colorless oil.
Methyl (E)-3-Ethyl-2-butyloct-2-enoate ((E)-1a-8)
Yield: 89 mg (74%, E/Z = >98:2); colorless oil.
IR (neat): 2956, 2871, 1717, 1627, 1459, 1433, 1196, 1116 cm–1
.
Methyl (Z)-2-Methoxy-3-phenyloct-2-enoate ((Z)-1h)6
Yield: 132 mg (99%, E/Z = 3:97); colorless oil.
1H NMR (300 MHz, CDCl3): δ = 0.84–0.94 (m, 6 H), 1.03 (t, J = 7.6 Hz, 3
H), 1.21–1.46 (m, 10 H), 2.08 (t, J = 7.6 Hz, 2 H), 2.16–2.31 (m, 4 H),
3.72 (s, 3 H).
Kumada–Tamao–Corriu Cross-Couplings; General Procedure
(Scheme 4)
13C NMR (75 MHz, CDCl3): δ = 13.4, 13.9, 13.9, 22.5, 22.5, 27.2, 28.1,
29.3, 31.5, 32.1, 51.0, 128.0, 149.7, 170.6.
R3MgBr (0.76 mL; 0.99 M in THF) was added to a stirred solution of an
(E)-enol tosylate (0.50 mmol), Pd(OAc)2 (6 mg, 0.025 mmol), and
SPhos (20 mg, 0.05 mmol) in MeCN (0.5 mL) at 40–45 °C under an ar-
gon atmosphere, and the mixture was stirred at that same tempera-
ture for 3 h. After cooling, 3 M aq HCl solution was added to the mix-
ture, which was extracted twice with AcOEt. The combined organic
phase was washed with water and brine, dried (Na2SO4), and concen-
trated. The obtained crude oil was purified by silica gel column chro-
matography (hexane/Et2O, 200:1 to 100:1) to give the desired prod-
uct.
Methyl (E)-3-Methyl-2-phenylpent-2-enoate ((E)-1i-1)
Yield: 79 mg (78%, E/Z = 94:6); colorless oil.
IR (neat): 2971, 2876, 1712, 1625, 1493, 1433, 1291, 1212 cm–1
1H NMR (300 MHz, CDCl3): δ = 0.96 (t, J = 7.6 Hz, 3 H), 1.97 (q, J = 7.6
Hz, 2 H), 2.12 (s, 3 H), 3.66 (s, 3 H), 7.13–7.20 (m, 2 H), 7.24–7.37 (m, 3
H).
.
13C NMR (75 MHz, CDCl3): δ = 12.4, 19.5, 29.3, 51.5, 126.9, 128.0,
129.3, 138.0, 150.6, 168.9.
R3MgBr (0.76 mL; 0.99 M in THF) was added to a stirred solution of a
(Z)-enol tosylate (0.50 mmol), Pd(OAc)2 (6 mg, 0.025 mmol), and
SPhos (20 mg, 0.05 mmol) in THF (0.5 mL) at 40–45 °C under an argon
atmosphere, and the mixture was stirred at that same temperature
for 3 h. After cooling, 3 M aq HCl solution was added to the mixture,
which was extracted twice with AcOEt. The combined organic phase
was washed with water and brine, dried (Na2SO4), and concentrated.
The obtained crude oil was purified by silica gel column chromatogra-
phy (hexane/Et2O, 200:1 to 100:1) to give the desired product.
Methyl (Z)-3-Methyl-2-phenylpent-2-enoate ((Z)-1i-1)
Yield: 79 mg (77%, E/Z = 4:96); colorless oil.
IR (neat): 2972, 2875, 1713, 1625, 1599, 1433, 1260, 1209 cm–1
1H NMR (300 MHz, CDCl3): δ = 1.16 (t, J = 7.6 Hz, 3 H), 1.67 (s, 3 H),
2.46 (q, J = 7.6 Hz, 2 H), 3.66 (s, 3 H), 7.13–7.21 (m, 2 H), 7.23–7.39 (m,
3 H).
.
13C NMR (75 MHz, CDCl3): δ = 12.9, 20.2, 29.2, 51.5, 126.9, 128.1,
129.4, 129.4, 138.1, 149.9, 168.8.
Methyl (Z)-2-Butyl-3-methyloct-2-enoate ((Z)-1a-7)
Yield: 109 mg (96%, E/Z = 3:97); colorless oil.
IR (neat): 2927, 2859, 1716, 1631, 1459, 1433, 1377, 1202 cm–1
Methyl (E)-3,4-Dimethyl-2-phenylpent-2-enoate ((E)-1i-2)
Yield: 56 mg (51%, E/Z = 96:4); colorless oil.
.
1H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 6.9 Hz, 3 H), 0.90 (t, J = 6.9
Hz, 3 H), 1.19–1.49 (m, 10 H), 1.77 (s, 3 H), 2.17–2.30 (m, 4 H), 3.71 (s,
3 H).
IR (neat): 2962, 2871, 1713, 1620, 1433, 1292, 1225, 1206 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.94 (d, J = 6.9 Hz, 6 H), 1.99 (s, 3 H),
2.55 (sept, J = 6.9 Hz, 1 H), 3.65 (s, 3 H), 7.13–7.19 (m, 2 H), 7.27–7.37
(m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 13.9, 14.0, 19.2, 22.5, 22.5, 28.1, 29.8,
31.1, 31.9, 36.4, 51.1, 128.2, 144.8, 170.5.
13C NMR (75 MHz, CDCl3): δ = 14.1, 20.2, 31.8, 51.5, 126.9, 128.1,
129.2, 138.0, 153.1, 169.2.
HRMS (ESI): m/z [M + Na]+ calcd for C14H18O2Na: 241.1204; found:
241.1193.
Methyl (E)-2-Butyl-3-methyloct-2-enoate ((E)-1a-7)
Yield: 111 mg (98%, E/Z = 97:3); colorless oil.
IR (neat): 2925, 1860, 1716, 1628, 1433, 1378, 1280, 1198 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.90 (t, J = 6.9 Hz, 6 H), 1.22–1.48 (m,
10 H), 1.90 (s, 3 H), 2.10 (t, J = 7.6 Hz, 2 H), 2.27 (t, J = 6.9 Hz, 2 H), 3.72
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 13.9, 14.0, 20.8, 22.5, 22.6, 27.6, 29.3,
31.6, 31.9, 35.2, 51.1, 128.2, 144.9, 170.7.
Methyl (Z)-3,4-Dimethyl-2-phenylpent-2-enoate ((Z)-1i-2)
Yield: 78 mg (71%, E/Z = 2:>98); colorless oil.
IR (neat): 2961, 1715, 1599, 1433, 1291, 1229, 1205, 1089 cm–1
1H NMR (300 MHz, CDCl3): δ = 1.11 (d, J = 6.5 Hz, 6 H), 1.56 (s, 3 H),
3.17 (sept, J = 6.9 Hz, 1 H), 3.68 (s, 3 H), 7.14–7.22 (m, 2 H), 7.23–7.38
(m, 3 H).
.
Methyl (Z)-2-Butyloct-2-enoate
13C NMR (75 MHz, CDCl3): δ = 13.9, 20.8, 32.5, 51.6, 127.0, 128.1,
129.2, 129.3, 137.8, 150.4, 169.4.
Yield: 34 mg (28%, E/Z = 3:93); colorless oil.
IR (neat): 2957, 2930, 2859, 1712, 1641, 1436, 1377, 1201 cm–1
.
Methyl (E)-2,3-Diphenylbut-2-enoate ((E)-1i-3)3
Yield: 111 mg (88%, E/Z = 71:29); colorless oil.
1H NMR (300 MHz, CDCl3): δ = 0.83–0.95 (m, 6 H), 1.21–1.46 (m, 10
H), 2.23 (t, J = 7.2 Hz, 2 H), 2.39 (t, J = 7.2 Hz, 2 H), 3.73 (s, 3 H), 5.84 (t,
J = 7.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 13.9, 14.0, 22.2, 22.5, 29.2, 29.5, 31.3,
31.5, 34.3, 51.1, 131.9, 141.8, 168.8.
Methyl (Z)-2,3-Diphenylbut-2-enoate ((Z)-1i-3)3
Yield: 114 mg (91%, E/Z = 19:81); colorless oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

H
Y. Sato et al.
Paper
Synthesis
Methyl (E)-2,4-Dimethyl-3-(tosyloxy)pent-2-enoate ((E)-3b-1)
Yield: 31 mg (16%, E/Z = >98:2); colorless oil.
13C NMR (125 MHz, CDCl3): δ = 5.6 (2 C), 14.4, 15.5, 51.1, 69.8, 113.4,
114.9, 121.3, 126.0, 127.4 (2 C), 127.8, 128.4, 128.5 (2 C), 137.0, 140.3,
148.9, 157.9, 170.1.
IR (neat): 1720, 1362, 1276, 1176, 1109, 1012 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.02 (d, J = 6.9 Hz, 6 H), 1.87 (s, 3 H),
2.47 (s, 3 H), 3.38–3.47 (m, 1 H), 3.76 (s, 3 H), 7.37 (d, J = 8.0 Hz, 2 H),
7.86 (d, J = 8.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 15.3, 19.5 (2 C), 21.7, 31.3, 52.0, 120.6,
127.7 (2 C), 129.7 (2 C), 134.6, 145.0, 161.6, 168.3.
Methyl (E)-3-(3-(Benzyloxy)phenyl)-2,4-dimethylpent-2-enoate
((E)-4b)
Yield: 41 mg (64%, E/Z = 95:5); colorless oil.
IR (neat): 1717, 1576, 1456, 1259, 1205, 1130, 1028 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.92 (d, J = 6.9 Hz, 6 H), 1.56 (s, 3 H),
3.24–3.30 (m, 1 H), 3.79 (s, 3 H), 5.06 (s, 2 H), 6.60–6.62 (m, 2 H),
6.90–6.92 (m, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.32–7.45 (m, 5 H).
HRMS (ESI): m/z [M + Na]+ calcd for C15H20O5SNa: 335.0929; found:
335.0927.
13C NMR (125 MHz, CDCl3): δ = 17.4, 21.4 (2 C), 31.9, 51.5, 70.0, 113.2,
115.3, 121.3, 124.5, 127.5 (2 C), 127.9, 128.5 (2 C), 128.9, 136.9, 139.7,
152.6, 158.3, 170.8.
HRMS (ESI): m/z [M + Na]+ calcd for C15H20O5SNa: 347.1623; found:
347.1643.
Methyl (E)-3-Cyclopropyl-2-methyl-3-(((4-nitrophenyl)sulfo-
nyl)oxy)acrylate ((E)-3a-2)
Yield: 51 mg (30%, E/Z = 91:9); colorless oil.
IR (neat): 1717, 1533, 1350, 1311, 1190, 1013 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.60–0.64 (m, 2 H), 0.70–0.75 (m, 2 H),
1.78 (s, 3 H), 7.05–7.18 (m, 1 H), 2.05–2.18 (m, 1 H), 3.79 (s, 3 H), 8.18
(d, J = 8.7 Hz, 2 H), 8.43 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 7.2 (2 C), 14.0, 14.9, 52.1, 124.4, 129.2,
142.7, 150.8, 156.8, 167.8.
Methyl (Z)-3-(3-(Benzyloxy)phenyl)-2,4-dimethylpent-2-enoate
((Z)-4b)
Yield: 92 mg (57%, E/Z = 33:67); colorless oil.
IR (neat): 1712, 1574, 1431, 1314, 1204, 1132, 1028 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C14H15NO7SNa: 364.0467; found:
364.0448.
1H NMR (500 MHz, CDCl3): δ = 0.93 (d, J = 6.9 Hz, 6 H), 2.02 (s, 3 H),
2.99–3.07 (m, 1 H), 3.32 (s, 3 H), 5.05 (s, 2 H), 6.61–6.65 (m, 2 H),
6.86–6.88 (m, 1 H), 7.18 (t, J = 8.0 Hz, 1 H), 7.29–7.43 (m, 5 H).
13C NMR (125 MHz, CDCl3): δ = 15.0, 20.7 (2 C), 30.5, 51.1, 69.8, 113.1,
115.2, 121.5, 125.4, 127.4 (2 C), 127.8, 128.2, 128.5 (2 C), 137.1, 141.0,
151.5, 157.8, 170.8.
Methyl (E)-2,4-Dimethyl-3-(((4-nitrophenyl)sulfonyl)oxy)pent-2-
enoate ((E)-3b-2)
Yield: 70 mg (41%, E/Z = >98:2); colorless oil.
IR (neat): 1717, 1533, 1350, 1277, 1184, 1109, 1007 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.02 (d, J = 6.8 Hz, 6 H), 1.88 (s, 3 H),
3.41–3.51 (m, 1 H), 3.78 (s, 3 H), 8.19 (d, J = 8.2 Hz, 2 H), 8.44 (d, J = 8.2
Hz, 2 H).
Funding Information
This research was partially supported by Grants-in-Aid for Scientific
Research on Basic Areas (B) ‘18350056’, Priority Areas (A) ‘17035087’
and ‘18037068’, (C) ‘15K05508’, and Exploratory Research ‘17655045’
from the Ministry of Education, Culture, Sports, Science and Technol-
13C NMR (75 MHz, CDCl3): δ = 15.4, 19.5, 31.2, 52.2, 121.0, 124.4,
128.9, 142.9, 150.7, 161.4, 167.9.
HRMS (ESI): m/z [M + Na]+ calcd for C14H17NO7SNa: 366.0623; found:
366.0623.
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Methyl (E)-3-(3-(Benzyloxy)phenyl)-3-cyclopropyl-2-methylacry-
late ((E)-4a)
Acknowledgment
Yield: 56 mg (88%, E/Z = 86:14); colorless oil.
IR (neat): 1709, 1574, 1431, 1319, 1255, 1194, 1107, 1047 cm–1
1H NMR (500 MHz, CDCl3): δ = 0.26–0.30 (m, 2 H), 0.62–0.67 (m, 2 H),
1.59 (s, 3 H), 2.59–2.64 (m, 1 H), 3.81 (s, 3 H), 5.05 (s, 2 H), 6.54–6.56
(m, 2 H), 6.88–6.90 (m, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.30–7.43 (m, 5
H).
Y.T. offers his warmest congratulations to Professor Ben L. Feringa
(University of Groningen, The Netherlands) on being awarded the
2016 Nobel Prize in Chemistry.
.
Supporting Information
13C NMR (125 MHz, CDCl3): δ = 5.5 (2 C), 14.6, 18.0, 51.3, 70.0, 113.6,
115.0, 121.2, 124.4, 127.5 (2 C), 128.0, 128.6 (2 C), 129.1, 136.8, 138.9,
151.6, 158.4, 170.5.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610652.
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Methyl (Z)-3-(3-(Benzyloxy)phenyl)-3-cyclopropyl-2-methylacry-
late ((Z)-4a)9
References
(1) (a) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698.
(b) Smith, M. B. March’s Advanced Organic Chemistry; Wiley:
New York, 2007, 6th ed., Chap. 12. (c) Kürti, L.; Czakó, B. Strate-
gic Applications of Named Reactions in Organic Synthesis; Else-
vier: Burlington, 2005, 196.
Yield: 75 mg (86%, E/Z = 2:>98); colorless oil.
IR (neat): 1717, 1575, 1431, 1321, 1249, 1192, 1028 cm–1
1H NMR (500 MHz, CDCl3): δ = 0.29–0.31 (m, 2 H), 0.70–0.74 (dq, J =
8.0 Hz, 2 H), 1.80–1.85 (m, 1 H), 2.14 (s, 3 H), 3.34 (s, 3 H), 5.04 (s, 2
H), 6.57 (d, J = 8.0 Hz, 1 H), 6.60 (s, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 7.17
(t, J = 8.0 Hz, 1 H), 7.30–7.43 (m, 5 H).
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

I
Y. Sato et al.
Paper
Synthesis
(2) (a) Baxter, J. M.; Steinhuebel, D.; Palucki, M.; Davies, I. W. Org.
Lett. 2005, 7, 215. (b) Steinhuebel, D.; Baxter, J. M.; Palucki, M.;
Davies, I. W. J. Org. Chem. 2005, 70, 10124. (c) Klapars, A.;
Campos, K. R.; Chen, C. Y.; Volante, R. P. Org. Lett. 2005, 7, 1185.
(d) Nakatsuji, H.; Ueno, K.; Misaki, T.; Tanabe, Y. Org. Lett. 2008,
10, 2131. (e) Nakatsuji, H.; Nishikado, H.; Ueno, K.; Tanabe, Y.
Org. Lett. 2009, 11, 4258. (f) Ashida, Y.; Sato, Y.; Honda, A.;
Nakatsuji, H.; Tanabe, Y. Synthesis 2016, 48, 4072. (g) Ashida, Y.;
Sato, Y.; Honda, A.; Nakatsuji, H.; Tanabe, Y. Synform 2017, A38.
(3) Nakatsuji, H.; Ashida, Y.; Hori, H.; Sato, Y.; Honda, A.; Taira, M.;
Tanabe, Y. Org. Biomol. Chem. 2015, 13, 8205.
(4) Rivera, A. C. P.; Still, R.; Franz, D. E. Angew. Chem. Int. Ed. 2016,
55, 6689.
(5) Ashida, Y.; Sato, Y.; Suzuki, T.; Ueno, K.; Kai, K.; Nakatsuji, H.;
Tanabe, Y. Chem. Eur. J. 2015, 21, 5934.
(6) Ashida, Y.; Honda, A.; Sato, Y.; Nakatsuji, H.; Tanabe, Y. Chemis-
tryOpen 2017, 6, 73.
(9) Christensen, M.; Nolting, A.; Shevlin, M.; Weisel, M.; Maligres, P.
E.; Lee, J.; Orr, R. K.; Plummer, C. W.; Tudge, M. T.; Campeau, L.-
C.; Ruck, R. T. J. Org. Chem. 2016, 81, 824.
(10) A 50 g-scale preparation was performed by Ti-Claisen self-con-
densation using methyl hexanoate with TiCl4 and Et3N at 0–5 °C
for 1 h (93% yield); see ref. 3.
(11) Tendency of (E/Z)-selectivities under the conditions
[K2CO3/iPrOH–H2O (7:1), 60 °C,
2
h] was as follows:
Pd(OAc)2/SPhos, 80:20; Pd(OAc)2/DavePhos, 70:30; Pd(dppe)Cl2,
62:38; Pd(PPh3)4, 60:40; Pd(PPh3)2Cl2, 53:47; Pd(OAc)2/XPhos,
47:53; Pd(dppf)Cl2, 46:54; Pd(dppb)Cl2, 39:61; Pd(OAc)2/PCy3,
24:76. The solvent effect on (E/Z)-selectivities using (E)-2a
under the identical conditions was as follows: THF, 14:86; tolu-
ene, 18:82.
(12) Negishi cross-coupling reactions are generally more reactive
with regard to catalyst loading than SM cross-coupling reac-
tions (ref. 6). Against this outcome in the previous report, the
(7) Nishikado, H.; Nakatsuji, H.; Ueno, K.; Nagase, R.; Tanabe, Y.
Synlett 2010, 2087.
(8) Ashida, Y.; Nakatsuji, H.; Tanabe, Y. Org. Synth. 2017, 94, 93.
present
SM
cross-coupling
protocol
using
Pd(OAc)2/SPhos/iPr2NEt catalysis displayed sufficient reactivity.
(13) Lu, G.-P.; Voigtritter, K. R.; Cai, C.; Lipshutz, B. H. J. Org. Chem.
2012, 77, 3700.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I