Coupling Reaction of Enol Derivatives with Silyl Ketene Acetals Catalyzed by Gallium Trihalides

Article abstract of DOI:10.1002/chem.201602150

A cross-coupling reaction between enol derivatives and silyl ketene acetals catalyzed by GaBr₃took place to give the corresponding α-alkenyl esters. GaBr₃showed the most effective catalytic ability, whereas other metal salts such as BF₃?OEt₂, AlCl₃, PdCl₂, and lanthanide triflates were not effective. Various types of enol ethers and vinyl carboxylates as enol derivatives are amenable to this coupling. The scope of the reaction with silyl ketene acetals was also broad. We successfully observed an alkylgallium intermediate by using NMR spectroscopy, suggesting a mechanism involving anti-carbogallation among GaBr₃, an enol derivative, and a silyl ketene acetal, followed by syn-β-alkoxy elimination from the alkylgallium. Based on kinetic studies, the turnover-limiting step of the reaction using a vinyl ether and a vinyl carboxylate involved syn-β-alkoxy elimination and anti-carbogallation, respectively. Therefore, the leaving group had a significant effect on the progress of the reaction. Theoretical calculations analysis suggest that the moderate Lewis acidity of gallium would contribute to a flexible conformational change of the alkylgallium intermediate and to the cleavage of the carbon?oxygen bond in the β-alkoxy elimination process, which is the turnover-limiting step in the reaction between a vinyl ether and a silyl ketene acetal.

Full text of DOI:10.1002/chem.201602150

DOI: 10.1002/chem.201602150
Full Paper
&
Cross-Coupling Reactions
Coupling Reaction of Enol Derivatives with Silyl Ketene Acetals
Catalyzed by Gallium Trihalides
Yoshihiro Nishimoto,*[a] Yuji Kita,[b] Hiroki Ueda,[b] Hiroto Imaoka,[b] Kouji Chiba,[c]
Makoto Yasuda,*[b] and Akio Baba[b]
Abstract: A cross-coupling reaction between enol deriva-
tives and silyl ketene acetals catalyzed by GaBr3 took place
to give the corresponding a-alkenyl esters. GaBr3 showed
the most effective catalytic ability, whereas other metal salts
such as BF3·OEt2, AlCl3, PdCl2, and lanthanide triflates were
not effective. Various types of enol ethers and vinyl carboxy-
lates as enol derivatives are amenable to this coupling. The
scope of the reaction with silyl ketene acetals was also
broad. We successfully observed an alkylgallium intermedi-
ate by using NMR spectroscopy, suggesting a mechanism in-
volving anti-carbogallation among GaBr3, an enol derivative,
and a silyl ketene acetal, followed by syn-b-alkoxy elimina-
tion from the alkylgallium. Based on kinetic studies, the turn-
over-limiting step of the reaction using a vinyl ether and
a vinyl carboxylate involved syn-b-alkoxy elimination and
anti-carbogallation, respectively. Therefore, the leaving
group had a significant effect on the progress of the reac-
tion. Theoretical calculations analysis suggest that the mod-
erate Lewis acidity of gallium would contribute to a flexible
conformational change of the alkylgallium intermediate and
to the cleavage of the carbonꢀoxygen bond in the b-alkoxy
elimination process, which is the turnover-limiting step in
the reaction between a vinyl ether and a silyl ketene acetal.
Introduction
The cross-coupling reaction of alkenyl electrophiles is one of
the most important methods for the construction of carbon
frameworks such as pharmaceuticals, natural products, and or-
ganic materials.[1] Generally, alkenyl halides are used as electro-
philic coupling partners because of their high reactivity; how-
ever, they have some problems such as relatively high cost
and potential toxicity, as well as the formation of metal halide
salts as by-products. In this context, enol derivatives such as
enol ethers and alkenyl carboxylates have attracted much at-
tention because they are inexpensive, readily available, and en-
vironmentally benign (Scheme 1, A).[2] However, the develop-
ment of a coupling reaction using enol derivatives remains
a challenging issue because the intrinsic feature of inert CꢀO
Scheme 1. Coupling reaction using enol derivatives as electrophiles.
bonds prevents the use of desirable coupling reactions. Al-
though several types of transition-metal-catalyzed couplings of
enol ethers,[3] alkenyl carboxylates,[4] alkenyl carbamates,[5] al-
kenyl phosphates,[6] and silyl enol ethers[7] have been reported,
applicable organometallic partners have been limited to alkyl
or aryl metals such as Grignard reagents (Scheme 1, B). For
other types of nucleophiles, such as metal enolates, only two
catalytic coupling reactions, the Pd-catalyzed dimerization of
silyl vinyl ethers[8] and our reported InBr3-catalyzed coupling of
enol ethers with ketene silyl imines,[9] have previously been
achieved.[10] To our knowledge, the cross coupling between
enol derivatives and metal enolates had never been achieved
prior to our previous report of a GaBr3-catalyzed coupling be-
tween enol ethers and silyl ketene acetals.[3d,11,12]
[a] Dr. Y. Nishimoto
Frontier Research Base for Global Young Researchers
Center for Open Innovation Research and Education (COiRE)
Graduate School of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
E-mail: nishimoto@chem.eng.osaka-u.ac.jp
[b] Y. Kita, H. Ueda, H. Imaoka, Prof. Dr. M. Yasuda, Prof. Dr. A. Baba
Department of Applied Chemistry, Graduate School of Engineering
Osaka University, Suita, Osaka 565-0871 (Japan)
E-mail: yasuda@chem.eng.osaka-u.ac.jp
[c] K. Chiba
Science and Technology System Division, Ryoka Systems Inc.
Tokyo Skytree East Tower, 1-1-2 Oshiage, Sumida-ku
Tokyo 131-0045 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201602150.
Chem. Eur. J. 2016, 22, 1 – 10
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Scheme 3. Unexpected coupling reaction based on our developed carbome-
tallation.
Scheme 2. Comparison of reaction mechanisms for the coupling reaction
using enol derivatives.
possible based on these results. Therefore, we investigated the
catalytic coupling of enol ethers with silyl ketene acetals in the
expectation of the regeneration of InBr3 by the transmetalla-
tion between Me3SiBr and InBr2(OEt).
Herein, we report full details of the coupling reaction of enol
derivatives such as enol ethers and alkenyl carboxylates with
silyl ketene acetals catalyzed by GaBr3 (Scheme 1, B). This
paper (1) elucidates the scope of enol derivatives and silyl
ketene acetals, and (2) describes a mechanistic scenario based
on kinetic experiments, the observation of a key intermediate,
and theoretical calculations. Typical transition-metal-catalyzed
coupling reactions using enol derivatives proceed through
a mechanism that includes oxidative addition and reductive
elimination (Scheme 2, A).[3,4,5,6,7] Recently, Kambe et al. report-
ed Rh-catalyzed coupling between enol ethers and Grignard
reagents through the syn-addition of an organorhodium and
anti-elimination of a rhodium alkoxide (Scheme 2, B).[3i] We re-
vealed that the present coupling reaction of enol derivatives
with silyl ketene acetals occurs through a novel reaction mech-
anism that involves anti-carbogallation by three components,
GaBr3, an enol derivative, and a silyl ketene acetal, followed by
syn-elimination of a gallium alkoxide (Scheme 2, C).
We examined the effect of catalysts on the coupling of butyl
vinyl ether (1a) with dimethylketene trimethylsilyl acetal 2a in
Table 1. Investigation of effects of catalysts and solvents.[a]
Entry
Catalyst
Solvent
Yield of 3aa [%][b]
1
2
3
4
5
6
7
8
none
InBr3
GaBr3
BiBr3
GaCl3
GaI3
Ga(OTf)3
InCl3
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
toluene
0
86
97
trace
100
96
64
100
94
9
InI3
In(OTf)3
BiCl3
10
11
12
13
14[c]
15[c]
16[c]
17[c]
18[c]
19[c]
20
21
22
23
24
25
26
27
28
29
30
31
92
trace
trace
17
52
95
94
trace
21
59
59
BiI3
Results and Discussion
Bi(OTf)3
GaCl3
GaBr3
GaI3
InCl3
InBr3
Coupling reaction of enol ethers with silyl ketene acetals
Optimization of reaction conditions in the coupling reaction
between enol ether and silyl ketene acetal
We recently developed carbometallations of alkenes and al-
kynes by using silyl ketene acetals and metal halides such as
InBr3,[13] GaBr3,[14] and BiBr3.[15] The moderate Lewis acidity of
these metal halides promoted the effective activation of
carbon–carbon multiple bonds without deactivation by the co-
ordination of an oxygen atom of ketene silyl acetates to ach-
ieve carbometallation in an anti-addition fashion (Scheme 3,
Carbometallation). During the course of a study on this carbo-
metallation, when ethyl vinyl ether was employed as an
alkene, the predicted alkylindium compound was not ob-
tained, but the corresponding coupling product was obtained
quantitatively (Scheme 3, cross-coupling). The generation of
Me3SiBr and InBr2(OEt) through carbogallation and b-elimina-
tion from the alkylindium compound, respectively, should be
InI3
ZnCl2
BF3·OEt2
AlCl3
2
trace
trace
trace
0
trace
trace
71
24
11
20
TiCl4
Sc(OTf)3
Y(OTf)3
CuBr2
PdCl2
GaBr3
GaBr3
GaBr3
GaBr3
hexane
CH3CN
THF
[a] Reaction conditions: 1a (1 equiv), 2a (1.5 equiv), catalyst (0.1 equiv),
solvent (0.5m), 808C, 2 h. [b] Yields were determined by GC analysis. [c]
508C, 30 min.
&
&
Chem. Eur. J. 2016, 22, 1 – 10
www.chemeurj.org
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
dichloroethane at 808C (Table 1). This coupling reaction did
not occur without a catalyst (entry 1). A survey of InBr3, GaBr3,
and BiBr3, which effectively promoted carbometallation,[13,14,15]
was then carried out. A catalytic amount of InBr3 (10 mol%)
smoothly accelerated the desired coupling reaction to afford
a-vinyl ester 3aa in 86% yield (entry 2). The reaction catalyzed
by GaBr3 gave an excellent yield (97%; entry 3). In contrast,
BiBr3 showed a low catalytic effect (entry 4). Other indium and
gallium salts such as InCl3, InI3, In(OTf)3, GaCl3, GaI3, and
Ga(OTf)3 effectively accelerated the coupling reaction to give
the product 3aa (entries 5–10), whereas other bismuth salts
were ineffective (entries 11–13). When employing indium and
gallium salts at a lower temperature (508C), GaBr3 and GaI3
showed high catalytic ability (entries 14–19). Whereas ZnCl2
showed modest catalytic ability (entry 20), typical strong Lewis
acids such as BF3·OEt2, AlCl3, and TiCl4, were ineffective (en-
tries 21–23). Sc(OTf)3 and Y(OTf)3 also produced no desired
product (entries 24 and 25). Transition-metal salts did not work
as catalysts (entries 26 and 27). These results show that the
characteristic features of gallium and indium halides are impor-
tant for the completion of a catalytic reaction system. The
effect of solvents was also investigated. Nonpolar solvents
such as toluene could be employed, however the reaction in
hexane gave low yield (entries 28 and 29). Polar solvents such
as CH3CN and tetrahydrofuran (THF) were unsuitable because
they coordinated with GaBr3 to disturb the reaction (entries 30
and 31). Finally, GaI3 and GaBr3 were the most effective cata-
lysts; thus, we selected the reaction parameters detailed in
entry 3 as the standard conditions.
Table 2. Scope of the coupling reaction of silyl ketene acetal 2 with butyl
vinyl ether 1a.[a]
Entry
1
Silyl ketene acetal 2
Product 3
Yield [%][b]
92
2
93
3
4
5
6
90
81
82
43
7
83
12
8[c]
9
80
84
10
Scope of the reaction with respect to ketene silyl acetals and
enol ethers
11
12
44
59
The scope of the reaction with respect to ketene silyl acetals 2
for the GaBr3-catalyzed coupling was investigated; the results
are summarized in Table 2. Dialkylketene silyl acetals 2b, 2c,
and 2d were more bulky than 2a, and afforded the corre-
sponding a-vinyl esters in high yields (entries 1–3). Alkyl arylke-
tene silyl acetal 2e was also a suitable nucleophile (entry 4).
For the monosubstituted ketene silyl acetal, reactions using
various types of alkylketene and arylketene silyl acetals gave
the desired products in high yields (entries 5–7). The reaction
with unsubstituted ketene silyl acetal 2i resulted in a low yield
because 2i decomposed under these conditions (entry 8). Het-
eroaryl-substituted ketene silyl acetals 2j and 2k worked as ef-
fective nucleophiles (entries 9 and 10). Furthermore, O- and S-
substituted ketene silyl acetals 2l and 2m were applicable,
and gave moderate yields of the corresponding functionalized
a-vinyl esters 3al and 3am, respectively (entries 11 and 12).
We then examined the scope of the reaction with respect to
enol ethers, as shown in Table 3. A variety of a-substituted
enol ethers 4 were found to be suitable substrates. The reac-
tion of alkyl-substituted enol ethers 4a and 4b smoothly oc-
curred to give the desired products 5an and 5bn in 77 and
69% yields, respectively (entries 1 and 2). Functional groups
such as internal alkene, chloro, and alkoxy moieties tolerated
these reaction conditions, and a loading of 30 mol% of GaCl3
[a] Reaction conditions: 1a (1 equiv),
ClCH2CH2Cl, 808C, 2 h. [b] Isolated yields. [c] 2 (3 equiv), GaBr3 (0.2 equiv).
2 (1.5 equiv), GaBr3 (0.1 equiv),
rather than GaBr3 effectively accelerated the reactions of sub-
strates 4c, 4d, and 4e to give the corresponding products
5cn, 5dn, and 5en, respectively (entries 3–5).[16] Methoxy
enyne 4 f also reacted with ketene silyl acetal to smoothly pro-
duce ester 5 fn, with an enyne moiety, in 73% yield (entry 6).
Aryl-substituted enol ethers 4g, 4h, 4i, and 4j were applicable
to the coupling reaction, although the yields were moderate
(entries 7–10). The isopropyl vinyl ether 1b as well as the butyl
vinyl ether 1a were applicable to this reaction system, howev-
er the yields were again moderate (entry 11). In contrast,
phenyl vinyl ether 1c gave a high yield even though the steric
hindrance of this compound was similar to that of isopropyl
vinyl ether 1b (entry 12).[17] Therefore, it can be concluded that
the leaving ability of the alkoxy group influenced the reaction
rate.
Chem. Eur. J. 2016, 22, 1 – 10
www.chemeurj.org
3
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Table 3. Scope of the coupling reaction of enol ethers with silyl ketene
acetal 2.[a]
Table 4. GaBr3-catalyzed coupling reaction of vinyl carboxylate 6 with
silyl ketene acetal 2a.[a]
Entry
1[c]
Enol ether 1 or 4
Product 3 or 5
Yield [%][b]
77
Entry
R
Yield of 3aa [%][b]
1
2
3
4
Me
CH(Et)Bu
tBu
6a
6b
6c
6d
29
84
80
74
Ph
2[c]
69
30
[a] Reaction conditions:
ClCH2CH2Cl (0.5m), 808C, 2 h. [b] Yields were determined by H NMR spec-
troscopic analysis.
6 (1 equiv), 2a (1.5 equiv), GaBr3 (0.1 equiv),
1
3[d]
noate 6b, vinyl pivalate 6c, and vinyl benzoate 6d, which pos-
sess the steric hindrance of a carboxylate moiety, afforded high
yields (entries 2–4). The low yield shown in entry 1 can likely
be ascribed to Claisen condensation between vinyl acetate 6a
and silyl ketene acetal 2a.[18]
4[d]
72
56
5[d]
The scope of the reaction with respect to silyl ketene acetals
2 was surveyed in the reaction of vinyl pivalate 6c (Table 5). Di-
alkylketene silyl acetals 2d and 2c were applicable to the cou-
pling reaction of vinyl pivalate 6c, whereas bulky diethylketene
silyl acetal 2c gave only 22% yield (entries 1 and 2). The reac-
tion using phenyl-substituted ketene silyl acetals 2e and 2h
afforded the corresponding products in moderated yields (en-
tries 3 and 4). Thiophenyl-substituted ketene silyl acetal 2j also
underwent cross coupling to give a high yield (entry 5). On the
whole, the yields of the reaction using vinyl carboxylate 6
were slightly lower than those of the reaction using vinyl ether
1. Therefore, vinyl carboxylate 6 had lower reactivity than vinyl
6
7
73
43
8
43
61
59
9
Table 5. Scope of the reaction with silyl ketene acetal 2 and vinyl piva-
late 6c.[a]
10
11[e]
12[e]
50[f]
98[f]
Entry
1
Silyl ketene acetal 2
Product 3
Yield [%][b]
79
[a] Reaction conditions: 1 or 4 (1 equiv), 2n (1.5 equiv), GaBr3 (0.1 equiv),
ClCH2CH2Cl (0.5m), 2 h, 808C. [b] Isolated yields. [c] Reaction time 12 h.
[d] GaCl3 (30 mol%), 2n (3 equiv). [e] 2a (1.5 equiv). [f] Yields were deter-
mined by GC analysis.
2
3
4
22
51
63
Coupling of vinyl carboxylates with silyl ketene acetals
Vinyl carboxylates as well as enol ethers are valuable as alkeny-
lation reagents because they are more stable and easier to
handle than enol ethers.[4] We investigated the coupling reac-
tion of various vinyl carboxylates 6 with silyl ketene acetal 2a
(Table 4). The reaction of vinyl acetate 6a with silyl ketene
acetal 2a at 808C in the presence of GaBr3 catalyst gave the
coupling product 3aa in 29% yield (entry 1). Vinyl 2-ethylhexa-
5
83
[a] Reaction conditions: 6c (1 equiv),
ClCH2CH2Cl (0.5m), 808C, 2 h. [b] Yields were determined by H NMR spec-
troscopic analysis.
2 (1.5 equiv), GaBr3 (0.1 equiv),
1
&
&
Chem. Eur. J. 2016, 22, 1 – 10
www.chemeurj.org
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
ether 1 in the present coupling reaction, although the yields
were satisfactory.
constant values, 2J (H1a,H1e)=14 Hz, 3J (H1a,H2)=3 Hz, and 3J
(H1e,H2)=4 Hz, of alkylgallium 8 clearly show that the PhO
group occupies the axial position in the chair-like six-mem-
bered ring due to the anomeric effect.[22,23] In contrast to vinyl
ether 1, the intermediate from vinyl carboxylate 6c was not
observed even at low temperature and only starting materials
and the coupling product were confirmed.
Monitoring of coupling reaction between vinyl ether and
silyl ketene acetal
To reveal the reaction mechanism, we monitored the coupling
reaction of vinyl ether 1 with silyl ketene acetal 2 by using
NMR spectroscopy. When conducting the coupling reaction
with vinyl ether 1d, silyl ketene acetal 2n, and GaBr3 at room
temperature, the alkylgallium intermediate 7, coupling product
Mechanistic studies on the coupling reaction of enol deriva-
tives with silyl ketene acetal
1
3dn, and Me3SiBr were observed in the H NMR spectra after
Kinetic studies were carried out to gain insight into the turn-
over-limiting step of the GaBr3-catalyzed coupling reaction of
vinyl ether 1 with silyl ketene acetal 2. We investigated the de-
pendence of the initial rate of the GaBr3-catalyzed coupling re-
action of vinyl ether 1a with silyl ketene acetal 2a in dichloro-
ethane at 308C on the concentration of each reagent
(Figure 2). The plots of the initial rates vs. the concentrations
5 min (Figure 1).[19] The methoxy signal of intermediate 7 ap-
Figure 1. Monitoring of the coupling reaction of vinyl ether 1d with silyl
1
ketene acetal 2n in the presence of GaBr3 by H NMR spectroscopic analysis.
Reagents and conditions: GaBr3 (0.5 equiv), 1d (1 equiv), 2n (1.5 equiv),
CD2Cl2, RT.
Figure 2. Initial rate kinetics of GaBr3-catalyzed coupling reaction of butyl
vinyl ether 1a with silyl ketene acetal 2a.
peared at 4.03 ppm (0.37 ppm downfield shift compared with
that of coupling product 3dn). This result indicated the intra-
molecular coordination of a carbonyl group to gallium to form
a six-membered ring.[20] Vinyl ether 1d was consumed after
25 min, and then intermediate 7 was transformed into the cou-
pling product 3dn after 70 min. To avoid overlapping of the
signals in the spectrum, the reaction of phenyl vinyl ether 1c
with deuterated silyl ketene acetal 2o was conducted
(Scheme 4). Alkylgallium intermediate 8 was successfully ob-
served without the corresponding coupling product under
low-temperature conditions.[21] This result suggested that the
elimination from the alkylgallium intermediate 8 to give the
coupling product was slower than the carbogallation. Coupling
of GaBr3, vinyl ether 1a, and ketene silyl acetal 2a are shown
in Figure 2. The kinetic analysis shows that this coupling reac-
tion was of zeroth order for vinyl ether 1a and silyl ketene
acetal 2a, and was of first order for GaBr3 (rate=kobs[GaBr3]).
We then performed kinetic studies for the GaBr3-catalyzed cou-
pling between vinyl pivalate 6c and silyl ketene acetal 2a; the
Scheme 4. Observation of alkylgallium intermediate 8 in the reaction of
1
vinyl ether 1c with deuterated silyl ketene acetal 2o by H NMR spectro-
scopic analysis. Reagents and conditions: GaBr3 (0.3 equiv), 1c (1 equiv), 2o
(1.5 equiv), CD2Cl2, ꢀ308C, 15 min.
Figure 3. Initial rate kinetics of GaBr3-catalyzed coupling reaction of vinyl
pivalate 6c with ketene silyl acetal 2a.
Chem. Eur. J. 2016, 22, 1 – 10
www.chemeurj.org
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
results are shown in Figure 3. In contrast to vinyl ether 1a,
a coupling reaction using vinyl pivalate 6c was of first order
for vinyl pivalate 6c and the GaBr3 catalyst, and was of zeroth
order for silyl ketene acetal (rate=kobs[GaBr3][6c]). Therefore,
the nature of the leaving group had a significant effect on the
turnover-limiting step.
using vinyl ether 1 occurs stereospecifically. Therefore, the pro-
posed anti-addition/syn-elimination is supported by our report-
ed carbometallations and by the deuterium labeling experi-
ments. The elimination process (9!10!3 and 11) is a turn-
over-limiting step because of the dependence of the reaction
rate on only the concentration of GaBr3 (rate=kobs[GaBr3])
(Figure 2), which was also shown by observation of the alkyl-
A plausible mechanism for the coupling reaction using vinyl
ether 1 based on the kinetic studies and a confirmation of the
alkylgallium intermediate is illustrated in Scheme 5.[24] GaBr3 is
gallium intermediate 9 (Figure 1 and Scheme 4).[26]
The coupling reaction of vinyl carboxylate 6 would also pro-
ceed through the anti-carbogallation/syn-elimination mecha-
nism illustrated in Scheme 6. The mechanism of vinyl carboxyl-
Scheme 5. Plausible mechanism for coupling of vinyl ether 1 with silyl
ketene acetal 2.
coordinated by not only vinyl ether 1 but also silyl ketene
acetal 2, so that the equilibrium between the GaBr3-vinyl ether
complex (GaBr3·1) and the GaBr3-ketene silyl acetal complex
(GaBr3·2) should be considered. The interaction between GaBr3
and the olefin moiety of vinyl ether 1 increases the positive
charge at the a-carbon of oxygen. The positive charge is stabi-
lized by the OR group. The nucleophilic attack of silyl ketene
acetal 2 occurs regioselectively in an anti-addition fashion (A)
to provide b-oxyalkylgallium intermediate 9 and Me3SiBr. The
gallium atom is coordinated by the intramolecular carbonyl
oxygen to form a six-membered ring. The OR group coordi-
nates to gallium to eliminate the ester moiety, and then syn-
elimination (10) between GaBr2 and the OR group proceeds to
give the coupling product 3.[25] Finally, transmetallation of
Br2Ga(OR) 11 with Me3SiBr regenerates the GaBr3 catalyst. Re-
cently, we reported that carbogallation, carboindation, and car-
bobismuthination of alkenes/alkynes using silyl ketene acetals
proceeded in an anti-addition manner.[13,14,15] In the deuterium
labeling experiments, the E-isomer of deuterated phenyl vinyl
ether 1c-d reacted with 2a to exclusively furnish E-isomer
product 3aa-d with retention of its stereochemical configura-
tion [Eq. (1)]. This result suggests that the coupling reaction
Scheme 6. Plausible mechanism for coupling of vinyl carboxylate 6 with silyl
ketene acetal 2.
ate 6 differs significantly from that of vinyl ether 1 in that the
syn-elimination occurs via the six-membered ring intermediate
14 including the coordination to gallium of the carbonyl
oxygen of the leaving group. The turnover-limiting step is
either the coordination of vinyl carboxylate 6 to GaBr3 or the
carbogallation because the rate equation is presented by
kobs[GaBr3][6] (Figure 3) and alkylgallium intermediates 12 and
13 could not be observed upon monitoring the coupling reac-
tion by using NMR spectroscopy. Bulky silyl ketene acetals
such as diethyl-, methylphenyl-, and phenyl-substituted ke-
tenes (2c, 2e, and 2h) had lower reactivities than dimethyl-
substituted ketene acetal 2a (Table 4, entry 3 and Table 5, en-
&
&
Chem. Eur. J. 2016, 22, 1 – 10
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
tries 2, 3, and 4), suggesting that silyl ketene acetal 2 partici-
pates in the turnover-limiting step. Therefore, we assumed
that silyl ketene acetal 2 has the inhibition effect through the
coordination to GaBr3 (GaBr3·6+2!6+GaBr3·2), and that car-
bogallation with GaBr3, vinyl carboxylate 6, and silyl ketene
acetal 2 is the turnover-limiting step. Actually, the experimental
rate equation, rate=kobs[GaBr3][6], is consistent with the theo-
four-membered ring structure of 10a is less stable than the
six-membered ring structure of 9a. The activation energy of
the path from 9a is 14.3 kcalmolꢀ1, which supports the possi-
bility of this conformational change. The elimination pathway
from the four-membered ring structure of 10a to 17a via tran-
sition state TS10a is exothermic and requires activation ener-
gies of 13.6 kcalmolꢀ1. The important bond lengths (GaꢀC1,
GaꢀO, C1ꢀC2, and C2ꢀO) of intermediate 10a and the transition
state of TS10a are shown in Figure 5. The C2ꢀO bond is elon-
retical rate equation, rate=k1k2k ꢀ1[GaBr3][6] (see the Support-
ꢀ1
ing Information).[27] In contrast to vinyl ether 1, the conforma-
tional change from the six-membered ring of intermediate 12
to the six-membered ring of intermediate 13 and b-elimination
via a six-membered cyclic transition state would easily occur.
On the other hand, the diminished stabilization effect of a posi-
tive charge imparted by the carboxylate group slowed the car-
bogallation step. Therefore, the turnover-limiting step in the
coupling reaction of vinyl carboxylate 6 was different from
that of vinyl ether 1.
Investigation of elimination process in coupling reaction of
vinyl ether 1
The conformational change (9!10) in the turnover-limiting
step of the coupling reaction of vinyl ether 1 (Scheme 5)
seemed unlikely to occur because the stable six-membered
ring structure, through coordination of the carbonyl group to
gallium, transforms into a strained four-membered ring struc-
ture. Therefore, we investigated our proposed elimination pro-
cess (9!10!3+11) by using theoretical calculations to verify
the possibility of this conformational change and to consider
the influence of conformational change and syn-elimination
(10!3+11) on the turnover-limiting step. Figure 4 shows the
potential energy profile of the elimination process from alkyl-
gallium intermediate 9a, which is afforded by the reaction of
butyl vinyl ether 1a with silyl ketene acetal 2n. In the confor-
mational change from the stable six-membered ring structure
of 9a to the strained four-membered ring structure of 10a,
the dissociation of the carbonyl group and the association of
the alkoxy group occur in concert (TS9a). As expected, the
Figure 5. Optimized structures and selected bond lengths in intermediate
10a and transition state TS10a (distances in ꢁ).
gated from 1.48 to 2.08 ꢁ, and the degree of its length change
is larger than that of the other bonds. The GaꢀO and C1ꢀC2
bonds are shortened. On the other hand, the GaꢀC1 bond dis-
tance is almost unchanged. Therefore, the cleavage of the C2ꢀ
O bond by the assistance of the gallium is precedent in the
elimination step. The overall potential energy surface of the
elimination process showed that both the conformational
change and the elimination step require a large energy barrier
in order to influence the reaction rate. These theoretical results
suggest that the moderate Lewis acidity of gallium is impor-
tant for the conformational change from the stable six-mem-
bered ring structure of 9a to the strained four-membered ring
structure of 10a, and for the syn-elimination with the cleavage
of the carbon–oxygen bond. If the Lewis acidity was strong,
such a flexible conformational change would not occur, and if
the Lewis acidity was weak, the carbon–oxygen bond would
not be cleaved.
We then considered the rate equation of the coupling reac-
tion between vinyl ether 1 and silyl ketene acetal 2 on the
basis of mechanistic studies. Theoretical calculations revealed
that the conformational change from a four-membered ring to
a six-membered ring (10!9) proceeds through a much small-
er energy barrier than that required for the elimination of
GaBr2(OR), so that the elimination process involves an equilibri-
um between 9 and 10 that lies toward 9 [Eq. (2)]. Therefore,
assuming a steady state for 10 allows the theoretical rate
Figure 4. Potential energy profile of the elimination step from 9a to 17a in
the reaction of vinyl ether 1a with silyl ketene acetal 2n.
Chem. Eur. J. 2016, 22, 1 – 10
www.chemeurj.org
7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Experimental Section
Typical procedure for the coupling reaction of enol ether with
ketene silyl acetal (Table 2, entry 1): Butyl vinyl ether 1a
(3.0 mmol, 0.300 g) was added to a solution of GaBr3 (0.05m in di-
chloroethane, 6 mL) and ethylmethylketene methyl trimethylsilyl
acetal 2b (4.5 mmol, 0.849 g). The mixture was stirred at 808C for
2 h, then the reaction was quenched by the addition of aq. 1m
HCl. The mixture was extracted with diethyl ether (10ꢂ3 mL) and
the collected organic layer was dried (MgSO4). The solvent was
evaporated and the residue was purified by column chromatogra-
phy (hexane/ethyl acetate, 98:2; column length 11 cm) to give 3ba
(0.391 g, 92%).
equation of the production of 3 to be expressed as rate=
k1k2k ꢀ1[GaBr3], which is consistent with the experimental rate
ꢀ1
equation [Eq. (3)] (see the Supporting Information).[27] Further-
ꢀ1
more, the constant term k1k2k
suggested that both confor-
ꢀ1
mational change and syn-elimination steps determine the reac-
Acknowledgements
tion rate. By using Equation (3), we obtained excellent fits with
k
obs (303 K) =4.2ꢂ10ꢀ4 sꢀ1 for the production of 3 in the catalytic
This work was supported by JSPS KAKENHI Grant Numbers
JP15H05848 in Middle Molecular Strategy and JP16K05719. We
thank Tonen General Sekiyu Research & Development Encour-
agement Foundation and Tokuyama Science Foundation for fi-
nancial support. Y.N. acknowledges support from the Frontier
Research Base for Global Young Researchers, Osaka University,
on the Program of MEXT.
run using different amounts of GaBr3, as shown in Figure 3. An
Arrhenius plot using experimentally determined kobs values at
a range of temperatures gave an activation energy of 15.6 kcal
molꢀ1 (see the Supporting Information).[28] This activation
energy approximated the computed activation energy
(Figure 4), which confirms that the elimination process re-
vealed by theoretical calculations is reasonable.
Keywords: cross-coupling
mechanism · silicon
·
enols
·
gallium
·
reaction
Conclusion
We have established a novel coupling reaction of enol deriva-
tives with silyl ketene acetals catalyzed by GaBr3 catalyst. Vari-
ous types of enol ethers such as vinyl ether 1 and a-substitut-
ed enol ether 4 were applicable to this reaction system. Func-
tionalized enol ethers possessing chloro, olefin, and ether moi-
eties afforded the corresponding products smoothly. We dem-
onstrated the wide scope of the reaction with respect to
suitable ketene silyl acetals 2 through the use of substrates
bearing phenoxy, thiophenyl, indolyl, and thiophenyl groups.
Vinyl carboxylate 6 as well as vinyl ether 1 were also found to
be feasible alkenylating reagents. In this paper, we revealed
the details of the reaction mechanism based on the observa-
tion of intermediates, kinetic studies, and computational analy-
[1] a) Metal-Catalyzed Cross-Coupling Reactions, 1st ed. (Eds.: F. Diederich,
P. J. Stang), Wiley-VCH: Weinheim, Germany, 1998; b) Cross-Coupling Re-
actions. A Practical Guide (Ed.: N. Miyaura), Springer-Verlag, Berlin, 2002;
c) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds.: A. de Meijere,
F. Diederich), Wiley-VCH, Weinheim, Germany, 2004; d) J. Tsuji, Palladi-
um Reagents and Catalysts: New Perspectives for the 21st Century, Wiley,
New York, 2003; e) J. P. Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651;
f) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. Int. Ed. 2005, 44,
4442; Angew. Chem. 2005, 117, 4516.
[2] For selected reviews: a) D.-G. Yu, B.-J. Li, Z.-J. Shi, Acc. Chem. Res. 2010,
43, 1486; b) B.-J. Li, D.-G. Yu, C.-L. Sun, Z.-J. Shi, Chem. Eur. J. 2011, 17,
1728; c) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.-M. Re-
smerita, N. K. Garg, V. Percec, Chem. Rev. 2011, 111, 1346; d) W.-N. Li, Z.-
L. Wang, RSC Adv. 2013, 3, 25565.
[3] a) E. Wenkert, E. L. Michelotti, C. S. Swindell, J. Am. Chem. Soc. 1979,
101, 2246; b) E. Wenkert, E. L. Michelotti, C. S. Swindell, M. Tingoli, J.
Org. Chem. 1984, 49, 4894; c) Y. Matsuura, M. Tamura, T. Kochi, M. Sato,
N. Chatani, F. Kakiuchi, J. Am. Chem. Soc. 2007, 129, 9858; d) S. Zhu, G.
Jin, H. Jiang, Can. J. Chem. 2005, 83, 2127; e) B. T. Guan, S. K. Xiang, T.
Wu, Z. P. Sun, B. Q. Wang, K. Q. Zhaob, Z. J. Shi, Chem. Commun. 2008,
1437; f) T. Shimasaki, Y. Konno, M. Tobisu, N. Chatani, Org. Lett. 2009, 11,
4890; g) A. J. Brockway, M. Gonzꢃlez-Lꢄpez, J. C. Fettinger, J. T. Shaw, J.
Org. Chem. 2011, 76, 3515; h) L. G. Xie, Z. X. Wang, Chem. Eur. J. 2011,
17, 4972; i) T. Iwasaki, Y. Miyata, R. Akimoto, Y. Fujii, H. Kuniyasu, N.
Kambe, J. Am. Chem. Soc. 2014, 136, 9260.
[4] a) K. W. Quasdorf, X. Tian, N. K. Garg, J. Am. Chem. Soc. 2008, 130,
14422; b) B. J. Li, Y. Z. Li, X. Y. Lu, J. Liu, B. T. Guan, Z. J. Shi, Angew.
Chem. Int. Ed. 2008, 47, 10124; Angew. Chem. 2008, 120, 10278; c) J. Y.
Yu, R. Kuwano, Angew. Chem. Int. Ed. 2009, 48, 7217; Angew. Chem.
2009, 121, 7353; d) H. W. Lee, F. Y. Kwong, Synlett 2009, 3151; e) B. J. Li,
L. Xu, Z. H. Wu, B. T. Guan, C. L. Sun, B. Q. Wang, Z. J. Shi, J. Am. Chem.
Soc. 2009, 131, 14656; f) D. Gꢅrtner, A. L. Stein, S. Grupe, J. Arp, A. J. von
Wangelin, Angew. Chem. Int. Ed. 2015, 54, 10545; Angew. Chem. 2015,
127, 10691.
1
sis. For the reaction of vinyl ether 1, by using H NMR spectros-
copy, we observed the alkylgallium intermediate of a reaction
of vinyl ether 1 with silyl ketene acetal 2, which strongly sup-
ported the carbogallation/elimination mechanism. Kinetic stud-
ies have shown that the coupling reaction of vinyl ether 1 is
on the order of zero for enol ether 1 and silyl ketene acetal 2,
and is of the first order for GaBr3 (rate=kobs[GaBr3]) and that
the turnover-limiting step is the elimination process. On the
other hand, the rate equation for the reaction of vinyl carbox-
ylate 6 can also be represented as rate=kobs[GaBr3][6], and the
turnover-limiting step involved carbogallation. Computational
analysis was used to investigate the details of the b-elimination
process in a coupling reaction using vinyl ether 1. The results
revealed that the moderate Lewis acidity of GaBr3 contributes
to the flexible conformational change of the alkylgallium inter-
mediate from a stable six-membered ring to a strained four-
membered ring and syn-elimination with CꢀO bond cleavage.
[5] a) F. H. Porꢆe, A. Clavel, J. F. Betzer, A. Pancrazi, J. Ardisson, Tetrahedron
Lett. 2003, 44, 7553; b) L. Xu, B. J. Li, Z. H. Wu, X. U. Lu, B. T. Guan, B. Q.
Wang, K. Q. Zhao, Z. J. Shi, Org. Lett. 2010, 12, 884.
&
&
Chem. Eur. J. 2016, 22, 1 – 10
www.chemeurj.org
8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
[6] a) A. S. E. Karlstrçm, K. Itami, J. E. Bꢅckvall, J. Org. Chem. 1999, 64, 1745;
b) Y. Nan, Z. Yang, Tetrahedron Lett. 1999, 40, 3321.
halide. Y. Inamoto, Y. Kaga, Y. Nishimoto, M. Yasuda, A. Baba, Chem. Eur.
J. 2014, 20, 11664.
[7] T. Hayashi, Y. Katsuro, M. Kumada, Tetrahedron Lett. 1980, 21, 3915.
[8] C. Chen, R. F. Jordan, J. Am. Chem. Soc. 2010, 132, 10254.
[19] NMR spectra of alkylgallium dihalides; a) O. T. Beachley, Jr., M. J. Noble,
M. R. Churchill, C. H. Lake, Organometallics 1992, 11, 1051; b) J. Ohshita,
H. Schmidbaur, J. Organomet. Chem. 1993, 453, 7; c) O. T. Beachley, Jr.,
J. C. Pazik, M. J. Noble, Organometallics 1994, 13, 2885; d) O. T. Bea-
chley, Jr., D. B. Rosenblum, M. R. Churchill, D. G. Churchill, L. M. Krajkow-
ski, Organometallics 1999, 18, 2543.
[20] This structural characteristic is consistent with our reported alkylindium
compound synthesized by carboindation among InBr3, octene, and di-
methylketene trimethylsilyl methyl acetal (Ref. [13b]).
[21] See the Supporting Information for NMR spectra of Scheme 4.
[22] Spectroscopic Methods in Organic Chemistry 2nd ed. (Eds.: M. Hesse, H.
Meier, B. Zeeh), Thieme, Stuttgart (Germany), 2008.
[23] R. U. Lemieux, B. Fraser-Reid, Can. J. Chem. 1965, 43, 1460.
[24] For the addition/elimination mechanism in GaCl3-catalyzed reactions,
see; a) R. Amemiya, A. Fujii, M. Arisawa, M. Yamaguchi, J. Organomet.
Chem. 2003, 686, 94; b) R. Amemiya, K. Suwa, J. Toriyama, Y. Nishimura,
M. Yamaguchi, J. Am. Chem. Soc. 2005, 127, 8252; c) R. Amemiya, Y.
Miyake, M. Yamaguchi, Tetrahedron Lett. 2006, 47, 1797; d) Y. Nishimura,
R. Amemiya, M. Yamaguchi, Tetrahedron Lett. 2006, 47, 1839.
[25] b-Eliminations from b-oxyalkylmetals. Reviews for Peterson olefinations;
a) D. J. Ager, Synthesis 1984, 384; b) A. G. M. Barrett, J. M. Hill, E. M. Wal-
lace, J. A. Flygare, Synlett 1991, 764; c) L. F. van Staden, D. Gravestock,
D. J. Ager, Chem. Soc. Rev. 2002, 31, 195. b-Eliminations from b-oxyalkyl-
metals. Peterson olefinations using b-hydroxymetals other than b-hy-
droxysilanes: D. J. Ager in, Organic Reactions, Vol. 38, Wiley, 1990, p. 1.
[26] The injection of Me3SiBr had no influence on the rate (see the Support-
ing Information), which suggested that Me3SiBr does not take part in
the syn elimination step unlike the mechanism we proposed in the pri-
mary report.
[9] Y. Nishimoto, T. Nishimura, M. Yasuda, Chem. Eur. J. 2015, 21, 18301.
[10] For coupling with arenol derivatives, Heck reactions using alkenes and
direct C-O/C-H cross-couplings using heteroarenes and carbonyl com-
pounds have been recently established. Heck reaction: a) A. R. Ehle, Q.
Zhou, M. P. Watson, Org. Lett. 2012, 14, 1202. Direct C-O/C-H cross-cou-
plings using heteroarenes and carbonyl compounds: b) K. Muto, J. Ya-
maguchi, A. Lei, K. Itami, J. Am. Chem. Soc. 2013, 135, 16384; c) R.
Takise, K. Muto, J. Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2014, 53,
6791; Angew. Chem. 2014, 126, 6909; d) M. Moselage, N. Sauermann,
S. C. Richter, L. Ackermann, Angew. Chem. Int. Ed. 2015, 54, 6352;
Angew. Chem. 2015, 127, 6450; e) E. Koch, R. Takise, A. Studer, J. Yama-
guchi, K. Itami, Chem. Commun. 2015, 51, 855; f) T. Chen, L.-B. Han,
Angew. Chem. Int. Ed. 2015, 54, 8600; Angew. Chem. 2015, 127, 8722.
[11] Y. Nishimoto, H. Ueda, M. Yasuda, A. Baba, Angew. Chem. Int. Ed. 2012,
51, 8073; Angew. Chem. 2012, 124, 8197.
[12] The coupling reaction of carbonyl group-substituted enol ethers
through 1,4-addition/elimination in the stoichiometric amount of
a base: a) N. Zanatta, R. Barichello, H. G. Bonacorso, M. A. P. Martins, Syn-
thesis 1999, 765.
[13] a) Y. Nishimoto, R. Moritoh, M. Yasuda, A. Baba, Angew. Chem. Int. Ed.
2009, 48, 4577; Angew. Chem. 2009, 121, 4647; b) Y. Nishimoto, H. Ueda,
Y. Inamoto, M. Yasuda, A. Baba, Org. Lett. 2010, 12, 3390.
[14] Y. Nishimoto, H. Ueda, M. Yasuda, A. Baba, Chem. Eur. J. 2011, 17, 11135.
[15] a) Y. Nishimoto, M. Takeuchi, M. Yasuda, A. Baba, Chem. Eur. J. 2013, 19,
14411; b) Y. Nishimoto, M. Takeuchi, M. Yasuda, A. Baba, Angew. Chem.
Int. Ed. 2012, 51, 1051; Angew. Chem. 2012, 124, 1075.
[16] Probably, Me3SiBr, which is generated temporarily, is not compatible
with functional groups such as alkene, chloro, and methoxy groups.
[17] A Values: isopropyl group (2.15 kcalmolꢀ1), phenyl group (2.7 kcal
molꢀ1), tert-butyl group (4.9 kcalmolꢀ1); M. B. Smith, J. March, March’s
Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th
ed., Wiley, New York, 2001.
[27] See the Supporting Information for the derivation of rate equations.
[28] See the Supporting Information for the details of Arrhenius plot.
Received: May 6, 2016
[18] We reported the sequential addition of two different carbon nucleo-
philes to esters through Claisen condensation catalyzed by gallium tri-
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 10
www.chemeurj.org
9
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Cross-Coupling Reactions
Y. Nishimoto,* Y. Kita, H. Ueda,
H. Imaoka, K. Chiba, M. Yasuda,* A. Baba
&& – &&
Coupling Reaction of Enol Derivatives
with Silyl Ketene Acetals Catalyzed by
Gallium Trihalides
Coupling with gallium: A cross-cou-
pling reaction between enol derivatives
and silyl ketene acetals catalyzed by
GaBr3 took place to give the corre-
sponding a-alkenyl esters (see scheme).
Various types of enol ethers and vinyl
carboxylates as enol derivatives are
amenable to this coupling. The scope of
the reaction with respect to silyl ketene
acetals was also broad. We propose
a mechanism involving anti-carbogalla-
tion among GaBr3, an enol derivative,
and a silyl ketene acetal followed by
syn-b-alkoxy elimination from the alkyl-
gallium.
&
&
Chem. Eur. J. 2016, 22, 1 – 10
www.chemeurj.org
10
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!