Multicatalytic Stereoselective Synthesis of Highly Substituted Alkenes by Sequential Isomerization/Cross-Coupling Reactions

Article abstract of DOI:10.1021/jacs.8b02134

Starting from readily available alkenyl methyl ethers, the stereoselective preparation of highly substituted alkenes by two complementary multicatalytic sequential isomerization/cross-coupling sequences is described. Both elementary steps of these sequences are challenging processes when considered independently. A cationic iridium catalyst was identified for the stereoselective isomerization of allyl methyl ethers and was found to be compatible with a nickel catalyst for the subsequent cross-coupling of the in situ generated methyl vinyl ethers with various Grignard reagents. The method is compatible with sensitive functional groups and a multitude of olefinic substitution patterns to deliver products with high control of the newly generated C=C bond. A highly enantioselective variant of this [Ir/Ni] sequence has been established using a chiral iridium precatalyst. A complementary [Pd/Ni] catalytic sequence has been optimized for alkenyl methyl ethers with a remote C=C bond. The final alkenes were isolated with a lower level of stereocontrol. Upon proper choice of the Grignard reagent, we demonstrated that C(sp²) - C(sp²) and C(sp²) - C(sp³) bonds can be constructed with both systems delivering products that would be difficult to access by conventional methods.

Full text of DOI:10.1021/jacs.8b02134

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Multicatalytic Stereoselective Synthesis of Highly Substituted Al-
kenes by Sequential Isomerization/Cross-Coupling Reactions
Ciro Romano, and Clément Mazet
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02134 • Publication Date (Web): 21 Mar 2018
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Multicatalytic Stereoselective Synthesis of Highly Substituted Al-
kenes by Sequential Isomerization/Cross-Coupling Reactions
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Ciro Romano, Clément Mazet*
Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva, Switzerland.
ABSTRACT: Starting from readily available alkenyl methyl ethers, the stereoselective preparation of highly substituted
alkenes by two complementary multicatalytic sequential isomerization/cross-coupling sequences is described. Both ele-
mentary steps of these sequences are challenging processes when considered independently. A cationic iridium catalyst
was identified for the stereoselective isomerization of allyl methyl ethers and was found to be compatible with a nickel
catalyst for the subsequent cross-coupling of the in situ generated methyl vinyl ethers with various Grignard reagents.
The method is compatible with sensitive functional groups and a multitude of olefinic substitution patterns to deliver
products with high control of the newly generated C=C bond. A highly enantioselective variant of this [Ir/Ni] sequence
has been established using a chiral iridium precatalyst. A complementary [Pd/Ni] catalytic sequence has been optimized
for alkenyl methyl ethers with a remote C=C bond. The final alkenes were isolated with a lower level of stereocontrol.
Upon proper choice of the Grignard reagent, we demonstrated that C(sp2)-C(sp2) and C(sp2)-C(sp3) bonds can be con-
structed with both systems delivering products that would be difficult to access by conventional methods.
modynamically more stable carbonyl group. In a broader
context, the propensity of nickel and palladium catalysts
v INTRODUCTION
The development of practical, economical and widely
applicable catalytic processes which enable a rapid in-
crease in molecular complexity from readily available
chemicals lies at the forefront of synthetic chemistry. In
this context, the remote functionalization of an organic
molecule by alkene migration along a hydrocarbon skele-
ton has attracted increased attention, leading to the de-
vise of particularly challenging and creative transfor-
mations.1-2 In such relay reactions, two distant functional
groups can be interconverted through a transmitting pro-
cess, independently of the length of their tether. The suc-
cessful realization of remote functionalization protocols
hinges on several key factors: (i) the triggering event that
initiates olefin migration; (ii) the nature of the terminal
functional group undergoing refunctionalization which
provides a favorable thermodynamic driving-force; (iii)
the kinetic ability of the catalyst to sustain olefin migra-
tion independently of the length of the hydrocarbon
chain.
to shµ¥¥¨• #Ë# ¢ØƧ≥ Ø∂•≤ ° £°≤¢ØÆ ≥´•¨•¥ØÆ ꢁ°©Æ-
∑°¨´©Æßï ∞≤Ø£•≥≥ꢂ5 combined with their widespread use in
cross-coupling chemistry has led to the development of
some of the most successful and elegant remote function-
alizations. Protocols where carbon-carbon bond for-
mation triggers isomerization can be distinguished from
methods where it participates in the terminal refunction-
alization event. For instance, inspired by pioneering ob-
servations made by Molpolder and Heck,6 Sigman has
established a series of highly enantioselective long-range
redox-relay reactions initiated by the arylation of a re-
mote alkene (Figure 1-B).7 Using a related Pd-catalyzed
Heck arylation as initiator and by combining a chain-
walking process with a selective cyclopropane ring-
opening event, Marek was able to generate stereochemi-
cally complex linear carbonyls (Figure 1-B).8 The Baudoin
group recently devised an impressive regioconvergent
strategy for the synthesis of functionalized linear alkanes
starting from (mixtures of) branched alkyl bromides.9 The
strategy relies on the identification of monodentate phos-
phine ligands able to retard reductive elimination of a
transient organopalladium complex with respect to metal
migration (Figure 1-C). Following a similar inspiration,
Martin elaborated a Ni-catalyzed site-selective carboxyla-
tion of remote C(sp3)ÅH positions with carbon dioxide
based on a bromination/isomerization/cross-coupling
concatenation starting from mixtures of simple chemical
feedstock. Remarkably, a switch in selectivity was
achieved by simple adjustment of the reaction conditions
(Figure 1-C).10 Zhu and coworkers disclosed a regioselec-
tive benzylic functionalization using a Ni-catalyzed isom-
erization/arylation sequence.11 The reaction is initiated by
Over the last decade, our laboratory has focused on
the development of stereoselective short- and long-
distance isomerizations of allylic and alkenyl alcohols
using well-defined [IrꢀH] and [PdꢀH] catalysts (Figure 1-
A).3 Whereas, iridium catalysts were applied to the highly
enantio- and diastereoselective isomerization of primary
allylic alcohols, palladium-hydrides enabled the long-
range isomerization of primary and secondary alkenyl
alcohols as well as the deconjugative isomerization of
a,b-unsaturated amides, esters and ketones.4 These reac-
tions are typically initiated by rate-determining hydro-
metallation of the C=C bond and driven by the final inter-
conversion of the elusive enol intermediates into a ther-
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Figure 1. (A) Ir- and Pd-catalyzed isomerization of alkenyl alcohols. (B) Remote refunctionalization reactions triggered by
a cross-coupling reaction. (C) Remote refunctionalizations terminated by a cross-coupling reaction. (D) Ni-catalyzed
cross-coupling reactions using C-OMe electrophiles. (E) Proposed isomerization/cross-coupling sequence starting from
alkenyl methyl ethers and affording stereodefined polysubstituted alkenes.
the hydrometallation of a remote (terminal or 1,2-
disubstituted) olefin and is driven by the formation of a
thermodynamically more stable benzyl-nickel intermedi-
ate prior to product formation (Figure 1-C).
methyl ethers.14 They display limited scope and are often
moderately stereoselective. In 1978, Baudry and Ephri-
tikhine reported the Ir-catalyzed isomerization of a hand-
ful of linear and cyclic primary allyl ethers into (E)-
configured methyl vinyl ethers.14o Later, Miyaura elabo-
rated on this study and developed related systems for the
preparation of a limited set of alkoxy-allylboronates and
silyl enol ethers15 While our studies were in progress,
Nishimura and coworkers disclosed an iridium-catalyzed
hydroarylation of alkenyl ethers based on an isomeriza-
tion/asymmetric CꢀH activation sequence affording sec-
ondary alkyl ethers with high levels of enantioselectivity.16
As is often the case in metal-catalyzed isomerization reac-
tions initiated by hydrometallation, in all these reports,
we note that more reactive terminal or 1,2-disubstituted
olefins are common substrates. Importantly, tri- or
tetrasubstituted olefinic substrates are much less employed
owing to their reduced ability to coordinate to transition
metal catalysts and therefore to react.3c,g,i,4,12
To further extend the current portfolio of long-range
refunctionalization reactions, we wondered whether we
could merge a [MꢀH]-catalyzed (long-range) isomeriza-
tion of alkenyl methyl ethers with a Ni-catalyzed cross-
coupling by CꢀO bond activation of the transiently gener-
ated methyl vinyl ethers to stereoselectively generate
structurally sophisticated polysubstituted olefins (Figure
1- E).12 Conceptually, this approach integrates the features
of an underdeveloped and potentially stereoselective re-
dox-economical isomerization with the modularity and
diversity of a challenging cross-coupling process for
C(sp2)ꢀC(sp2) and C(sp2)ꢀC(sp3) bond formation. Moreo-
ver, as it bypasses preformation of electrophilic coupling
partners that are notoriously difficult to synthesize and
isolate, it bears the potential to substantially impact syn-
thetic efficiency. The successful realization of our objec-
tive requires addressing the specific challenges associated
with each individual step as well as the difficulties inher-
ent to the development of a sequential one-pot multicata-
lytic process employing two distinct transition metal cata-
lysts.13
Recent years have witnessed a renewed interest in the
use of CÅO electrophiles as alternative to aryl halides in
metal-catalyzed cross-coupling reactions.17,18 Since the
seminal report of Wenkert,18a,b the superiority of Ni cata-
lysts over Pd catalysts has been clearly established. De-
spite their much reduced reactivity compared to other CÅ
O electrophiles, aryl, benzyl and styrenyl methyl ethers
have attracted great attention (Figure 1-D). This is moti-
vated by their synthetic availability, the inertness of the
waste generated and their compatibility with a variety of
Vinyl methyl ethers are particularly reactive molecules
and methods for their stereoselective preparation are
scarce. Base-assisted or metal-catalyzed isomerizations
approaches are restricted to a 1-carbon migration of allyl
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Table 1. Reaction optimizationa
nucleophiles. Specifically, organoboron, organozinc and
1
2
3
4
5
6
7
8
Grignard reagents have been established as excellent cou-
pling partners in Suzuki-Miyaura, Negishi and Kumada-
Tamao-Corriu type cross-couplings respectively, leading
to the development of a number of efficient catalytic
technologies.18 In sharp contrast, a survey of the recent
and ever-growing literature on this topic reveals that alkyl
vinyl ethers have been found to be competent coupling
partners only on very rare occasions.18a-b,h Mechanistically
this may be explained by the lack of beneficial p interac-
tions of the metal center with the neighboring aromatic
system.19
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entry
substrate
2a
solvent
toluene
toluene
toluene
THF
t (h)
0.5
2
conv.(%)b
<5
E/Zb
ndc
1
In this article, we report the development of two high-
ly efficient one-pot multicatalytic processes which
streamline access to a wide variety of structurally complex
polysubstituted alkenes with high levels of olefin stere-
ocontrol. These sequential reactions combine either one-
carbon (Ir) or long-range (Pd) catalytic isomerizations of
allyl or alkenyl methyl ethers with a subsequent and
equally challenging Ni-catalyzed cross-coupling between
the in situ generated methyl vinyl ethers and various Gri-
gnard reagents. By capitalizing on the compatibility of
mechanistically distinct metal-catalyzed transformations
as well as on the complementarity of the two isomeriza-
tion reactions, this approach bypasses isolation of sensi-
tive reaction intermediates while increasing catalytic effi-
ciency and molecular complexity. The unusual reactivity
observed for highly substituted prochiral olefinic sub-
strates enabled the development of an enantioselective
variant of the [Ir/Ni] catalytic sequence.
2
2a
66
dec.d
10:1
ndc
3
2a
18
4
5
2a
0.5
3
70
18:1
2a
THF
79
2.2:1
2.2:1
>20:1
8.3:1
2:1
6
7
2a
THF
18
80
69e
2a
THF
18
8
9
10
11
12
a
2a
2-MeTHF
2-MeTHF
2-MeTHF
THF
0.5
18
63
2a
80
2a
18
74e
14:1
2b
0.5
0.5
>99e
>99e
8.8:1
>20:1
2b
2-MeTHF
Reaction conditions: 2a-b (0.05-0.1 mmol), [0.1]. The
precatalyst is activated by H2 for 1 min. followed by degassing
of the solution prior to substrate addition. Determined by
b
1H NMR of the crude mixture using an internal standard.
c
Not determined. d Decomposition. e Using 2.5 mol% of 1a.
Table 2. Reaction optimizationa
v RESULTS AND DISCUSSION
Reaction development (I): Ir-catalyzed isomerization
of allyl methyl ethers. We commenced our study by
•∂°¨µ°¥©Æß ¥®• 0¶°¨¥∫ ≠ا©¶©•§ ∂•≤≥©ØÆ Ø¶ #≤°¢¥≤••ï≥ £°¥a-
lyst (1a) in the isomerization of two representative allyl
methyl ethers 2a-b (Table 1).20 This iridium catalyst was
selected for its ability to isomerize a broad range of pri-
mary allylic alcohols under mild reaction conditions once
activated with molecular hydrogen.3c,g,21 While no reaction
occurred with 2a after 0.5 h in toluene, 66% conversion
into 3-methoxyallyl-benzene 3a was attained within 2 h
with a satisfactory E/Z ratio (10:1). A prolonged reaction
time led to decomposition of the product (Entry 1-3). Rap-
id isomerization into 3a was achieved in THF (0.5 h, 70%
conv., 18:1 E/Z). Prolonging the reaction time did not im-
prove significantly conversion and was accompanied by
noticeable erosion in stereoselectivity (Entry 4-6). These
results are in line with observation made by Miyaura and
coworkers in the isomerization of allyl silyl ethers.15 Re-
markably, reducing the catalyst loading to 2.5 mol% ena-
bled to achieve a similar productivity while maintaining a
high level of stereoselectivity (Entry 7). Similar results
were obtained in 2-methyl-tetrahydrofuran (2-MeTHF), a
solvent derived from biomass (Entry 8-10). Gratifyingly,
isomerization of (E)-(3-methoxybut-1-en-1-yl)cyclohexane
2b was achieved under similar conditions affording 3b
quantitatively with excellent stereocontrol (E/Z >20:1;
Entry 12). This result is more surprising as only primary
Entry
[Ni] (x)
L (y)
solvent
yield (%)b
E/Zb
-
1
[Ni(cod)2] (5)
[Ni(cod)2] (5)
[(Ph3P)2NiCl2] (5)
[Ni(cod)2] (5)
[Ni(OAc)2] (5)
[Ni(OAc)2] (5)
[Ni(OAc)2] (5)
PCy3 (20)
PCy3 (20)
THF
dec.c
47d
20
2
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
>20:1
>20:1
-
3
4
dcpe (5)e
L1 (10)
nrf
5g
6g
7g
37
>20:1
>20:1
>20:1
L2 (10)
L3 (10)
31
56
a
Reaction conditions: 2a-b (0.1-0.25 mmol), [0.1]. The
precatalyst is activated by H2 for 1 min. followed by degassing
b
of the solution prior to substrate addition. Determined by
1H NMR of the crude mixture using an internal standard.
Decomposition. After purification by column chromatog-
c
d
e
f
raphy. dcpe = 1,2-bis(dicyclohexylphosphino)ethane. No
cross-coupling product observed although 3b was generated
quantitatively. g Using 1.3 equiv. of PhMgBr 4a.
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Figure 2. Scope of the [Ir/Ni]-catalyzed isomerization/cross-coupling sequence with variations both on the nucleophilic
and electrophilic component of the reaction (0.25 mmol, [0.1]). Conditions A: L3, 70 °C. Conditions B: L1, 120 °C. a Isomer-
ization: 18 h. b 3 equiv. of RMgBr. c 2 h. d 5 mol% 1a. e 95% purity. f 10 mol% Ni(OAc)2, 20 mol% L1. g 10 mol% 1a.
allylic alcohols were isomerized effectively with 1a.3c,g
clohexyl-N-substituted ligand L3 delivered 4ba in 56%
yield as a single stereoisomer.23
Reaction development (II): Sequential [Ir/Ni]-
catalyzed isomerization/cross-coupling of allyl me-
thyl ethers using Grignard reagents. Having identified
suitable reaction conditions for the isomerization of two
model allyl methyl ethers, we next set out to assess
whether this system could be combined with a Ni-
catalyzed cross-coupling reaction following a one-pot/
sequential approach (Table 2). To this end, preliminary
investigations were conducted under relatively mild con-
ditions using 2b, phenylmagnesium bromide 4a as nucle-
The generality of the reaction was next examined us-
ing a broad range of primary and secondary allyl methyl
ethers with diversely substituted olefinic moieties (Figure
2). Although the conditions identified in Table 2 (L3, 70
°C) were applicable to several substrate combinations, a
second set of reaction conditions was developed for more
difficult cases using L1 and higher temperatures (120 °C).
Remarkably, with both protocols, the newly generated
olefinic products were quasi-systematically obtained with
high to very high levels of stereocontrol (4.5:1 to >20:1)
and in moderate to very good yields (42-88%). Electron-
rich and electron-deficient aryl Grignard reagents were
successfully cross-coupled with in situ generated methyl
vinyl ethers derived from allyl methyl ethers lacking a
proximal aromatic substituent able to stabilize reactive
intermediates by favorable secondary interactions (4ca-
cf).19 Substrates with diverse alkene substitution patterns
(R1, R2, R3; 4ba-ga) were also found to be compatible with
our strategy and even 2g which possesses a tetrasubstitut-
ed olefinic moiety was reacted to afford the final product
4ga in 49% yield and a E/Z ratio >20:1. Similarly, particu-
larly congested allyl methyl ethers were engaged in a pro-
ductive and selective one-pot [Ir/Ni]-catalyzed isomeriza-
tion/cross-coupling sequence (4ha-4ka). While allyl me-
ophilic coupling
partner
and
the
ubiquitous
PCy3/[Ni(cod)2] combination for activation of CÅO elec-
trophiles. Only decomposition of the starting materials
was observed in THF (Entry 1). In contrast, complete con-
sumption of 2b was obtained in 2-MeTHF and (E)-4ba
1
was the only detectable product by H NMR analysis of
the crude reaction mixture after evaporation of all volatile
residues (Entry 2). Although the cross-coupling product
was isolated in only 47% after purification, this result
clearly validates our initial design plan. Variation of the
nickel source and/or the phosphine ligand did not lead to
significant improvements (Entry 3-4; see SI for additional
screening results).22 Subsequently, a small set of N-
heterocyclic carbene precursors L1-L3 was evaluated using
[Ni(OAc)2] (Entry 5-7). Much to our satisfaction, the cy-
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(Figure 4).3e,g In line with previous observations made for
1
2
3
4
5
6
7
8
the iridium-catalyzed isomerization of primary allylic
alcohols, the reactivity of the chiral catalyst was lower
than that of 1a and THF was found to be the optimal sol-
vent in this system. Ligand L1 was best suited for the
nickel-catalyzed cross-coupling reaction. The products
were therefore isolated in moderate yield but with partic-
ularly high levels of stereo- and enantiocontrol for aryl
containing substrates (E/Z >20:1; 91-92% ee). For alkyl
containing substrates, lower levels of enantiocontrol were
obtained while maintaining a high level of stereocontrol
(E/Z >20:1; 59-67% ee). These results are in contrast with
the consistently high levels of enantioselectivity obtained
across a broad range of substrates in the related Ir-
catalyzed isomerization of allylic alcohols and point to
subtle mechanistic differences.3b
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Figure 3. Demonstration of the stereoconvergency of the
[Ir/Ni]-catalyzed isomerization/cross-coupling sequence
using (Z)-2t.
Reaction development (III): Sequential [Pd/Ni]-
catalyzed long-range isomerization/cross-coupling
of alkenyl methyl ethers. Because attempts to isomerize
homoallylic methyl ethers or more remote alkenyl methyl
ethers with iridium catalyst 1a were not met with success,
we decided to evaluate the compatibility between some of
the palladium catalysts developed in our group for long-
range isomerizations with the nickel-catalyzed cross-
coupling of methyl vinyl ethers potentially generated in
situ.3g-i,4,25
Figure 4. Proof-of-principle for the [Ir/Ni]-catalyzed en-
antioselective isomerization/cross-coupling sequence.
Reactions conducted on a 0.1 mmol scale. Yield after puri-
fication by column chromatography.
thyl ethers with additional C=C bonds and/or proximal
stereocenters did not undergo parasitic isomerization
and/or epimerization (4la-4oa), O- and Si-containing
substrates were well tolerated (4oa-4ra). Finally, methyl
magnesium bromide could also be employed as nucleo-
phile in the cross-coupling reaction, highlighting the pos-
sibility to also create C(sp2)-C(sp3) bonds with high levels
of stereocontrol. Other alkyl Grignard reagents were also
successfully cross-coupled. Unfortunately product for-
mation was systematically accompanied by generation of
inseparable terminal olefins resulting from protodemetal-
lation as well as products of homocoupling of the Gri-
gnard reagents (See SI).24 Submitting (Z)-2t to the same
sequence delivered 4ta in 63% yield as a single stereoiso-
mer (E/Z >20:1). Aliquots taken during the isomerization
reaction already showed that 3t was generated in a E/Z
ratio >20:1, indicating the Ir-catalyzed process is stereo-
convergent in nature (Figure 3).
Figure 5. [Pd/Ni]-catalyzed long-range isomeriza-
tion/cross-coupling sequence starting from alkenyl me-
a
thyl ethers (0.25 mmol). The major isomer is displayed.
Isomerization conducted at 530 °C. Isomerization con-
b
ducted at 80 °C. c Contains 15% of internal olefins derived
from 2x.d Isomerization conducted at 50 °C
For this sequence to be operative, we found that two
different solvents had to be used for each individual reac-
tion (1,2-dichloroethane then 2-MeTHF) (Figure 5). In the
The one-pot isomerization/cross-coupling sequence
was next conducted with five prochiral allyl methyl ethers
(2h-i,k,u-v) and chiral catalyst 1b was used instead of 1a
1
case of 2w and 2x, H NMR monitoring of the isomeriza-
tion reaction indicated that generation of the targeted
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methyl vinyl ether was not quantitative and was systemat-
Page 6 of 9
phenyl magnesium bromide afforded 4fa quantitatively in
a >20:1 E/Z ratio (Eq. (2)). A similar result was obtained
when this reaction was conducted in presence of iridium
complex 1a previously activated by molecular hydrogen
(Eq. (3)). When the cross-coupling reaction between 3f
(E/Z = 1.5:1) and PhMgBr was conducted in presence of
the activated palladium complex 5, 4fa was generated in a
2:1 ratio (Eq. (4)). Collectively, these data indicate that in
the case of the [Ir/Ni] sequence, if the isomerization is
not perfectly stereoselective, the nickel catalyst exerts a
corrective effect that increases the E/Z ratio of the final
olefinic product. In contrast, in the [Pd/Ni] catalytic se-
quence such corrective effect is marginal. Because no
isomerization of (E)-4fa was detected when using 5 alone
(Eq. (5)), we propose that interactions between both tran-
sition metals are likely to be responsible for this phenom-
enon rather than competing post-reaction isomerizations.
1
2
3
4
5
6
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8
ically accompanied by the formation of ca. 20% of several
internal olefins. This is in contrast with the long-range
isomerization of alkenyl alcohols and deconjugative
isomerization of a,b-unsaturated carbonyls for which the
refunctionalization into a ketone or an aldehyde seems to
constitute a stronger driving force as these reactions are
often quantitative.2h,3 Interestingly, the isomerization of
2w could be conducted at Å30 °C and followed - after sol-
vent exchange - by the nickel-catalyzed cross-coupling
using phenyl magnesium bromide to yield 4wa (54%; E/Z
= 1.7:1). The secondary alkenyl methyl ethers 2x-z were
less reactive and required a temperature of 50-80 °C for
the isomerization to proceed but were nonetheless suc-
cessfully cross-coupled with aryl magnesium bromide 3a
or 3c and methyl magnesium bromide 3g (4xc: 64%; 4xg:
57%; 4yc: 58%; 4za: 71%).
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In conclusion, we have developed two complementary
one-pot multicatalytic sequences that provide access to
polysubstituted olefins. Both elementary steps of these
sequences are challenging processes when considered
independently. The first sequence consists in a combina-
tion of an iridium-catalyzed isomerization of allyl methyl
ethers followed by a nickel catalyzed-cross coupling of the
in situ generated methyl vinyl ethers with Grignard rea-
gents which delivers the products with high degree of
olefin stereocontrol. The method is compatible with a
variety of functional groups and a multitude of olefinic
substitution patterns to afford products with high control
of the newly generated C=C bond and in practical yields.
Upon proper choice of the Grignard reagent, we demon-
strated that C(sp2)-C(sp2) and C(sp2)-C(sp3) bonds can be
efficiently constructed. A highly enantioselective variant
of the [Ir/Ni] catalytic sequence has been designed for a
selected number of aryl-containing prochiral allyl methyl
ethers. A complementary [Pd/Ni] catalytic sequence was
optimized where the use of palladium catalysts enabled
isomerization of the remote C=C bond in several alkenyl
methyl ethers, delivering the final alkenes with a lower
level of stereocontrol. A corrective effect induced by the
nickel catalyst on the olefin geometry was observed dur-
ing the cross-coupling event in some [Ir/Ni] sequences.
This effect is only negligible using the [Pd/Ni] system ꢀ
presumably due to detrimental interactions between both
transition metals.
A noticeable difference between the [Ir/Ni] and
[Pd/Ni] sequences is the much reduced levels of stere-
ocontrol measured with the latter. In order to better un-
derstand the origin of this dichotomy several experiments
were conducted using a 1.5:1 E/Z stereoisomeric mixture
of methyl vinyl ether 3f (itself prepared by an independ-
ent Wittig olefination reaction. See Supporting Informa-
tion) (Figure 6).
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, charac-
terization of all new compounds and spectral data. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Figure 6. Evaluation of potential interactions between
the transition metal catalysts used in the [Ir/Ni] and
[Pd/Ni] catalytic sequences.
* Prof. Clément Mazet. University of Geneva, Organic Chem-
istry Department. Quai Ernest Ansermet 30, Geneva 1211 -
Switzerland. clement.mazet@unige.ch
Subjecting 3f to the prototypical Ni-catalyzed cross-
coupling reaction conditions using [Ni(OAc)2], L1 and
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Journal of the American Chemical Society
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Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
We thank the University of Geneva and the Swiss National
Science Foundation (project 200021_159199) for financial
support and Johnson Matthey for a generous gift of iridium
and palladium precursors.
9
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