Highly E-Selective, Stereoconvergent Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling of Alkenyl Ethers

Article abstract of DOI:10.1021/acs.orglett.9b00946

An improved method for the nickel-catalyzed Suzuki-Miyaura cross-coupling of alkenyl ethers is reported. This stereoconvergent protocol allows for the utilization of a wide range of alkenyl ethers and aryl boronic esters for the synthesis of variously sub

Full text of DOI:10.1021/acs.orglett.9b00946

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly E‑Selective, Stereoconvergent Nickel-Catalyzed Suzuki−
Miyaura Cross-Coupling of Alkenyl Ethers
Guo-Ming Ho, Heiko Sommer, and Ilan Marek*
Schulich Faculty of Chemistry, TechnionIsrael Institute of Technology, Technion City, Haifa, 3200009, Israel
S
* Supporting Information
ABSTRACT: An improved method for the nickel-catalyzed Suzuki−Miyaura cross-coupling of alkenyl ethers is reported. This
stereoconvergent protocol allows for the utilization of a wide range of alkenyl ethers and aryl boronic esters for the synthesis of
variously substituted styrene derivatives. An olefinic mixture with respect to the alkenyl ethers can be employed, thereby
circumventing the stereodefined synthesis of starting materials. Preliminary mechanistic investigations indicate a nickel-
catalyzed olefin isomerization following initial stereoretentive cross-coupling.
Scheme 1. Nickel-catalyzed Kumada and Suzuki-Miyaura
cross-coupling of alkenyl ethers
ickel-catalyzed activations of classically inert bonds have
1
Nreceived considerable attention in the last decades.
Pioneering studies by Wenkert and others2 have resulted in the
development of practical protocols for the nickel-catalyzed
Kumada cross-coupling of various aryl and alkenyl ethers
(Scheme 1a−c).3 In all of these cross-coupling protocols,
nickel(II) salts were successfully employed as precatalysts as
sacrifical organomagnesium coupling partners led to the in situ
formation of the catalytically active species via a trans-
metalation/reductive elimination. Since these initial findings,
milder reaction conditions and broadened substrate scope led
to significant improvements,4 such as the extension of coupling
partners from highly reactive organomagnesium to organo-
boron compounds (Scheme 1d).5 Despite these contributions,
several challenges remain to be addressed and as organoboron
coupling partners only sluggishly undergo this cross-coupling
6
reaction, and highly air- and moisture-sensitive Ni(COD)2 or
laboriously prepared nickel(0) precatalysts have to be
employed.7 Apart from operational challenges, control over
double-bond geometry decisively influences the synthetic
utility of the present method. Early studies by Chatani and
Tobisu have demonstrated that under the reaction conditions
the intermediately obtained olefinic mixture of styrenes
isomerizes in favor of the thermodynamically more stable E-
isomer.5a This important finding was subsequently briefly
examined in the cross-coupling of cyclic alkenyl ethers albeit
with limited success.5e The authors propose the intermediacy
of a Ni−H species to cause olefin isomerization.
We became interested in this topic as part of our ongoing
research program combining remote functionalization via
chain-walking with various postfunctionalization processes.8
Recently, we and Mazet have independently reported an
efficient combined metal-catalyzed chain-walking/nickel-cata-
lyzed Kumada cross-coupling of alkenyl ether to access a
variety of styrene products (Figure 1).9 During these studies,
we realized that the major limitation of this transformation was
Received: March 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00946
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Nickel-Catalyzed Suzuki-Miyaura
a
Cross-Coupling of Alkenyl Ether 1a
b
c
entry
ligand (mol %)
dcype (20)
dcypf (20)
T (°C)
3a (%)
E/Z
1
2
3
4
5
6
7
8
9
105
105
105
105
105
105
105
105
105
105
105
105
85
nr
nr
nr
nr
nr
nr
nr
25
86
62
60
90
nd
nd
nd
nd
nd
nd
nd
dppe (20)
Xantphos (20)
ICy·HBF4 (40)
6,6′-Me2-2,2′-pyridine (20)
SPhos (40)
PPh3 (40)
PCy3 (40)
Figure 1. Previously reported tandem metal-catalyzed ’chain-
walking’/nickel-catalyzed Kumada cross-coupling.
85:15
96:04
95:05
95:05
95:05
97:03
96:04
that the moderate E/Z-selectivity of the enol ether, obtained
by isomerization of the double bond, was retained during the
cross-coupling event. Based on these findings, we decided to
embark on a study and identify conditions that would address
this shortcoming, ideally resulting in the development of a
mild, stereoconvergent cross-coupling of alkenyl ethers.
At the outset of this study, we wondered whether an in situ
generated Ni(0) could successfully promote a stereoconver-
gent cross-coupling of our model enol ether 1a, keeping in
mind that we were concerned by delineating a new protocol
that would be efficient and easy to manipulate with air stable
Ni species. As it has been demonstrated that treatment of
Ni(acac)2 with DIBAL in the presence of suitable ligands could
furnish a range of catalytically active LnNi species,10 we were
interested in applying those conditions to our transformation.
Building on Chatani and Murai’s finding of superior reactivity
of neopentyl boronic esters,11 we chose 2a as the model
coupling partner and toluene as the standard solvent (Table 1).
A range of mono- and bidentate ligands were tested under
the reaction conditions (Table 1, entries 1−9). Bidentate
phosphines, NHC, or bipyridine ligands failed to promote
product formation along with sterically demanding Buchwald-
type ligand (Table 1, entries 1−7). Only PPh3 and PCy3
furnished the desired product in low and high yield,
respectively (Table 1, entries 8 and 9). More importantly,
PCy3 provided the product with excellent levels of stereo-
control over the double-bond geometry (E/Z 96:04).
Reducing the catalyst loading (Table 1, entry 10) or utilizing
CsF as additive (Table 1, entry 11) results in diminished
product formation. Some improvement was achieved by
reducing the ligand to metal ratio (Table 1, entry 12).
Ultimately, lowering the reaction temperature to 85 °C
allowed the isolation of 3a in 92% yield with an excellent E/
Z ratio (Table 1, entry 13). Further reduction of the
temperature to 65 °C resulted in decreased reactivity (Table
1, entry 14).
d
10
PCy3 (20)
PCy3 (40)
e
11
12
13
14
PCy3 (30)
PCy3 (30)
PCy3 (30)
f
92
57
60
a
All reactions were carried out using 1a (0.27 mmol) and 2a (0.32
b
mmol, 120 mol %) in 1.4 mL of toluene. Yields determined by
analysis of the unpurified mixture of products by H NMR with an
1
c
internal standard in chloroform-d. Ratio determined by analysis of
d
the unpurified mixture of products by 1H NMR. Ni(acac)2 (5.0 mol
e
f
%), DIBAL (10 mol %). CsF (120 mol %). Yields of isolated
products after purification by column chromatography.
conditions. Interestingly, when various anisole derivatives were
used as coupling partners, no subsequent cross-coupling
products were observed on the aromatic ring (Scheme 2, 3h
and 3i). Steric hindrance resulted in slightly diminished E/Z
ratios (Scheme 2, 3c and 3g). Additional steric bulk resulted in
no product formation (Scheme 2, reactant 2p) in addition to
boronic esters possessing either a nitro, pyridine, or thiophene
unit (Scheme 2, reactant 2q−t).
With these encouraging results in hand, we then explored
the scope of alkenyl ethers as coupling partners with 2a as a
model boronic ester. To this end, a variety of cyclic and acyclic
alkenyl ethers were subjected to the previously optimized
reaction conditions (Table 2). Simple acyclic alkenyl ethers
cleanly furnished the products in good to high yield with
excellent E/Z ratios (Table 2, entries 1−6). Additional degrees
of unsaturation were well-tolerated given that the olefin is
embedded within a trisubstituted olefin (Table 2, entry 4), but
less-substituted olefins undergo a well-precedented nickel-
catalyzed chain-walking, giving rise to a mixture of isomers
along with partial reduction product (Table 2, entry 3).
Nevertheless, the efficiency of the projected cross-coupling
remained unaffected, and the products were obtained in
excellent combined yield as virtually single geometrical
isomers. The same phenomenon of partial isomerization of
the double-bond was also observed in the case of the sensitive
enol ether 1g (Table 2, entry 6), which provided a mixture of
two styrene products. This result further advocates the notion
of a nickel-mediated olefin isomerization following the cross-
coupling event.
With the optimal conditions in hand (Table 1, entry 13), we
set out to explore the scope of boronic esters as coupling
partners (Scheme 2). A wide range of aromatic and
heteroaromatic boronic esters delivered the products in usually
high yield with excellent control of the double-bond geometry.
Electron-withdrawing (Scheme 2, 3d, 3l, and 3n) as well as
electron-donating substituents are well-tolerated (Scheme 2,
3h, 3j, 3k, and 3m). Heteroaromatic moieties, i.e., indole and
furan, efficiently undergo the cross-coupling reaction (Scheme
2, entries 3m and 3o) albeit in lower yield in the latter case,
most probably due to insufficient stability under the reaction
Cyclic enol ether 1h could be converted successfully into
linear alkenol 3v in good yield with reasonable control over the
double-bond geometry (Table 2, entry 7). Interestingly, the
corresponding six-membered alkenyl ether failed to undergo
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DOI: 10.1021/acs.orglett.9b00946
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Cross-Coupling of Alkenyl Ether 1a with
Different Boronic Esters
Table 2. Cross-Coupling of Boronic Ester 2a with Different
Alkenyl Ethers 1b−m
a
a
All reactions were carried out using 1a (0.27 mmol) and 2b−t (0.33
mmol, 120 mol %) in 1.4 mL of toluene. Yields were individually
obtained after purification by column chromatography on silica gel.
1
The E/Z ratio was determined by H NMR spectroscopic analysis of
b
the unpurified mixture of products. The reaction was carried out at
105 °C.
the desired transformation (see the Supporting Information).
Alkenyl ethers bearing an aromatic moiety finally provided
access to variously substituted stilbenes in good yields and
excellent E/Z ratios (Table 2, entries 8−11). As expected,
trisubstituted olefin 1m only partially underwent isomerization,
furnishing the product with a low E/Z ratio (Table 2, entry
12).
Having established a robust protocol for the transformation
of a variety of alkenyl ethers and boronic esters into substituted
styrenes and stilbenes, we decided to test the applicability of
this method to the synthesis of biologically relevant molecules.
At the outset, a scale-up experiment established our confidence
in the robustness of the current method (Scheme 3a).
Subsequently, the synthesis of DMU-212, a resveratrol
analogue with potential anticancer properties for the treatment
of human ovarian cancer,12 was successfully executed (Scheme
3b).
In order to gain additional insight into this intriguing
double-bond isomerization process, a series of control
experiments were designed (Table 3). To this end, Z-3p was
independently synthesized and exposed to our established
reaction conditions (Table 3, entry 1). It was found that under
standard conditions, complete double-bond isomerization took
place. The same result was obtained in the absence of boronic
ester coupling partner 2a (Table 3, entry 2) and even without
ligand (Table 3, entry 3). From the above presented results it
appears reasonable to assume that a nickel hydride may
a
All reactions were carried out using 1b−m (0.27 mmol) and 2a
(0.33 mmol, 120 mol %) in 1.4 mL of toluene. Yields were
individually obtained after purification by column chromatography on
silica gel. The E/Z ratio was determined by H NMR spectroscopic
analysis of the unpurified mixture of products. Reaction was carried
out at 105 °C. Reaction was carried out using Ni(acac)2 (20 mol %),
DIBAL (40 mol %), and PCy3 (60 mol %) in 1.4 mL of toluene at 105
°C.
1
b
c
intermediately be formed, which causes double-bond isomer-
ization or migration (Table 2, entry 3). Indeed, in the absence
of DIBAL, no olefin isomerization of Z-3p was observed and
only starting material was retrieved (Table 3, entry 4). To rule
out a thermal process, the reaction was conducted at 60 and 25
°C in the presence of DIBAL and Ni catalyst (Table 3, entries
5−7). In both cases, E-3p was obtained as a single geometrical
isomer, therefore excluding a thermally induced process. It
should be noted that the pure thermal treatment of Z-3p does
not produce the E-isomer either. These results support the
C
DOI: 10.1021/acs.orglett.9b00946
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
generally excellent control over the double-bond geometry.
Various aromatic and heteroaromatic boronic esters could be
successfully employed in this transformation. Both acyclic and
cyclic alkenyl ethers participated well in this process
comprising Lewis basic groups or additional degrees of
unsaturation. Mechanistic investigations led us to propose
that the olefin isomerization is subsequent to the cross-
coupling reaction.
Scheme 3. Scale-up Experiment of 3a and Synthesis of
Potential Anticancer Agent DMU-212 (3ab)
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00946.
Experimental procedures and characterization data for
all new compounds (PDF)
Table 3. Control Experiments To Identify Isomerization-
Active Species
a
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chilanm@technion.ac.il.
ORCID
Ilan Marek: 0000-0001-9154-2320
Notes
entry [Ni] DIBAL PCy3
2a
T (°C) time (h)
E/Z
The authors declare no competing financial interest.
1
2
3
4
5
6
√
√
√
√
√
√
√
√
√
×
√
√
√
√
×
×
×
√
×
×
×
×
×
105
105
105
105
60
16
16
16
16
16
48
98:02
96:04
95:05
n.r.
>95:05
>95:05
ACKNOWLEDGMENTS
■
This project has received funding from the European Union’s
Horizon 2020 research and innovation program under Grant
Agreement No. 786976. H.S. acknowledges the Max-Planck-
Society for a Minerva Fellowship.
×
25
a
All reactions were carried out using Z-3p (0.27 mmol) and, if
applicable, 2a (0.33 mmol, 120 mol %) in 1.4 mL of toluene. The E/Z
ratio was determined by 1H NMR spectroscopic analysis of the crude
mixture.
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