Metal-Catalyzed Remote Functionalization of ω-Ene Unsaturated Ethers: Towards Functionalized Vinyl Species

Article abstract of DOI:10.1002/anie.201802434

The combined ruthenium-catalyzed chain walking with the nickel-catalyzed cross-coupling reaction of ω-alkenyl ethers provide a unique entry to functionalized vinyl species. This transformation illustrates the power and flexibility of remote functionalization by demonstrating the compatibility of two independent reactions involving unrelated sites.

Full text of DOI:10.1002/anie.201802434

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Accepted Article
Title: Metal-Catalyzed Remote Functionalization of ω-Ene Unsaturated
Ethers as A New Entry to Functionalized Vinyl Species
Authors: Ilan Marek, Guo-Ming Ho, Lina Judkele, and Jeffrey Bruffaerts
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802434
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10.1002/anie.201802434
Angewandte Chemie International Edition
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Metal-Catalyzed Remote Functionalization of ω-Ene Unsaturated
Ethers as A New Entry to Functionalized Vinyl Species
Guo-Ming Ho, Lina Judkele, Jeffrey Bruffaerts and Ilan Marek*
Dedication ((optional))
Abstract: The combined Ru-catalyzed chain walking with the Ni-
catalyzed cross-coupling reaction of -alkenyl ethers provide an
Alternatively, the reaction of enol ether with low-valent transition
metals should provide 9 with the creation of a -metal bond.
Reaction with a sp3-centered electrophile should then provide the
expected product 10 where a new sp3-sp2 bond would be created
(Scheme 1d).
unique entry to functionalized vinyl species
.
Contrary to the traditional functionalization at the most reactive
site of an organic molecule, the functionalization at a distant and
generally non-reactive position has and will continue to strongly
modify our perception of performing synthetic transformations.
This alternative strategy, coined Remote Functionalization,[1] has
therefore attracted considerable attention as it allows carbon-
carbon bond forming events at non-classical positions (Scheme
1a).[2] Among several possibilities to address this issue, the ability
of a transition-metal complex to undergo a rapid ‘metal-walk’
along an hydrocarbon chain to functionalize the terminus position
has proven to be a valuable strategy to build molecular complexity
(Scheme 1b).[3] In this context, we reported the zirconocene-
mediated transformation of unsaturated fatty alcohol derivatives
1, through successive allylic C-H bond activations followed by an
a, Remote functionalization
remote functionalization
FG
FG
H
n
n
remote site
b, Metal-walk functionalization
metal-walk functionalization
R
H
R
MLn
n
n
remote site
c, Zirconocene-mediated remote functionalization
Cp2Zr(C4H8)
Et2O, 34 °C
R
ZrCp2OR1
n
R
OH
n
1
2
irreversible
-elimination
reaction,
into
substituted
R
R
Cp2Zr(C4H8)
allylzirconocene species 2 (Scheme 1c).[4] We have then
extended this concept to the selective preparation of
stereodefined dienylzirconocene species 4 from -ene enol ether
derivatives 3[5] and to acyclic bifunctionalized products 6 through
a combined Zr-walk and selective ring-opening of ω-ene
cyclopropanes 5.[6] Outstanding catalytic processes based on
Pd,[7] Ni,[8] Ru,[9] Rh,[10] Ir[11] and Co[12] complexes promoting rapid
isomerization across hydrocarbon chains have been also
developed allowing the design of various valuable synthetic
transformations.[2,3] However, an important transformation that
was missing in the arsenal of remote activations until this work
and the work of Mazet[13] was the preparation of a distant vinyl
metal species from a simple ether possessing a remote double
bond (Scheme 1d) that could subsequently undergo various
functionalization to provide functionalized alkenes 10. Our
proposed strategy would rely on the in-situ transformation of -
alkenyl ether 7 into enol ether 8 via a metal-catalyzed migration
of the double bond. As enol ether could be seen as an interesting
alternative to organohalide derivative,[14] the transition-metal
catalyzed cross-coupling reaction of 8 should directly provide 10
in which a sp2-sp2 carbon-carbon bond would be created.
Et2O, 34 °C
OMe
n
n
ZrCp2OMe
3
5
4
Cp2Zr(C4H8)
n
R1
R2
THF, 55°C
E
E
then E1-X
n
R1 R2
6
and E2-X
dr up to 98:2
d, The missing element: Preparation of vinyl metal species
OMe
[M]
R
R
n
n
9
Metal-mediated
interconversion
8
Electrophilic
trapping
Chain-walking process
metal-walk functionalization
R
OMe
R
MLn
n
n
7
10
Metal-catalyzed
cross-coupling
reaction
Chain-walking process
OMe
R
n
8
Scheme 1. Remote functionalization as precursor of vinylmetal species
Several important questions arise such as: 1) What would be the
best catalyst and experimental conditions for the isomerization of
7 into 8 that could also be compatible with the second
transformation (8 to 10)? 2) Is the chain length could be elongated
while preserving the efficiency of the metal-walk? 3) What would
be the effect of the stereochemistry of the initial alkene for the
metal-walk? 4) Would it be possible to control the directionality of
the metal-walk and only reacenol ether 8? 5) What would be the
[a]
Dr. Guo-Ming Ho, Lina Judkele, Dr. Jeffrey Bruffaerts, Prof. Dr. Ilan
Marek
Schulich Faculty of Chemistry. Technion - Israel Institute of
Technology
Haifa 32000, Israel
E-mail: chilanm@technion.ac.il
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201802434
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stereochemistry of the formed enol ether 8? 6) What would be the
best catalyst and conditions for the transformation of 8 into either
the vinyl metal 9 or directly to the cross-coupled product 10? 7)
What would be the stereochemistry of the functionalized alkene
10?
So before performing the entire one-pot transformation, we
initially focused our attention to the initial isomerization of model
substrate 7a into enol ether 8a. We started our study by testing
the ruthenium-based “alkene zipper” catalyst 11,[15] known to
allow a large number of positional isomerization when acetone
was used as solvent and successfully used for isomerization
catalyzed cross-coupling reaction was compatible with the
[RuHCl(CO)(PPh3)3]-catalyzed chain-walking process as we
observed the desired cross-coupling product 10a with an
acceptable E:Z selectivity (E:Z ratio ranging from 75:25 to
80:20, Table 1, entries 1-3). On the basis of these preliminary
results, we subsequently concentrated on improving the
cross-coupling reaction by using various phosphine-nickel
catalysts (Table 2, entries 4-9). We found that 20 mol% of
NiCl2(PPh3)2 in a mixture of THF and toluene as solvent
provided 10a in 53% yield while maintaining a similar
selectivity (E:Z = 78:22, Table 1, entry 6). It should be noted
that when the Ni-catalyzed cross-coupling reaction of
independently prepared enol ether 8a (E:Z ratio: 58:42,
prepared from entry 3, Table S1 of supplementary material)
was performed in pure toluene, 10a was obtained in 56%
yield with similar E/Z ratio (Table 1, entry 7). Further
optimization indicates that the best experimental conditions
combined with
a remote retro-ene reaction of -alkenyl
cyclopropyl carbinols (Scheme 2).[16]
Cp
Ru
N
PF6
[Ru] (5 mol%)
OMe
iPr
OMe
MeCN
solvent, temperrature
P
7a
8a
iPr
Me
time
tBu
N
were found when
RuHCl(CO)(PPh3)3 in THF at 90
addition of 10 mol% of NiCl2(PPh3)2 in toluene with PhMgBr
and further heating at 90 C for additional 16 h (Table 1, entry
7
was first treated with 5 mol% of
[Ru]
solvent
Temp
time
Yield (%)
E/Z
11
11
acetone
toluene
56
5
2
90
30
99:1

C for 16 h followed by the
RuH2(CO)(PPh3)3
120
57:43
RuHCl(CO)(PPh3)3 toluene
120
90
6
72
86
57:43
61:39

RuHCl(CO)(PPh3)3
THF
16
8). Hex-1-enylbenzene 10a was obtained in 63% isolated
yield as a mixture of two geometrical isomers (E:Z = 78:22).
A further decrease of the Ni-catalyst loading gave similarly
the product 10a albeit in lower yield (Table 1, entry 9).
Scheme 2.
Although 11 was proved to be a very efficient catalyst for this
isomerization, acetone as solvent could not be considered
Table 1. Reaction optimization of the [Ru/Ni]-catalyzed chain walking/cross-
coupling sequence.a
for the subsequent step (transformation of
8 into 10) and any
attempts to replace acetone by different solvents (THF, DMF,
DMSO, DME) failed to promote the desired isomerization.
Although acetone could formally be removed under vacuum
to perform the subsequent metal-catalyzed cross-coupling
step, yields of the final cross-coupled products were
unfortunately low. Moreover, all our attempts to perform the
isomerization of internal double bond failed to proceed with
entry
[Ni] (x)
solvent
T
(°C)
50
t
conv.
(%)b
38
E:Z b
(h)
16
1
2
Ni(acac)2 (10)
THF
75:25
80:20
79:21
80:20
79:21
78:22
55:45
78:22
75:26
Ni(acac)2 (10)
THF
70
90
90
90
90
90
90
90
16
16
16
2
42
34
3
Ni(acac)2 (20)
THF
4
NiCl2(dppf) (20)
NiCl2(dppp) (20)
NiCl2(PPh3)2 (20)
NiCl2(PPh3)2 (20)
NiCl2(PPh3)2 (10)
NiCl2(PPh3)2 (5)
THF/tol
THF/tol
THF/tol
toluene
THF/tol
THF/tol
43
the alkene-zipper catalyst 11
.
We the turned our attention
5
47
to various different Ru catalysts and after extensive
experimentation (see supporting Information for details), we
found that 5 mol% of [RuHCl(CO)(PPh3)3][17] catalyzed the
chain-walking reaction in THF to afford the unsaturated ether
8a in 86% yield as a 61:39 E:Z mixture. Although
[RuH2(CO)(PPh3)3][17c,18] was also able to promote the
6
2
53
7c
16
16
16
56
67(63)d
8
9
51
a Except for entry 7, all other entries were carried out using 7a (0.438
mmol), 5 mol% Ru catalyst in 1.5 mL of THF followed by 5-20 mol% Ni-
catalyst and PhMgBr (0.876 mmol) in 3.0 mL of a mixture of solvent
(THF/toluene 1:1). b Determined by analysis of the crude 1H NMR with
internal standard in chloroform-d1. c Intermediate 8a from the entry 3 of
isomerization of
7, the desired enol ether
8 was obtained in
only 30% yield. Alternatively,
8
could also be produced in a
shorter reaction time but at higher temperature in toluene
albeit in slightly lower yield. Having in hands an efficient and
conveniently air-stable catalyst to promote the isomerization
of the double bond into enol ether, we then investigated the
d
Table S1, see SI. Yield was obtained after purification by column
chromatography on silica gel.
second step, namely the transformation of enol ether
8 into
With this reliable bis-catalytic procedure in hand, we further
explored the scope of this protocol with respect to the
Grignard reagent (Scheme 3). Various Me-substituted aryl
Grignard reagents afforded the coupling products 10b-e in
satisfying yields (based on two chemical steps) with moderate
selectivities (E:Z ratio ranging from 61:39 to 78:22). Surprisingly,
the more congested mesitylmagnesium bromide did not inhibit
the formation of the product as 10e could be isolated in 50%
yield with a similar E:Z ratio. The use of naphthyl and bisphenyl
Grignard reagents gave the desired products 10f-h in
functionalized product 10 We initially concentrated our efforts
.
on the metal-catalyzed cross-coupling reaction of 8 and following
the pioneering work of Wenkert[19] and Kumada,[20] who
reported the Ni-catalyzed cross-coupling reaction of enol
ethers with aryl Grignard reagents
. We combined the
sequential Ru-catalyzed chain walking process with the
subsequent Ni-catalyzed cross-coupling reaction as
described in Table 1. Gratifyingly, and despite initial low
yields, our initial results show that the in-situ Ni(acac)2-
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10.1002/anie.201802434
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moderate overall yields (41-46% still based on the two-step
sequence) but with higher E:Z-selectivities. Furthermore,
electron-rich aryl Grignard reagents were also cross-coupled
giving the desired coupling products 10i-k in moderate
overall yields with moderate to very good selectivities (Scheme
3). Different Grignard reagents were also tested for the cross-
coupling reactions such as PhCH2CH2CH2MgBr, PhCH2MgBr,
C6H11MgBr, PhCCMgBr and MeMgBr but didn’t provide the
desired products in decent yields (maximum 30%) as coupling
dienes were always obtained (reductive coupling).
transform the in-situ formed enol ether 8 into vinylic
organometallic species that could subsequently react with
electrophiles of different nature to create sp2-sp3 bonds.
Table 2. Combined Ru-catalyzed isomerization/Ni-cross-coupling reactionsa
1) RuHCl(CO)(PPh3)3 (5 mol%), THF, 90 oC, 16 h
Ph
OR
n
n+m
m
2) NiCl2(PPh3)2 (10 mol%), PhMgBr (2 equiv)
THF/Toluene, 90 oC, 16 h
entry
1
Starting material
Product
Yieldb
63
E:Z c
78:22
60:40
47:53
49:51
82:18
2
3
4
5
79
60
82
61
OBn
7b
7c
7d
OTBS
O
OMe
C3H7
OMe
OMe
OMe
7e
6
63
80:20
C2H5
C5H11
C2H5
3
7f
7
8
64
50
82:18
80:20
7g
4
OMe
7h
7i
9
52
56
54
83:17
71:29
68:32
C5H11
2
OMe
OMe
10
11
C8H17
Scheme 3. Scope of the [Ru/Ni]-catalyzed chain walking/cross-coupling
sequence with different aryl Grignard derivatives.
7j
OMe
8
7k
Most importantly, the exact same conditions still proceeded on
analogous substrates with different ether end-group
functionalities, different chain-lengths (n and m) and various initial
stereochemistry of the double bond further demonstrating the
efficient combination of Ru chain-walking mechanism with the Ni-
cross-coupling reaction (Table 2). Benzyl- (Table 2, entry 2), silyl-
(Table 2, entry 3) and methoxyethoxy methyl ether (Table 2, entry
4) could be used similarly in this tandem bis-catalytic process to
provide the cross-coupled product in decent yields as two
isomers. Terminal as well as internal alkenes (Table 2, entries 1-
4 and 11 versus entries 5-10 respectively) could be indifferently
used for the combined catalyzed Ru-walk and Ni-catalyzed cross-
coupling reactions. Similarly, internal alkene of Z- (Table 2, entries
5-8) or E-stereochemistry (Table 2, entry 10) could equally be
potential partners for this transformation without any major
differences. Finally, the chain length between the unsaturation
and the ether could be varied from 1 to 9 methylene units without
drastic change in yields and E:Z ratio of the formed terminal
alkenes. These results show that our combined Ru-catalyzed
walk with the Ni-catalyzed cross coupling protocol is
a
All reactions were carried out using substrates 7a-k (0.438 mmol), 5
mol% Ru catalyst in 1.5 mL THF followed by using 10 mol% Ni catalyst
and PhMgBr (0.876 mmol) in 3.0 mL of a mixture of solvent (THF/toluene
1:1) for Ni-catalyzed arylation. b Yields of the E/Z mixture were obtained
after purification by column chromatography on silica gel. c Determined by
1H NMR spectroscopic analysis of the crude mixture in chloroform-d1.
As we reported that E- and Z-enol ethers,[21a] vinyl sufides,
vinyl sulfoxides, vinyl sulfones[21b] and vinyl carbamates[21c]
could be used as precursors of pure E-vinyl zirconocene
derivatives,[22] we were interested to merge these two
transformations. Our strategy started with the previously
described Ru-catalyzed chain walking process to transform
7
into 8 followed by the subsequent addition of the Negishi reagent
Cp2ZrC4H8, easily obtained by addition of 2 equiv. of nBuLi to
Cp2ZrCl2 in THF, and further heating for 2 h at 60 C (Scheme 4).
Following these conditions, we were pleased to observe the
formation of terminal alkene after hydrolysis of the formed
vinylzirconocene moiety with excellent conversions. Although the
ionic character of the sp2 C-[Zr] bond is similar to a C-Mg bond,
only small size electrophiles such as proton proved to efficiently
react with the sp2 C-[Zr] bond, presumably owing to the steric
shielding of the two cyclopentadienyl ligands at the metal center.
To circumvent the lack of reactivity, transmetalation to copper was
compatible for
-cis- and trans-alkenyl ethers as well as for
-terminal alkenyl ether with different chain length between
the two reacting functional groups. To further expand the
power of our proposed strategy, we were also interested to
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unique E-isomer in moderate yields.
n-C4H8ZrCp2
RuHCl(CO)(PPh3)3
(5 mol%)
OMe
OMe
(2.0 equiv.)
n
n
THF, 90oC, 16 h
THF,−78 oC to rt
then 60 oC, 2 h
7a (n=2)
7k (n=7)
8a (n=2); E/Z 61:39
8k (n=7); E/Z 61:39
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Br
O
O
CuCl 2LiCl
(20 mol%)
OBn
13
OBn
ZrCp2OMe
n
n
0oC to rt
16 h
THF, 0oC
30 min
12a (n=2)
12k (n=7)
14a (n=2); 47%; E/Z >95:5
14b (n=7); 32%; E/Z >95:5
Scheme 4. [Ru/Zr]-mediated chain walking/E-selective zirconation/
functionalization sequence
[9]
In conclusion, we have developed the [Ru/Ni]-catalyzed
chain walking/cross-coupling sequence as well as the
[Ru/Zr]-mediated sequence allowing the transformation of -
alkenyl ether into functionalized alkenyl species. Importantly,
this transformation illustrates the power and flexibility of
remote functionalization by demonstrating the compatibility
of two independent reactions involving unrelated sites.
Acknowledgements
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This research was supported by a grant from the European
Research Council under the seventh Framework Program of the
European Community (ERC Grant agreement 338912) and by the
Israel Science Foundation (grant No. 330/17).
Keywords: metal walk• cross-coupling • zirconocene • remote
functionalization• Grignard
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Guo-Ming Ho, Lina Judkele, Jeffrey
Bruffaerts and Ilan Marek*
RuHCl(CO)(PPh3)3 (5 mol%)
NiCl2(PPh3)2 (10 mol%), ArMgBr
OMe
Ar
n
n
Page No. – Page No.
Metal-Catalyzed
Functionalization of ω-Ene Unsaturated
Ethers as New Entry to
Functionalized Vinyl Species
Remote
A
The combined Ru-catalyzed chain walking with the Ni-catalyzed cross-coupling
reaction of -alkenyl ethers provide an unique entry to functionalized vinyl species
.
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