Stereoretentive Pd-catalyzed kumada-corriu couplings of alkenyl halides at room temperature

Article abstract of DOI:10.1021/ol501535w

Stereoselective palladium-catalyzed Kumada-Corriu reactions of functionalized alkenyl halides and a variety of Grignard reagents, including those bearing β-hydrogen atoms and sensitive functional groups, can be carried out at room temperature using a new combination of reagents.

Full text of DOI:10.1021/ol501535w

Letter
pubs.acs.org/OrgLett
Open Access on 08/07/2015
Stereoretentive Pd-Catalyzed Kumada−Corriu Couplings of Alkenyl
Halides at Room Temperature
Arkady L. Krasovskiy,† Stephen Haley,‡ Karl Voigtritter,‡ and Bruce H. Lipshutz*,‡
†The Dow Chemical Company, Core R&D, 1776 Building, E4-A, Midland, Michigan 48674, United States
‡Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: Stereoselective palladium-catalyzed Kumada−Corriu re-
actions of functionalized alkenyl halides and a variety of Grignard reagents,
including those bearing β-hydrogen atoms and sensitive functional groups,
can be carried out at room temperature using a new combination of
reagents.
a
Table 1. Screening of Representative Catalyst Systems
umada−Corriu cross-couplings are among the earliest
Ktransition-metal-catalyzed reactions introduced as a means
of forming carbon−carbon bonds.1 Initially reported as nickel-
catalyzed processes between Grignard reagents and aryl or
alkenyl halides, subsequent developments in palladium-catalyzed
couplings have led to variations based on this less toxic and more
functional group tolerant process, as first reported by Murahashi.2
While these Pd-catalyzed couplings are highly effective for biaryl
formation, those involving alkenyl halides together with alkyl
Grignard reagents bearing β-hydrogens are notoriously problem-
atic, owing to the considerable potential for competing β-hydride
elimination.3 Although great progress has been made toward
minimizing this undesired pathway through careful tuning of
phosphine-based ligands,4,5 room for further optimization and
improvements remain, especially regarding functionalized
Grignard reagents.6 We now describe Pd-catalyzed Kumada−
Corriu cross-couplings with alkenyl halides that take place rela-
tively rapidly under ambient conditions and that minimize side-
product formation. Notably, mild reaction conditions allow for the
synthesis of alkenes bearing sensitive functionality, such as cyano
and ester groups.7
Early work by Kumada revealed that careful selection of the
phosphine ligand could prove highly effective at controlling the
pathways that can lead to undesired byproducts.8 Indeed, in the
absence of a coordinating ligand or additive, reactions catalyzed
by PdCl2 strongly favor β-hydride elimination to ultimately afford
product 3 (Table 1, entry 1). The addition of bidentate amine
ligand TMEDA dramatically increased the relative amounts of the
desired cross-coupled product 2 (compare entries 1, 2, 6, and 7).
By replacing monodentate-phosphine ligands (entries 4, 5) with
bidentate analogs derived from diphenyl ether or ferrocene, the
relative yield of cross-coupled product2 was increased significantly
(entries 6, 10). Bidentate 1,2-bis(diphenylphosphino)benzene
(entry 8) was ineffective at catalyzing the desired cross-coupling
reaction. Eventually it was found that a mixed catalyst system
involving both TMEDA and the sterically demanding bidentate
phosphine ligands DPEPhos or dtbpf led to efficient formation of
the desired product (entries 7, 11).9 We hypothesized that the
b
entry
ligand (L)
2
3
4
1
none
3
85
8
12
9
2
TMEDA (1.1 equiv)
TMEDA (0.1 equiv)
PPh3
83
11
16
10
65
90
0
3
76
82
90
25
8
13
2
4
5
P(o-Tol)3
0
6
DPEPhos
10
2
7
DPEPhos/TMEDA
1,2-di-PPh2-C6H4
1,2-di-PPh2-C6H4/TMEDA
dtbpf
8
79
50
7
21
0
9
50
91
94
10
11
2
dtbpf/TMEDA
6
0
a
Conditions: 0.3 mmol of alkenyl halide substrate (0.25 M in THF).
Palladium catalyst (2 mol %), Grignard reagent (1.75 equiv), TMEDA
b
(1.85 equiv). GC ratio.
effects might be additive, although not necessarily of equal impact,
since the bidentate phosphine ligand likely coordinates strongly to
the palladium, while the amine ligand should show a preference for
Received: May 28, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
coordination to magnesium.10 Support for this hypothesis can
be found in the significant erosion in selectivity observed when the
diamine ligand was reduced to less than 1 equiv relative to the
Grignard reagent (entry 2 vs 3).
Table 2. Pd-Catalyzed Couplings of Alkenyl Halides with sp3-
Grignard Reagents
a
The vastly improved selectivity upon addition of the dtbpf
ligand to palladium was attributed to the bulky di-tert-butyl-
phosphine residues appended to the ferrocene rings that may
distort the expected square planar geometry of the transition
state in a manner similar to that proposed by Espinet.11 In this
way the group derived from the Grignard is forced into closer
proximity to the alkenyl moiety, and a more rapid reductive
elimination ensues favoring the cross-coupled product. More-
over, this ligand seems well suited to minimize homodimeriza-
tion of the alkenyl halide, presumably by generating a steric
environment around palladium that effectively discourages ligand
exchange between palladium centers. The role of TMEDA, that
likely coordinates to the Grignard as described by Nakamura,9 may
hasten transmetalation, as is commonly seen with organozinc
reagents.12 The combination of these two ligands leads to the
desired cross-couplings in less than 3 h (0.25 M in THF) at room
temperature in most cases with excellent selectivity.13 Additional
screening of the reaction conditions for the cross-coupling
of β-bromostyrene with PhMgBr, along with the effect of
different amines (e,g., TEEDA), confirmed our initial findings
(see Supporting Information).
This methodology compares favorably with the procedures
and results reported by Oshima14 (Scheme 1, path A; CyOMe =
cyclopentyl methyl ether) and Cahiez15 (Scheme 1, path B).
a
Scheme 1. Comparison to Literature Work
a
Conditions: 0.3 mmol of alkenyl halide (0.25 M in THF), Pd catalyst
(2 mol %), Grignard reagent (1.75 equiv), TMEDA (1.85 equiv), 3 h.
b
Isolated yield.
was undertaken (Table 2). Both primary and secondary sp3-
magnesium reagents were shown to be excellent cross-coupling
partners. The acetal in Grignard reagent 15 (entry 4) did not
impede coupling. The example involving phenethyl Grignard 17
(entry 5) is noteworthy in that although the β-hydrogens present
are also benzylic, β-hydride elimination was not a major pathway.
Cross-coupling of alkenyl halide with a secondary alkyl Grignard
reagent 20 (entry 6) afforded the trisubstituted olefinic product
22 in good yield. Attempts to affect the same reaction using t-
BuMgCl, however, led to only trace amounts of the desired
adduct, with the corresponding reduced styrene being formed
efficiently (ca. 97%). Use of the more hindered α-bromostyrene,
together with a primary alkyl Grignard reagent, increased the
β-hydride elimination pathway (ca. 30%). Tetrahydropyranyl
(THP; entries 1 and 2) as well as benzyl ethers (entry 5) present
in the alkenyl coupling partner are well tolerated and afforded the
desired products in good to excellent yields.
a
Conditions: palladium catalyst (2 mol %), Grignard reagent (1.75 equiv),
TMEDA (1.85 equiv).
Interestingly, in this case once again both DPEPhos and dtbpf
ligands afforded desired product 6 with very similar conversions
and isolated yields. Likewise, direct comparison with the classical
work of Hayashi,16 e.g., conversion of Grignard 7 and alkenyl
halide 8 to product 9 (path C), is again indicative of the positive
effect of both the change in ligand, as well as the use of TMEDA.
With this new catalyst system in place, an investigation of the
scope and limitations of the reaction of alkyl-Grignard reagents
Aromatic and heteroaromatic Grignard reagents were also
investigated (Table 3). Cross-coupling of room temperature
B
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Letter
more slowly reacting Z-alkenyl bromides (entry 3).16 The
TIPS protected pyrrole 31 served as an excellent partner leading
to an efficient coupling with the E-trisubstituted vinyl iodide 32
(entry 4).
Table 3. Pd-Catalyzed Couplings of Alkenyl Halides with
Aryl- and Heteroaryl Grignard Reagents
a
Under these standard conditions ((dtbpf)PdCl2/TMEDA),
reactions of Grignard reagents bearing sensitive functionalities17
were complicated with unidentified byproducts and, thus,
required tedious purification. Fortunately, these competing
pathways could be averted using our modified conditions
(DPEPhosPdCl2/TMEDA). Moreover, with 5 mol% of DPEPhos
as ligand, only 1.3 equiv of the corresponding Grignard reagent
were needed to achieve full conversion (entries 5−8). Grignard
reagents such as ortho-bromophenylmagnesium chloride (34) are
known to be unstable at room temperature,17,18 serving as precursors
to benzyne via elimination of MgBr2. Under our conditions,
however, this reagent was successfully cross-coupled at room
temperature with both E- and Z-alkenyl halides (35 and 37)
affording the corresponding alkenes with complete retention
of stereochemistry and high yields.
Interestingly, both cyano- (entry 7) and ester functions
(entry 8) are fully tolerated,7 while these groups are normally
incompatible with the presence of Grignard reagents at room
temperature. We did not observe any byproducts that can be
explained by nucleophilic attack of these aryl Grignard reagents
(39, 41) to the cyano or ester residues, suggesting that ligation
of magnesium by TMEDA may afford additional stabilization of
functionalized Grignards, thereby reducing their nucleophilicity.
At 60 °C, an alkenyl chloride could be successfully introduced
using this cross-coupling reaction under our standard conditions
(entry 9).
The prospects for use of vinyl-, allyl-, and alkynyl Grignard
reagents were also briefly ascertained (Scheme 2). Both conjugated
a
Scheme 2. Synthesis of Dienes and Enynes
a
Conditions: Palladium catalyst (2−5 mol %), Grignard reagent (1.3
equiv), TMEDA (1.5 equiv), 3 h.
47 and skipped dienes 49 were prepared in good yields, starting
from commercially available Grignard reagents. Here again, we
observed greater efficiency employing DPEPhosPdCl2. Likewise, an
acetylenic Grignard reagent 50 led to the desired enyne 51 in high
isolated yield.
a
Conditions: 0.3 mmol of alkenyl halide, DPEPhosPdCl2 (5 mol %),
b
Grignard reagent (1.3 equiv), TMEDA (1.5 equiv), 8 h. Isolated
yield. (dtbpf)PdCl2 (2 mol %) was used. Reaction time is 16 h. Run
for 4 h at 60 °C.
c
d
e
In summary, the sterically hindered bidentate diphosphine
ligands dtbpf and DPEPhos, in the presence of TMEDA, form an
effective combination leading to efficient Pd-catalyzed Kumada−
Corriu coupling reactions of alkenyl halides in THF at room tem-
perature. In the case of cross-coupling of the Grignard reagents
stable phenylmagnesium chloride 23 (entry 1) and dimethoxy-
phenylmagnesium bromide 25 (entry 2) led to the desired
products in high yields. Thiophene-derived Grignard reagent 28
gave the desired product in modest yield, as expected for the
C
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Letter
bearing reactive functionalities, DPEPhos/TMEDA proved to be
a better system leading to the desired products in higher yields.
Importantly, electrophilic functionality within the Grignard reagent
can be tolerated. Both in situ derived catalyst systems minimize
β-hydride elimination commonly associated with the use of Grignard
reagents for such reactions, thereby affording cross-coupled products
usually in high yields.
ASSOCIATED CONTENT
* Supporting Information
■
S
Contains experimental procedures and copies of NMR spectra
of all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lipshutz@chem.ucsb.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the NIH (GM
86485). We also thank Johnson Matthey for providing (dtbpf)
PdCl2 and Boulder Scientific for Cp2ZrCl2.
REFERENCES
■
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D
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