A Dual Palladium and Copper Hydride Catalyzed Approach for Alkyl–Aryl Cross-Coupling of Aryl Halides and Olefins

Article abstract of DOI:10.1002/anie.201703400

We report an efficient means of sp²–sp³ cross coupling for a variety of terminal monosubstituted olefins with aryl electrophiles using Pd and CuH catalysis. In addition to its applicability to a range of aryl bromide substrates, this process was also suitable for electron-deficient aryl chlorides, furnishing higher yields than the corresponding aryl bromides in these cases. The optimized protocol does not require the use of a glovebox and employs air-stable Cu and Pd complexes as precatalysts. A reaction on 10 mmol scale further highlighted the practical utility of this protocol. Employing a similar protocol, a series of cyclic alkenes were also examined. Cyclopentene was shown to undergo efficient coupling under these conditions. Lastly, deuterium-labeling studies indicate that deuterium scrambling does not take place in this sp²-sp³ cross coupling, implying that β-hydride elimination is not a significant process in this transformation.

Full text of DOI:10.1002/anie.201703400

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International Edition: DOI: 10.1002/anie.201703400
German Edition: DOI: 10.1002/ange.201703400
Homogeneous catalysis
Hot Paper
A Dual Palladium and Copper Hydride Catalyzed Approach for Alkyl–
Aryl Cross-Coupling of Aryl Halides and Olefins
Stig D. Friis, Michael T. Pirnot, Lauren N. Dupuis, and Stephen L. Buchwald*
Abstract: We report an efficient means of sp2–sp3 cross
coupling for a variety of terminal monosubstituted olefins
with aryl electrophiles using Pd and CuH catalysis. In addition
to its applicability to a range of aryl bromide substrates, this
process was also suitable for electron-deficient aryl chlorides,
furnishing higher yields than the corresponding aryl bromides
in these cases. The optimized protocol does not require the use
of a glovebox and employs air-stable Cu and Pd complexes as
precatalysts. A reaction on 10 mmol scale further highlighted
the practical utility of this protocol. Employing a similar
protocol, a series of cyclic alkenes were also examined.
Cyclopentene was shown to undergo efficient coupling under
these conditions. Lastly, deuterium-labeling studies indicate
that deuterium scrambling does not take place in this sp2-sp3
cross coupling, implying that b-hydride elimination is not
a significant process in this transformation.
ciencies are also sometimes observed due to competitive b-
hydride elimination of intermediate alkylpalladium(II) com-
plexes. To address some of these deficiencies, several new
strategies for alkyl-aryl cross coupling have been developed.
Seminal reports by Fu demonstrated that alkyl halides can
readily couple with aryl boronic acids with the use of
a trialkylphosphine-supported palladium catalyst or a bipyr-
idyl-supported nickel catalyst.[4] In addition, palladium and
nickel-catalyzed cross-electrophile strategies have allowed
the coupling of alkyl halides with aryl electrophiles in the
presence of an exogenous reductant.[5–8]
We reasoned that a complementary approach for sp2-sp3
cross coupling reactions using a-olefins as starting materials
would allow us to overcome some of the shortcomings
associated with the use of organoboron reagents and the
limited commercial availability of alkyl halide coupling
partners. Encouraged by a recent report from our lab[9] and
previous work utilizing Pd and Cu catalysis in a synergistic
fashion,[10] we envisioned that aryl halides and a-olefins could
be brought together to form sp2-sp3 cross coupled products
using a similar dual catalytic approach (Scheme 1). In
particular, we rationalized that we could employ olefins as
latent nucleophiles and, due to their stability and commercial
availability, would serve as an attractive starting material for
T
ransition metal-catalyzed sp2–sp3 cross coupling has
become a vibrant area of research due to its potential to
À
serve as a strategic C C bond forming process. Furthermore,
this approach provides opportunities for appending fragments
to complex, functionalized starting materials, thus expediting
the synthesis of their analogs. Classically, a stoichiometric
alkyl metal reagent is used as a coupling partner to enable
facile transmetalation with a transition metal catalyst.[1]
Despite their synthetic utility, many of these methods suffer
from promiscuous reactivity of the organometallic reagent
and synthesis of the reagent is often nontrivial.
The palladium-catalyzed Suzuki cross coupling with
alkylboron reagents is perhaps the most frequently utilized
strategy for appending an alkyl fragment to an arene.[2] In
general, this approach has proven to be a versatile and
reliable method that tolerates a broad range of functional
groups. In addition, alkyl boron reagents are often readily
accessible from the corresponding olefin via hydroboration.[3]
This method, however, suffers from several drawbacks with
respect to the requisite boron reagents. In the case of
trialkylboranes, the reagent is sensitive to air. Regarding
more air-stable alkyl boronic acid/ester or trifluoroborate
derivatives, multistep synthetic routes must often be
employed for their preparation. Diminished synthetic effi-
[*] Dr. S. D. Friis, Dr. M. T. Pirnot, L. N. Dupuis, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201703400.
Scheme 1. Pd- and CuH-catalyzed reductive cross coupling of terminal
olefins with aryl electrophiles.
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sp2-sp3 cross coupling. This formal reductive Heck reaction
would thus provide access to useful compounds, albeit with
perfect selectivity for the linear product.[11]
Table 1: Optimization of the Pd/Cu-catalyzed reductive cross coupling of
terminal alkenes with aryl bromides.
A detailed postulated mechanism of our strategy is shown
in Scheme 1. Olefin insertion should readily occur in the
presence of alkene B and CuH catalyst A to generate CuI-
alkyl C. In line with previous work,[12] we believed that olefin
insertion should occur in an anti-Markovnikov fashion with
a simple a-olefin. Concomitant oxidative addition of Pd0 D
into aryl electrophile E would generate PdII aryl complex F.
Transmetalation between CuI-alkyl C and PdII-aryl F should
furnish (alkyl)(aryl)palladium(II) complex G, which upon
reductive elimination, would form the desired product and
close the catalytic cycle for palladium. Base mediated
regeneration of phosphine ligated CuH species A then
closes the catalytic cycle for copper. For this proposed
synergistic process to be successful, the rates of these two
catalytic cycles would need to be matched to enable efficient
catalysis to take place. In addition, palladium-catalyzed
reduction/silylation of the aryl electrophile could also affect
the overall efficiency of this process.
The optimization of this cross coupling protocol is
detailed in Table 1. A series of ligands typically employed
for Cu-catalyzed reactions were examined (entries 1–5), and
a significant yield was observed only with DTBM-SEGPHOS
(entry 5, 53% yield). Dialkylbiarylphosphine ligands have
previously shown excellent activity as supporting ligands for
Pd-catalyzed cross coupling reactions.[13] Examination of
several ligands of this family (entries 5–8) showed BrettPhos
to be the most promising supporting ligand examined. CuCl
was found to give the highest yield out of a variety of CuI and
CuII salts tested (entries 5 and 9–11) (entry 11, 63% yield). A
variety of Pd sources were also tested, with [Pd(cinnamyl)Cl]2
providing the best reactivity (entry 11–14). Increasing the
reaction temperature above 458C was not beneficial for
product formation (entry 15, 56% yield). However, the use of
Me2PhSiH as the silane provided a significant increase in the
yield of the desired product, largely due to a decreased
propensity for unproductive aryl halide reduction (entry 16,
78% yield). Importantly, we found that this reaction could be
set up outside of the glovebox using air-stable DTBM-
SEGPHOS-ligated CuCl precatalyst P1 when the loading of
silane was increased slightly (entry 17, 75% isolated yield).
This precatalyst retained full catalytic activity when stored for
prolonged periods of time (> 1 month) in a desiccator outside
of the glovebox.[14]
Entry Pd source[a] Ligand A
Cu source Ligand B Yield,%[b]
1
2
3
4
[Pd(cin)Cl]2 BrettPhos
[Pd(cin)Cl]2 BrettPhos
[Pd(cin)Cl]2 BrettPhos
[Pd(cin)Cl]2 BrettPhos
[Pd(cin)Cl]2 BrettPhos
CuOAc
CuOAc
CuOAc
IPrCuCl
CuOAc
XantPhos
5
6
4
0
53
26
40
9
BINAP
PPh3
–
L1
L1
5
6
[Pd(cin)Cl]2 tBuBrettPhos CuOAc
7
[Pd(cin)Cl]2 XPhos
CuOAc
CuOAc
L1
L1
8
9
[Pd(cin)Cl]2 CPhos
[Pd(cin)Cl]2 BrettPhos
[Pd(cin)Cl]2 BrettPhos
[Pd(cin)Cl]2 BrettPhos
Cu(OAc)2 L1
33
61
63
35
15
23
56
78
79 (75)
10
11
12
13
14
15[c]
16[d]
17[e]
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
P1
L1
L1
L1
L1
L1
L1
L1
–
Pd(OAc)2
Pd2dba3
BrettPhos
BrettPhos
Pd(cod)Cl2 BrettPhos
[Pd(cin)Cl]2 BrettPhos
[Pd(cin)Cl]2 BrettPhos
[Pd(cin)Cl]2 BrettPhos
[a] cin=p-cinnamyl. [b] Yields determined by GC analysis of the crude
reaction mixture using tetradecane as an internal standard, isolated yield
is in parenthesis and is an average of two runs performed with 1 mmol of
olefin. [c] Reaction run at 558C. [d] Me2PhSiH used as the silane.
[e] Reaction was run outside of the glovebox and with 2.6 equiv of
Me2PhSiH as the silane.
pyrimidines (3l and 3n). Electron-neutral and electron-rich
aryl bromides generally perform well in this chemistry, while
more electron-poor aryl and heteroaryl bromides proved to
be problematic. For these substrates, the reduced aryl
bromide was observed as a major side-product. We reasoned
that electron-deficient aryl chlorides would be more recalci-
trant to reduction in this chemistry, and could complement the
aryl electrophile scope. In line with this rationale, 2-chloro-6-
methylpyridine showed an enhanced efficiency in product
formation over the corresponding bromide in the anti-
Markovnikov hydroarylation of terminal olefins (Sche-
me 2A). This trend also applied to vinylarenes, with 2-
chloroquinoline providing higher yield and enantioselectivity
compared to 2-bromoquinoline in the hydroarylation of 2-
vinylanisole (Scheme 2B).[16]
After optimization of our model reaction was completed,
we examined the substrate scope of this protocol (Table 2).[15]
A variety of functional groups were tolerated, including:
ethers (such as 3b), an amide (3c), a carbamate (3c), esters
(such as 3e), an alkyl chloride (3d), thioethers (such as 3g),
amines (3g, 3h, and 3o), and silyl ethers (such as 3l). A free
alcohol was tolerated (3m), but excess silane was required
and the efficiency of the process was significantly diminished.
The coupling of 2 f displaying both a terminal and internal
alkene proved highly selective for the more reactive a-olefin.
A series of heterocycles were also tolerated, including
quinolines (3 f, 3m, and 3o), an indazole (3h), an electron-
rich pyridine (3j), a benzothiophene (3k), and electron-rich
2
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Table 2: Substrate scope for the Pd/Cu-catalyzed reductive cross
coupling of monosubstituted olefins with aryl bromides.[a]
Scheme 2. Comparison of electron-deficient aryl chlorides and bro-
mides in Pd/CuH-catalyzed reductive cross coupling reactions. A) Anti-
Markovnikov reductive cross coupling with a-olefins. B) Enantioselec-
tive Markovnikov hydroarylation of vinylarenes. [a] All yields represent
the average of isolated yields from two runs performed with 1 mmol of
olefin. [b] Enantiomeric excess determined by chiral HPLC.
Scheme 3. Scale-up of the reductive cross coupling. Yields represent
the average of isolated yields from two runs performed with 10 mmol
of olefin.
[a] All yields represent the average of isolated yields from two runs
performed with 1 mmol of olefin. [b] Reaction was run with 1 mol%
[Pd(cinnamyl)Cl]2, 2.2 mol% BrettPhos, and 3 mol% P1. [c] Reaction run
with 3.6 equiv of Me2PhSiH. [d] Reaction was run at 0.25 M. [e] Reaction
was run at 0.5 M.
To highlight the practical utility of this transformation,
a reaction was performed on a 10 mmol scale again without
the aid of a glovebox. Even with lowered catalyst loadings
(3 mol% Cu, 2 mol% Pd), the reaction exhibited excellent
efficiency, providing the desired product 3q in a consistently
high yield (Scheme 3, 2.4 grams, 88%).
Scheme 4. Investigation of cyclic alkenes as substrates in the Pd/CuH-
catalyzed reductive cross-coupling. [a] Yield represents the average of
isolated yields from two runs performed with 1 mmol of aryl bromide.
[b] Yield determined by analysis of the crude reaction mixture via H-
NMR spectroscopy using 1,3-benzodioxole as an internal standard.
1
We were also interested in further exploring this chemis-
try with other classes of olefins. In particular, we investigated
the use of cheap, readily available cyclic alkenes that could be
used in excess for the synthesis of cross-coupled products
containing cycloalkyl groups (Scheme 4). This strategy would
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serve to both obviate the need for expensive cycloalkyl zinc
reagents as required for the corresponding Negishi reactions
while also simplifying the reaction setup.[17] In this context,
cyclopentene was found to couple in excellent efficiency with
para-bromoanisole to afford product 5a. A high concentra-
tion of cyclopentene and copper catalyst was required for
productive reactivity, presumably due to a more challenging
hydrocupration step. Application of this protocol to alkenes
of larger ring size led to reduced efficiency in the case of
cycloheptene and cyclooctene, while cyclohexene was unreac-
tive. We hypothesize that this trend is due to the decreased
ring strain of the larger cyclic olefins, which reduces the
propensity for the olefin to undergo hydrocupration with the
CuH catalyst.[18,19]
As mentioned above, aryl halide reduction constitutes the
major unproductive side-reaction of this transformation. To
this end, deuterium-labeling studies were pursued in this dual-
catalyzed CuH/Pd protocol. We believed this could clarify
two aspects of this chemistry: 1) the mechanism of aryl
electrophile reduction and 2) whether the transient CuI-alkyl
or PdII-alkyl aryl complex presumed to form during the course
of the reaction undergo b-hydride elimination at any point
(Scheme 1, C and G). The results of our study, using the four
combinations of labeled and unlabeled silane and alkene, are
displayed in Scheme 5. First, use of deuterated silane resulted
cross-coupled products. This protocol tolerates a broad range
of functional groups and heterocycles, and does not require
the preparation of any sensitive or specialized coupling
partners. In addition, electron-deficient heteroaryl chlorides
were shown to be effective in this reaction as well, comple-
menting the efficiency observed for electron-rich and elec-
tron-neutral aryl bromides. The synthetic utility of this system
was highlighted in a scale-up of the reaction to a 10 mmol
scale using air-stable Cu and Pd precatalysts at reduced
catalyst loadings. Studies using cyclic alkenes demonstrate
that cyclopentene is also an effective coupling partner for this
chemistry, likely due to the relief of ring-strain via hydro-
cupration. Finally, deuterium-labeling studies clarify the
mechanism for aryl halide reduction and discount b-hydride
elimination as a significant process in the protocol.
Acknowledgements
Research reported in this publication was supported by the
National Institutes of Health under award number GM46059.
M.T.P. thanks the National Institutes of Health for a postdoc-
toral fellowship (1F32GM113311). S.D.F. thanks the Carls-
berg Foundation and the Danish Council for Independent
Research: Natural Sciences for postdoctoral fellowships
(4181-00452). L.N.D. thanks the MIT Summer Research
Program. We thank Sigma–Aldrich for the generous donation
of BrettPhos ligand used in this work and Dr. Yiming Wang
for his advice on the preparation of this manuscript.
Conflict of interest
MIT has or has filed patents on ligands/precatalysts that are
described in the paper from which SLB and former/current
coworkers receive royalty payments.
Keywords: alkenes · copper · cross-coupling ·
homogeneous catalysis · palladium
Scheme 5. Deuterium-labeling studies for the Pd/CuH-catalyzed reduc-
tive cross coupling of terminal alkenes with aryl bromides. Deuterium
incorporation was quantified by H-NMR spectroscopy of the purified
products.
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1
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4
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Manuscript received: March 31, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Homogeneous catalysis
S. D. Friis, M. T. Pirnot, L. N. Dupuis,
S. L. Buchwald*
&&&& — &&&&
A Dual Palladium and Copper Hydride
Catalyzed Approach for Alkyl–Aryl Cross-
Coupling of Aryl Halides and Olefins
Cross-coupling: A protocol for sp2–sp3
cross-coupling of terminal alkenes and
aryl halides is reported. A broad substrate
scope based on air-stable precatalysts is
detailed. This reaction is shown on
a 10 mmol scale, along with preliminary
studies with cyclic alkenes that highlight
cyclopentene as an effective coupling
partner.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!