Bimetallic Catalysis for C-C and C-X Coupling Reactions

Abstract

Bimetallic catalysis represents an alternative paradigm for coupling chemistry that complements the more traditional single-site catalysis approach. In this perspective, recent advances in bimetallic systems for catalytic C-C and C-X coupling reactions are reviewed. Behavior which complements that of established single-site catalysts is highlighted. Two major reaction classes are covered. First, generation of catalytic amounts of organometallic species of e.g. Cu, Au, or Ni capable of transmetallation to a Pd co-catalyst (or other traditional cross-coupling catalyst) has allowed important new C-C coupling technologies to emerge. Second, catalytic transformations involving binuclear bond-breaking and/or bond-forming steps, in some cases involving metal-metal bonds, represent a frontier area for C-C and C-X coupling processes.

Full text

Chemical
Science
ISSN 2041-6539
rsc.li/chemical-science
Volume 8 Number 3 March 2017 Pages 1671–2466
PERSPECTIVE
Dominic R. Pye and Neal P. Mankad
Bimetallic catalysis for C–C and C–X coupling reactions

Bimetallic catalysis for C–C and C–X coupling
reactions
Dominic R. Pye and Neal P. Mankad*
Bimetallic catalysis represents an alternative paradigm for coupling chemistry that complements the more
traditional single-site catalysis approach. In this perspective, recent advances in bimetallic systems for
catalytic C–C and C–X coupling reactions are reviewed. Behavior which complements that of
established single-site catalysts is highlighted. Two major reaction classes are covered. First, generation
of catalytic amounts of organometallic species of e.g. Cu, Au, or Ni capable of transmetallation to a Pd
co-catalyst (or other traditional cross-coupling catalyst) has allowed important new C–C coupling
technologies to emerge. Second, catalytic transformations involving binuclear bond-breaking and/or
bond-forming steps, in some cases involving metal–metal bonds, represent a frontier area for C–C and
C–X coupling processes.
1. Introduction
Coupling reactions that allow for catalytic C–CorC–Xbond
formation (X ¼e.g. B, N, O) have revolutionized synthetic chem-
istry by allowing complex organic structures to be created from
simpler building blocks, even at late stages of multistep synthetic
sequences.
1–5
The dominant paradigm in coupling chemistry is to
utilize single-site homogeneous catalysts and tailor reactivity and
selectivitypatternsusingliganddesign.Forexample,muchof
cross-coupling catalysis involves palladium–phosphine systems
that operate by a canonical oxidative addition/reductive elimina-
tion cycling mechanism. Decades have been spent designing
elaborate phosphine ligands to provide reactivity suitable for
modern applications.
6–9
Exquisite levels of catalytic activity,
regioselectivity, and/or stereoselectivity ultimately have been
achieved using this paradigm.
Pursuing alternative catalytic paradigms that go beyond this
single-site approach has the potential to uncover complemen-
tary reactivity and selectivity regimes.
10
In addition, in some
cases catalytic reactivity can become accessible with inexpensive
and earth-abundant metals not typically utilized extensively in
cross-coupling catalysis. This perspective highlights one such
alternative approach: the use of bimetallic catalysis for C–C and
Dominic studied chemistry at
the University of Manchester,
where he obtained an MChem in
2010 aer completing his nal
year project with Dr Peter
Quayle. He then moved to the
University of Bristol where he
undertook his PhD on iron-cat-
alysed cross-coupling reactions
under the supervision of Profes-
sors Robin Bedford and Timothy
Gallagher. In 2015 he moved to
the University of Illinois at Chi-
cago to work as a post-doctoral research associate investigating
heterobimetallic-catalysed carbonylation reactions with Professor
Neal Mankad.
Before starting his independent
career at the University of Illi-
nois at Chicago (UIC) in 2012,
Neal conducted undergraduate
research at MIT with Joseph
Sadighi, graduate research at
Caltech with Jonas Peters, and
postdoctoral research at the
University of California-Berkeley
with Dean Toste. At UIC, his
group conducts research on
bimetallic catalysis in organic
systems, multimetallic catalytic
sites in biology, and other topics related to energy and health
sciences. Neal's recent awards include an Alfred P. Sloan Research
Fellowship, a Thieme Chemistry Journal Award, and the UIC
Rising Star Researcher of the Year. He likes exercising, eating,
drinking, and traveling (sometimes all on the same day).
Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago,
IL 60607, USA. E-mail: npm@uic.edu
Cite this: Chem. Sci.,2017,8,1705
Received 19th December 2016
Accepted 14th January 2017
DOI: 10.1039/c6sc05556g
www.rsc.org/chemicalscience
This journal is © The Royal Society of Chemistry 2017 Chem. Sci.,2017,8,1705–1718 | 1705
Chemical
Science
PERSPECTIVE

C–X bond forming reactions.
11
The focus of the perspective is on
recent developments in bimetallic catalysis as applied to catalytic
C–C and C–X bond formation in molecular organic systems. All of
the included examples involve catalytic amounts of two d-block
metals cooperating during catalysis. The following topics are
excluded from this perspective: reactions involving d-block
metals cooperating with main-group elements (e.g. Na, Al, B, P)
during catalysis;
12,13
cases with one of the two metals not
participating directly in bond-breaking/forming events (e.g. pho-
toredox catalysis,
14
Wacker oxidation
15
); cases with one of the two
metals present in stoichiometric quantities; tandem, cascade, or
domino reactions
16
that do not involve direct communication
between codependent catalytic metals; and cluster systems where
mechanistic understanding is limited.
17
Also excluded from the
perspective are catalytic polymerization reactions,
18–20
reductions
of unsaturated organics (e.g. hydrogenation, hydrosilylation),
21–25
and transformations of small-molecule inorganics (e.g. H
2
,H
2
O,
CO, CO
2
,N
2
,O
2
,etc.),
26–30
all of which have had recent advances in
their own right using bimetallic approaches.
The contribution of this perspective is timely, as bimetallic
catalysis for C–C and C–X coupling is a burgeoning area that
stands to make important contributions to the synthetic toolkit.
In this perspective, these contributions are categorized into two
broad subdivisions, with representative mechanistic schemes
shown in Scheme 1. First are bimetallic systems involving
catalytic generation of an organometallic nucleophile that
undergoes transmetallation with a “traditional”coupling cata-
lyst that operates using its canonical single-site mechanism
(Scheme 1a). Here, no binuclear steps are utilized for breaking
the bonds of the coupling partners or forming the bonds of the
products.
31
Second are bimetallic systems that involve binuclear
bond activation and/or bond elimination events (Scheme 1b).
Here, metal–metal bonds oen (though not always) play key
roles during catalysis.
32
2. Bimetallic catalysis with
mononuclear bond breaking & forming
mechanisms
2.1 Organocopper nucleophiles
It was demonstrated in 1966 by Owsley and co-workers that
copper-acetylides react in a stoichiometric fashion with aryl
halides.
33
The harsh reaction conditions (reux in pyridine) lead
to the formation of side products, such as aryl halide reduction
and acetylene dimerization. Monometallic, palladium-catalysed
coupling of aryl halides and terminal alkynes was reported by
both Cassar
34
and Heck
35
in 1975; however both catalyst systems
still required elevated temperature for high conversion. In 1975
Sonogashira and co-workers reported that the addition of
copper salts greatly accelerated the reaction, leading to room
temperature reactivity, greater functional group tolerance, and
a generally more useful procedure.
36
It is now accepted that the
role of copper in these reactions is to react with the alkyne in the
presence of a base to give a copper acetylide.
37
The acetylide
moiety then undergoes transmetallation from copper to palla-
dium to give the key arylpalladium(II) acetylide (Scheme 2),
which subsequently releases the desired product by reductive
elimination. The key step, transmetallation of an organic frag-
ment to palladium, has proven the inspiration for all the
copper–palladium bimetallic-catalysis described in this section.
2.1.1 Borylcupration and hydrocupration of unsaturated
C–C bonds. Traditional cross-coupling requires the pre-
synthesis of organometallic or organo-main group nucleophiles
for use. Organometallic nucleophiles are oen unstable, and
require synthesis immediately prior to use. Organo-main group
nucleophiles are usually bench stable, but also require
synthesis and purication prior to use. In addition to these
drawbacks, stoichiometric metal or main group byproducts are
unavoidable in such couplings.
An alternative mechanistic paradigm is the catalytic, in situ
formation of organometallic species from catalytic amounts of
a precatalyst and an organic pro-nucleophile. This avoids the pre-
formation and purication of the nucleophilic component, and
the organic pro-nucleophilesare generally more stable and readily
available than organometallic or main group nucleophiles. One
example of this approach is the insertion of unsaturated organic
compounds into copper-element bonds (Scheme 3). The product
of this insertion is a reactive organo-copper nucleophile ready for
further reaction. A further advantage in catalytic formation of the
nucleophile is that low concentrations of reactive species leads to
fewer undesired side reactions. The functionalisation of an
Scheme 1 Representative mechanistic schemes for bimetallic catal-
ysis (a) without and (b) with binuclear bond breaking and forming
events. Scheme 2 Cu/Pd cooperation in Sonogashira coupling.
1706 |Chem. Sci.,2017,8,1705–1718 This journal is © The Royal Society of Chemistry 2017
Chemical Science Perspective

unsaturated bond also leads to further complexity build up in
asinglestep.
The insertion of alkenes in to copper–boron bonds has been
implicated in many copper-catalysed C–B bond forming
processes, such as copper-catalysed hydroboration of alkenes.
In 2006 Sadighi proved this unambiguously by the isolation of
b-boryl alkyl copper species from the reaction of IPrCu(Bpin)
with styrenes (Scheme 4).
38
In 2014 Semba/Nakao
39
and Brown
40
independently showed
that this intermediate could be used as a transmetallating reagent
from copper to an arylpalladium(II), which reductively eliminates
to form an carboborylated product and Pd(0). The copper boryl
species is regenerated through alkoxide assisted transmetallation
with B
2
(pin)
2
, and palladium(0) undergoes oxidative addition
with an aryl bromide to complete two synergistic catalytic cycles.
Both groups reported (NHC)copper(I)andPd(II)/dicyclohex-
ylbiarylphosphine precatalyst mixtures (Scheme 5).
Brown and co-workers also showed that when cyclic styrene
derivatives (such as 1,2-dihydronapthalene) were employed as
substrates, in most cases the reaction gave the trans diaste-
reomer with high selectivity. As the addition of (SIMes)CuB(pin)
across the alkene is likely to proceed in a syn-fashion, it was
stated that the transmetallation Cu–Pd must proceed with
inversion of stereochemistry to give the trans isomer aer
stereoretentive reductive elimination. Under the described
conditions, acyclic, 1,2-disubstituted styrenes gave low diaster-
eoselectivity. Brown later reported modied conditions under
which both the syn- and anti-carboboration diastereomers of
acyclic disubstituted styrenes could be obtained, selectivity
being determined by a change in solvent and ligand (Scheme
6).
41
It was found that the use of THF and RuPhos would
selectively provide the syn-product, presumably through a ster-
eoretentive transmetallation of the putative syn-Cu-alkyl inter-
mediate, followed by reductive elimination. Diastereoselectivity
was found to be reversed if the solvent was changed to toluene,
and the Pd ligand to triisobutylphosphine. It should be noted
that both the change of solvent and ligand were required; both
Pd-RuPhos in toluene and Pd-PiBu
3
in THF gave low
diastereoselectivity.
Liao and co-workers reported an enantioselective variant of
the Cu/Pd carboboration reaction in 2015 (Scheme 7).
42
Here
they use copper(I) acetate with a chiral sulfoxide–phosphine
ligand to achieve enantioselective borylcupration of a styrene,
followed by transmetallation to a palladium-allyl species
generated from the oxidative addition of allyl-tert-butylcar-
bonates to Pd(0). Products were generated with ee > 90%. When
racemic, cyclic allylic carbonates were used as electrophiles,
diastereomeric control of the two contiguous chiral centres was
achieved. It was also demonstrated that iodobenzene could be
used in place of the allylic carbonate to give an enantioselective
version of the Nakao–Brown carboboration, albeit in lower
yield.
In 2016 Semba/Nakao reported a procedure for the carbo-
boration of alkenes, this time using nickel rather than palla-
dium to activate the aryl electrophile.
43
As a rst-row transition
metal, nickel is preferable to palladium in terms of cost and
earth abundance. It was also found that the Nakao–Brown
conditions were not suitable for the use of aryl chlorides, or
phenol derived electrophiles (other than triates). Semba/
Nakao demonstrated that styrenes could be converted to their
carboborylated product using a precatalyst system of CuCl,
Ni(acac)
2
, and tricyclopentylphosphine, whilst using aryl chlo-
rides or tosylates as the electrophilic carbon source (Scheme 8).
Drawbacks, in comparison with the copper/palladium-catalysed
Scheme 3 General scheme for organocopper nucleophiles generated
by element-cupration.
Scheme 4 Borylcupration of styrenes demonstrated by Sadighi.
Scheme 5 Cu/Pd catalysis for arylboration developed by the groups of
Semba/Nakao and Brown.
Scheme 6 Diastereoselective carboboration developed by Brown.
This journal is © The Royal Society of Chemistry 2017 Chem. Sci.,2017,8,1705–1718 | 1707
Perspective Chemical Science

systems are the requirement for higher temperatures (80 Cvs.
room temperature) and the poor reactivity of b-substituted
styrenes (30–40% yield).
In 2016 Semba/Nakao reported a system wherein borylcup-
ration could be replaced with hydrocupration, thereby furnishing
1,1-diarylalkanes (Scheme 9).
44
(NHC)CuH is generated in situ by
the reaction of (NHC)CuOtBu with HSi(OEt)
3
. The use of
a deuterium labelled silane gave conrmation of syn-addition
across the double bond, and subsequent stereoinversion upon
transmetallation. Theoretical calculations suggest an S
E
2(back)
mechanism, which is consistent with stereoinversion.
Later that year Buchwald used a chiral bisphosphine Cu(I)
precatalyst to give an enantioselective Cu/Pd hydroarylation of
styrenes (Scheme 10).
45
The enantiodetermining step is the
addition of a chiral copper hydride across the double bond.
Riant and co-workers have described an asymmetric reduc-
tion/allylation of a,b-unsaturated ketones using a copper–
palladium bimetallic catalyst system, a silane, and allyl
carbonates.
46
The products of these reactions are highly valu-
able, chiral all-carbon quaternary centres. In this instance the
enantioselective step is governed by the palladium catalyst,
bearing a chiral PHOX ligand, as opposed to a chiral copper
hydride vide supra. Copper-catalysed 1,4-reduction of the
unsaturated ketone gives a copper-enolate, which will then
transmetallate to palladium. Mechanistic studies suggest that
this transmetallation can give both the C- and O-bound Pd-
enolate, which, aer reductive elimination, release both the
desired product and an allyl-enol ether. The allyl-enol ether
converts to the desired product under the reaction conditions
via a palladium-catalysed Cope rearrangement (Scheme 11).
The reaction of copper(I) complexes with silyl boranes is
known to give copper-silyl species, which Riant and co-workers
showed will add across electron decient alkynes to catalytically
generate a vinyl-copper species to be used in palladium-cata-
lysed cross-coupling (Scheme 12).
47
In this instance allylic
carbonates were used as the electrophiles. The authors found
that the regioselectivity of the double bond could be controlled,
switching between the Z- and E-isomers by omitting triphenyl-
phosphine from the reaction conditions, and switching from
simple copper chloride to NHC ligated IMesCu(DBM) (DBM ¼
dibenzoylmethanate).
The effect of triphenyl phosphine on the regioselectivity is
ascribed to the relative reactivity of the palladium(II) allyl
present, and the steric hindrance of the initial syn-silylcupration
product compared to its tautomeric allenolate. In the absence of
Scheme 7 Enantioselective carboboration developed by Liao.
Scheme 8 Cu/Ni catalysis developed by Semba/Nakao.
Scheme 9 Hydroarylation catalysis developed by Semba/Nakao.
Scheme 10 Enantioselective hydroarylation developed by Buchwald.
Scheme 11 Reductive allylation of a,b-unsaturated ketones devel-
oped by Riant.
Scheme 12 Silylation catalysis developed by Riant.
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Chemical Science Perspective

phosphine, palladium dimer [Pd(allyl)Cl]
2
forms. Trans-
metallation from copper gives an allyl-, vinyl-palladium interme-
diate from which C–C bond formation occurs via an inner-sphere
mechanism. In the presence of excess phosphine, cationic
[(Ph
3
P)
n
Pd(allyl)]
+
forms, which does not transmetallate with
copper. In this instance the less sterically hindered allenolate
reacts with the Pd-allyl complex via an outer-sphere mechanism,
giving the products of formal anti-addition.
2.1.2 C–C cross-coupling. Faul and co-workers demon-
strated a C–H activation/biaryl coupling, catalysed by copper
and palladium (Scheme 13).
48
In this instance an organocopper
intermediate is formed by the C–H activation of pharmaceuti-
cally privileged benzo-thiozoles, -oxazoles and -imidazoles. This
then acts as a nucleophilic coupling partner for palladium-
catalysed cross-coupling with an aryl halide. A related example
was reported by Cazin.
49
The use of tri(organo)silanol nucleophiles in C–C cross-
coupling (Hiyama–Denmark coupling) is an attractive alterna-
tive to Sn, Mg, Zn, Al, and B based nucleophiles due to the
bench stability and low toxicity of silicon compounds. Whilst
monometallic systems have been shown to successfully couple
C(sp
2
)–silicon nucleophiles with aryl halides and sulfonates, no
general procedure has been developed for the coupling of alkyl-
silicon nucleophiles with aryl sulfonates.
The Nakao group have developed aryl[2-(2-hydroxyprop-2-yl)
cyclohexyl]dimethylsilanes (Fig. 1) for nickel-catalysed biaryl
coupling with aryl sulfonates.
50
This reaction, however, suffers
from poor tolerance of sensitive functional groups and sterically
demanding substrates.
In 2016 Nakao published a revised procedure consisting of
a bimetallic, Cu/Pd catalyst system which displays much
greater functional and steric compatibility, as well as being
compatible with alkyl[2-(2-hydroxyprop-2-yl)cyclohexyl]dime-
thylsilanes (Scheme 14).
51
In this reaction the difunctional silyl-alcohol reagent initially
coordinates to copper through deprotonation/salt metathesis of
the alcohol, followed by intramolecular [2 + 2] s-bond metath-
esis to give an organocopper intermediate (Scheme 14). This
transmetallates to arylpalladium(II) (from Pd(0) and aryl tosy-
late). Reductive elimination furnishes the product and closes
the dual catalytic cycle.
2.1.3 Modular imine synthesis. Imines are highly desirable
synthetic intermediates due to the high number of functional
group transformations and C–C bond forming reactions that
they can undergo. Traditional methods for their synthesis, such
as Friedel–Cras or organometallic additions to nitriles require
harsh conditions and display poor functional group compati-
bility. Condensation of ketones with amines, whilst proceeding
under mild conditions, does not allow for one pot, fully
modular synthesis, as both R
1
and R
2
must be already dened in
the ketone starting material. Goossen and co-workers have
described a modular, three-component coupling of amines, a-
ketocarboxylates and aryl halides catalysed by copper and
palladium.
52,53
In situ formation of an a-iminocarboxylate by
amine-carbonyl condensation is followed by salt metathesis
with copper-bromide. Decarboxylation provides an iminoacyl-
copper species which transmetallates to Pd(II) aryl. Reductive
elimination provides the desired imine and renders the cycle
catalytic (Scheme 15).
2.2 Organogold nucleophiles
In 2009 Blum and co-workers published a gold/palladium-cat-
alysed rearrangement of allyl allenoates to butenolides.
54
The
reaction proceeds smoothly at room temperature in the pres-
ence of an in situ generated gold(I) triate complex and
Pd
2
(dba)
3
(5 mol% each) (Scheme 16). The initial step in the
catalytic cycle is coordination of gold to the allene followed by
cyclisation to give an activated gold–oxonium species. The allyl
Scheme 13 Cu/Pd cross-coupling developed by Faul.
Fig. 1 Alkylsilane reagent developed by Nakao.
Scheme 14 Cu/Pd variant of Hiyama–Denmark coupling developed
by Nakao. Scheme 15 Cu/Pd-catalyzed imine synthesis.
This journal is © The Royal Society of Chemistry 2017 Chem. Sci.,2017,8,1705–1718 | 1709
Perspective Chemical Science

moiety is now activated towards oxidative addition by Pd(0)
(oxidative addition does not occur in the absence of gold acti-
vation). Transmetallation from gold to palladium, followed by
reductive elimination, give the butenolide product.
Included in the above publication was similar rearrange-
ment of allyl esters onto alkynes to give lactones (Scheme 17).
The scope of this rearrangement was expanded, and mecha-
nistic details disclosed, in a 2014 report.
55
It is worth noting
that, in 2012, Hashmi showed that, when more activated esters
are used as substrates (i.e. benzyl or cinnamyl in place of allyl)
high yields of the products were obtained under monometallic
gold-catalysed conditions.
56
In 2016 Nevado and co-workers published another rear-
rangement of allenoates; however in this report the gold-cata-
lysed rearrangement is coupled with a palladium-catalysed aryl
cross-coupling cycle (Scheme 18).
57
Gold-catalysed carbocycli-
sation of the initial allenoate is followed by transmetallation to
Pd(II) aryl and reductive elimination.
As part of the mechanistic investigations on allenoate rear-
rangements, Blum and co-workers noted that cationic oxonium
species did not undergo palladium-catalysed cross-coupling,
however the neutral analogue would.
54
It is the judicious choice
of aryl iodides as coupling partners that allow the Nevado
reaction to proceed. The iodide formed on oxidative addition of
Ar-I to Pd(0) acts as a dealkylating agent, giving iodoethane and
a neutral butenolidyl gold species (Scheme 19). This reaction
also sequesters iodide from the reaction medium, which is
benecial as Nevado reported that (p-F
3
CPh)
3
PAuI is inactive.
2.3 Others
Many other organometallic nucleophile cycles have been
combined with Pd catalysis, following upon pioneering early
examples.
58,59
In 2016 Lee and co-workers demonstrated
a rhodium–palladium-catalysed method that uses triazoles as
precursors to rhodium-carbenes, which then couple with
palladium-allyl complexes generated in situ.
60
This procedure is
unusual, in that the anion formed in oxidative generation of Pd-
allyl is incorporated into the nal product, increasing atom
economy. Rhodium(II) is known to activate triazoles to give a-
iminocarbenoids. This underdoes nucleophilic attack by the
carboxylate anion formed on oxidative addition of an allyl
ester by Pd(0). The resultant imine-ester coordinates palla-
dium in a seven-membered intermediate, from which rho-
dium(II)iseliminated.Reductive elimination of the allyl
fragment with N-tosyl furnishes the product and regenerates
Pd(0) (Scheme 20).
Vanadium(V) esters are known to catalyse the rearrangement
of propargylic alcohols via their corresponding vanadium
Scheme 16 Au/Pd catalysis developed by Blum.
Scheme 17 Au/Pd catalysis for lactone formation developed by Blum.
Scheme 18 Au/Pd catalysis developed by Nevado. Scheme 20 Rh/Pd catalysis developed by Lee.
Scheme 19 Au/Pd mechanistic results from Blum.
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Chemical Science Perspective

allenolate. These can be trapped by various N-, O-orC-based
nucleophiles. Trost and co-workers reported twice in 2011 on
the interception of these intermediates with palladium-allyl
complexes to give a-allyl-a,b-unsaturated ketones in a vana-
dium–palladium dual-catalysed process (Scheme 21). The rst
report details conditions for the use of aromatic propargylic
alcohols.
61
As they found that this aromatic activation was
essential for the initial vanadium-catalysed rearrangement,
later than year they expanded the scope to include aliphatic
propargylic alcohols with an activating alkoxy group on the
alkyne fragment.
62
Weix and co-workers demonstrated in 2014 that titanium(III)-
catalysed radical ring-opening of epoxides could be used in
conjunction with reductive nickel catalysis to give an enantio-
selective coupling of epoxides and aryl bromides.
63
The study
utilised the fact that Ti(III) is known to catalyse reductive ring
opening of epoxides to give a-radical Ti(IV) alkoxides. Weix has
shown in previous reductive cross-couplings that carbon cen-
tred radicals will react with arylnickel(II) species to give Ni(III)
which rapidly undergoes reductive elimination. The resultant
Ni(I) reduces Ti(IV) produced in epoxide ring opening to give
Ni(II) and regenerate Ti(III), and Ni(II) is in turn reduced to Ni(0)
by manganese to complete both catalytic cycles (Scheme 22).
The use of a chiral titanium precatalyst bearing Cp ligands
derived from menthol allowed enantioselective ring opening of
meso-epoxides, giving trans aryl-alcohols in high enantiopurity.
Weix and co-workers have also used multimetallic catalysis
for the reductive coupling of two aryl electrophiles.
64
A 4,40-
bipyridine nickel precatalyst was employed for the activation of
aryl bromides, and (dppp)PdCl
2
for the activation of aryl tri-
ates. Each monometallic catalyst reacts selectively with its
intended aryl-electrophile, to give high selectivity for the cross-
coupled product over the two possible homo-coupled side
products. This selectivity also allows for the use of the electro-
philes in a 1 : 1 ratio, whereas previous, monometallic,
reductive cross-coupling of aryl halides had required excess of
one reagent to obtain selectivity. Aer each metal undergoes
oxidative addition of its respective electrophile, arylnickel(II)
transmetallates with arylpalladium(II) to give bis(aryl)palladiu-
m(II) intermediate, which reductively eliminates the desired
product. Zinc metal is the terminal reductant, which regener-
ates nickel(0) and completes the catalytic cycle (Scheme 23).
In 2010, Goossen and co-workers reported a silver–palla-
dium-catalysed decarboxylative biaryl coupling (Scheme 24).
65
Here, an organosilver intermediate is generated by silver-cata-
lysed decarboxylation of a benzoic acid, and then employed
as the nucleophilic partner for palladium-catalysed biaryl-
coupling. This report is an extension of previous, analogous
copper/palladium-catalysed reactions.
66
Silver salts had previ-
ously been found to be more efficient in mediating the decar-
boxylation of benzoate salts, however they were found to be
incompatible with cross-coupling conditions, as silver halide
salts formed during the reaction would precipitate and prevent
catalytic turnover. Goossen found that if aryl triates were used
as coupling partners, this salt precipitation was avoided and
turnover achieved. Due to the greater efficiency of silver over
Scheme 21 V/Pd catalysis developed by Trost.
Scheme 22 Ti/Ni catalysis developed by Weix.
Scheme 23 Ni/Pd catalysis developed by Weix.
This journal is © The Royal Society of Chemistry 2017 Chem. Sci.,2017,8,1705–1718 | 1711
Perspective Chemical Science

copper to mediate decarboxylation, reaction temperatures
could be lowered from 170 to 120 C. Shen and coworkers have
reported related Ag/Pd catalysis for diuoromethylation of aryl
electrophiles.
67
In 2011 Chen and Ma published an iron/palladium-catalysed
cyclisation/cross-coupling of allenoates with allyl electrophiles,
which they claim is the rst example of transmetallation of an
organic fragment from iron to palladium (Scheme 25).
68
The
mechanism is similar to the gold/palladium-catalysed cyclisa-
tion/cross-coupling of allenoates published by Blum and
Nevado; however in this instance iron(III) chloride acts as the
Lewis acidic metal, giving rise to formation of a metallo-lactone.
Oxidative addition of allylic bromides to palladium(0) give
electrophilic Pd(II), which receives the lactone fragment from
iron, and reductive elimination gives the allylic lactone as the
product.
3. Bimetallic catalysis with binuclear
bond breaking & forming mechanisms
3.1 Serendipitous bimetallic catalysis
While the dominant paradigm in homogeneous catalysis is to
design reactions based on single-site mechanisms, in some
cases a post hoc analysis of these reactions can reveal that two
catalyst sites actually cooperate under the catalytic conditions
even when bimetallic chemistry was unintended. Ideally, the
elucidation of such serendipitous bimetallic reactions can be
leveraged towards the rational design of bimetallic catalysts for
useful transformations.
3.1.1 Lewis acid catalysis. One prominent example of
serendipitous bimetallic catalysis is the set of asymmetric
epoxide ring-opening reactions advanced by Jacobsen.
69
The
initial design concept being pursued in these systems involved
coordination of the epoxide substrate to a Lewis acidic Cr site
buried within a chiral salen pocket, followed by stereospecic
attack on the bound epoxide by an external nucleophile.
However, the asymmetric ring-opening reaction involving azide
as the nucleophile was found obey an experimentally-deter-
mined rate law with second-order dependence on the active
catalyst, (salen)Cr(N
3
), thus implying the involvement of two
catalyst molecules in the rate-determining step.
70
The proposed
model for this bimetallic step invokes intermolecular attack by
a (salen)Cr(N
3
) nucleophile on an epoxide activated at a sepa-
rate catalyst site (Scheme 26a). A similar model is operative for
the unique regiodivergent ring-opening reactions of chiral
aziridines developed by Parquette and RajanBabu using
a related Y dimer where the two Lewis acidic catalyst sites are
linked by bridging ligands.
71
In addition to kinetics data, solid-
state and solution-phase structural determination data are
consistent with a rate-determining, intramolecular bimetallic
step in this dimeric catalyst system.
72
Shibasaki and others have
produced many useful synthetic methods involving asymmetric
reactions with related heterobimetallic Schiffbase-ligated
catalysts (Scheme 26b).
73–75
These systems likely belong to the
same mechanistic motif involving asymmetric bond formation
induced by adjacent metal sites within a chiral pocket.
3.1.2 Oxidative C–X coupling. Oxidative C–X bond forma-
tion catalyzed by Pd is oen assumed to involve single-site
Pd(II)/Pd(IV) redox cycling.
76
In 2009, Ritter and coworkers
identied metal–metal bonded Pd(III) intermediates that
assembled under catalytic conditions and were competent at
undergoing bimetallic reductive elimination of C–O and C–Cl
bonds (Scheme 27).
77
The nature of these bimetallic bond
elimination reactions was subsequently analyzed in detail both
experimentally and computationally.
78
This discovery raised the
possibility of bimetallic intermediates being involved in oxidative
Pd catalysis and presented bimetallic Pd(II)/Pd(II)/Pd(III)–Pd(III)
redox cycling (facilitated by bridging carboxylate ligands) as an
alternative mechanistic manifold to the more traditional single-
site Pd(II)/Pd(IV) redox cycling model.
79
Subsequent studies by
Ritter, Sanford, Canty, Yates, and others have revealed that
thebimetallicandsingle-sitemanifoldsbothareviable
under typical reaction conditions,
80
implying that partitioning
between mononuclear and binuclear pathways needs to be
evaluated on a case-by-case basis in such oxidative catalysis.
Nonetheless, this new intellectual framework allowed for the
rational development of a bimetallic Pd catalyst for C–H
oxidation with O
2
by Ritter.
81
Scheme 24 Ag/Pd catalysis developed by Goossen.
Scheme 25 Fe/Pd catalysis developed by Chen and Ma.
Scheme 26 (a) Asymmetric epoxide ring-opening catalysis developed
by Jacobsen; (b) heterobimetallic catalyst design of Shibasaki.
1712 |Chem. Sci.,2017,8,1705–1718 This journal is © The Royal Society of Chemistry 2017
Chemical Science Perspective

Furthermore, similar binuclear intermediates have come to
be proposed in various coinage metal-catalyzed C–X bond
forming oxidations, again raising the possibility of binuclear
catalytic mechanisms being operative under certain conditions.
First, in 2010, Ritter proposed that Ag(I)-catalyzed C–F coupling
under oxidative conditions involves the intermediacy of bime-
tallic Ag(II)–Ag(II)–F species capable of binuclear C–F elimina-
tion,
82
thus avoiding the invocation of high-valent Ag(III)–F
intermediates (Scheme 28). Indirect evidence for this bimetallic
mechanism was obtained from the observed rate acceleration of
C–F elimination from AgOTf additive during reaction of
Selectuor with isolated arylsilver(I) species.
Contemporaneously, Zhang, Toste, Nevado, Gouverneur,
Hashmi, Lloyd-Jones, and others developed oxidative alkene
heteroarylation reactions using Au(I) catalysts combined with
a stoichiometric oxidant, commonly Selectuor. These reaction
are typically proposed to involve single-site Au(I)/Au(III) redox
cycling, as was reviewed recently by Gouverneur.
83
Among these
various studies, both mononuclear and binuclear gold catalysts
were employed. In one study, Toste found that the binuclear
dppm(AuBr)
2
catalyst exhibited superior performance when
compared to mononuclear Ph
3
PAuBr.
84
Furthermore, this effect
disappeared when dppm was replaced with a longer and more
exible dppb tether. These observations led Toste and workers
to propose a revised mechanism involving Au(II)–Au(II) inter-
mediates capable of C–C coupling with arylboronic acid nucle-
ophiles (Scheme 29).
85
The bimetallic mechanism had support
from computational studies. Additionally, cyclic voltammetry
measurements were used to show that binuclear Au(I)/Au(I)
aggregates featuring aurophilic interactions facilitated by
bridging ligands are more readily oxidized than single-site Au(I)
species lacking bridging ligands. Presumably the difference
arises from stabilization of oxidized Au(II)–Au(II) species in
comparison to high-valent Au(III) species. Thus, under oxidative
conditions, it is possible that bimetallic Au(II)–Au(II) interme-
diates assemble during catalysis even in the absence of bridging
ligands.
In the Ag-catalyzed uorination studied by Ritter and the
Au-catalyzed heteroarylation studied by Toste, the binuclear
coinage metal mechanisms serve to facilitate oxidative catalysis
by providing a lower-barrier alternative to the high-potential
M(I)/M(III) redox couple. This concept is analogous to the
binuclear Pd
2
catalysis unveiled by Ritter. This intellectual
framework led to the rational design of a binuclear Au(I) catalyst
for C(sp
3
)–C(sp
2
) coupling with arylboronic acids developed by
Toste.
86
3.1.3 Multicomponent coupling. In 2015, Lalic and
coworkers disclosed a Cu-catalyzed hydroalkylation of terminal
alkynes.
87
The reaction conditions utilized a silane as the
reductant, alkyl triates as the electrophilic coupling partners,
and uoride as an additive to facilitate transmetallation.
Although a single-site Cu mechanism was originally proposed,
subsequent mechanistic studies led Lalic to revise the mecha-
nism and propose binuclear intermediates throughout the
Scheme 27 Oxidative catalysis involving dipalladium(III) intermediates
identified by Ritter.
Scheme 28 Bimetallic mechanism for Ag-catalyzed fluorination
proposed by Ritter.
Scheme 29 A representative example of oxidative Au catalysis, and
the bimetallic mechanism proposed by Toste.
This journal is © The Royal Society of Chemistry 2017 Chem. Sci.,2017,8,1705–1718 | 1713
Perspective Chemical Science

catalytic cycle (Scheme 30).
88
Stoichiometric reactivity studies
indicated that the relevant mononuclear Cu intermediates
would readily facilitate both reduction and uorination of the
alkyl triate electrophile in competition with productive
hydroalkylation, while binuclear Cu intermediates were shown
to be less reactive towards these unproductive side processes.
Because the catalytic conditions produced the hydroalkylation
product in high yields without observation of unwanted alkyl
reduction and uorination products, it was proposed that the
binuclear intermediates assemble as the active species during
catalysis. Unlike the coinage metal chemistry described above,
here binuclearity plays no role in facilitating redox cycling.
Instead, the binuclear species here serve to attenuate the reac-
tivity of hydride and uoride intermediates during catalysis,
thus imparting useful selectivity onto the multicomponent
reaction.
3.2 Pre-assembled bimetallic catalysts
The examples in the previous section involve serendipitous
bimetallic assembly under catalytic conditions. Beyond such
examples, the rational design of bimetallic catalysis involving
metal–metal bonds and/or bifunctional metal sites has long
been a goal in the organometallic chemistry community.
Historically, perhaps the most well-known set of bimetallic
catalysts in organic synthesis are the dirhodium(II) carboxylate
paddlewheel complexes that catalyze various group transfer
reactions that allow for C–C and C–N bond formation.
89–91
In
addition, the bimetallic species Co
2
(CO)
8
is known to mediate
C–C coupling reactions of alkynes such as the Pauson–Khand
reaction, although stoichiometric Co is oen required.
92
Recent
developments in these areas highlighted below indicate that
pre-assembled bimetallic systems, oen featuring metal–metal
bonds with or without bridging ligands, are promising candi-
dates for further catalyst development.
3.2.1 Bifunctional catalysts. In analogy to the emergence of
frustrated Lewis pairs in metal-free catalysis,
93
a powerful
concept in transition metal catalysis is to harness the bifunc-
tional reactivity of Lewis acid/base bimetallic pairs.
94
A partic-
ularly illustrative example of this approach was reported by
Coates and coworkers in 2005.
95
A bimetallic catalyst consisting
of [(OEP)Cr(THF)
2
]
+
and [Co(CO)
4
]

as a separated ion pair was
used to catalyse the stereospecic carbonylation of epoxides to
b-lactones (OEP ¼octaethylporphyrinate). In related studies the
cationic Cr fragment has been replaced with a variety of metal
and non-metal motifs such as [(salen)Al]
+
cations, even allowing
for enantioselective variants to emerge.
96,97
For all cases,
a bimetallic mechanism is proposed (Scheme 31) wherein both
metal sites cooperate to ring-open the epoxide substrate. Upon
carbonylation of the resultant alkylcobalt intermediate, the
bifunctional nature of the system allows for product release by
ring-closing lactonization.
Beginning in 2013, our group began studying bifunctional
catalysts closely related to these heterobimetallic ion pairs. A
series of (NHC)Cu–[M
CO
] catalysts, including derivatives with
[M
CO
]¼Co(CO)
4
, were characterized (NHC ¼N-heterocyclic
carbene).
98
Although these complexes do feature Cu–Mbonds
in the solid state, theoretical analysis indicates that these
copper–metal bonds are highly polarized donor/acceptor-
type dative interactions. Furthermore, crossover experiments
are consistent with equilibrium concentrations of [(NHC)
Cu]
+
[M
CO
]

pairs forming in solution.
99
One derivative,
a(NHC)Cu–FeCp(CO)
2
species, was shown to catalyse dehy-
drogenative borylation of unactivated arenes upon photo-
chemical activation (Scheme 32).
100
Based on stoichiometric
reactivity studies and computational analysis,
99
it was proposed
that the bifunctional Cu/Fe catalyst reacts with the boron source
to generate CpFe(CO)
2
(Bpin) as the active borylating species
(HBpin ¼pinacolborane). An analogous boryliron complex had
previously been shown by Hartwig to mediate stoichiometric
C–Hborylation.
101
The bifunctional Cu/Fe pair is thought to be
crucial for cleaving the B–H bond of HBpin in order to generate
the active borylating intermediate. Upon C–H borylation, the
Cu/Fe catalyst is regenerated through a binuclear H
2
elimination
that proceeds through a highly polar transition state.
102
The
bifunctional nature of this series of catalysts is actively being
pursued for a variety of other catalytic applications.
21,30
Scheme 30 Hydroalkylation of alkynes developed by Lalic, and
proposed binuclear catalytic mechanism.
Scheme 31 Bifunctional catalysis for epoxide carbonylation devel-
oped by Coates.
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Chemical Science Perspective

3.2.2 Persistent binuclear catalysts. Pd catalysis is domi-
nated by single-site oxidative addition/reductive elimination
mechanisms involving Pd(0)/Pd(II) redox cycling. Under oxida-
tive conditions, Ritter has shown that bimetallic intermediates
assemble under certain reaction conditions, as discussed
above. However, very little bimetallic Pd catalysis has been
developed through rational design for C–CorC–X coupling
purposes. Schoenebeck and coworkers have recently reported
a series of studies indicating that robust metal–metal bonded
Pd(I)–Pd(I) dimers are promising candidates that have reactivity
complementary to standard Pd(0) catalysts. In their initial foray
in 2013, Schoenebeck and coworkers denitively showed that
the dinuclear Pd(I) catalyst [tBu
3
Pd(m-I)]
2
, and not any mono-
nuclear Pd(0) species that might form from reduction or
disproportionation, is the active catalyst for an unusual I-for-Br
aryl halide exchange reaction.
103
Subsequently, Pd(I)-catalysed
C–S and C–Se coupling reactions were reported using the same
approach.
104,105
All three of these transformations are proposed
to proceed by analogous bimetallic mechanisms that involve
Pd(I)–Pd(I)/Pd(II)/Pd(II) redox cycling (Scheme 33). In addition
to the complementary reactivity exhibited by these Pd(I) dimers,
advantages of this approach include operational simplicity and
facile recyclability due to the air- and moisture-stability of the
Pd(I) catalysts.
In another Pd-catalyzed C–X coupling process, Nagashima
reported that the heterobimetallic cation [Cl
2
Ti(NtBuPPh
2
)
2
-
Pd(h
3
-CH
2
C(CH
3
)CH
2
)]
+
was capable of extremely efficient
allylic amination catalysis.
106
Michaelis, Ess, and coworkers
conducted a combined experimental/computational mecha-
nistic study on the empirically observed rate acceleration
compared to monometallic Pd-allyl cation catalysts.
107
A model
for rate-determining C–N bond formation was proposed, with
the dative Pd /Ti interaction stabilizing Pd(0) character in the
transition state and therefore lowering the reductive elimina-
tion barrier (Scheme 34). When compared to appropriate
monometallic counterparts, rate enhancements of up to 10
5
were documented in some cases. A Co/Zr-catalyzed Kumada
coupling reaction studied by Thomas and coworkers is likely
another example of this mechanistic motif.
108
In part due to the known reactivity of the metal–metal
singled bonded Co
2
(CO)
8
towards alkynes and in part due to the
potential of using metal–metal multiple bonds to engage
unsaturated substrates in pericyclic reactions, bimetallic cata-
lysts have long been examined for catalytic alkyne cyclo-
trimerisation reactions. This topic was reviewed thoroughly by
Mashima recently.
109
Among the most exciting advances is
a bimetallic Ni catalyst supported by a binucleating naphthyr-
idine-diimine (NDI) ligand that Uyeda and coworkers reported
in 2015 is effective at selective and efficient alkyne cyclo-
trimerisation.
110
The metal–metal bonded binuclear catalyst
was highly active for coupling terminal alkynes to provide
1,2,4-substituted arene products selectively in preference to
1,3,5-substituted regioisomers or cyclotetramers. On the other
hand, related mononuclear Ni catalysts supported by bipyr-
idine, diimine, or pyridylimine ligands were signicantly less
active and gave complex product mixtures. Based on stoichio-
metric model reactions, a mechanism was proposed by which
alkyne dimerization occurs to yield a nickelacyclopentadiene
intermediate, which subsequently couples with a third alkyne
equivalent to release arene. The terminal arene-releasing reac-
tion was proposed to be the key selectivity-determining step.
Crystallographic and theoretical evidence based on model
Scheme 32 Bifunctional catalysis for C–H borylation developed by
Mankad.
Scheme 33 Pd(I)-catalyzed C–X coupling developed by
Schoenebeck.
Scheme 34 Allylic amination-catalysed by a Pd–Ti heterobimetallic
complex, and the proposed rate-determining C–N coupling transition
state proposed by Michaelis and Ess.
This journal is © The Royal Society of Chemistry 2017 Chem. Sci.,2017,8,1705–1718 | 1715
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intermediates was consistent with the cyclic fragment located at
the reactive Ni site engaging in a secondary p-interaction with
the spectator Ni site. This secondary p-interaction was
proposed to stabilise one C]C bond and thereby direct the
third alkyne substrate towards the uncoordinated C]C bond
(Scheme 35). Approach of the least hindered carbon centre to
this reactive C]C moiety thus provides the observed 1,2,4-
substituted regioisomer.
4. Conclusions
In conclusion, bimetallic catalysis allows for novel modes of
C–C and C–X bond formation to occur. Rate enhancements,
selectivity control, and/or non-precious metal chemistry have all
been enabled by bimetallic strategies, as summarized in this
perspective. A large portion of the bimetallic catalysis literature
as applied to C–C and C–X bond formation involves interfacing
classical Pd catalysis with catalytically generated organometallic
nucleophiles. Furthermore, at this time the preponderance of
such examples involve organocopper nucleophiles and therefore
descend from the seminal Sonogashira coupling reaction. Cata-
lytic transformations that employ binuclear bond activation/
formation steps, particularly by rational design, are compara-
tively underdeveloped and ripe for exploration.
Acknowledgements
Funding support from the NSF (CHE-1362294), the ACS Green
Chemistry Institute (Pharmaceutical Roundtable Grant), and
the Alfred P. Sloan Foundation (Research Fellowship to N. P. M.)
is gratefully acknowledged.
Notes and references
1 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–2483.
2 R. F. Heck, Acc. Chem. Res., 1979, 12, 146–151.
3 P. Ruiz-Castillo and S. L. Buchwald, Chem. Rev., 2016, 116,
12564–12649.
4 J. F. Hartwig, Nature, 2008, 455, 314–322.
5 I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy
and J. F. Hartwig, Chem. Rev., 2010, 110, 890–931.
6 D. S. Surry and S. L. Buchwald, Chem. Sci., 2011, 2,27–50.
7 J. F. Hartwig, Acc. Chem. Res., 2008, 41, 1534–1544.
8 R. Martin and S. L. Buchwald, Acc. Chem. Res., 2008, 41,
1461–1473.
9 P. G. Gildner and T. J. Colacot, Organometallics, 2015, 34,
5497–5508.
10 A. E. Allen and D. W. C. MacMillan, Chem. Sci., 2012, 3, 633.
11 E. K. van den Beuken and B. L. Feringa, Tetrahedron, 1998,
54, 12985–13011.
12 S. Okumura, S. Tang, T. Saito, K. Semba, S. Sakaki and
Y. Nakao, J. Am. Chem. Soc., 2016, 138, 14699–14704.
13 J. Zhang, S.-C. Sha, A. Bellomo, N. Trongsiriwat, F. Gao,
N. C. Tomson and P. J. Walsh, J. Am. Chem. Soc., 2016,
138, 4260–4266.
14 C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem.
Rev., 2013, 113, 5322–5363.
15 M. S. Sigman and E. W. Werner, Acc. Chem. Res., 2012, 45,
874–884.
16 T. L. Lohr and T. J. Marks, Nat. Chem., 2015, 7, 477–482.
17 P. Buchwalter, J. Ros´
e and P. Braunstein, Chem. Rev., 2015,
115,28–126.
18 J. A. Garden, P. K. Saini and C. K. Williams, J. Am. Chem.
Soc., 2015, 137, 15078–15081.
19 J. P. McInnis, M. Delferro and T. J. Marks, Acc. Chem. Res.,
2014, 47, 2545–2557.
20 M. R. Radlauer, M. W. Day and T. Agapie, J. Am. Chem. Soc.,
2012, 134, 1478–1481.
21 M. K. Karunananda and N. P. Mankad, J. Am. Chem. Soc.,
2015, 137, 14598–14601.
22 W. Zhou, S. L. Marquard, M. W. Bezpalko, B. M. Foxman
and C. M. Thomas, Organometallics, 2013, 32, 1766–1772.
23 R. C. Cammarota and C. C. Lu, J. Am. Chem. Soc., 2015, 137,
12486–12489.
24 A. Chakraborty, R. G. Kinney, J. A. Krause and H. Guan, ACS
Catal., 2016, 6, 7855–7864.
25 T. J. Steiman and C. Uyeda, J. Am. Chem. Soc., 2015, 137,
6104–6110.
26 C. W. Machan, J. Yin, S. A. Chabolla, M. K. Gilson and
C. P. Kubiak, J. Am. Chem. Soc., 2016, 138, 8184–8193.
27 R. B. Siedschlag, V. Bernales, K. D. Vogiatzis, N. Planas,
L. J. Clouston, E. Bill, L. Gagliardi and C. C. Lu, J. Am.
Chem. Soc., 2015, 137, 4638–4641.
28 X.-F. Jiang, H. Huang, Y.-F. Chai, T. L. Lohr, S.-Y. Yu, W. Lai,
Y.-J. Pan, M. Delferro and T. J. Marks, Nat. Chem., 2016, 9,
188.
29 C. Uyeda and J. C. Peters, J. Am. Chem. Soc., 2013, 135,
12023–12031.
30 S. Bagherzadeh and N. P. Mankad, J. Am. Chem. Soc., 2015,
137, 10898–10901.
31 J. M. Lee, Y. Na, H. Han and S. Chang, Chem. Soc. Rev., 2004,
33, 302–311.
32 I. G. Powers and C. Uyeda, ACS Catal., 2016, 936–958.
33 C. E. Castro, E. J. Gaughan and D. C. Owsley, J. Org. Chem.,
1966, 31, 4071–4078.
34 L. Cassar, J. Organomet. Chem., 1975, 93, 253–257.
35 H. A. Dieck and F. R. Heck, J. Organomet. Chem., 1975, 93,
259–263.
Scheme 35 Dinickel-catalysed alkyne cyclotrimerisation developed
by Uyeda, and the proposed bimetallic transition state that steers
regioselectivity.
1716 |Chem. Sci.,2017,8,1705–1718 This journal is © The Royal Society of Chemistry 2017
Chemical Science Perspective

36 K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron
Lett., 1975, 16, 4467–4470.
37 K. Sonogashira, J. Organomet. Chem., 2002, 653,46–49.
38 D. S. Laitar, E. Y. Tsui and J. P. Sadighi, Organometallics,
2006, 25, 2405–2408.
39 K. Semba and Y. Nakao, J. Am. Chem. Soc., 2014, 136, 7567–
7570.
40 K. B. Smith, K. M. Logan, W. You and M. K. Brown, Chem.–
Eur. J., 2014, 20, 12032–12036.
41 K. M. Logan, K. B. Smith and M. K. Brown, Angew. Chem.,
Int. Ed., 2015, 54, 5228–5231.
42 T. Jia, P. Cao, B. Wang, Y. Lou, X. Yin, M. Wang and J. Liao,
J. Am. Chem. Soc., 2015, 137, 13760–13763.
43 K. Semba, Y. Ohtagaki and Y. Nakao, Org. Lett., 2016, 18,
3956–3959.
44 K. Semba, K. Ariyama, H. Zheng, R. Kameyama, S. Sakaki
and Y. Nakao, Angew. Chem., 2016, 128, 6383–6387.
45 S. D. Friis, M. T. Pirnot and S. L. Buchwald, J. Am. Chem.
Soc., 2016, 138, 8372–8375.
46 F. Nahra, Y. Mac´
e, D. Lambin and O. Riant, Angew. Chem.,
Int. Ed., 2013, 52, 3208–3212.
47 S. Vercruysse, L. Cornelissen, F. Nahra, L. Collard and
O. Riant, Chem.–Eur. J., 2014, 20, 1834–1838.
48 J. Huang, J. Chan, Y. Chen, C. J. Borths, K. D. Baucom,
R. D. Larsen and M. M. Faul, J. Am. Chem. Soc., 2010, 132,
3674–3675.
49 M. Lesieur, F. Lazreg and C. S. J. Cazin, Chem. Commun.,
2014, 50, 8927–8929.
50 S. Tang, S.-H. Li, Y. Nakao and T. Hiyama, Asian J. Org.
Chem., 2013, 2, 416–421.
51 A. Ohgi, K. Semba, T. Hiyama and Y. Nakao, Chem. Lett.,
2016, 45, 973–975.
52 F. Rudolphi, B. Song and L. J. Goossen, Adv. Synth. Catal.,
2011, 353, 337–342.
53 F. Collet, B. Song, F. Rudolphi and L. J. Goossen, Eur. J. Org.
Chem., 2011, 6486–6501.
54 Y. Shi, K. E. Roth, S. D. Ramgren and S. A. Blum, J. Am.
Chem. Soc., 2009, 131, 18022–18023.
55 J. J. Hirner, K. E. Roth, Y. Shi and S. A. Blum,
Organometallics, 2012, 31, 6843–6850.
56 A. S. K. Hashmi, C. Lothsch¨
utz, R. D¨
opp, M. Ackermann,
J. De Buck Becker, M. Rudolph, C. Scholz and
F. Rominger, Adv. Synth. Catal., 2012, 354, 133–147.
57 P. Garc´
ıa-Dom´
ınguez and C. Nevado, J. Am. Chem. Soc.,
2016, 138, 3266–3269.
58 M. Sawamura, M. Sudoh and Y. Ito, J. Am. Chem. Soc., 1996,
118, 3309–3310.
59 S. Ko, C. Lee, M.-G. Choi, Y. Na and S. Chang, J. Org. Chem.,
2003, 68, 1607–1610.
60 Z.-S. Chen, L.-Z. Huang, H. J. Jeon, Z. Xuan and S.-G. Lee,
ACS Catal., 2016, 6, 7855–7864.
61 B. M. Trost and X. Luan, J. Am. Chem. Soc., 2011, 133, 1706–
1709.
62 B. M. Trost, X. Luan and Y. Miller, J. Am. Chem. Soc., 2011,
133, 12824–12833.
63 Y. Zhao and D. J. Weix, J. Am. Chem. Soc., 2015, 137, 3237–
3240.
64 L. K. G. Ackerman, M. M. Lovell and D. J. Weix, Nature,
2015, 524, 454–457.
65 L. J. Goossen, P. P. Lange, N. Rodr´
ıguez and C. Linder,
Chem.–Eur. J., 2010, 16, 3906–3909.
66 L. J. Goossen, G. Deng and L. M. Levy, Science, 2006, 313,
662–664.
67 Y. Gu, X. Leng and Q. Shen, Nat. Commun., 2014, 5, 5405.
68 B. Chen and S. Ma, Chem.–Eur. J., 2011, 17, 754–757.
69 E. N. Jacobsen, Acc. Chem. Res., 2000, 33, 421–431.
70 K. B. Hansen and J. L. Leighton, J. Am. Chem. Soc., 1996,
118, 10924–10925.
71 B. Wu, J. R. Parquette and T. V. RajanBabu, Science, 2009,
326, 1662.
72 B. Wu, J. C. Gallucci, J. R. Parquette and T. V. RajanBabu,
Chem. Sci., 2014, 5, 1102–1116.
73 S. Matsunaga and M. Shibasaki, Chem. Commun., 2014, 50,
1044–1057.
74 S. Matsunaga and M. Shibasaki, Synthesis, 2013, 45, 421–
437.
75 J. Park and S. Hong, Chem. Soc. Rev., 2012, 41, 6931–7013.
76 S. R. Neufeldt and M. S. Sanford, Acc. Chem. Res., 2012, 45,
936–946.
77 D. C. Powers and T. Ritter, Nat. Chem., 2009, 1, 302–309.
78 D. C. Powers, D. Benitez, E. Tkatchouk, W. A. Goddard III
and T. Ritter, J. Am. Chem. Soc., 2010, 132, 14092–14103.
79 D. C. Powers and T. Ritter, Acc. Chem. Res., 2012, 45, 840–
850.
80 D. C. Powers, E. Lee, A. Ariafard, M. S. Sanford, B. F. Yates,
A. J. Canty and T. Ritter, J. Am. Chem. Soc., 2012, 134, 12002–
12009.
81 G. J. Chuang, W. Wang, E. Lee and T. Ritter, J. Am. Chem.
Soc., 2011, 133, 1760–1762.
82 P. Tang, T. Furuya and T. Ritter, J. Am. Chem. Soc., 2010,
132, 12150–12154.
83 M. N. Hopkinson, A. D. Gee and V. Gouverneur, Chem.–Eur.
J., 2011, 17, 8248–8262.
84 W. E. Brenzovich Jr, D. Benitez, A. D. Lackner,
H. P. Shunatona, E. Tkatchouk, W. A. Goddard III and
F. D. Toste, Angew. Chem., Int. Ed., 2010, 49, 5519–5522.
85 E. Tkatchouk, N. P. Mankad, D. Benitez, W. A. Goddard and
F. D. Toste, J. Am. Chem. Soc., 2011, 133, 14293–14300.
86 M. D. Levin and F. D. Toste, Angew. Chem., Int. Ed., 2014, 53,
6211–6215.
87 M. R. Uehling, A. M. Suess and G. Lalic, J. Am. Chem. Soc.,
2015, 137, 1424–1427.
88 A. M. Suess, M. R. Uehling, W. Kaminsky and G. Lalic, J. Am.
Chem. Soc., 2015, 137, 7747–7753.
89 M. P. Doyle, R. Duffy, M. Ratnikov and L. Zhou, Chem. Rev.,
2010, 110, 704–724.
90 H. M. L. Davies and M. S. Long, Angew. Chem., Int. Ed., 2005,
44, 3518–3520.
91 K. P. Kornecki, J. F. Briones, V. Boyarskikh, F. Fullilove,
J. Autschbach, K. E. Schrote, K. M. Lancaster,
H. M. L. Davies and J. F. Berry, Science, 2013, 342, 351–354.
92 J. Blanco-Urgoiti, L. A˜
norbe, L. P´
erez-Serrano,
G. Dom´
ınguez and J. P´
erez-Castells, Chem. Soc. Rev., 2004,
33,32–42.
This journal is © The Royal Society of Chemistry 2017 Chem. Sci.,2017,8,1705–1718 | 1717
Perspective Chemical Science

93 D. W. Stephan, Science, 2016, 354, 1248.
94 L. H. Gade, Angew. Chem., Int. Ed., 2000, 39, 2658–2678.
95 J. A. R. Schmidt, E. B. Lobkovsky and G. W. Coates, J. Am.
Chem. Soc., 2005, 127, 11426–11435.
96 Y. D. Y. L. Getzler, V. Mahadevan, E. B. Lobkovsky and
G. W. Coates, J. Am. Chem. Soc., 2002, 124, 1174–1175.
97 M. Mulzer, B. T. Whiting and G. W. Coates, J. Am. Chem.
Soc., 2013, 135, 10930–10933.
98 S. Banerjee, M. K. Karunananda, S. Bagherzadeh,
U. Jayarathne, S. R. Parmelee, G. W. Waldhart and
N. P. Mankad, Inorg. Chem., 2014, 53, 11307–11315.
99 S. R. Parmelee, T. J. Mazzacano, Y. Zhu, N. P. Mankad and
J. A. Keith, ACS Catal., 2015, 5, 3689–3699.
100 T. J. Mazzacano and N. P. Mankad, J. Am. Chem. Soc., 2013,
135, 17258–17261.
101 K. M. Waltz, X. He, C. Muhoro and J. F. Hartwig, J. Am.
Chem. Soc., 1995, 117, 11357–11358.
102 M. K. Karunananda and N. P. Mankad, Organometallics,
2017, 36, 220–227.
103 K. J. Bonney, F. Proutiere and F. Schoenebeck, Chem. Sci.,
2013, 4, 4434–4439.
104 G. Yin, I. Kalvet and F. Schoenebeck, Angew. Chem., Int. Ed.,
2015, 54, 6809–6813.
105 M. Auero, T. Sperger, A. S. K. Tsang and F. Schoenebeck,
Angew. Chem., Int. Ed., 2015, 54, 10322–10326.
106 H. Tsutsumi, Y. Sunada, Y. Shiota, K. Yoshizawa and
H. Nagashima, Organometallics, 2009, 28, 1988–1991.
107 W. K. Walker, B. M. Kay, S. A. Michaelis, D. L. Anderson,
S. J. Smith, D. H. Ess and D. J. Michaelis, J. Am. Chem.
Soc., 2015, 137, 7371–7378.
108 W. Zhou, J. W. Napoline and C. M. Thomas, Eur. J. Inorg.
Chem., 2011, 2029–2033.
109 K. Yamamoto, H. Nagae, H. Tsurugi and K. Mashima,
Dalton Trans., 2016, 45, 17072–17081.
110 S. Pal and C. Uyeda, J. Am. Chem. Soc., 2015, 137, 8042–
8045.
1718 |Chem. Sci.,2017,8,1705–1718 This journal is © The Royal Society of Chemistry 2017
Chemical Science Perspective