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Activation Strategies for Earth-Abundant Metal Catalysis
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Peng, J & Thomas, SP 2020, 'Activation Strategies for Earth-Abundant Metal Catalysis', Synlett: Accounts
and Rapid Communications in Synthetic Organic Chemistry. https://doi.org/10.1055/s-0039-1690873
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10.1055/s-0039-1690873
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Synlett Account / Synpacts
Template for SYNLETT © Thieme Stuttgart · New York 2020-03-09 page 1 of 7
Activation Strategies for Earth-abundant Metal Catalysis
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Abstract The use of Earth-abundant metal-catalysed organic transformations
has increased significantly in recent years. Where low oxidation-state
catalysts are required, the in situ activation of metal(II/III) salts offers an
operationally simple method to access these catalysts. Here we present the
development of activation strategies from the use of reducing organometallic
reagents to endogenous activation. Applications in alkene and alkyne
hydrofunctionalisation reactions will be used to highlight the synthetic
applications of the activation methods discussed.
1 Introduction
2 in situ Activation using Organometallic Reagents
3 in situ Activation using Non-organometallic Reagents
4 ‘Activator-Free’ Systems
5 Conclusions
Key words alkene hydrofunctionalisation, low oxidation-state, activation,
Earth-abundant metal catalysis
1. Introduction
Modern synthetic chemistry has been profoundly influenced by
the use of organometallic catalysis, and is dominated by systems
based on platinum-group metals.
1
Despite the huge success of
precious metal systems, these catalytic processes suffer from
long-term sustainability issues.
2
Firstly, the terrestrial deposits
of platinum-group metals are rare, with major mines in Russia,
South Africa and Montana, leading to price volatility and a lack
of supply security.
3
The quantity of platinum-group metal
exploitation declined by 20% between 2010 to 2015.
4
Secondly,
platinum-group metals have high toxicity and the cost of
removing these metals to low ppm levels from active
pharmaceutical intermediates can be considerable.
5
These
limitations have inspired the search for more sustainable and
environmentally benign catalysts derived from Earth-abundant
first-row transition metals such as iron, cobalt and manganese.
However, many Earth-abundant catalytic protocols rely on the
use of low oxidation-state precursors to facilitate productive
catalysis.
Hydrofunctionalisation reactions are a class of reaction in which
low oxidation-state Earth-abundant metal catalysts have been
used as sustainable alternatives to late transition-metal
catalysts. A number of strategies have been reported as a means
to access these low oxidation-state species and enable
successful chemical transformations.
6
This account will explore
progress towards simple activation strategies for low oxidation-
state Earth-abundant metal catalysis.
The potential application of Earth-abundant metal catalysis in
hydrofunctionalisation reactions was shown by Chirik’s seminal
work using reduced analogs of Gibson
7a
and Brookhart’s
7b
bis(imino)pyridine iron catalyst.
8
These low oxidation-state
iron complexes were prepared by the reduction of the
corresponding iron(II) complexes with strong reducing agents
including sodium amalgam, sodium triethylborohydride and
sodium naphthalene, under an atmosphere of nitrogen (1-4,
Scheme 1).
9
Scheme 1 Examples of bis(imino)pyridine iron(0) dinitrogen complexes 1-4
used in alkene hydrofunctionalisation reactions developed by Chirik.
2. in situ Activation using Organometallic Reagents
Despite the high reactivity achieved using well-defined low
oxidation-state complexes, the translation of these systems to
an industrial scale remains challenging. The highly air- and
moisture sensitive nature of these low oxidation-state
complexes requires special preparation and handling
techniques. To overcome these limitations, in situ activation
strategies have been developed.
6a-d,
10
This enables the use of
iron(II/III) or cobalt(II/III) halide complexes by use of a
Jingying Peng
a
Stephen P. Thomas*
a
a
EaStCHEM School of Chemistry, University of Edinburgh,
Joseph Black Building, Edinburgh, EH9 3FK, UK.
* indicates the main/corresponding author.
stephen.thomas@ed.ac.uk
Click here to insert a dedication.
Synlett Account / Synpacts
Template for SYNLETT © Thieme Stuttgart · New York 2020-03-09 page 2 of 7
strongly reducing reagent to generate the low oxidation-state
species in situ which can then catalyse the reaction.
We began in this area by identifying a common low oxidation-
state iron species in cross-coupling and hydrogenation
reactions. We postulated that these common low oxidation-state
species could be exploited in a tandem cross-coupling-
hydrogenation reaction to remove the need to prepare the
challenging formally iron(0) hydrogenation pre-catalysts. We
were able to successfully perform a one-pot reductive cross-
coupling of vinyl halides and Grignard reagents under hydrogen,
by in situ generation of a low oxidation-state iron catalyst
(Scheme 2a).
11
Grignard reagent was used in to act as both the
pre-catalyst activating agent and also the nucleophilic coupling
partner. We also investigated this iron pre-catalyst and Grignard
activation in hydride-mediated reductive cross-coupling
reactions (Scheme 2b).
12
β-Halostyrene derivatives were
coupled with Grignard reagents using iron(III) chloride and a
tetradentate ligand and the intermediate alkene reduced in situ
to an alkane using superstoichiometric lithium
aminoborohydride.
Scheme 2 (a) Iron-catalysed reductive cross-coupling of vinyl halides and
Grignard reagents. (b) Iron-catalysed, hydride-mediated reductive cross-
coupling of vinyl halides and Grignard reagents.
The iron-catalysed reduction of alkenes and alkynes was
performed using sodium triethylborohydride as the
stoichiometric hydride source.
13
The system was active for the
formal hydrogenation of aryl- and alkyl alkenes and internal
alkenes (Scheme 3). However, an attempt to make this reaction
enantioselective by the replacement of the NMP with
enantiopure ligands was not successful. Deuterium labelling
experiments showed that both hydrogen atoms originated in the
borohydride reagent.
Scheme 3 Iron-catalysed, NaHBEt
3
-mediated, formal hydrogenation of
alkenes.
In a further simplification, we used air- and moisture stable
iron(III) salts and sodium borohydride, in ethanol for the formal
hydrogenation of terminal alkenes (Scheme 4a).
14
Use of radical
traps completely inhibited alkene hydrogenation, but no
trapped substrate was observed, indicating irreversibly binding
to the catalyst. Deuterium labelling studies indicate that this
reaction proceeds by an ionic rather than radical mechanism,
but offer little information on either the identity of the
catalytically active species or the mechanism of hydrogenation.
A number of nitroarenes and heteroarenes were also
successfully reduced using these simple reaction conditions
(Scheme 4b).
Scheme 4 (a) Iron-catalysed formal hydrogenation of alkenes using Fe(OTf)
3
and NaBH
4
.
(b) Iron-catalysed formal hydrogenation of nitroarenes using
Fe(OTf)
3
and NaBH
4
.
We reported an iron-catalysed formal hydrocarboxylation of
styrene derivatives using stoichiometric ethyl magnesium
bromide as the hydride source and in situ activator. proceeded
by the hydromagnesiation of styrene derivatives to form a
nucleophilic benzylic Grignard reagent (Scheme 5a).
15
The
reaction gave the carboxylic acid products in excellent yields
and regioselectivities. We also reported a simplified version of
this procedure using tetramethylethylenediamine (TMEDA)
instead of bis(imino)pyridine, which was applied to the reaction
of 18 different electrophiles (Scheme 5b).
16
Scheme 5 (a) Iron-catalysed hydrocarboxylation of styrenes, using
stoichiometric EtMgBr as hydride donor and activator. (b) The application of
hydromagenesiation to the formal hydrofunctionalisation of aryl alkenes with
different electrophiles.
After much effort, a formally Fe(0) ‘ate’ species
[
iPr
BIPFe(Et)(ethene)]
-1
5a was identified as the resting state in
the hydromagnesiation. In contrast to our originality proposed
iron-hydride intermediate, it was determined that a β-hydride
of an ethyl ligand was the active hydrometallation species. The
[
iPr
BIPFe(Et)(ethene)]
-1
complex 5a could loss ethylene and
transiently coordinate the styrene derivative and mediate a
rapid and reversible direct β-hydride transfer to give the
benzylic iron species 5c, negating the necessity of a discrete iron
hydride intermediate. Catalyst turnover was achieved by
transmetallation with ethylmaganesium bromide to regenerate
[
iPr
BIPFe(Et)(ethene)]
-1
5a and the benzylic Grignard reagent.
17
Synlett Account / Synpacts
Template for SYNLETT © Thieme Stuttgart · New York 2020-03-09 page 3 of 7
Scheme 6 Proposed reaction mechanism for iron-catalysed
hydromagenesiation of styrene derivatives
We next sought to identify an alternative hydride source to
replace ethyl magnesium bromide and further simplify the
hydromagnesiation reaction. When attempting to use silane (H-
Si) or borane (H-B) reductants, we noted that instead of
hydromagenesiation we observed hydrosilylation and
hydroboration, respectively (Scheme 7).
18
A bis(imino)pyridine
iron(II) complex 6 was in situ activated using substoichiometric
ethylmagnesium bromide or n-butyllithium to generate a low
oxidation-state active iron species, which catalysed the
hydrofunctionalisation reactions.
Scheme 7 Iron-catalysed anti-Markovnikov selective hydroboration,
hydrosilylation and hydrogermylation using in situ activation by EtMgBr
3. in situ Activation using Non-organometallic Reagents
Although many strategies have been developed using
organometallic activators, the air- and moisture sensitivity of
the organometallic activators limits adoption by the wider
community. Ideally, the development of activation strategies
using readily available, bench-stable and easily-handled
reagents as activators, instead of pyrophoric organometallic
reagents, would allow access to low oxidation-state Earth-
abundant metal catalysis in a highly operationally simple and
safe manner.
We reported that the bis(imino)pyridine iron(II) triflate pre-
catalyst 7, could be activated in situ with a tertiary amine
(Hünig’s base) to catalyse the hydrosilylation of alkenes and
alkynes (Scheme 8).
19
Significantly, these reactions proceeded in
equal yield under air and inert reaction conditions. The use of
triflate counterions was demonstrated to be crucial to the in situ
generation of the active catalyst as the weak binding affinity of
the anion makes the iron(II) precursor amenable to the amine-
induced activation. Amines have been reported to reduce late
transition metal complexes by coordination and β-hydride
elimination.
20
However, the products of such a reaction, such as
an aldehyde or imine, were not observed. In addition, no direct
evidence for the formation of a silicon ‘ate’ complexes could be
obtained.
Scheme 8 Iron-catalysed hydrosilylation reaction using in situ activation by
Hünig’s base.
In an attempt to minic the hydride transfer seen in the
hydromagnesiation reaction, we next explore non-
organometallic activating reagents bearing available β-
hydrogens. Serendipity and an excellent PhD student led to the
discovery of alkoxide activation.
21, 22
We found that
commercially available, bench-stable and non-toxic alkoxide
salts offered a generic activation strategy for Earth-abundant
metal complexes across a range of transformations (Scheme
9a).
19
The activation was shown to proceed through the in situ
generation of a hydridic boron or silicon ‘ate’ complex, which
were observed by
11
B and
29
Si NMR spectroscopy, respectively.
The boron or silicon ‘ate’ complexes activated the pre-catalyst
by hydride transfer and reduction (Scheme 9b).
Scheme 9 (a) Earth-abundant metal-catalysed hydrofunctionalisation
reactions using in situ activation by NaO
t
Bu. (b) Proposed pre-catalyst
activation pathway, by the generation of hydridic boron or silcon ‘ate’
species.
Using a combination of an alkoxide salt and pinacolborane
allowed iron and cobalt pre-catalysts to be applied across
hydrovinylation, hydrogenation and [2π+2π] cycloaddition
reactions. We used the alkoxide activation to develope a cobalt-
catalysed Markovnikov selective hydroboration of aryl
alkenes
23
and a manganese-catalysed hydrofunctionalisation of
alkenes.
24
Moreover, this activation protocol was applied to a
number of Earth-Abundant metal-catalysed industrially
relevant transformations.
25
4. ‘Activator-Free’ Systems
‘Activator-free’ hydrofunctionalisation systems have recently
been reported, in which Earth-abundant metal pre-catalysts
undergo activation without the need for external activators.
This represents the state-of-the-art for Earth-abundant metal
catalysis. Metal complexes bearing nucleophilic ligands are
generally used in these ‘activator-free’ systems.
We developed a regioselective alkene hydroboration using two
alkoxy-tethered NHC iron(II) complexes (Scheme 10a).
26
These
iron(II) complexes 8a-b were designed with aryl- or alkyl-oxy
anions, which would react with borane (H-B) to give hydridic
Synlett Account / Synpacts
Template for SYNLETT © Thieme Stuttgart · New York 2020-03-09 page 4 of 7
boron ‘ate’ complex and activate the pre-catalyst. This was
supported by in situ reaction monitoring using mass
spectrometry, in which the borylated iron complexes 8a·Bpin,
and 8b·Bcat were observed (Scheme 10b). It was proposed that
these species were derived from the corresponding iron hydride
complexes.
Markovnikov selective alkene hydroboration with
pinacolborane was achieved for the first time using an iron(II)
catalyst 8a. anti-Markovnikov selective alkene hydroboration
was observed using catecholborane and a modified ligand
backbone.
Scheme 10 (a) Iron-catalysed regiodivergent alkene hydroboration without
the need for an external activator (b) in situ Reaction monitoring by ESI-MS
Iron- and cobalt carboxylate salts have been shown to act as pre-
catalysts for ‘activator free’ alkene hydrosilylation.
27
Similarly, a
tridentate PNN-cobalt(II) dichloride pre-catalyst could be in situ
activated at elevated temperature for alkene hydrosilylation.
28
The carboxylate and thermal activation protocols were
proposed to proceed by a σ-bond metathesis reaction between
the metal carboxylate and silane (Scheme 11). We took a
different approach and used tetrafluoroborate salts. We
proposed that using tetrafluroborate counterion enable the pre-
catalyst activation by release of fluoride for regiodivergent
hydrosilylation and anti-Markovnikov hydroboration reactions
were carried out without the need for an external activator, thus
simplifying the procedure of hydrofunctionalisation reactions
(Scheme 12a).
29
This endogenous activation was shown to
proceed by the dissociation of fluoride from the metal
tetrafluoroborate pre-catalysts, which led to the formation of a
hydridic boron or silicon ‘ate’ complex. The ‘ate’ complex
activated the metal pre-catalyst by hydride transfer, generating
a metal hydride complex, which was followed by reductive
elimination to generate the low oxidation-state species to
catalyse the reaction (Scheme 12b).
27
Scheme 11 Endogenous activation with iron- and cobalt complexes.
Scheme 12 (a) Iron- or cobalt-catalysed regiodivergent hydrosilylation and
hydroboration of alkenes, using tetrafluroborate metal salts and
bis(imino)pyridine ligands. (b) Proposed tetrafluroborate activation: hydridic
‘ate’ complex formation to reduce metal complex.
The use of the tetrafluoroborate activation as a general platform
to access low oxidation-state, catalytically active species, was
also investigated. The combination of tetrafluoroborate pre-
catalysts and a hydrofunctionalisation reagent, such as
phenylsilane and pinacolborane, produced a hydridic ‘ate’
complex, which gave a low oxidation-state catalyst capable of
hydrogenation, [2π+2π] cycloaddition and C-H borylation
reactions.
All the previously mentioned activation strategies proceed by
the reaction of external hydride source (borane or silane) with
either an external activator or internal activator to generate
hydride species used to reduce iron- and cobalt pre-catalysts. A
limitation of these strategies is the need for a reagent containing
Si-H or B-H bonds to enable pre-catalyst activation. A more ideal
scenario enables activation without the need of any external
hydride. We proposed that a self-activating catalysis system
could be achieved by incorporating hydride source onto the
ligand and using iron and cobalt salts with nucleophilic counter
ions. However, our initial investigations into this area have been
hindered by challenging ligand syntheses and low reactivity
(Scheme 13).
SiPhH2
TerpyFeCl
2
9 was prepared with a SiH
2
Ph
group incorporated onto the terpyridine ligand. Endogenous
activation failed, and even the addition of an alkoxide activator
gave only low yields in alkene hydrogenation reactions.
30
However, the need to incorporate a silane of borane into a ligand
severely limits this strategy going forward. Thus, there are still
significant hurdles to overcome and novel synthetic strategies