A Ball-Milling-Enabled Cross-Electrophile Coupling

Article abstract of DOI:10.1021/acs.orglett.1c02096

The nickel-catalyzed cross-electrophile coupling of aryl halides and alkyl halides enabled by ball-milling is herein described. Under a mechanochemical manifold, the reductive C-C bond formation was achieved in the absence of bulk solvent and air/moisture sensitive setups, in reaction times of 2 h. The mechanical action provided by ball milling permits the use of a range of zinc sources to turnover the nickel catalytic cycle, enabling the synthesis of 28 cross-electrophile coupled products.

Full text of DOI:10.1021/acs.orglett.1c02096

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Letter
A Ball-Milling-Enabled Cross-Electrophile Coupling
Andrew C. Jones, William I. Nicholson, Jamie A. Leitch, and Duncan L. Browne*
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ABSTRACT: The nickel-catalyzed cross-electrophile coupling of aryl
halides and alkyl halides enabled by ball-milling is herein described.
Under a mechanochemical manifold, the reductive C−C bond formation
was achieved in the absence of bulk solvent and air/moisture sensitive
setups, in reaction times of 2 h. The mechanical action provided by ball
milling permits the use of a range of zinc sources to turnover the nickel
catalytic cycle, enabling the synthesis of 28 cross-electrophile coupled
products.
mechanochemical catalysishas been highlighted for its
wing to the ability to rapidly assemble molecules and
Orelated analogues, transition-metal-catalyzed cross-cou- compatibility with the 12 principles of green chemistry,11
and highly pertinent to sustainability metrics such as atom
economy and process mass intensity,12 which are of increasing
importance in industrial route design and development.
Advances in mechanochemical cross coupling13 have estab-
lished the fusion of electrophilic aryl halides and a variety of
nucleophilic species including organozinc reagents,14 boronic
acids,15 amines,16 alkenes/alkynes,17 and thiols18 (Scheme 1A,
bottom). Despite this, these techniques remain in their infancy
and further exploration is needed to fully uncover the
opportunities that mechanochemistry can offer, in turn
increasing adoption of this enabling technology. Accordingly,
a mechanochemical approach to cross-electrophile coupling
(XEC), negating the need for prefunctionalized regents,
forging C−C bonds using a base-metal catalyst, under an air
atmosphere, and all in the absence of bulk reaction solvent,
would be of interest to synthetic communities and facilitate
further implementation of this synthetic transformation in both
industrial and academic settings, and herein we wish to report
our findings (Scheme 1C).
Our investigations into mechanochemical cross-electrophile
coupling began via assessing the reaction of 4-iodobenzonitrile
(1a, Scheme 2A) and 1-iodooctane (2a) with a variety of
nickel-based catalyst systems using zinc metal as the reductant.
Preliminary optimization studies (see Supporting Information
for further details) revealed that cross electrophile coupled
product (XEC product, 3a) could be achieved in good yield in
a mechanochemical environment in just 2 h (compared to 12 h
+ routinely used in XEC coupling methodology)2 by
pling methodology has become a stalwart approach in both
industrial and academic settings.1 Cross electrophile coupling
(XEC), pioneered in contemporary synthesis by Weix and co-
workers,2,3 represents a particularly promising advancement in
this area in terms of broadening the accessible chemical space
through cross-coupling chemistry. These recent developments
have employed nickel catalysis to enable the coupling of two
traditionally “electrophilic” species, for example a C(sp2) aryl
electrophile and a C(sp3) alkyl electrophile (Scheme 1A, top).
Extensive mechanistic studies on this transformation have
elucidated that a unified single electron transfer mechanism is
in operation for the activation of alkyl halides to the
corresponding alkyl radical species which then engages in
subsequent coupling with aryl halides through a reductive
elimination pathway (Scheme 1B).4 Uncovering this key
interplay of redox activation has opened avenues in reaction
design in cross-electrophile coupling and has sparked new
discoveries in the area.5 However, despite the advances to date,
a majority of the reductive methodologies developed have
relied on the use of highly inert glovebox reaction setups.2,3,6
These methods can also suffer from capricious activation of
zinc (or manganese) metal reductants as well as long reaction
times and high reaction temperatures in some instances.
While mechanochemistry has held a key role in crystal
engineering and formulation science for decades,7 in recent
years rapid and wide-ranging developments have established
mechanochemistry as a powerful enabling technology in
sustainable synthetic method development.8 This is primarily
due to the unique ability to run organic reactions without the
need for bulk reaction solvent, often coupled with drastically
reduced reaction times vs solution-phase counterparts.9
Furthermore, mechanochemical ball-milling offers new oppor-
tunities in carrying out reaction systems classically requiring
air-/moisture-sensitive setups under an air atmosphere.10 For
these reasons mechanochemical synthesisand especially
Received: June 25, 2021
https://doi.org/10.1021/acs.orglett.1c02096
© XXXX American Chemical Society
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Scheme 1. Mechanochemistry in Transition-Metal-
Catalyzed Cross-Coupling
Scheme 2. Optimization of the Mechanochemical Cross-
Electrophile Coupling of Aryl Iodides and Alkyl Iodides
General reaction conditions: 4-iodobenzonitrile (1a, 1.0 mmol), 1-
iodooctane (2a, 1.5 mmol), [Ni] catalyst (10 mol %, 0.1 mmol),
Ligand (20 mol %, 0.2 mmol), Zn (granular 20−30 mesh, 2.0 mmol),
N,N-dimethylacetamide (3.0 mmol), under an air atmosphere. The
reaction was milled at 30 Hz for 2 h in a stainless steel 15 mL milling
jar using a 3 g (7 mm diameter) stainless steel milling ball (see
employing 1.5 equiv of alkyl halide, 2 equiv of zinc metal as a
reductant, and 3 equiv of DMA as a liquid-assisted grinding
(LAG) agent (64%, Scheme 2A, entry 1).19 Further screening
of precatalysts and ligand systems uncovered that while
NiCl2(PPh3)2 provided increased yields (85%, entry 2),
inexpensive, readily available salt NiCl2·6H2O provided further
improved yields, when coupled with bipyridyl-based ligand
sets, with 1,10-phenanthroline (L4) proving optimal (91%,
entry 5). Interestingly, the use of tridentate ligand systems
substantially increased the observation of homocoupled biaryl
product 3a′ (entries 7−8). Notably, in the absence of ligand,
no cross-electrophile product was observed, and the reaction
returned both halide starting materials untouched (entry 9).
To probe the reaction further, several control reactions were
performed (Scheme 2B). It was shown that, in the absence of
the zinc reductant, no reaction occurs, and without the DMA
additive, the reaction performs very poorly returning <5%
product (3a).20 Furthermore, an alternative reductant
frequently used in cross-electrophile coupling, manganese
metal, was shownin the place of zincto maintain excellent
reactivity affording the XEC product 3a in 78% yield.2,3
With optimal conditions in hand, application of our
operationally simple method (Scheme 3A) to a range of aryl
halide fragments was explored (Scheme 3B). To our delight,
the reaction system could be readily translated to bromo-
arenes with no appreciable drop in efficiency (3a−b).21
Furthermore, the reductive mechanochemical methodology
a
1
Supporting Information for more details). Yield determined by H
b
NMR using mesitylene (0.33 mmol) as an internal standard. Isolated
yield after silica gel column chromatography.
was shown to be efficient across a spectrum of haloarene
electronics, showcasing reactivity with both electron-poor (3d,
3e), electron-rich (3i−j) and unactivated electron neutral
systems (3b, 3c, 3g−h), when a selection of iodo-/
bromoarenes were employed. Moreover, sterically hindered
ortho-substituted arenes also proceeded with negligible
suppression of reaction efficiency (3g, 3h). Substrates
containing highly electrophilic sites such as aldehydes
selectively underwent cross-coupling and showed no undesired
reactivity of the carbonyl functionality (3k). A well-established
advantage of cross-electrophile coupling is the lack of
requirement for a stoichiometric base in the reaction medium,
as would typically be seen with an analogous Suzuki coupling,
allowing for the successful coupling of substrates with acidic
sites such as free phenols (3l). Importantly, aryl halides bearing
boronate esters and tosylates were entirely selective for
coupling at the halide site affording products with important
functional handles for orthogonal downstream derivatization
through subsequent coupling reactions (3m, 3n). In addition,
pseudohalides were shown to be compatible with our
mechanochemical system, where coupling of a vinyl triflate
B
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Scheme 3. Scope of the Reductive Cross-Electrophile Coupling of Aryl and Alkyl Halides Enabled by Ball-Milling
derivative afforded the desired product in excellent yield (78%,
3o). Following this, attention turned to investigating the
variation of the alkyl halide partner (Scheme 3C). A
convenient solution for low-yielding alkyl bromide substrates
(2b) was found in the addition of 1 equiv of sodium iodide to
facilitate an in situ Finkelstein reaction.22,2b This modification
to the reaction conditions provided a remarkable increase in
yield from 34% to 75%, and throughout the remaining scope,
this technique was used for alkyl bromide coupling partners.23
Using these conditions, a range of alkyl halides were coupled to
model aryl halides 4-iodobenzonitrile (1a) and 4-iodobenzene
(1b). Carboxylic ester (4a), protected amine (4d), and
chloroarene (4e) functionality were tolerated with great
efficiency alongside a selection of skeletal aliphatic side chains.
Notably, secondary alkyl iodides were demonstrated to be
excellent coupling partners in this methodology (4b, 80%), in
conjunction with the smooth introduction of sterically
demanding neopentyl chains (4c). For longer chain alkyl
bromides, it was shown that higher yields were achieved using
electron-neutral iodobenzene (3b) when compared to 4-
iodobenzontrile (3a). Citronellyl bromide was also successfully
coupled with iodobenzene in 61% yield (4k). Coupling of alkyl
mesylates is particularly desirable, as it provides an efficient,
indirect route from commodity alcohols.5a Exploring this
concept, under our conditions, 39% of 4k (55% on addition of
NaI) was delivered upon reaction of iodobenzene with 3-
phenylpropyl methanesulfonate. This transformation was
readily scaled up to gram-scale, where using 30 mL milling
C
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jars and 7 g milling balls, 1.48 g of the cross-electrophile-
coupled product 3b could be achieved using the two milling
jars, in comparable yields to previously achieved (78%, Scheme
3D).
established cyclopropylmethyl radical fragmentation of [I] to
[II], Scheme 4B). To this end, the latter radical fragmentation
product was formed exclusively in excellent yield (77%) in the
reaction mixture, suggesting that this mechanochemical
manifold operates under the unified mechanism observed in
the solution-phase transformations.24
In conclusion, the mechanochemical cross-electrophile
coupling of aryl halides and alkyl halides has been described.
Negating the use of bulk reaction solvent and air/moisture
sensitive reaction setups, the coupling of two electrophilic
species through a reductive nickel catalytic cycle is achieved.
Perhaps most notable is the ability to render the reaction with
increased robustness owing to mechanical activation of zinc or
manganese metal in a variety of physical forms. Moreover, the
reaction methodology was then demonstrated on gram-scale
with maintained efficiency.
The use of Zn0 metal as a reagent can lead to variation in
reproducibility and performance of reactions. It is critical to
achieve effective activation of the zinc, and this in turn is highly
dependent on the physical form of the zinc metal employed.
Our previous reports on the mechanochemical generation and
downstream reactivity of organozinc species have denoted that
the unique reaction environment of the mixer mill enables the
use of a wide range of zinc forms without substantial yield
variations and, critically, with excellent reproducilbity.10
Pleasingly, in this methodology, excellent reactivity was
maintained when using granular, mossy, flake, wire, or foil
forms of Zn0 metal (Scheme 4A). Notably exchanging for the
ASSOCIATED CONTENT
* Supporting Information
Scheme 4. Studies into the Form of the Reductant and the
Presence of Radical Intermediates
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02096.
Synthetic procedures and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Duncan L. Browne − Department of Pharmaceutical and
Biological Chemistry, School of Pharmacy, London WC1N
1AX, United Kingdom; orcid.org/0000-0002-8604-
229X; Email: Duncan.Browne@ucl.ac.uk
Authors
Andrew C. Jones − Cardiff Catalysis Institute, School of
Chemistry, Cardiff University, Cardiff CF10 3AT, United
Kingdom
William I. Nicholson − Cardiff Catalysis Institute, School of
Chemistry, Cardiff University, Cardiff CF10 3AT, United
Kingdom
Jamie A. Leitch − Department of Pharmaceutical and
Biological Chemistry, School of Pharmacy, London WC1N
1AX, United Kingdom; orcid.org/0000-0001-6997-184X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02096
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
alternative reductant of manganese pieces (78%) or manganese
powder (56%) was also possible. Cross-electrophile coupling
mechanisms have been extensively explored in previous
studies.15 The overall mechanism (exemplified above in
Scheme 1B) details a single electron transfer mechanism for
the activation of the alkyl halide. Despite this, via in situ
generation of an alkyl organozinc intermediate (through
mechanochemical reaction of Zn0 and the alkyl iodide), a
Negishi-type coupling may also be in operation. This was
probed through employing cyclopropylmethyl iodide as the
alkyl halide substrate, where a two-electron Negishi-type
process would lead to the ring closed product, and a single-
electron process (akin to those detailed by Weix)4 would lead
to the ring-opened homoallylarene structure (via the well-
■
The authors gratefully acknowledge T. Linford-Wood and C.
Parsons (both Cardiff University) for preliminary experiments.
D.L.B. is grateful to the European Union, WEFO and Cardiff
University for a Knowledge Economy and Skills Scholarship
(KESS2) to A.C.J. W.I.N. thanks Cardiff University for a
studentship. J.A.L. thanks the Leverhulme Trust (RPG-2019-
260) for a research fellowship.
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