Efficient Pd-Catalyzed Direct Coupling of Aryl Chlorides with Alkyllithium Reagents

Article abstract of DOI:10.1002/anie.202008866

Organolithium compounds are amongst the most important organometallic reagents and frequently used in difficult metallation reactions. However, their direct use in the formation of C?C bonds is less established. Although remarkable advances in the coupling of aryllithium compounds have been achieved, Csp²?Csp³ coupling reactions are very limited. Herein, we report the first general protocol for the coupling or aryl chlorides with alkyllithium reagents. Palladium catalysts based on ylide-substituted phosphines (YPhos) were found to be excellently suited for this transformation giving high selectivities at room temperature with a variety of aryl chlorides without the need for an additional transmetallation reagent. This is demonstrated in gram-scale synthesis including building blocks for materials chemistry and pharmaceutical industry. Furthermore, the direct coupling of aryllithiums as well as Grignard reagents with aryl chlorides was also easily accomplished at room temperature.

Full text of DOI:10.1002/anie.202008866

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Efficient Pd-Catalyzed Direct Coupling of Aryl Chlorides with
Alkyllithium Reagents
Authors: Viktoria H. Gessner, Thorsten Scherpf, Henning Steinert,
Angela Großjohann, Katharina Dilchert, Jens Tappen, and Ilja
Rodstein
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10.1002/anie.202008866
Angewandte Chemie International Edition
RESEARCH ARTICLE
Efficient Pd-Catalyzed Direct Coupling of Aryl Chlorides with
Alkyllithium Reagents
Thorsten Scherpf, Henning Steinert, Angela Großjohann, Katharina Dilchert, Jens Tappen, Ilja
Rodstein and Viktoria H. Gessner*[a]
In memory of Professor Hans J. Reich, a pioneer in organolithium chemistry.
[a]
Dr. T. Scherpf, M.Sc. H. Steinert, M.Sc. A. Grooßjohann, Dr. K. Dilchert, M.Sc. J. Tappen, M.Sc. I. Rodstein, Prof. Dr. V.H. Gessner
Department: Faculty of Chemistry and Biochemistry, Chair of Inorganic Chemistry
Institution: Ruhr-Universität Bochum
Address: Universitätsstraße 150, 44801 Bochum (Germany).
E-mail: viktoria.gessner@rub.de
Abstract: Organolithium compounds are amongst the most important
organometallic reagents and frequently used in difficult metallation
reactions. However, their direct use in the formation of C-C bonds is
less established. Although remarkable advances in the coupling of
aryllithium compounds have been achieved, Csp2-Csp3 coupling
reactions are very limited. Here, we report the first general protocol
for the coupling or aryl chlorides with alkyllithium reagents. Palladium
catalysts based on ylide-substituted phosphines (YPhos) were found
to be excellently suited for this transformation giving high selectivities
at room temperature with a variety of aryl chlorides without the need
for an additional transmetallation reagent. This is demonstrated in
gram-scale synthesis including building blocks for materials chemistry
and pharmaceutical industry. Furthermore, the direct coupling of
aryllithiums as well as Grignard reagents with aryl chlorides was also
easily accomplished at room temperature.
nucleophiles would be highly desirable. This would also allow for
the reduction of inorganic waste (tin or boron salts) and production
costs. While Kumada couplings5 are routinely used since several
years and reliable protocols for sp2-sp2 and sp2-sp3 couplings
have been developed with phosphines6 as well as N-heterocyclic
carbenes[7,8] using nickel or palladium as well as base metals,[9,10]
the corresponding reactions with organolithium compounds are
far less developed. Feringa and coworkers greatly improved the
first protocols reported by Murahashi,[ 11 ] and in the case of
aryl/alkenyl bromides, protocols exist to couple almost any
conceivable lithium reagent even at low temperatures (Figure
1).[12] For the more desirable and readily available aryl chlorides,
the coupling is much less general. Reagents like aryl/alkenyl
lithium or (trimethylsilyl)methyllithium, that cannot undergo β-
hydride elimination (BHE) work efficiently, whereas primary and
secondary alkyl lithium reagents are problematic.[13] Attempts with
nickel-based system were somewhat more successful, but the
reaction seems to be restricted to polyaromatic aryl halides[14] and
electron-poor aryl chlorides.[15] Until today, there is no general
protocol for the coupling of organolithium reagents with aryl
chlorides available.
Introduction
Palladium-catalyzed cross-coupling reactions have become a
powerful tool for the formation of C-C and C-X bonds in organic
synthesis and are nowadays frequently used to produce fine
chemicals such as agrochemicals and pharmaceuticals.[1] The
success of these methodologies lies in the breadth of
electrophiles and nucleophiles which can be used in this protocol
and the myriad of reagents which are accessible. Albeit many
limitations in coupling chemistry have been overcome over the
years by the development of new, more sophisticated and
specialized ligands,[2] still many challenges remain, which seem
to be related to the intrinsic limitations in the ligand design.[3] In
case of Csp2-Csp2 and Csp2-Csp3 coupling reactions the Suzuki-
Miyaura, Stille, Kumada and Negishi couplings are the most
important protocols.[ 4 ] Particularly, the Suzuki reaction which
makes use of boron nucleophiles has become the method of
choice for the formation of biaryl compounds, especially in
pharmaceutical industry. This is mainly based on the high group
tolerance and the facile access of boronic acids, esters or borates,
which are typically generated from readily available organolithium
or Grignard reagents. The same is also true for organotin
compounds used in Stille couplings, which however are often
toxic and thus less frequently applied. To facilitate synthetic
protocols by preventing a further transmetallation step the
development of reliable protocols with magnesium and lithium
Figure 1. Cross coupling of aryl and alkyl lithium reagents with aryl halides
This limitation is mainly due to two obstacles in the mechanism
(Figure 2) of the coupling reaction: i) Aryl chlorides are difficult
substrates since oxidative addition of the C-Cl bond is usually
rate-limiting and slow at low temperatures. Thus, many side
reactions with the highly reactive organolithium reagents can
occur (e.g. Cl/Li exchange) prior to the addition step, leading to
protodehalogenation and homocoupling. ii) The second limitation
concerns the alkyllithium reagents. These reagents are more
reactive than aryllithium species and hence more readily undergo
the undesired Cl/Li exchange (homocoupling product). This was
1
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10.1002/anie.202008866
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RESEARCH ARTICLE
for example used in the synthesis of symmetric biaryls, where tert-
butyllithium instead of acting as nucleophile solely enabled
lithiation of the aryl halide and hence biaryl formation.[ 16 ]
Furthermore, the alkyl palladium species formed after the
transmetallation step are prone to BHE, which can lead to
isomerization and/or protodehalogenation. This competition
between “normal” and migratory cross-coupling of alkylmetal
reagents has been addressed in recent studies, in particular in the
context of Negishi coupling reactions,[17] but remained unexplored
with lithium nucleophiles. Thus, the coupling of aryl chlorides with
alkyllithium reagents represents the most challenging
combination and an unresolved problem.
electron-rich phosphines or N-heterocyclic carbenes (NHC) to
couple aryl and alkenyllithiums.[12,13] Yet, these ligands seem to
reach a limit in case of alkyllithium compounds. Recently, we
reported on a new class of electron-rich phosphines for homo-
genous catalysis, the ylide-substituted phosphines, YPhos.[ 18 ]
Due to the carbanionic charge next to the phosphorus center,
these ligands are particularly strong donors, also surpassing the
donor strength of NHCs. Accordingly, high activities in Buchwald
Hartwig aminations[19] and α-arylations of aryl chlorides at room
temperatures were observed.[ 20,21] This encouraged us to test
these ligands for their activities in the coupling of organolithium
compounds including alkyllithiums with aryl chlorides, which led
us to the development of the first generally applicable reaction
protocol.
Results and Discussion
As a first step, the coupling of sec-butyllithium with 4-chloro-
anisole (1) was studied using the three YPhos ligands L1-L3
together with Pd2dba3·dba as Pd source. The combination of an
electron-rich aryl chloride with a secondary alkyllithium reagent
represents one of the most challenging reactions and – if being
successful – promised a broad applicability of the optimized
reaction protocol. We started with reaction conditions similar to
those reported by Feringa et al., i.e. room temperature and slow
addition of the diluted organolithium reagent to a toluene solution
of the aryl chloride and the catalyst. Optimization of the reaction
conditions showed that 3 mol% catalyst loading are necessary for
high conversion (Figure 3, see Supporting Information for details
on the optimization). To our delight, YPhos ligand joYPhos (L3)
gave high conversions of 78% to the desired coupling product 2a
after only 1 h reaction time. While some protodechlorination
Figure 2. Catalytic cycle of the Murahashi cross-coupling reaction with possible
side-reactions.
To promote the coupling of aryl chlorides, very electron-rich
ligands are required which facilitate fast oxidative addition at mild
temperatures. Therefore, Feringa and coworkers used highly
Figure 3. Comparison of catalytic activity of different ligands and palladium complexes in the cross-coupling of s-BuLi with 4-chloroanisole. Reaction conditions:
4-Chloroanisole (1 mmol), Pd (3 mol%), ligand (3 mol%) and toluene (1 ml). s-Buli (1.3 M in cyclohexane/hexane, 1.2 mmol; diluted with toluene), 1 h addition
period at 22 °C (or 35 °C). Yields were determined by GC using n-tetradecane as internal standard; Pd(dba) = [Pd2(dba)3∙dba].
2
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10.1002/anie.202008866
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product 3 (12%) was formed, very small amounts of the
homocoupling product 4 (4%) and the isomerized product 2b (3%)
were obtained. This is especially important, since separation of
these isomers are often laborious using standard techniques.
Other palladium sources and other YPhos ligands (L1 and L2)
also showed high activities in this reaction, albeit with a slightly
Grignard reagents, like iPrMgCl, also gave low amounts of the
isomerized products. It is worth mentioning that tBuMgCl also
selectively provided the isomerization product, but in this case,
almost no proto-dehalogenation or biphenyl formation was
observed (entry 12). This led us to conclude that the lower
selectivities observed wit tBuLi were mostly the result of fast side
lower selectivity. In addition, air-stable palladium complexes of L3, reactions, mainly lithium-halogen exchange, while the complete
which are easy to apply showed similar results.[22] Here, [L3-
Pd(indenyl)Cl] (L3-P3) showed the highest activity, similar to L3
and Pd2(dba)3, and thus represents a convenient alternative to
using the free ligand and an additional Pd source.
isomerization of the alkyl group results from an inherent property
of the catalytic system. We find it particularly interesting that the
same catalyst provides high selectivities for the coupling of
secondary alkyllithium and Grignard reagents with little
isomerization, while at the same time giving complete
isomerization in the coupling of tertiary lithium/Grignard reagents.
It is also worth mentioning, that in case of tBuMgCl it was not
necessary to dilute and slowly add the magnesium reagent.
Instant addition of a 1.7M solution of tBuMgCl in THF and stirring
for 1 hour only slightly lowered the yield compared to a slow
addition over a period of 1 hour. In contrast, instant addition of all
other lithium and magnesium nucleophiles resulted in the
formation of only small amounts of the desired product.
We compared the activity of the YPhos ligands with that of other
catalysts, including those reported in the literature for the coupling
of aryl and alkenyllithium compounds. As shown in Figure 3, none
of these catalysts delivered comparable good results. While other
phosphines (PtBu3, QPhos, XPhos, DavePhos) gave no product
at all, the NHC- based PEPPSI catalysts delivered small amounts
of product. Presumably, only the NHC catalysts can perform the
oxidative addition at room temperature under the coupling
conditions. However, conversions and selectivities were low with
these catalysts, and for sBuLi, several unidentified higher
molecular weight products were found, indicating further
undesired side reactions. Increasing the reaction temperature to
35°C to facilitate the oxidative addition of the aryl chloride didn’t
improve the selectivity or yield of the reaction. The YPhos ligand
joYPhos (L3) is the only ligand that allows for a sufficiently fast
oxidative addition of the aryl chloride at room temperature thus
preventing or minimizing the competing homocoupling or proto-
dechlorination, and at the same time minimizes BHE. To our
delight, this optimized protocol with L3 was also capable of
effecting the coupling with nBuLi (Table 1, Entry 1). In this case,
only trace amounts (<0.1%) of the isomerized product were found,
and the amount of protodehalogenation (6%) was likewise small.
Again, none of the other catalyst systems (Figure S2) could
produce similar good results. Only the NHC-derived catalysts
yielded the desired coupling product, but with low selectivities.
Motivated by the initial catalysis results, we turned our attention
towards the examination of the generality of the established
reaction protocol and a screening of different commercially
available alkyllithium and magnesium reagents and aryl halides
(Table 1). Aryl bromides were similar efficiently coupled to the
desired products (entry 3 and 4), but interestingly the coupling
with sBuLi showed slightly higher amounts of the isomerized
product. Aryl iodides on the other hand showed only low
conversion and poor selectivities (entry 5, 6), presumably due to
fast iodine/lithium exchange. This suggests that for the successful
coupling of alkyllithium reagents, activity towards aryl chlorides is
particularly important to obtain high selectivities. While
methyllithium and phenyllithium were also efficiently coupled
(entry 8, 9), lower selectivities were found with tert-butyllithium,
which is more reactive towards lithium-halogen exchange.
Nonetheless, 65% of product were formed (entry 7). Interestingly,
instead of the expected product, complete isomerization to the
isobutyl product was observed. No traces of the expected tert-
butyl product could be detected. Such a complete isomerization
has been reported earlier for similar reactions.[22]
Table 1. Results of the reaction of different organometallic reagents with aryl
halides.
Product ratio
br:ln
Entry
X
R-M
Conversion
ratio
2
3
4
1
Cl
Cl
Br
Br
I
nBuLi
93%
90
85
90
84
57
3
6
4
-
2
sBuLi
95%
12
6
3
96:4
3
nBuLi
100%
100%
100%
92%
4
-
4
sBuLi
9
7
88:12
5
nBuLi
6
37
93
16
5
-
6
I
sBuLi
4
78:22
7
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
tBuLi
99%
65
83
95
98
95
100
97
94
100
100
20
12
0
0:100
8
iPrLi
86%
95:5
9
PhLi
81%
5
-
10
11
12
13
14
15
16
MeLi
83%
0
2
-
CyMgCl
iPrMgCl
tBuMgCl
tBuMgCl[a]
MeMgCl
PhMgCl
96%
2
3
-
100%
100%
100%
100%
100%
0
0
95:5
3
0
0:100
6
0
0:100
0
0
-
-
0
0
Besides C-C couplings with organolithium reagents, L3·Pd2dba3
is also an extremely efficient catalyst for Kumada coupling
reactions (Entries 11-16). Due to the lower reactivity of Grignard
reagents higher selectivities for the coupling products were
obtained (c.f. entry 8 and 12 or 9 and 116) and secondary alkyl
Reaction conditions: 4-Haloanisole (1 mmol), Pd2dba3xdba (15.62 wt% Pd, 3
mol% [Pd]), L3 (3 mol%) and toluene (1 ml), lithium/Grignard reagent (see SI,
1.2 mmol) diluted with toluene (0.36 M) and added over 1 h at 22 °C. Yields and
br:ln ratios were determined by GC using n-tetradecane as internal standard.
[a] Addition over 30s, 1h reaction time.
3
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To gain insight into the reaction process and to understand the
observed selectivities, we performed mechanistic studies. At first,
we tested the oxidative addition of an aryl chloride to the
palladium complex with L3 by means of a stoichiometric
experiment using Pd2dba3 and L3 together with 10 equiv. of 4-
chlorotoluene. Typically, elevated temperatures are required to
reach significant conversion to the Pd(II) chloride complex. With
L3 however, the oxidative addition complex L3∙Pd(Tol)Cl was
formed at room temperature albeit one day was required for the
reaction to complete as evidenced by monitoring of the reaction
with 31P NMR spectroscopy. The complex could be isolated in
63 % yield as an air-stable solid, which is poorly soluble in
common organic solvents. In the solid state, L3∙Pd(Tol)Cl forms
a dimer (Fig. 4) with a planar (Pd-Cl)2 four membered ring as was
observed for other phosphine and carbene ligands.[23] Attempts to
obtain any information about the transmetallation process
revealed to be impossible at room temperature. Addition of n-
butyllithium to [L3∙Pd(Tol)Cl]2 immediately resulted in the final
coupling product. This was also the case when using methyl-
lithium, even though the methyl palladium complex should be less
prone to reductive elimination due to the decreased steric bulk.
No intermediate compounds could be observed by NMR studies
even at low temperature, thus confirming the fast reaction process.
It is also important to note that, isolated [L3∙Pd(Tol)Cl]2 can be
used as a potent precatalysts. In the coupling of sec-butyllithium
with 4-chloroanisole under the optimized reaction conditions as
discussed above, 87% conversion with slightly lower selectivities
than those found with L3-Pd2(dba)3xdba or precatalyst L3-P3
were observed.
Figure 4. Molecular structure of L3∙Pd(Tol)Cl.
Since experimental studies could not provide any further
information about the mechanism, DFT calculations
(PW6B95D3/def2TZVP) were performed to understand the
observed selectivities. To this end, we examined the possible
reaction steps after transmetallation (Figure 5). From here
onwards, complex I can either undergo reductive elimination (RE)
to the desired product Pro or reversible BHE to form the
isomerized products IsoPro. These reactions steps were
calculated with keYPhos (L1) and joYPhos (L3) with tert-butyl (a),
sec-butyl (b), iso-propyl (c) and ethyl (d) as alkyl groups. Figure
5 depicts the potential energy surface for the energetically most
favored pathways for alkyl complexes Ia-d with L3 (see SI for
more details, e.g. energies related to rotamers and isomers as
well as all results with L1). The calculations show that there are
three distinct scenarios characterized by the energy differences
between the transition states of the two reductive elimination
Figure 5. Reaction profile of the reductive elimination and β-hydride elimination from the alkyl Pd complexes I with L3. Energies (PW6B95D3/def2TZVP) are
given relative to the respective alkyl complex Ia-Id.
4
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10.1002/anie.202008866
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RESEARCH ARTICLE
processes (TSRE and TSIso-RE) and the isomerization (olefin
rotation TSIII-IV) 1). For the tert-butyl palladium complex Ia (red
line) the BHE and isomerization process is the kinetically most
favored pathway, showing a considerably lower activation barrier
(22.8 kJ/mol for TSIso-RE) than the RE to the non-isomerized
product TSRE (33.9 kJ/mol). This energetic difference is in line with
the complete isomerization observed in experiment. In contrast,
for the ethyl complex Id, BHE to the hydrido palladium complex III
is energetically uphill and rotation of the olefin more energy-
consuming than TSRE (ΔΔGǂ = 19 kJ/mol), resulting in the
selective RE without isomerization as observed in experiment for
n-BuLi.
An intermediate situation to both extremes is found for the iPr and
sBu complexes Ic and Ib (green and purple line, only most
favored conformers shown). Here, the barrier for the rotation of
the olefin is energetically similar to the RE. Thus, all three
transition states determine the product formation. No classical
Curtin-Hammett conditions are reached. The activation barriers
TSRE, TSIII-IV and TSIso-RE lie within only 1-5 kJ/mol, being in line
with the observed formation of product mixtures. Although the
calculations reflect the trends observed in experiment, the
observed selectivities for the secondary alkyl groups should be
lower. The reason for this discrepancy is not yet clear. Although
inaccuracies of the DFT calculations cannot be ruled out, it might
also be possible, that due to the high speed of the reaction (note
that all activation barriers are very low) the equilibrium state is not
always reached. Therefore, the reaction may simply continue
from complex I to product Pro before equilibrating to the other
agostic intermediate V.
Overall, steric effects seem to be the main reason for the
observed selectivities since the least sterically demanding alkyl
groups provide the highest selectivities for the desired product.
However, also the difference in the strengths of the agostic
interactions between the Pd center and the PCy3 moiety of the
ligand (complex I) and the alkyl group (complex II) seem to play a
crucial role in this context. The more stable the agostic interaction
to the phosphonium group, the less favored the interaction with
the alkyl substituent and hence BHE. Since the agostic interaction
to the tert-butyl group is clearly favored (by 25.7 kJ/mol), the tert-
butyl group selectively undergoes isomerization to form IsoPro.
For the complexes with the primary and secondary alkyl groups,
the alkyl palladium species I is either more stable or only slightly
disfavored over intermediate II, suggesting that the agostic inter-
actions by the ligand and the alkyl groups are equally strong. Here,
the different activation barriers are decisive. The whole reaction
profile with the YPhos ligands contrasts the behavior of NHC-
based catalysts, where only the barriers of the reductive
elimination and BHE were found to be decisive for the final isomer
ratio.[24]
To test the broadness of the reaction protocol, we next addressed
a detailed study of the substrate scope (Figure 6). To this end,
either a combination of L3 and Pd2(dba)3∙dba (method A) or
Figure 6. Substrate scope. Reaction conditions: aryl halide (3 mmol), [Pd] (0.09 mmol), nucleophile (3.6 mmol), 1h, RT. See SI for details. Yields are isolated
yields of the mixture of branched and linear products, if applicable. br:ln ratios were determined using 1H-NMR-Spectroscopy and GC analysis. [a] GC yield.
[b] 7.2 mmol of nucleophile, 2h addition time, [c] from tBuMgCl.
5
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Figure 7. (left) Synthesis of alkylated aromatics which are important building
blocks in material science and pharmaceutical industry; isolated yields; reaction
conditions according to Figure 5. (right) Selective alkylation of 1-bromo-4-
chlorobenzene with n-butyllithium, GC yield with n-tetradecane as internal
standard.
precatalyst [L3-Pd(indenyl)Cl] (L3-P3) (method B) was used. It is
important to note that this does not represent an optimization of
the reaction conditions. Rather one of the two systems was
randomly chosen before the reaction, since both seem to be
equally active. Fortunately, a wide variety of aryl chlorides could
be coupled via the optimized reaction protocol and the products
isolated in moderate to excellent yields. Electron-rich and
electron-poor aryl chlorides as well as heteroaryl halides could be
alkylated. Likewise, dialkylations such as to 2k are possible. Most
remarkably, also 2-chlorofluorobenzene was coupled in high
isolated yields with n-hexyllithium (2m) and iso- and
cyclopropyllithium (2h and 2i), respectively, showing no indication
of Li/Cl exchange and competing aryne formation. The
magnesium compounds also allowed for a surprising group
tolerance. Nitriles and esters could be coupled (2y, 2z). For the
secondary alkyl reagents, the br:ln ratios were generally good. In
general, more electron poor aryl chlorides with substituents in
meta- and ortho-position formed larger amounts of the linear
product (2d, 2h), as was previously observed by Organ and
coworkers in Negishi coupling reactions.[24a] Most importantly,
sp2-sp2-bond formations are in general easily achieved using the
corresponding aryllithium and magnesium compounds (2r-2u).
Here, isolated yields greater than 80% are obtained also with
aryllithium reagent which were produced by direct lithiation, thus
allowing the synthesis of more complex biaryls from simple
precursors (2t, 2u). Furthermore, aryl bromides were also
successfully coupled (2q, 2w), showing that the protocol is not
limited to the chlorides.
After having established the successful catalysis protocol, we
turned our attention towards the synthesis of substrates useful for
the formation of compounds in materials science and
pharmaceuticals (Figure 7). The synthesis of these compounds
has been described by other routes, sometimes in multiple step
procedures. We were pleased to see that for example 3-
chlorothiophene can be readily alkylated with hexyllithium also in
gram-scale to compound 5, which is a typical precursor for the
synthesis of polythiophenes. Likewise, compound 6, a building
block for the synthesis of Siponimod (brand name Mayzent; a
sphingosine 1-phosphate receptor modulator for treating multiple
sclerosis) could be synthesized in one step from ortho-
trifluoromethylchlorobenzene in 60% isolated yield. This
compound was first prepared via a three-step procedure from
Due to the facile coupling of aryl chlorides at room temperature,
we envisioned that the coupling of aryl bromides should readily
proceed at low temperatures. This would provide the possibility of
two subsequent, different C-C coupling reactions by temperature
control. Such a methodology has recently been reported by
Feringa and Organ.[12d] However, no dialkylation reactions were
possible, due to the reasons highlighted in the introductory section.
Fortunately, 1-bromo-4-chlorobenzene was found to be easily
alkylated at the bromo position at –40 °C. Subsequent warming
to room temperature gave compound 8 in high yields. This shows
that the selectivity of the C-C coupling of bromo-substituted aryl
chlorides can easily be controlled by temperature, thus allowing
step-wise coupling reactions e.g. different C-C couplings[28] (such
as to 2f) or C-C coupling followed by C-N coupling reactions, for
which joYPhos (L3) and its palladium complexes also showed
high activities.[19]
Conclusion
In conclusion, we reported on the first successful and broadly
applicable protocol for the direct sp2-sp3 coupling of aryl chlorides
with alkyllithium reagents. While all the previously reported
catalysts for Murahashi couplings with aryllithium reagents failed
in this transformation, catalysts based on ylide-substituted
phosphines (YPhos) gave good to excellent yields with high
selectivities. The reason for this superior performance is the ability
of the catalyst to undergo the oxidative addition of the aryl chloride
fast enough to prevent side reactions such as lithium halogen
exchange, while also minimizing isomerization due to the ligand
architecture. The breadth of application was shown by means of
a variety of substrates including ortho-fluorinated arenes as well
as heteroaromatics. The catalyst was also shown to be highly
effective in Kumada couplings as well as in gram-scale isolations
and the synthesis building blocks in materials science and
pharmaceutical industry. Overall, the described protocol offers the
direct use of readily available aryl and alkyllithium reagents in
coupling reactions without the need of a further transmetallation
step and thus represents an easily applicable protocol, which
reduces the production of additional salt wastes by sp2-sp3
couplings in a single reaction step.
cyclohexanone including
a
Pd-catalyzed hydrogenation
reaction[25] and a Negishi-type coupling of the aryl bromide at
elevated temperatures with 5 mol% of Pd(PtBu3)2.[26] Additionally,
the introduction of the cyclopropyl group could be performed in
gram-scale to yield compound 7 which is a building block in the
synthesis of Lesinurad, a uric acid salt transport protein 1
(URAT1) inhibitor for the treatment of gout.[27] These examples
demonstrate that the Pd-catalyzed alkylation of aryl chlorides with
alkyllithium reagents could become a viable method for the
synthesis of building blocks in chemical and pharmaceutical
industries.
Acknowledgements
This project has received funding from the European Research
Council (ERC) under the European Union’s Horizon 2020
research and innovation programme (Starting Grant:
YlideLigands 677749) and was supported by RESOLV, funded by
the Deutsche Forschungsgemeinschaft (DFG, German Research
Foundation) under Germany's Excellence Strategy – EXC-2033 -
Projektnummer 390677874. The authors thank UMICORE AG &
Co. KG as well as Albemarle Germany GmbH for the donation of
chemicals and UMICORE AG & Co. KG for additional financial
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202008866
Angewandte Chemie International Edition
RESEARCH ARTICLE
support. Julian Löffler is acknowledged for his assistance in the
synthesis work.
The authors have filed patent WO2019030304 covering the
YPhos ligands and precatalysts discussed, which is held by
UMICORE AG & Co. KG and products will be made commercially
available from.
Conflict of Interest.
Keywords: Ylides • Phosphine ligands • Catalysis •
Organolithium • Cross-coupling reactions
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10.1002/anie.202008866
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
Finally tamed. A general protocol for the Pd-catalyzed coupling of aryl chlorides with alkyllithium reagents is reported. The use of the
ylide-substituted phosphines joYPhos allowed for high selectivities at room temperature, thus minimizing side reaction typical for
these highly reactive reagents. This was demonstrated for a large substrate scope including the gram-scale synthesis of building
blocks for pharmaceutical industry.
Institute and/or researcher Twitter usernames: @ViktoriaGessner
8
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