Nickel-Catalyzed Mono-Selective α-Arylation of Acetone with Aryl Chlorides and Phenol Derivatives

Article abstract of DOI:10.1002/anie.202006826

The challenging nickel-catalyzed mono-α-arylation of acetone with aryl chlorides, pivalates, and carbamates has been achieved for the first time. A nickel/Josiphos-based catalytic system is shown to feature unique catalytic behavior, allowing the highly selective formation of the desired mono-α-arylated acetone. The developed methodology was applied to a variety of (hetero)aryl chlorides including biologically relevant derivatives. The methodology has been extended to the unprecedented coupling of acetone with phenol derivatives. Mechanistic studies allowed the isolation and characterization of key Ni⁰ and Ni^II catalytic intermediates. The Josiphos ligand is shown to play a key role in the stabilization of Ni^II intermediates to allow a Ni⁰/Ni^II catalytic pathway. Mechanistic understanding was then leveraged to improve the protocol using an air-stable Ni^II pre-catalyst.

Full text of DOI:10.1002/anie.202006826

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Accepted Article
Title: Nickel-Catalyzed Mono-Selective α-Arylation of Acetone with Aryl
Chlorides and Phenol Derivatives
Authors: Sary Abou Derhamine, Tetiana Krachko, Nuno Monteiro,
Guillaume Pilet, Johannes Schranck, Anis Tlili, and
Abderrahmane Amgoune
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COMMUNICATION
Nickel-Catalyzed Mono-Selective -Arylation of Acetone with Aryl
Chlorides and Phenol Derivatives
[
a]
[a]
[a]
[b]
[c,
Sary Abou Derhamine, Tetiana Krachko, Nuno Monteiro, Guillaume Pilet, Johannes Schranck,
&
]
Anis Tlili*[a] and Abderrahmane Amgoune*[a]
[
a]
S. A. Derhamine, Dr. T. Krachko, Dr. N. Monteiro, Dr. A. Tlili, Prof. Dr. A. Amgoune
Univ Lyon, Université Lyon 1, Institute of Chemistry and Biochemistry (ICBMS – UMR CNRS 5246), CNRS, INSA, CPE-Lyon
1
Rue victor Grignard, F-69622 Villeurbanne (France)
E-mail : anis.tlili@univ-lyon1.fr; abderrahmane.amgoune@univ-lyon1.fr
[b]
[c]
[&]
Dr. G. Pilet
Univ Lyon, Université Lyon 1, Laboratoire des Multimatériaux et Interfaces (LMI), UMR 5615, CNRS
Bâtiment Chevreul, Avenue du 11 novembre 1918, 69622 Villeurbanne cedex (France)
Dr. J. Schranck
Solvias AG,
Römerpark 2, 4303 Kaiseraugst, Switzerland
Current address: Johnson Matthey, Life Science Technologies
2001 Nolte Drive, West Deptford, NJ 08066, USA
Supporting information for this article is given via a link at the end of the document
Abstract: The challenging nickel-catalyzed mono α-arylation of
acetone with aryl chlorides, pivalates and carbamates has been
achieved for the first time. A nickel/Josiphos-based catalytic system
is shown to feature unique catalytic behavior allowing highly
selective formation of the desired mono α-arylated acetone. The
developed methodology was applied to a variety of (hetero)aryl
chlorides including biologically relevant derivatives. The
methodology has been extended to the unprecedented coupling of
acetone with phenol derivatives. Mechanistic studies allowed the
isolation and characterization of key Ni(0) and Ni(II) catalytic
intermediates. The Josiphos ligand is shown to play a key role in the
stabilization of Ni(II) intermediates to allow a Ni(0)/Ni(II) catalytic
pathway. Mechanistic understanding was then leveraged to improve
the protocol using an air-stable Ni(II) pre-catalyst.
transposition of this technology to nickel catalysis has proven
highly challenging. Recently, only a few examples of nickel
catalyzed -arylation of substituted ketones have been
reported,[ 6 , 7 , 8 ] but arylation of acetone remains yet
undocumented using nickel catalysts. To fill this methodological
gap, we aimed to develop a nickel-catalyzed mono-selective -
arylation of acetone with aryl chlorides as well as phenol
derivatives. The use of nickel catalysts for this challenging
transformation may raise some problems to be overcome. The
main problem to address stands in the documented propensity
of Ni species to readily transmute from Ni(II) to inefficient Ni(I)
species.[ 9 ] The exclusive mono-arylation of acetone is also
challenging. The resulting mono-arylated ketone products
featuring more acidic CH bonds are prone to further arylation,
making the selective mono -arylation of acetone difficult.[ In
the present work, we show that these challenges could be
addressed thanks to the use of an appropriate ancillary ligand,
and report the development of an efficient Ni/Josiphos based
catalytic system for the challenging monoarylation of acetone
10]
Direct functionalization of ubiquitous carbonyl compounds
represents a very powerful class of carbon-carbon bond forming
reactions.[ 1 ] In this respect, significant advances have been
achieved in the development of efficient catalytic methods for
the -arylation of substituted carbonyl compounds, particularly
with transition metal catalysts, via the formation of enolate
intermediates.[1, 2 ] This methodology has proven applicable to
various CH-acidic nucleophiles such as ketones, nitriles, esters,
aldehydes and amides.
(
Scheme 1).
In striking contrast, the functionalization of simple and
readily accessible compounds such as acetone has been under-
developed and appears much more challenging.[3] Most of the
catalytic systems developed for the -arylation of carbonyl
moieties are not active with acetone which bears much less
acidic C–H bonds. To date, only very few efficient catalytic
systems, all based on noble palladium catalysts, have been
recently reported for the selective mono-arylation of acetone,
using aryl halide electrophiles.[4] From an economic point of view,
especially when considering the industrial interest in employing
the monoarylation of acetone for the synthesis of
[5]
Scheme 1. Current development of nickel catalyzed -arylation of acetone.
pharmaceutically relevant substrates, the development of more
sustainable and cost-effective transition metals, such as nickel,
would provide a highly valuable alternative. However, the
1
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The development of this catalytic system relied on
mechanistic studies guided by several isolated key
intermediates. Comparative studies with other nickel complexes
afforded some rationale to the unique reactivity of
nickel/Josiphos combination. From the mechanistic rationale
gained in this study, we were able to develop an air stable
We found to our delight that the combination of Ni(COD)
2
and Josiphos ligands is an efficient catalytic system for this
transformation. Such class of ligands has been recently shown
to be efficient for Ni-catalyzed cross-coupling of small molecules
including ammonia,[12] but they have not been used for nickel-
catalyzed arylation of carbonyl derivatives.
Ni(II)/Josiphos complex for
methodology.
a
simplistic and practical
The best result was obtained when the reaction was carried
out in trifluorotoluene using CsF as a base, 10 mol% of
We initially set out to investigate the feasibility of nickel-
catalyzed -arylation of acetone with chlorobenzene under
various conditions (base, solvents, temperature) (Table 1 and
SI). The reaction was examined using a selection of chelating
phosphine ligands reported to favor Ni(0)/Ni(II) catalysis.[6,8b,11]
2
Ni(COD) and 20 mol% of Josiphos (L1). Under these conditions
the desired product was obtained in 72% isolated yield (Table 1,
entry 5). Remarkably, the mono -arylation product was
obtained selectively without any traces of bis-arylation product.
The yield of the reaction is significantly reduced when an
equimolar amount instead of 2 equiv of ligand L1 is used (Table
1
, entry 12). Decreasing the temperature to 100 °C led to
Table 1. Optimization of reaction conditions.[a]
significant diminution of the yield (Table 1, entry 16). Control
experiment carried out in the absence of the ligand resulted in
no product formation (Table 1, entry 7). More strikingly, all the
other ligands evaluated, including diphosphine type ligands such
as dppf, BINAP and Xantphos, were ineffective under these
reaction conditions.
With optimal conditions in hand, the scope of the reaction
was examined with a wide range of aryl chlorides, including
extended -electron 2-chloronaphtalene, chloroarenes bearing
electron-withdrawing or electron-donating substituents, and
heteroarenes. In each case examined, mono-arylated product
was obtained selectively as the sole product of the reaction
(
Table 2). The arylation of acetone with electron-poor aryl
chlorides could be achieved in moderate to good yields. Para-
and ortho-substituted cyano aryl chlorides were converted
selectively with good yields (2c, 2d). Fluorinated compounds
were also obtained in 30% yield (2e–2g). Full selectivity toward
the
arylation
of
acetone
was
achieved
with
3-
chloroacetophenone affording compound 2h in a very good
isolated yield. Interestingly, employment of electron-rich aryl
chlorides delivered the corresponding products in excellent
yields (2i-2l). The cross-coupling could tolerate pyridines,
quinolines (2m–2o), benzodioxoles (2p), pyrroles (2q), and
azaindoles (2r), allowing the isolation of heteroarylation products
in good to excellent yields. Furthermore, the developed
methodology was also amenable to the functionalization of
biologically relevant aryl chlorides. Indeed, Clofibrate (Atromid-
Yield
(
Entry
Ligand
Solvent
Base
CsF
%)[
b]
L1
L1
1
2
3
4
5
6
7
8
9
1,4-dioxane
Diglyme
DME
43
36
59
62
72
22
0
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
L1
L1
Toluene
®
L1
S ) as well as Fenofibrate (TriCor®), both used for treatment of
PhCF
3
L2
abnormal blood lipid levels, were successfully converted to the
corresponding mono -arylated products with moderate to
excellent yields (2s and 2t).
In order to further emphasize the complementarity of this
nickel-catalyzed process with the precedent methods using
palladium catalysts,[4] the scope of the electrophiles was
expanded to phenol derivatives.[13] Very satisfyingly, a primary
selection of aryl pivalates as well as aryl carbamates were found
to be suitable substrates for arylation providing the
corresponding products in moderate to good yields (X = OPiv,
PhCF
PhCF
PhCF
PhCF
PhCF
PhCF
PhCF
PhCF
PhCF
PhCF
PhCF
3
3
3
3
3
3
3
3
3
3
3
–
dppf
dcype
R)-BINAP
trace
trace
0
(
1
0
1
Xantphos
1
trace
40
2[c]
L1
L1
L1
L1
L1
1
1
3
4
5
Cs
NaOtBu
PO
CsF
2
CO
3
70
1
33
2
2b, 2c, 2n; X = OC(O)NEt , 2c, 2k, 2u). Although the conditions
1
K
3
4
48
have not been optimized with phenol derivatives, it is worth
noting that the coupling reaction is not limited to -extended aryl
substrates.[
1
6[d]
41
14]
[
3
a] Reactions were performed with PhCl (0.3 mmol, 1equiv), acetone (9 mmol,
0 equiv), Base (0.6 mmol, 2 equiv), Ni(COD) (0.1 equiv), ligand (0.2 equiv)
2
and solvent (1 mL). The reaction mixture was stirred, unless otherwise noted,
for 18 hours at 120 °C. [b] Determined by 1H NMR spectroscopy with 1,3,5-
trimethoxybenzene as an internal standard. [c] Reaction performed with 10
mol% of ligand L1. [d] Reaction performed at 100 °C.
2
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COMMUNICATION
Table 2. Substrate scope.[a]
and (ii) the stability and reactivity of Ni(II) intermediates at high
2
temperature (Figure 1). The reaction of Ni(COD) with an excess
of chelating Josiphos ligands, as carried out in our catalytic
protocol, may result in the formation of 4-coordinate
(
2
Josiphos) Ni(0) species, raising the question of its reactivity in
catalysis.[
15]]
Figure 1. Proposed catalytic cycle with potential side reactions.
Using the same conditions as in the catalytic protocol, we
performed the reaction between Ni(COD) and 2 equivalents of
2
the ligand L1 in trifluorotoluene. The reaction occurred at room
temperature and resulted in the rapid precipitation of complex I
[
2
(L1)Ni(COD)]. Consistently, treatment of Ni(COD) with 1.1
equivalent of the ligand also afforded rapid precipitation of
complex I from trifluorotoluene, which was isolated in 88% yield.
The complex was fully characterized in solution and in the solid
state. Both NMR spectroscopic data and X-Ray diffraction
analysis revealed the exclusive formation of a 4-coordinate
nickel(0) species surrounded by the bidentate Josiphos ligand
4
and the COD ligand featuring  coordination (Figure 2A). The
excess of the ligand remained free in the solution, as indicated
3
1
1
by P{ H} NMR analysis of the reaction mixture at room
temperature. However, heating the solution of Ni(COD) and 2
2
equivalents of L1 in trifluorotoluene at 90°C for several hours
resulted in the formation of complex I and a new species
[
3
a] Reactions were performed with ArCl (0.3 mmol, 1 equiv), acetone (9 mmol,
0 equiv), CsF (0.6 mmol, 2 equiv), Ni(COD) (0.1 equiv), ligand (0.2 equiv)
and PhCF (1 mL). The reaction mixture was stirred for 18 hours at 120 °C.
Yields shown are those of isolated products. [b] Yields determined by H NMR
Ni, as indicated by 31P{ H} NMR
1
corresponding to (Josiphos)
2
2
spectroscopy and HRMS analysis, in a 1:1 ratio (Figure S6).[
Then, we evaluated the reactivity of complex I with 4-
chlorobenzonitrile, chlorobenzene and 4-cyanophenyl pivalate.
These smoothly and quantitatively converted to the desired
oxidative addition complexes IIa, IIb and IIc, which have been
isolated in 98%, 65% and 62% yields, respectively, and
structurally characterized (Figure 2B, S2, S3).[16] As expected,
the less active unsubstituted chlorobenzene required heating at
16]
3
1
2 3
spectroscopy using 1,3,5-trimethoxybenzene as internal standard. [c] Cs CO
instead of CsF.
Having examined the scope and the complementarity of
the nickel-catalyzed acetone -arylation methodology, we turned
our attention to the reaction mechanism. We were particularly
interested in delineating the key influence of the ancillary ligand.
Based on previous mechanistic work on nickel-catalyzed cross-
coupling reactions with diphosphine ligands,[6,11a] it is reasonable
to envision a Ni(0)/Ni(II) pathway. However, the feasibility of
such a mechanism for the challenging -arylation of acetone
under the developed catalytic conditions raises some questions
about (i) the exact structure and the reactivity of Ni(0) species
toward aryl chloride and pivalate substrates in the presence of
an excess of coordinating and non-sterically hindered acetone
80 °C to obtain similar yields. Of note, the same results were
observed when the reaction of complex I with chlorobenzene
was carried out in the presence of high excess of acetone,
showing that acetone does not inhibit the oxidative addition
process.[17] Moreover, addition of chlorobenzene to a 1/1 mixture
of I and (L1) Ni(0) led to quantitative formation of the oxidative
2
2
addition product IIb (Figure S7), indicating that (L1) Ni(0) is a
reactive species.[15, 18]
In all cases, the ensuing Ni(II) aryl complexes were found to
be stable both in the solid state and in solution. Remarkably, in
3
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COMMUNICATION
contrast with previously reported Ni(II) aryl complexes featuring
BINAP,[6,19] dppf,[11a,20] or Xantphos[21] ligands, complexes IIa,b,c
are stable in solution even upon heating at 80 °C for several
hours.[ Of note, bisphosphine ligated Ni(II) aryl intermediates
generally require ortho-substituted aryl moieties to feature
enhanced stability,[ 22 ] and very rapid decomposition to Ni(I)
evaluated the catalytic behavior of Ni(0) and Ni(II) species for
the coupling of acetone with 4-chlorobenzonitrile and
chlorobenzene (Figure 2D). In both cases, monitoring of the
16]
31
reactions by P{1H} NMR spectroscopy indicated the presence
of L1Ni(II)-Aryl species as the catalysts resting state.[ Overall,
mechanistic studies support the occurrence of Ni(0)/Ni(II)
catalytic cycle as the main pathway. The influence of the second
equivalent of ligand vs. Ni was analyzed by comparing the
16]
species
is
observed
with
non-substituted
phenyl
moieties.[
11a,19,21]
Very satisfyingly, Nickel(II) complex IIa proved
to be a reactive intermediate for the coupling with acetone
affording the corresponding product in high yield (Figure 2C).
2
catalytic activity of complex I and Ni(COD) /2Josiphos (Figure
2D). While very similar results were obtained with 4-
chlorobenzonitrile, the reaction yield is higher with electron
neutral chlorobenzene with Ni(COD)
2
/2Josiphos (72% yield vs
Ni(0) intermediate,
43% with I). These results indicate that (L1)
2
generated in-situ during catalysis with an excess of ligand, is
catalytically active and suggest that the second equivalent of
ligand may enhances the stability of Ni(0) species.[ In the case
of 4-chlorobenzonitrile, the stability and activity of the Ni(0)
16]
2
species can be improved by the η -coordination of the cyano
group of the substrate.[11a,12a]
Remarkably, the mono -arylation product was obtained
selectively without any traces of bis-arylation product. The
selectivity of the catalytic systems may arise from the sterically
hindered Josiphos ligand that prevent coordination of bulky
ketones to the L1Ni(II)-aryl intermediate. In line with this
hypothesis, the reaction of 4-chlorobenzonitrile with 1-(p-
tolyl)propan-2-one 2k catalyzed by Josiphos/Ni system did not
occur. The catalytic system was also unreactive with a series of
bulky ketones (table S12).[ The nickel(II) complex IIa was also
evaluated as a catalyst under the standard conditions using 10
mol% catalytic loading. Interestingly, compared to nickel(0)
species, the aryl nickel complex IIa presented enhanced
catalytic activity, leading to quantitative coupling reactions with
both aryl chlorides. Based on these observations, the catalytic
cross-coupling of a set of aryl chlorides was re-evaluated using
complex IIa as a pre-catalyst (Scheme 2).[12c] From a practical
point of view, Ni(II) complex IIa offers several advantages: it is
air stable, commercially available and features enhanced
catalytic efficiency. Furthermore, the reaction can proceed at
lower temperature (95% yield at 80 °C), at shorter reaction time
16]
(
65% yield after 1h) and the catalyst loading could be reduced
down to 1 mol% while maintaining substantial activity.[
18]
Figure 2. (A) Synthesis of (L1)Ni(COD) complex
I (left) and molecular
structure of I (right; hydrogen atoms are omitted for clarity). (B) Oxidative
addition of aryl chlorides and pivalate to Ni(0) complex I with and without
excess of acetone (left) and molecular structure of IIc (right; hydrogen atoms
and Et O solvent molecule are omitted for clarity). (C) Isolated reactivity of
2
Ni(II) complex IIa with acetone in the presence of CsF. (D) Comparative
catalytic activities of nickel species.
These results emphasize that chelating Josiphos ligand L1
plays a key role in the stabilization of the Ni(II) aryl intermediates
towards decomposition to Ni(I) species. Therefore, the higher
propensity of Josiphos ligand to stabilize Ni(II) intermediates
compared to other diphosphines such as dppf or BINAP, is likely
to be the key difference to achieve the challenging coupling
reaction of aryl halides and pivalates with acetone. Finally, we
Scheme 2. Improved reaction conditions and catalytic efficiency with air stable
nickel (II) complex IIa. Reactions were performed under the standard
conditions on 0.3 mmol scale. Yields determined by H NMR spectroscopy
1
using 1,3,5-trimethoxybenzene as internal standard.
4
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COMMUNICATION
In conclusion, we present herein an unprecedented
methodology for the selective mono--arylation of acetone with
11006–11009; g) W. C. Fu, C. M. So, W. K. Chow, O. Y. Yuen, F. Y.
(
hetero)aryl chlorides and phenolic derivatives using earth
Kwong, Org. Lett. 2015, 17, 4612–4615; h) W. C. Fu, Z. Zhou, F. Y.
Kwong, Organometallics 2016, 35, 1553–1558. For an example of
palladium-catalysed α-arylation of acetone with aryl mesylate
substrates, see: i) P. G. Alsabeh, M. Stradiotto, Angew. Chem. 2013,
abundant and cost effective nickel complexes as efficient
catalysts. Key to implementing this methodology was the
privileged structure of Josiphos ligand L1. The catalytic system
demonstrated a high compatibility with several functional groups
and the desired products are usually obtained in good to
excellent yields. Interestingly, complex structures could also be
encompassed in the substrate scope. Furthermore, the
methodology has been extended to the unprecedented coupling
of acetone with phenol derivatives. Mechanistic studies allowed
the isolation and characterization of key Ni(0) and Ni(II) catalytic
intermediates. The difference in the reactivity between
Ni/Josiphos systems and other Ni/diphosphine catalyst systems
likely results from enhanced stabilization of Ni(II)-aryl
intermediates with Josiphos ligands. Finally, we demonstrate
that air and thermally stable Ni(II) aryl complexes display
enhanced catalytic activity providing a very practical protocol.
Future developments with this catalytic system are under
investigation in our laboratory.
1
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5]
6]
2
[
For enantioselective reactions with cyclic ketones, see: S. Ge, J. F.
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For reactions with benzylic ketones, see: a) M. Henrion, M. J. Chetcuti,
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21, 3906–3909.
[8]
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[
Acknowledgements
2
Brasacchio, G. W. Brudvig, L. M. Guard, N. Hazari, D. J. Vinyard, J. Am.
Chem. Soc. 2017, 139, 922–936.
Financial support from the Université de Lyon, IDEXLYON
project (ANR-16_IDEX-0005) and the Agence Nationale de la
Recherche (ANR-JCJC-2016-CHAUCACAO) is gratefully
acknowledged. S. A. D. thanks the French Ministry of Higher
[
12] a) R. A. Green, J. F. Hartwig, Angew. Chem. 2015, 127, 3839–3843;
Angew. Chem. Int. Ed. 2015, 54, 3768–3772; b) A. Borzenko, N. L.
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Chem. 2017, 3496–3500; d) P. M. MacQueen, M. Stradiotto, Synlett
Education and Research for
a doctoral fellowship. We
acknowledge Solvias AG for generous donations of Josiphos
ligands L1 (SL-J004-1), L2 (SL-J003-1), SL-J001-1, SL-J505-1
as well as Ni/Josiphos complexes IIa (SK-J004-1n), SK-J003-1n,
SK-J002-1n, SK-J014-1n.
2017, 28, 1652-1656.
[
13] For rare examples of Nickel-catalyzed arylation of substituted ketones
with phenol derivatives, see ref [8].
[
14] -extended systems are generally required in nickel catalyzed C–O
bond cleavage processes, for a general discussion see: M. Tobisu, N.
Chatani, Acc. Chem. Res. 2015, 48, 1717–1726.
Keywords: Synthetic method • Oxidative addition • Nickel
intermediates • Josiphos ligands • Mechanism
[15] For a recent study on the reactions between chelating phosphines and
Ni(COD)
L. Rheingold, R. T. Vanderlinden, J. Louie, Organometallics 2018, 37,
259–3268.
2
, see: A. L. Clevenger, R. M. Stolley, N. D. Staudaher, N. Al, A.
3
[
16] See Supporting Information for details.
[
1]
2]
a) A. Ehrentraut, A. Zapf, M. Beller, Adv. Synth. Catal. 2002, 344, 209–
[
17] The presence of carbonyl moiety has been shown to possibly inhibit the
oxidative addition of aryl halides to Ni(0) species by leading to
thermodynamically stable carbonyl ligated nickel species, see: A. K.
Cooper, D. K. Leonard, S. Bajo, P. M. Burton, D. J. Nelson, Chem. Sci.
2
17; b) D. A. Culkin, J. F. Hartwig, Acc. Chem. Res. 2003, 36, 234–
45; c) F. Bellina, R. Rossi, Chem. Rev. 2010, 110, 1082–1146; d) C. C.
2
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2
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2
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8
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[
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2
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1
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[
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Angewandte Chemie International Edition
10.1002/anie.202006826
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Nickel/Josiphos-based catalytic system is shown to be very efficient for the mono α-arylation of acetone with (hetero)aryl chlorides
and phenols derivatives for the first time. Broad functional group tolerance was observed and the desired products are usually
obtained in good to excellent yields. Mechanistic studies allowed the isolation of catalytic intermediates and provided rationale for the
key role of the ligand.
Institute and/or researcher Twitter usernames: @ICBMSLyon
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