From acetone metalation to the catalytic α-arylation of acyclic ketones with NHC-nickel(II) complexes

Article abstract of DOI:10.1039/c4cc00959b

Air-stable N-heterocyclic carbene-nickel(II) complexes at concentrations as low as 1 mol% exhibit high catalytic activity for the α-arylation of acyclic ketones and join a highly restricted list of nickel catalysts for this key reaction. Mechanistic investigations suggest a radical pathway. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00959b

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From acetone metalation to the catalytic
a-arylation of acyclic ketones with
NHC–nickel(II) complexes†
Cite this: Chem. Commun., 2014,
50, 4624
Received 5th February 2014,
Accepted 10th March 2014
Mickael Henrion,a Michael J. Chetcuti*a and Vincent Ritleng*ab
¨
DOI: 10.1039/c4cc00959b
www.rsc.org/chemcomm
Air-stable N-heterocyclic carbene–nickel(II) complexes at concentrations demanding conditions (10 mol% catalyst) were required to
as low as 1 mol% exhibit high catalytic activity for the a-arylation of observe respectable yields.8
acyclic ketones and join a highly restricted list of nickel catalysts for this
key reaction. Mechanistic investigations suggest a radical pathway.
In this context, we recently reported that cyclopentadienyl
(Cp) nickel–N-heterocyclic carbene (NHC) complexes are able to
activate C–H bonds of labile acetonitrile9,10 and acetone11 ligands
The palladium-catalyzed a-arylation of ketones has been the in the presence of a strong base. In the latter case, the reaction
method of choice to access the a-aryl carbonyl motifs found in resulted in the formation of a rare example of nickel–acetonyl
many organic compounds that possess interesting pharmacological complex 3,12–14 as well as that of a unique example of dinickel–
and biological properties.1 Nevertheless, from the perspective of its oxyallyl complex 4 resulting from the double base-promoted
use in commercial syntheses, it suffers from the high costs of nickelation of acetone (Scheme 1).
palladium and its associated ligands. The search for less expensive
catalytic systems, is therefore of interest.2
The isolation of such nickel C-bound enolate complexes,
which are important intermediates in a-arylation reactions of carbonyl
Whilst copper has also received some attention,1,2 the first-row derivatives,1 coupled with the fact they could be protonated back from
counterpart of palladium, nickel, is an attractive surrogate to the 4 to 3,11 and from 3 to 1,15 suggested that this family of CpNi(II)–NHC
latter in terms of its abundance and low cost.3 Moreover, thanks complexes might be used as catalyst precursors in such C(sp2)–C(sp3)
notably to its easy access to multiple oxidation states and to its couplings through C–H bond cleavage.
increased nucleophilic character, it might allow a different and
Initial studies focused on the coupling of propiophenone
complementary reactivity.4 Notwithstanding the fact that direct with 4-bromotoluene in toluene at 110 1C in the presence of
a-arylation of ketone and ester enolates were first reported with 1.5 equiv. of NaOtBu as a base and of 5 mol% of complexes 1, 5,
this metal in the 1970s,5,6 nickel systems have, since then, barely 6, 7 or 8 as possible catalytic precursors (Fig. 1). Under these
been studied. Moreover, almost all of the few reported examples conditions, iodide complex 5, which we have shown to be
involve the highly air sensitive Ni(COD)2 complex with relatively highly active in the Suzuki coupling,16 proved to be totally inert
high loadings – typically ranging from 5 to 10 mol% – and excess (Table 1, entry 2). In contrast, complex 1,17 which bears the more
ligand.7 In addition, these systems only achieve the arylation of bulky 1,3-dimesitylimidazol-2-ylidene (Mes2NHC), together with
cyclic ketones or esters. Thus, to date, we are aware of only one
example using a well-defined nickel(II) catalyst precursor (for the
arylation of acyclic ketones). Nevertheless, here too, relatively
a
´
´
Laboratoire de Chimie Organometallique Appliquee, UMR CNRS 7509,
´
`
´
´
Ecole europeenne de Chimie, Polymeres et Materiaux, Universite de Strasbourg,
25 rue Becquerel, 67087 Strasbourg, France. E-mail: vritleng@unistra.fr,
michael.chetcuti@unistra.fr; Tel: +33 3 6885 2797
b
´
´
Institut d’Etudes Avancees de l’Universite de Strasbourg (USIAS),
´
´ ´
5 allee du General Rouvillois, 67083 Strasbourg, France
† Electronic supplementary information (ESI) available: Synthesis and full char-
acterization of complexes 7, 9 and 10, experimental details of all control experi-
ments, catalytic procedures, spectroscopic data and 1H and 13C{1H} spectra of all
a-arylation products. CCDC 983811 (7) and 983818 (10). For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c4cc00959b
Scheme 1 Base-promoted acetone metalation to give the nickel C-bound
enolate complexes 3 and 4.
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Table 2 a-Arylation of ketones with arylhalides catalyzed by 6a
Yieldb
Aryl halide Coupling product Time (h) (%)
Fig. 1 Selected half-sandwich NHC–nickel complexes.
Entry Ketone
1
Table 1 a-Arylation of propiophenone with 4-bromotoluene catalyzed
by complexes 1, 5–8a and [Ni{(iPr2Ph)2NHC}(PPh3)Cl2]8
24
24
24
24
73
o1c
92
2
3
4
Entry
Catalyst (mol%)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
1 (5)
5 (5)
6 (5)
7 (5)
8 (5)
6 (3)
6 (1)
6 (1)
24
24
24
24
24
24
24
48
24
25
0
65
60
61
78
60
497
65
65
5
6
24
48
10
17
[Ni{(iPr2Ph)2NHC}(PPh3)Cl2] (10)
a
Reaction conditions: propiophenone (1.2 mmol), 4-bromotoluene
(1 mmol), NaOtBu (1.5 mmol), 1, 5–8 (1–5 mol%) in toluene (3 mL)
b
at 110 1C. Yields determined by GC; average value of two runs.
7
24
89
a chloride instead of an iodide ligand, gave an encouraging 25% GC
yield after 24 h of reaction (entry 1). Switching to the even more bulky
1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene [(iPr2Ph)2NHC]
containing complex 618 allowed a further yield enhancement to
65% (entry 3). However, using the cationic (ESI†) and Cp*19
derivatives of 6 yielded no further improvement (entries 4 and 5).
This was encouraging, as this catalytic activity superseded
the results reported using the only other known well-defined
Ni(II) catalyst precursor for this reaction, the related trans-
[Ni{(iPr2Ph)2NHC}(PPh3)Cl2] (entry 9).8 Nevertheless, since 6 is
known to catalyze dehalogenation of aryl halides under similar
conditions,18 and this process may compete with a-arylation, we
subsequently decided to test whether the reaction could be further
optimized by decreasing the catalyst loading. Satisfyingly, lowering the
catalyst loading to 3 mol% allowed a significant yield improvement to
78% (entry 6), and reducing this even further to 1 mol% allowed us to
observe a full conversion after 48 h of reaction (entry 8). The latter
observation also clearly demonstrated that the active catalytic species
is long-lived. These results make the 6–NaOtBu mixture in toluene20
the most efficient nickel-based system reported to date for the
a-arylation of ketone enolates in terms of pre-catalyst loading.6–8
With these optimized conditions in hand, we then examined the
scope of the a-arylation reaction (Table 2), by reacting propiophe-
none with a series of haloarenes (entries 1–12) on one hand, and by
reacting 4-bromotoluene with various ketones (entries 13–23) on the
other. Propiophenone was arylated in good to excellent yields with
iodo- and bromo-substituted benzene or p-toluene (entries 1, 3
and 4). However, it does not react with chloro derivatives
(entry 2). This allowed us to obtain 2-( p-chlorophenyl)propiophenone
selectively in 89% yield from 4-iodo-chlorobenzene (entry 7).
The presence of electron-withdrawing or -donating groups on
8
9
24
48
53
93
10
11
24
48
52
85
12
24
42
13
14
24
48
66
89
15
24
71
16
17
24
48
84
92
18
19
24
48
13
21
20
24
o1c
21
22
24
48
68
79
23
24
55d
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Table 2 (continued)
Yieldb
Aryl halide Coupling product Time (h) (%)
Entry Ketone
24
24
o1e
Scheme 2 Preparation of possible intermediates in the a-arylation pro-
cess: the nickel C-bound enolate complex 9 and the nickel–phenyl
complex 10.
a
Reaction conditions: ketone (1.2 mmol), aryl halide (1 mmol), NaOtBu
(1.5 mmol), 6 (3 mol%) in toluene (3 mL) at 110 1C for 24 or
b
c
48 h. Isolated yields; average value of two runs. Yield determined
by GC; average value of two runs. A 2 :1 mixture of 2-( p-tolyl)-4-methyl-
pentan-3-one and 2-( p-tolyl)-2-methyl-pentan-3-one was obtained. Aldol
d
e
condensation products were observed.
the aryl halide seems to have little influence, and moderate yields
were obtained with both electron-rich and electron-poor derivatives
after 24 h of reaction (entries 8, 10 and 12). Running the reactions
for 48 h, nevertheless, allowed us to obtain excellent yields with
p-methoxy and p-tert-butyl bromobenzene (entries 9 and 11).
Finally, the sterically encumbered 2-bromotoluene gave poor
yields, even after 48 h of reaction (entries 5 and 6).
Fig. 2 Molecular structure of 10 showing all non-H atoms. Ellipsoids are
shown at the 50% probability level and key atoms are labelled. Selected
distances (Å) and angles (1) with esd’s in parenthesis: Ni–C1, 1.875(2); Ni–
C2, 1.908(2); Ni–Cpcent, 1.785; C1–Ni–C2, 95.35(9); C1–Ni–Cpcent, 136.45
and C2–Ni–Cpcent, 128.18.
On the other hand, 4-bromotoluene gave high to excellent yields
with various ketones, including substituted propiophenones and
dialkyl ketones. Thus, p-chloro-propiophenone, the electron-
poor p-fluoro-propiophenone and the electron-rich p-methoxy-
propiophenone were arylated in good to excellent yields in
24 and/or 48 h (entries 13–17). In addition, the reaction of
3-pentanone with 4-bromotoluene gave the monoarylated product
selectively with up to 79% isolated yield (entries 21 and 23). This latter
result is rather surprising and contrasts with the 2 : 1 mixture of
coupling products obtained with 2-methyl-pentan-3-one (entry 23). As
observed with propiophenone and 2-bromotoluene (entries 5 and 6),
the more sterically encumbered iso-butyrophenone gave poor yields
(entries 18 and 19). The cyclic indanone yielded no conversion at all
(entry 20), probably also due to steric reasons. This latter result makes
our system complementary to Ni(COD)2/ligand-based catalysts, which
only achieve the a-arylation of cyclic ketones.7 Finally, acetophenone
gave only aldol condensation products (entry 24), as observed by
Matsubara et al. with [Ni{(iPr2Ph)2NHC}(PPh3)Cl2].8
in 63% yield (eqn (2), Scheme 2). Both complexes were fully
characterized, and an X-ray diffraction study confirmed the
structure of 10 (Fig. 2 and ESI†).
To assess the viability of complexes 9 and/or 10 as intermediate(s)
in the catalytic process, we conducted a series of experiments
depicted in Scheme 3. The stoichiometric reaction of 9 with
4-bromotoluene in toluene at reflux gave a complicated mixture
from which a violet complex, which we have identified as
[Ni(Mes2NHC)BrCp] (see ESI†), was isolated in 21% yield
(eqn (1), Scheme 3). The latter would mostly result from the
dehalogenation of 4-bromotoluene, as propiophenone was
the major organic product, but could also partly result from
the coupling of the C-bound propiophenone enolate and
To get an insight into the mechanism, we first checked
whether the a-arylation process was the result of a true homo-
geneous catalysis by conducting the coupling of propiophenone
and 4-bromotoluene in the presence of 100 equiv. of Hg (relative
to nickel – see ESI†). No inhibition was observed, and thus a
process catalyzed by nickel particles is unlikely.21 This being
established, we then checked whether a nickel C-bound enolate
analogue of 3 could be prepared by the base-induced metalation of
propiophenone. Thus, complex 1 was treated with propiophenone
in the presence of KOtBu, and [Ni(Mes2NHC){CH(CH3)C(O)Ph}Cp]
9 was isolated as an air- and thermally-sensitive reddish solid in
45% yield (eqn (1), Scheme 2).‡ Additionally, the phenyl deri-
vative of 1, [Ni(Mes2NHC)PhCp] 10, was also prepared as a
possible intermediate of the arylation process by reaction of 1
with phenyllithium. It was isolated as air-stable brown crystals
Scheme 3 Assessment of the potential of complexes 9 and/or 10 as
intermediate(s) in the catalytic process.
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Notes and references
‡ The (iPr2Ph)2NHC analogue of 9 (i.e.: the C-bound propiophenone
enolate derivative of 6) could not be isolated, most probably due to
steric reasons.
1 C. C. C. Johansson and T. J. Colacot, Angew. Chem., Int. Ed., 2010, 49, 676.
2 G. Danoun, A. Tlili, F. Monnier and M. Taillefer, Angew. Chem., Int.
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3 (a) C. E. Tucker and J. G. de Vries, Top. Catal., 2002, 19, 111;
(b) P. Enghag, Encyclopedia of the elements, Wiley, Weinheim, 2004.
4 R. H. Crabtree, The Organometallic Chemistry of Transition Metals,
John Wiley and Sons, New York, 5th edn, 2009.
Scheme 4 Effect of radical inhibitors and initiators.
4-bromotoluene, as traces of the expected coupling product were
identified by 1H NMR spectroscopy in one organic fraction.
To verify this latter hypothesis, we then conducted the coupling
of propiophenone and 4-bromotoluene in the presence of a
catalytic amount of 9; an 11% yield of 1-phenyl-2-( p-tolyl)-
propan-1-one was measured by GC (eqn (2), Scheme 3). Thus,
complex 9 is a possible intermediate in the nickel-catalyzed
a-arylation, but the higher yield observed using 1 as a catalyst
precursor (Table 1, entry 1) suggests that, at least, some of the
product is formed via another intermediate and/or via a different
type of mechanism.
To assess the possibility of 10 being an intermediate in the
a-arylation process, we reacted it, under stoichiometric condi-
tions, with propiophenone in the presence of NaOtBu in
toluene at reflux (eqn (3), Scheme 3). No coupling product
was observed and most of the propiophenone was recovered,
thus ruling out 10 as an intermediate.
5 (a) M. F. Semmelhack, R. D. Stauffer and T. D. Rogerson, Tetrahedron Lett.,
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V. Ritleng, L. F. Veiros and M. J. Chetcuti, Organometallics, 2011, 30, 3400.
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12 Similar acid–base reactions usually generate O-bound nickel–eno-
late complexes: (a) D. Matt, M. Huhn, J. Fischer, A. De Cian,
¨
W. Klaui, I. Tkatchenko and M. C. Bonnet, J. Chem. Soc., Dalton
´
Trans., 1993, 1173; (b) J. Campora, C. M. Maya, P. Palma,
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pathway.22 Experiments performed in the presence of radical sca-
vengers supported this hypothesis. Thus, the addition of 1 equiv. of
TEMPO or galvinoxyl completely inhibited the reaction (Scheme 4).
Moreover, a metal-free version of the reaction using AIBN as a
radical initiator – although far less efficient – indeed led to some
a-arylation (Scheme 4, and Table S3 – ESI†). Consequently, we believe
that the principal mechanism at work in this nickel-catalyzed
a-arylation process is of a radical nature, and that a C-bound
ketone enolate derivative of 6, if involved, has only a minor role.
In summary, we have demonstrated that the inexpensive
and easy-to-handle complex, [Ni{(iPr2Ph)2NHC}ClCp] 6, is an
efficient pre-catalyst for the a-arylation of acyclic ketones, and
the most productive nickel-based catalyst reported to date.
Mechanistic evidence suggests a radical pathway. However, a
nickel C-bound ketone enolate intermediate generated by base-
promoted metalation may also be involved. Current investiga-
tion to achieve the a-arylation of nitriles is underway.
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ment with potassium or lithium enolates: E. R. Burkhardt,
R. G. Bergman and C. H. Heathcock, Organometallics, 1990, 9, 30.
14 For an example of equilibrium between nickelacyclic C- and O-bound
´
enolates: (a) J. Campora, C. M. Maya, P. Palma, E. Carmona,
´
E. Gutierrez-Puebla and C. Ruiz, J. Am. Chem. Soc., 2003, 125, 1482;
´
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15 In CDCl3, a pure sample of 3 slowly converted to 1: V. Ritleng,
unpublished results.
16 A. M. Oertel, V. Ritleng and M. J. Chetcuti, Organometallics, 2012, 31, 2829.
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´
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18 R. A. Kelly III, N. M. Scott, S. Dıez-Gonzalez, E. D. Stevens and
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20 Comment: Various other solvents and bases were screened with 6,
but the combination of NaOtBu and toluene was found to be the
best: see Table S2, ESI†.
21 J. A. Widegren and R. G. Finke, J. Mol. Catal. A, 2003, 198, 317.
22 For other nickel-catalyzed C–C bond-forming reactions involving a
radical intermediate, see for instance: S. L. Zultanski and G. C. Fu,
J. Am. Chem. Soc., 2013, 135, 624.
´
We are grateful to the Universite de Strasbourg and the
CNRS for their financial help. The Agence Nationale de la
Recherche is also acknowledged for its support to V.R. and
the doctoral fellowship of M.H. (ANR 2010 JCJC 716 1; SBA-15-
NHC-NiCat).
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