General and mild Ni0-catalyzed α-arylation of ketones using aryl chlorides

Article abstract of DOI:10.1002/chem.201406457

A general methodology for the α-arylation of ketones using a nickel catalyst has been developed. The new well-defined [Ni(IPr)(cin)Cl] (1c) pre-catalyst showed great efficiency for this transformation, allowing the coupling of a wide range of ketones, including acetophenone derivatives, with various functionalised aryl chlorides. This cinnamyl-based Ni-N-heterocyclic carbene (NHC) complex has demonstrated a different behaviour to previously reported NHC-Ni catalysts. Preliminary mechanistic studies suggest a Ni⁰/Ni^II catalytic cycle to be at play.

Full text of DOI:10.1002/chem.201406457

DOI: 10.1002/chem.201406457
Communication
&
Cross-Coupling Reactions
General and Mild Ni0-Catalyzed a-Arylation of Ketones Using Aryl
Chlorides
Josꢀ A. Fernꢁndez-Salas,[a] Enrico Marelli,[a] David B. Cordes,[a] Alexandra M. Z. Slawin,[a] and
Steven P. Nolan*[a, b]
has received significant attention as a palladium surrogate,
Abstract: A general methodology for the a-arylation of
ketones using a nickel catalyst has been developed. The
and has been employed in a plethora of transformations.[8,9]
Since Buchwald and co-workers described the enantioselective
new well-defined [Ni(IPr*)(cin)Cl] (1c) pre-catalyst showed
nickel-catalyzed a-arylation of a-substituted butyrolactones,[10]
great efficiency for this transformation, allowing the cou-
nickel has become a valuable (and possibly viable) alternative
pling of a wide range of ketones, including acetophenone
to the established palladium catalytic systems for the a-aryla-
derivatives, with various functionalised aryl chlorides. This
tion of ketones. In spite of this early result, nickel–phosphine
cinnamyl-based Ni–N-heterocyclic carbene (NHC) complex
systems have shown narrow reaction scope,[11] as only a-substi-
has demonstrated a different behaviour to previously
tuted cyclic ketones were found to be suitable substrates.[10,11]
reported NHC-Ni catalysts. Preliminary mechanistic studies
suggest a Ni0/NiII catalytic cycle to be at play.
Two examples of well-defined NHC-based (NHC: N-heterocyclic
carbenes) nickel complexes have been reported as active pre-
catalysts for this transformation.[12] Despite the improvement
that these protocols provide, both suffer from several
a-Arylated carbonyl compounds are recognizable structural
motifs in biologically active molecules and are of interest to
the pharmaceutical industry.[1] Therefore, over the last few
years significant efforts have been devoted to the develop-
ment of more efficient and milder methodologies for their
preparation. For example, the use of transition-metal catalysts
has allowed one to dispense with the use of stoichiometric
amounts of toxic reagents and harsh reaction conditions typi-
cally required by more conventional approaches.[2] Since initial
reports of the intermolecular palladium-catalyzed a-arylation
of ketones by the groups of Miura,[3] Buchwald[4] and Hartwig,[5]
this reaction has rapidly become one of the most powerful
and atom-economical strategies for the formation of CÀC
bonds.[1d,6] Moreover, this reaction generates little side-
products and makes use of simple and widely available
substrates.[1d,6b]
shortcomings, particularly regarding a narrow reaction scope
limited to the coupling of aryl bromide derivatives with
propiophenone.
Very recently, Itami and co-workers have described
a
challenging a-arylation of ketones with aryl pivalates using
a [Ni(cod)2]/biphosphine catalytic system.[13] However, the use
of high catalyst loading (10 mol%), a large excess of the ligand
(20 mol%) and high temperatures (1508C), hamper the general
use of this methodology. Studies conducted by Ritleng and
co-workers showed that the [Ni(NHC)CpCl]-catalyzed (NHC=N-
heterocyclic carbene; Cp=cyclopentadienyl) reaction might
proceed via a radical pathway.[12b] However, the mechanism
regarding the nickel-catalyzed a-arylation of ketones is not yet
clearly defined and might, in the end, be dependent on the Ni
source used.
Taking into account the state-of-the-art, we took up the
challenge of developing a general nickel-catalyzed a-arylation
of ketones using easily accessible, widely available and
inexpensive aryl chlorides, under significantly milder reaction
conditions. Our approach made use of our prior experience
with more easily initiated palladium cinnamyl NHC-based
catalysts[14] and of the reported high activity displayed by
[(dppf)Ni(cin)Cl] in the Suzuki–Miyaura cross coupling.[15] We
describe here the synthesis of [Ni(NHC)(cin)Cl] complexes and
their application in the a-arylation of ketones, in a general and
efficient nickel-catalyzed procedure for this transformation
using aryl chlorides.
Although palladium-based catalysts are very active in this
transformation, the development of new catalytic systems that
use less expensive and more earth-abundant metals is a crucial
challenge for modern chemists. Despite the importance of this
challenge, only a handful of non-palladium systems have been
described for this purpose.[7] In recent years, nickel catalysis
[a] Dr. J. A. Fernꢀndez-Salas,+ E. Marelli,+ Dr. D. B. Cordes, Prof. A. M. Z. Slawin,
Prof. Dr. S. P. Nolan
EaStCHEM, School of Chemistry, University of St Andrews
North Haugh, St Andrews, Fife, KY16 9ST (UK)
E-mail: snolan@st-andrews.ac.uk
The synthesis of [Ni(NHC)(cin)Cl] complexes with SIPr, IPr,
IPr* and IPr*OMe as NHC ligands,[16] was accomplished following
the protocol described by Sigman for the IPr derivative.[17] This
straightforward, one-pot procedure provided the desired Ni
complexes in good yields (Scheme 1).
[b] Prof. Dr. S. P. Nolan
Chemistry Department, College of Science
King Saud University, Riyadh 11451 (Saudi Arabia)
[+] Both authors contributed equally.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406457.
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Table 1. Nickel-catalyzed a-arylation of propiophenone optimization.[a]
Entry
1 [mol%]
Conv. [%][b]
Yield [%][c]
1
2
3
4
5
6
7
8[e]
[Ni(IPr)(cin)Cl] (1a) (3 mol%)
[Ni(SIPr)(cin)Cl] (1b) (3 mol%)
[Ni(IPr*)(cin)Cl] (1c) (3mol%)
[Ni(IPr*OMe)(cin)Cl] (1d) (3 mol%)
[Ni(IPr*OMe)(cin)Cl] (1d) (1 mol%)
[Ni(IPr*)(cin)Cl] (1c) (1 mol%)
[Ni(IPr*)(cin)Cl] (1c) (2 mol%)
[Ni(IPr*)(cin)Cl] (1c) (3 mol%)
35
30
99
99
70
80
92
99
–
–
92 (90)[d]
89
–
–
84
80
Scheme 1. Synthesis of the well-defined [Ni(NHC)(cin)Cl] (1)complexes.
All complexes (1) were fully characterized by NMR spectros-
copy, and their purity was confirmed by elemental analysis. To
unequivocally establish the atom connectivity in 1, the
molecular structures of 1c[18] and 1d[19] (see the Supporting
Information) were elucidated by X-ray diffraction analysis of
single crystals (Figure 1).
[a] Reaction conditions: propiophenone (2a) (1 mmol, 2 equiv), 4-chloro-
toluene (3a) (0.5 mmol, 1 equiv), NaOtBu (1 mmol, 2 equiv), 1 (mol%), in
toluene (2.5 mL). [b] Conversion of the 4-chlorotoluene (3a), as measured
by GC. [c] NMR yields using dimethyl malonate as internal standard.
[d] Isolated yield in parentheses. [e] Using 4-bromotoluene as coupling
partner.
active than the latter (entries 5 and 6). Under the optimized
conditions, 3 mol% of 1c were sufficient to obtain full
conversion (entry 3 vs. 7). Notably, the use of p-bromotoluene
as coupling partner consistently gave lower yields compared
to reactions involving its chloride analogue (entry 3 vs. 8).
These results suggest that a different mechanism might be in-
volved in the NHC cinnamyl-based nickel-catalyzed reaction
compared to the previously reported Cp-based family of com-
plexes, which are not reactive with aryl chlorides.[12b] Under the
optimized reaction conditions, a wide variety of ketones (2)
and aryl chlorides (3) were examined (Table 2). Firstly, several
aryl chorides with varied electronic and steric properties were
tested. Electron-donating groups in either para or meta posi-
tion led to the arylated ketones in excellent isolated yields (4a,
4b and 4g), whereas electron-withdrawing groups such as CF3
(4c) proved to be less suitable for this transformation. Hin-
dered aryl chlorides (4e and 4 f) were coupled less efficiently,
although reasonable yields (60% and 68%, respectively) could
be obtained. Additionally, 1-chloronaphtalene led to the de-
sired product in 77% (4j). These coupling reaction outcomes
represent the best results so far when using hindered aryl
chlorides for the nickel-catalyzed a-arylation of ketones, even
when aryl bromides are considered as coupling partners.[12]
Ketone- and methylsulfone-containing aryl chlorides, despite
their relative sensitivity towards basic conditions, led to the
corresponding aryl ketones with 89% and 65% yields, respec-
tively (4i, 4d). A benzodioxole chloride derivative reacted very
efficiently (4h), and nitrogen- or sulfur-containing heterocycles
were tolerated (4k and 4l). The nature of the ketone was also
studied. Electron-rich propiophenone derivatives proved suita-
ble for this transformation (4m, 79%). Moreover, the analo-
gous cyclohexanone derivative led to the formation of 4n in
high yield. In contrast, electron-poor ketones proved inade-
quate and no conversion to the desired product was observed
using p-CF3-substituted propiophenone (see the Supporting In-
formation). To our delight, aliphatic ketones were also suitable
Figure 1. Molecular structure of 1c. Selected bond lengths [ꢃ] and angles
[8]: Ni1ÀCl1 2.1684(9), Ni1ÀC72 1.997(3), Ni1ÀC74 2.123(4), Ni1ÀC1 1.903(3),
Ni1ÀC73 1.982(4); Cl1-Ni1-C1 96.16(8), Cl1-Ni1-C74 96.66(10), C1-Ni1-C74
70.58(14).
Complete optimization studies defining best solvent, base
and temperature for the coupling of propiophenone (2a) and
p-chlorotoluene (3a) as model reaction, using the nickel cata-
lyst bearing the IPr* ligand (1c) were next performed (see Sup-
porting Information for details). The use of NaOtBu in toluene
provided optimum results, giving full conversion at 808C after
16 h. It should be noted that 2 equivalents of NaOtBu are re-
quired, as lower amounts of base reduce the yield. Then, the
role of the ligand (1a–d) was tested (Table 1). Less sterically
demanding NHCs (IPr and SIPr) afforded low conversion to the
desired product in both cases (entries 1 and 2). The bulkier
IPr*-based ligands (IPr* and IPr*OMe) were required to obtain
full conversion (entries 3 and 4). Only at low catalyst loadings
(1 mol%) was it possible to observe a difference in the reactivi-
ty between IPr* and IPr*OMe, the former being slightly more
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for the reaction, leading to the desired mono-arylated product
in good yield (4o). These results encouraged us to further
extend the scope of the system and test the challenging mono
arylation of acetophenone derivatives. We were pleased to find
that electron-rich acetophenones were well tolerated, giving
good (67%) and very good yields (86%) for the p-NMe2 (4q)
and p-OMe (4p) substituted derivatives, respectively, without
any observable formation of bis-arylated products. However,
non-activated acetophenones led to complex mixtures (see the
Supporting Information). An electron-rich naphthalene deriva-
tive led successfully to the desired adduct (4t). p-OMe aceto-
phenone was also tested in the presence of electron-rich aryl
chlorides (4r and 4u), showing good efficiency. The coupling
with
a hindered 2,6-disubstituted chloroarene was also
possible (4s).
Several experiments were carried out in order to gain insight
into the reaction mechanism. Stoichiometric reactions involv-
ing [Ni(IPr*)(cin)Cl] (1c) and NaOtBu, in the presence
([Eq. (1)]) or absence of chlorotoluene ([Eq. (2)]), did
not proceed, and in both cases the starting materials
were recovered. To our delight the stoichiometric re-
action of [Ni(IPr*)(cin)Cl] with propiophenone and
NaOtBu, in the absence of the aryl chloride ([Eq. (3)]),
gave, as major species (84% isolated yield), the re-
gioisomeric mixture (75:25) of the allylic substitution
products between the propiophenone nucleophile
and the cinnamyl ligand 5 and 5’.
Table 2. Substrate scope for the [Ni(IPr*)(cin)Cl] catalyzed a-arylation of ketones.[a]
The isolation of these products (5 and 5’), together
with the fact that chloride derivatives performed
comparably to bromide analogues, suggest to us
that the activation of the NiII pre-catalyst takes place
via a nucleophilic attack of the enolate formed in
situ,[20] generating a Ni0 active species, which may in-
volve the formation, if only as a transient species, of
[(h6-toluene)Ni(IPr*)] under catalytic conditions.[21] Ox-
idative addition leads to NiII intermediate A, which
transmetalates in the presence of another molecule
of enolate (B), allowing the final reductive elimination
to achieve the CÀC bond formation (Scheme 2).
Further investigations are currently ongoing in our
laboratory to completely elucidate the mechanism of
this coupling reaction using nickel catalysts and to
expand the scope of this reaction to other carbonyl-
containing compounds.
In summary, we have described, for the first time,
a general nickel-catalyzed methodology for the a-
arylation of ketones using aryl chlorides as coupling
partners at relatively low loadings of Ni (3 mol%).
Various coupling partners, including challenging
acetophenone derivatives and functionalized aryl
chlorides, were successfully coupled. In addition, stoi-
chiometric reactions permitted the isolation of the
pre-catalyst activation products (5 and 5’), strongly
suggesting that a Ni0/NiII catalytic cycle is responsible
for the unique reactivity displayed by this catalyst.
[a] Reaction conditions: ketone (2) (1 mmol, 2 equiv), chloroarene (3) (0.5 mmol,
1 equiv), NaOtBu (1 mmol, 2 equiv), 1c (3 mol%), in toluene (2.5 mL). Isolated yields.
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EPSRC and King Saud University for funding. We thank the
EPSRC NMSSC in Swansea for mass spectrometric analyses.
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Keywords: aryl chlorides · cross-coupling reactions · ketone
arylation · N-heterocyclic carbenes · nickel · synthetic methods
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Received: December 12, 2014
Published online on && &&, 0000
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COMMUNICATION
A NiÀN-heterocyclic carbene pre-cata-
lyst was shown to be very active in the
a-arylation of ketones, coupling a broad
range of aryl chlorides and ketones. The
isolation of the activation product
resulting from the nucleophilic attack of
the enolate onto the nickel pre-catalyst
suggests a Ni0/NiII catalytic cycle is at
play.
&
Cross-Coupling Reactions
J. A. Fernꢀndez-Salas, E. Marelli,
D. B. Cordes, A. M. Z. Slawin, S. P. Nolan*
&& – &&
General and Mild Ni0-Catalyzed a-
Arylation of Ketones Using Aryl
Chlorides
Chem. Eur. J. 2015, 21, 1 – 5
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ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ