Nickel-catalyzed α-arylation of ketones with phenol derivatives

Article abstract of DOI:10.1002/anie.201403823

The nickel-catalyzed α-arylation of ketones with readily available phenol derivatives (esters and carbamates) provides access to useful α-arylketones. For this transformation, 3,4-bis(dicyclohexylphosphino) thiophene (dcypt) was identified as a new, enabling, air-stable ligand for this transformation. The intermediate of an assumed C-O oxidative addition was isolated and characterized by X-ray crystal-structure analysis. The nickel-catalyzed α-arylation of ketones with readily available phenol derivatives (esters and carbamates) provides access to useful α-arylketones. The use of 3,4-bis(dicyclohexylphosphino)thiophene (dcypt) as an air-stable ligand enables this transformation. The intermediate of an assumed C-O oxidative addition was isolated and characterized by X-ray crystal-structure analysis.

Full text of DOI:10.1002/anie.201403823

Angewandte
Chemie
DOI: 10.1002/anie.201403823
À
C O Activation
Nickel-Catalyzed a-Arylation of Ketones with Phenol Derivatives**
Ryosuke Takise, Kei Muto, Junichiro Yamaguchi,* and Kenichiro Itami*
Abstract: The nickel-catalyzed a-arylation of ketones with
readily available phenol derivatives (esters and carbamates)
provides access to useful a-arylketones. For this transforma-
tion, 3,4-bis(dicyclohexylphosphino)thiophene (dcypt) was
identified as a new, enabling, air-stable ligand for this trans-
À
formation. The intermediate of an assumed C O oxidative
addition was isolated and characterized by X-ray crystal-
structure analysis.
T
he palladium-catalyzed a-arylation of carbonyl compounds
with aryl halides or pseudohalides is of great importance in
organic synthesis, as the resulting a-aryl carbonyl compounds
form the core structures of pharmaceuticals, natural products,
and organic materials.[1] After the independent discovery of
intermolecular a-arylation of ketones with aryl halides by the
groups of Miura, Buchwald, and Hartwig,[2] significant
progress has been made in this field. For example, the
applicable carbonyl substrates have been expanded to esters,
amides, and aldehydes, and the development of improved
catalysts and ligands continues to evolve at a rapid pace.[1a]
The most commonly employed conditions require haloarenes
as arylating agents along with Pd catalysts (Scheme 1). Cu-[3]
and Ni-catalyzed[4] a-arylation reactions of carbonyl com-
pounds with haloarenes have also been reported. The use of
phenol derivatives as arylating agents is of great importance,
because it avoids the requirement for halogenated starting
materials and the subsequent generation of halogen-contain-
ing waste, and because phenols are usually less expensive and
more readily available than haloarenes. In addition, com-
pared with haloarenes, phenols constitute completely differ-
Scheme 1. Catalytic a-arylation of ketones producing useful a-aryl-
ketones.
ent chemical feedstock, including a number of naturally
occurring molecules. Although Pd- or Ni-catalyzed a-aryla-
tion reactions using sulfonates of phenols (Ar-OSO2R, in
which R = CF3, p-tolyl, methyl, and imidazolyl) have been
reported recently (Scheme 1),[5,6] this mode of activation
generates a considerable amount of sulfur-containing waste.
Herein, we report the first a-arylation of ketones with readily
available phenol derivatives, such as aryl pivalates and
carbamates (Ar-OCOR with R = tBu, NMe2), by employing
a unique Ni catalyst.
À
During our development of Ni-catalyzed C H coupling
reactions,[7,8] we discovered a Ni-catalyzed C H/C O cou-
pling of azoles and phenol derivatives, which was highly
À
À
dependent on the choice of the ligand for the effective
[7c,9,10]
À
À
activation of C H and C O bonds in these substrates.
This reaction necessitates the use of 1,2-bis(dicyclohexyl-
phosphino)ethane (dcype) as ligand. Being aware of the
aforementioned challenges in a-arylation chemistry, we then
hypothesized that the similarity of the pKa values of ketones
[*] R. Takise, K. Muto, Prof. Dr. J. Yamaguchi, Prof. Dr. K. Itami
Institute of Transformative Bio-Molecules (WPI-ITbM) an
Graduate School of Science, Nagoya University
Chikusa, Nagoya 464-8602 (Japan)
E-mail: junichiro@chem.nagoya-u.ac.jp
À
À
and azoles could be translated into a C H/C O coupling (a-
arylation) of ketones with simple phenol derivatives using an
appropriate Ni catalyst. To this end, we screened catalysts for
the a-arylation of ketones with phenol derivatives by varying
the ligand on nickel (Table 1).
itami@chem.nagoya-u.ac.jp
Prof. Dr. K. Itami
JST, ERATO, Itami Molecular Nanocarbon Project
Nagoya University
Chikusa, Nagoya 464-8602 (Japan)
We evaluated the efficacy of catalysts (ligands) by the
reaction of 2-phenylacetophenone (1A) and naphthalen-2-yl
pivalate (2a) to produce the corresponding a-arylation
product 3Aa. In early studies, we identified dcype as superior
ligand compared with other ligands such as PCy3, dppf, and N-
heterocyclic carbenes in the present a-arylation.[11] For
example, when a mixture of 1A (1.5 equiv), 2a (1.0 equiv),
and K3PO4 (1.5 equiv) in toluene was heated at 1508C in the
presence of [Ni(dcype)(CO)2][7d,12] (10 mol%), 3Aa was
produced in 25% yield (Table 1, entry 1). We next examined
the effect of cycloalkyl groups in the ligand structure (cyclo-
butyl, L1; cyclopentyl, L2; cycloheptyl, L3), which resulted in
[**] We thank Dr. Yasutomo Segawa and Dr. Hideto Ito for assistance
with X-ray crystal structure analysis. Dr. Keiko Kuwata (ITbM) is
acknowledged for HRMS measurements. We thank Prof. Cathleen
M. Crudden for discussions. This work was supported by the
Funding Program for Next Generation World-Leading Researchers
from JSPS (220GR049 to K.I.), a Grant-in-Aid for Scientific Research
on Innovative Areas “Molecular Activation Directed toward
Straightforward Synthesis” (25105720 to J.Y.), KAKENHI (25708005
to J.Y.) from MEXT, and a JSPS research fellowship for young
scientists (to K.M.). ITbM is supported by the World Premier
International Research Center (WPI) Initiative (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403823.
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Table 2: Substrate scope.[a]
Communications
Table 1: Ni-catalyzed a-arylation of 1A with 2a; screening of catalysts.[a]
Entry
Ni catalyst (mol%)
Yield of 3Aa [%][b]
1
2
[Ni(dcype)(CO)2] (10)
[Ni(L1)(CO)2] (10)
25
61
3
[Ni(L2)(CO)2] (10)
30
4
[Ni(L3)(CO)2] (10)
18
5
6
7
8
[Ni(dcypbz)(CO)2] (10)
[Ni(dcypt)(CO)2] (10)
[Ni(cod)2]/dcypt (10)[c]
[Ni(cod)2]/dcypt (10)[e]
[Ni(cod)2]/dcypt (5)[c]
[Ni(cod)2]/dcypt (1)[c]
[Ni(cod)2]/dcypt (10)[c]
[NiCl2(PPh3)2]/dcypt (10)[c]
46
79
98 (91)[d]
92
9
95
59
92
66
10
11[f]
12
[a] Unless otherwise noted, the reaction conditions were as follows:
1A (0.45 mmol), 2a (0.3 mmol), Ni source (0.03 mmol), ligand
(0.03 mmol), K3PO4 (0.45 mmol), toluene (1.2 mL), 1508C, 24 h.
[b] Yield of 3Aa was determined by NMR analysis. [c] Ni/ligand=1:2.
[d] Yield of isolated product. [e] Ni/ligand=1:1. [f] The reaction was
conducted at 1008C for 96 h.
varying yields of 3Aa (entries 2–4). The use of cyclobutyl
analogue L1 was promising at this stage, but we later found
that there is a lack of substrate generality with this ligand.[13]
Next, the ethylene linker of dcype was changed to benzene
and thiophene bridges (entries 5 and 6). To our delight, the
use of thiophene-bridged diphosphine ligand (dcypt) gave the
best yields (79%, entry 6). Interestingly, we found that the
catalyst prepared in situ from [Ni(cod)2] (cod = 1,5-cyclo-
octadiene) and dcypt gave even better results. For example, in
the presence of 10 mol% [Ni(cod)2] and 20 mol% dcypt, 3Aa
was obtained in 98% yield (91% yield of isolated product,
entry 7). The ratio of Ni/dcypt (1:2) can be modified (1:1,
entry 8), and the reaction proceeded well even when the
amount of catalyst is lowered to 5 mol% (entry 9). At a Ni
loading of 1 mol%, the product yield suffered, but not
tremendously (59%, entry 10). A reaction temperature of
1008C sufficed, but longer reaction times were required
(entry 11). Furthermore, air-stable [NiCl2(PPh3)2] could also
be used as a nickel precursor, albeit with slightly decreased
yield (66%, entry 12). It should be emphasized that unlike
dcype and other related ligands, the thiophene-bridged dcypt
ligand is an air-stable solid.
[a] Unless otherwise noted, the reaction conditions were as follows:
1A (0.45 mmol), 2a (0.3 mmol), [Ni(cod)2] (0.03 mmol), dcypt
(0.06 mmol), K3PO4 (0.45 mmol), toluene (1.2 mL), 1508C, 24 h.
[b] Naphthalen-2-yl dimethylcarbamate (2a’; 0.3 mmol) was used. [c] 4-
Methoxyacetophenone (2D; 0.6 mmol) was used. [d] 3-Acetyl-1-methyl-
indole (1N; 0.5 mmol), (S)-4-(2-(N-benzylpivalamido)-3-methoxy-3-
oxopropyl)phenyl pivalate (2l; 0.25 mmol), [Ni(cod)2] (0.025 mmol),
dcypt (0.05 mmol), K3PO4 (0.38 mmol), toluene (1.0 mL), 1508C, 24 h.
[e] 2D (1.2 mmol) was used.
With optimal conditions in hand, we examined the
substrate scope of the a-arylation of various ketones and
phenol derivatives catalyzed by [Ni(cod)2]/dcypt (Table 2).
2
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When the reaction was conducted with naphthalen-2-yl
dimethylcarbamate (2a’) instead of the corresponding piv-
alate 2a, the resulting product 3Aa was obtained in 77%
yield. A broad range of phenol pivalates, such as those
derived from 6-quinolinol 2b, 6-methoxycarbonyl-2-naphthol
2c, phenol 2d, and 4-functionalized phenols (methoxy 2e,
ester 2 f, and phenyl 2g), could be coupled with 1A to afford
the corresponding a-arylation products 3Ab–3Ag in good
yields.
Ketones for which the substituent on the a-position was
changed from phenyl to methyl (1B) and isopropyl (1C) gave
the desired products 3Ba and 3Ca in moderate yields.
Acetophenone derivatives with a functional group at the C4
position, such as 4-methoxy- (1D), 4-methyl- (1E), 4-
dimethylamino- (1F), 3,4,5-trimethoxy- (1G), 4-fluoro-
(1H), and 4-trifluoromethylacetophenone (1I), were coupled
with naphthalen-1-yl pivalate (2h) to furnish the expected
products 3Dh–3Ih in good to excellent yields. Heteroarylke-
tones based on pyridine (1J), furan (1K), thiophene (1l),
pyrrole (1M), and indole (1N) were tolerated. Aliphatic
ketone 1O was successfully coupled with arylpivalates 2h and
2a to give the corresponding products 3Oh and 3Oa in
moderate yields. Other examples include the coupling of
ketone 1D with various arylpivalates to give products 3Di,
3Dj, 3Dk, and 3Dc. Notably, the coupling reaction was also
successful with complex phenol derivatives, such as amino
acid 2l and estrone 2m.
Figure 1. a) Synthesis of arylnickel(II) pivalate complex 4. b) ORTEP
representation of one of two independent molecules of 4. Hydrogen
atoms are omitted for clarity; thermal ellipsoids are drawn at 50%
probability. Selected bond lengths [ꢀ] and angles [deg]: Ni1–P1=
2.2242(14), Ni1–O1=1.946(4), Ni1–P2=2.1364(14) Ni1–C1=
1.912(5), P1-Ni-P2=90.91(5), P2-Ni1-C1=89.97(15), P1-Ni1-C1=
174.27(16), P2-Ni1-O1=165.49(15), P1-Ni1-O1=94.51(12),
O1-Ni1-C1=85.99(18).
To shed light on the reaction mechanism of this Ni-
catalyzed a-arylation, we carried out experiments to identify
key intermediates. Recently, we reported the first isolation,
structure, and reactivity of an arylnickel(II) pivalate that
bears the dcype ligand, which was obtained by the oxidative
[7f]
À
addition of an aryl C O bond to a nickel complex.
Similarly, we attempted to isolate the Ni/dcypt complex
shown in Figure 1a. The stoichiometric reaction of naphtha-
len-2-yl pivalate (2a, 1.0 equiv) with [Ni(cod)2] (1.0 equiv)
and dcypt (1.0 equiv) in toluene at 1008C successfully gave
arylnickel(II) pivalate complex 4 in 77% yield of isolated
product. It should be noted that the oxidative addition of 2a
to Ni/dcypt is faster than that to Ni/dcype (dcypt: 2 h, dcype:
1
8 h at 1008C, confirmed by H NMR analysis). This observa-
tion correlates to an enhanced reactivity and increased yield
of coupling products in the Ni/dcypt system.
The structure of 4 was confirmed by X-ray crystallo-
graphic analysis (Figure 1b). The X-ray crystal structure
showed that the nickel atom is in a square-planar arrange-
ment surrounded by two phosphines, a carbon atom, and an
oxygen atom. The dcypt ligand was coordinated to the nickel
Scheme 2. Stoichiometric and catalytic a-arylation with 4.
a catalyst (10 mol%). These results are completely consistent
with complex 4 operating as the catalyst, as well as one of the
intermediates in the catalytic cycle. It is also of note that the
presence of a base is critical for this a-arylation reaction.
Taking all these experimental data into consideration, we
propose a mechanism for this a-arylation reaction as shown in
Scheme 3. The reaction proceeds by a Ni0/NiII redox catalytic
atom in a cis configuration, as expected. These results clearly
0
À
show that the C O oxidative addition of 2a to Ni takes place
under the conditions similar to those employed in catalytic
reactions.
As a part of our studies to investigate the reactivity of
complex 4 in oxidative additions, we next examined stoichio-
metric and catalytic reactions of 4 to produce the expected a-
arylation product (Scheme 2). When 4 was treated with
stoichiometric amounts of 1A and K3PO4 at 1208C in toluene,
the a-arylation product 3Aa was obtained in 50% yield.
Similarly, 3Aa was obtained in 82% yield when 4 was used as
cycle, consisting of 1) CO oxidative addition of phenol
0
À
derivative (Ar OR) onto Ni /dcypt complex A to form an
À
À
Ar Ni OR complex B (which is identical to complex 4),
2) C H nickelation of a ketone with base to yield diorgano-
À
nickel(II) complex C, and 3) reductive elimination of the
coupling product 3 and regeneration of Ni0 species A.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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Communications
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Scheme 3. A plausible reaction mechanism.
In summary, we have developed the first a-arylation of
ketones with readily available phenol derivatives (esters and
carbamates) employing Ni catalysts to give useful a-aryl-
ketones without producing halogen- or sulfur-containing
waste. The air-stable 3,4-bis(dicyclohexylphosphino)thio-
phene (dcypt) was discovered as an enabling ligand for this
transformation. A plausible Ni0/NiII catalytic cycle consisting
À
À
of C O oxidative addition, C H nickelation, and reductive
elimination was supported by the stoichiometric reaction that
À
gave the C O oxidative addition complex and its stoichio-
metric and catalytic reactions furnishing the corresponding a-
arylation product. The successful applications to complex
molecules such as amino acid and estrone shows the potential
[8] For a review, see: J. Yamaguchi, K. Muto, K. Itami, Eur. J. Org.
Chem. 2013, 19.
[9] Reviews on C-O activation: a) B.-J. Li, D.-G. Yu, C.-L. Sun, Z.-J.
Shi, Chem. Eur. J. 2011, 17, 1728; b) B. M. Rosen, K. W.
Quasdorf, D. A. Wilson, N. Zhang, A.-M. Resmerita, N. K.
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Z.-J. Shi, Acc. Chem. Res. 2010, 43, 1486; d) T. Mesganaw, N. K.
Garg, Org. Process Res. Dev. 2013, 17, 29; e) S. I. Kozhushkov,
H. K. Potukuchi, L. Ackermann, Catal. Sci. Technol. 2013, 3, 562.
À
of the present reaction. Further developments in C H and
[9,10]
À
C O bond activation,
and the design of a new ligand are
ongoing in our laboratory.
Received: March 30, 2014
Published online: && &&, &&&&
À
[10] For recent examples of C O activation, see: a) M. Tobisu, T.
Shimasaki, N. Chatani, Angew. Chem. 2008, 120, 4944; Angew.
Chem. Int. Ed. 2008, 47, 4866; b) D.-G. Yu, Z.-J. Shi, Angew.
Chem. 2011, 123, 7235; Angew. Chem. Int. Ed. 2011, 50, 7097;
c) K. W. Quasdorf, A. Antoft-Finch, P. Liu, A. L. Silberstein, A.
Komaromi, T. Blackburn, S. D. Ramgren, K. N. Houk, V.
Snieckus, N. K. Garg, J. Am. Chem. Soc. 2011, 133, 6352; d) C.
Zarate, R. Martin, J. Am. Chem. Soc. 2014, 136, 2236; e) A.
Correa, T. Leꢁn, R. Martin, J. Am. Chem. Soc. 2014, 136, 1062.
[11] See the Supporting Information for details.
[12] This complex (CAS No. 141974-66-5) is currently commercially
available from Kanto Chemicals Co. (Product No. 08470-55).
[13] When acetophenone was used as a substrate, the a-arylation
product was obtained only in 6% yield (see the Supporting
Information).
À
Keywords: a-arylation · C O activation · nickel ·
oxidative addition · synthetic methods
.
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4
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Communications
À
C O Activation
R. Takise, K. Muto, J. Yamaguchi,*
K. Itami*
&&&& — &&&&
Nickel-Catalyzed a-Arylation of Ketones
The nickel-catalyzed a-arylation of
thiophene (dcypt) as an air-stable ligand
with Phenol Derivatives
ketones with readily available phenol
derivatives (esters and carbamates) pro-
vides access to useful a-arylketones. The
use of 3,4-bis(dicyclohexylphosphino)-
enables this transformation. The inter-
À
mediate of an assumed C O oxidative
addition was isolated and characterized
by X-ray crystal-structure analysis.
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These are not the final page numbers!