Catalytic α-Arylation of Ketones with Heteroaromatic Esters

Article abstract of DOI:10.1055/s-0036-1589120

Heteroaromatic esters were found to be applicable as an arylating agent for the Pd-catalyzed α-arylation of ketones in a decarbonylative fashion. The use of our in-house ligand, dcypt, enabled this unique bond formation. Considering the ubiquity and low cost of aromatic esters, the present work will allow for rapid access to valuable α-aryl carbonyl compounds.

Full text of DOI:10.1055/s-0036-1589120

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Catalytic α-Arylation of Ketones with Heteroaromatic Esters
Ryota Isshikia
Ryosuke Takiseb
S
Kenichiro Itamib,c
Kei Mutoa
Junichiro Yamaguchi*a
O
P
P
O
O
Ar
+
Ar
Pd
Pd/dcypt
α-Arylation of Ketones with Aromatic Esters
N
N
OPh
Ar
Ar
a Department of Applied Chemistry, Waseda University,
3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555, Japan
junyamaguchi@waseda.jp
b Graduate School of Science and Institute of Transformative
Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa,
Nagoya 464-8602, Japan
c JST-ERATO, Itami Molecular Nanocarbon Project, Nagoya
University, Chikusa, Nagoya 464-8602, Japan
Published as part of the Cluster C–O Activation
Received: 22.07.2017
Accepted after revision: 26.09.2017
Published online: 23.10.2017
A. Arylating agents of Catalytic α-Arylation of Ketones
O
M
R
O
catalyst
base
Emerging: Phenol Derivatives
OSO2R
DOI: 10.1055/s-0036-1589120; Art ID: st-2017-s0573-c
Ar
X
Ar
+
R
Abstract Heteroaromatic esters were found to be applicable as an ary-
lating agent for the Pd-catalyzed α-arylation of ketones in a decarbon-
ylative fashion. The use of our in-house ligand, dcypt, enabled this
unique bond formation. Considering the ubiquity and low cost of
aromatic esters, the present work will allow for rapid access to valuable
α-aryl carbonyl compounds.
Classic: Haloarenes
Hal
OPiv
Ar
Ar
Ar
R = CF3, tolyl, etc.
Pd
Pd
Ni
Ni
Key words α-arylation, aromatic esters, decarbonylative coupling,
palladium, heteroarenes, ketones
B. This Work: α-Arylation of Ketones with (Hetero)aromatic Esters
Base
O
α-Aryl carbonyls are fundamental building blocks be-
cause they can be transformed into a range of pharmaceuti-
cals, agrochemicals, and π-conjugated materials. To access
these compounds, transition-metal-catalyzed α-arylation
of carbonyls with haloarenes is one of the most powerful
and straightforward methods (Scheme 1, A).1 Inspired by
pioneering developments by Miura,2 Buchwald,3 and
Hartwig,4 catalytic α-arylations have resulted in a rapid de-
velopment of new catalysts and ligands. Due to these ef-
forts, α-arylations of esters, amides, and aldehydes, as well
as enantioselective reactions are now feasible. Further-
more, recent research has enabled the use of alternative
arylating agents such as aryl triflates5 and tosylates6. Our
group has also contributed to this area by developing a re-
action using aryl pivalates or carbamates under the influ-
ence of an original nickel catalyst, Ni-dcypt (dcypt: 3,4-
bis(dicyclohexylphosphino)thiophene).7–9 Shortly thereaf-
ter, the Martin group reported an elegant enantioselective
α-arylation of ketones with aryl pivalates by using a Ni-
BINAP catalytic system.10
Ar
Ar
O
R
Claisen Condensation
Predominant Pathway
O
O
+
Ar
R
OPh
O
Pd Catalyst
R
Aromatic Esters
Decarbonylative
α-Arylation
Scheme 1 Catalytic α-arylation of ketones using a variety of arylating
agents
ing aromatic esters and amides, which led to the realization
of a variety of unique bond formations.13,14 Arenecarboxyl-
ates are present in a wide range of commercially available
building blocks and synthetic intermediates, thus, their use
in coupling can give rise to new opportunities involving un-
conventional synthetic strategies. However, the use of es-
ters for α-arylation is anticipated to be challenging because,
the predominant reactivity of esters, led to a Claisen con-
densation to give diketones, particularly in the presence of
a strong base (Scheme 1, B). Thus, development of an effi-
cient catalyst is essential to conduct the reaction under
mild basic conditions. Herein, we report our efforts to
Meanwhile, our group11 and others12 have extensively
studied the development of catalytic coupling reaction us-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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R. Isshiki et al.
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develop a catalytic α-arylation of ketones with aromatic es-
ters.
products 3Ab and 3Ac. Both o-methyl- and p-methyl-sub-
stituted acetophenones 2d and 2e were converted into α-
arylated ketones 3Ad and 3Ae in 59% and 47% yields, re-
spectively. For reasons that are currently unclear, the addi-
tion of a catalytic amount of MeOH slightly increased the
reaction yields of 3Ad, 3Ae, and 3Af. Substrates 2g–i bear-
ing electron-donating groups were capable of coupling with
1A. Electron-poor aromatics tended to diminish the reac-
tion efficiency as showcased in 3Aj.16 Ketones with an ami-
no group (2k) as well as a heteroarene (2l) were compatible
with the transformation. Although the yield is not satisfac-
tory, the reaction of 2-acetyl fluorene (2m) provided the α-
arylated product 3Am without arylation at the C9 position
of fluorene. This result indicated that deprotonation by a
base is unlikely to be involved in the reaction mechanism
because fluorenes have more acidic C–H (pKa = 22.6 in
DMSO) than the α-C–H of ketones (cf. acetophenone, pKa = 24.7
in DMSO).17,18 An aliphatic ketone, pinacolone (2n) was also
reactive under the present conditions to afford 3An in ac-
ceptable yield. Possibly due to the mild nature of the pres-
ent catalytic system, Claisen condensation products were
not observed in any of these reactions.
Our study began with the optimization of reaction con-
ditions using 1A and 2a as coupling partners (Table 1). To
our delight, the desired α-arylation occurred smoothly us-
ing catalytic Pd(OAc)2/dcypt in the presence of CsF (Table 1,
entry 1). Similar ligands such as dcype and L1 were found to
be effective for this reaction, albeit generating 3Aa in lower
yields (Table 1, entries 2 and 3). P(n-Bu)3 and N-heterocyclic
carbenes (NHCs), which are effective ligands for a decarbo-
nylative biaryl coupling11c as well as the functionalization of
inert C–heteroatom bonds,12r,15 only resulted in recovered
starting materials (Table 1, entries 5 and 6). The effect of
CsF was intriguingly significant, as poor yields of product
were obtained when no additives or other alkali fluorides
were used (Table 1, entries 6–8; see Supporting Information
for details). The use of K2CO3 delivered the desired product
3Aa in moderate yield, however, the decomposition of 1A to
the corresponding carboxylic acid and Claisen condensation
product was also accelerated, probably due to its higher ba-
sicity compared to CsF (Table 1, entry 9). With these results,
we identified our ‘standard’ reaction conditions:
Pd(OAc)2/dcypt/CsF in toluene at 150 °C.
Next, the scope of aromatic esters is summarized in
Scheme 3. The electronic properties of the aryl moiety at the
C2 position of the quinoline were not influential. A fluorine
atom on the quinoline was tolerated in the reaction. Unfor-
tunately, this reaction was found to be specific to 2-phenyl-
With these optimized conditions in hand, we examined
the scope of ketones for this reaction (Scheme 2). Simple ar-
omatic ketones such as acetophenone (2b) and 2-acet-
onaphthone (2c) reacted well, furnishing the corresponding
Table 1 Optimization of Reaction Conditionsa
Pd(OAc)2 (5.0 mol%)
ligand (X mol%)
O
O
O
OMe
additive (2.0 equiv)
+
N
OMe
N
toluene (0.80 mL)
150 °C, 18 h
OPh
Ph
Ph
1A (0.20 mmol)
2a (2.0 equiv)
3Aa
S
S
P
P
P
P
P
P
dcypt
L1
dcype
Entry
Ligand (X mol%)
Additive
GC yield (%)b
1
2
3
4
5c
6
7
8
9
dcypt (10)
dcype (10)
L1(10)
CsF
69
44
56
0
CsF
CsF
P(n-Bu)3 (20)
ICy·HBF4(10)
dcypt (10)
dcypt (10)
dcypt (10)
dcypt (10)
CsF
CsF
0
none
KF
trace
11
1
NaF
K2CO3
41
a Conditions: 1A (0.20 mmol), 2 (2.0 equiv), Pd(OAc)2 (5.0 mol%), dcypt (10 mol%), CsF (2.0 equiv), toluene (0.80 mL), 150 °C, 18 h.
b GC yield was determined by using n-decane as an internal standard.
cNaOt-Bu (25 mol%) was added.
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O
Pd(OAc)2 (5.0 mol%)
dcypt (10 mol%)
CsF (2.0 equiv)
O
O
Ar
Ar
+
N
N
toluene (1.6 mL)
150 °C, 18 h
OPh
Ph
1A (0.40 mmol)
Ph
2 (2.0 equiv)
3
O
O
O
OMe
N
N
N
Ph
Ph
Ph
3Aa: 69%
3Ab: 50%
3Ac: 68%
O
O
O
Me
N
N
N
Me
MeO
3Ad: 59%b
3Ae: 47%b
3Af: 38%b
Ph
Ph
Ph
OMe
OMe
OMe
O
O
O
OMe
N
N
N
OMe
MeO
Ph
Ph
Ph
3Ag: 47%
3Ah: 67%
3Ai: 66%
O
O
O
F
NMe2
S
N
N
N
Ph
Ph
Ph
3Aj: 44%
3Ak: 68%
3Al: 49%
O
O
N
N
Ph
Ph
3Am: 38%
3An: 44%
Scheme 2 Scope of ketones. a Reagents and conditions: 1A (0.40 mmol), 2 (2.0 equiv), Pd(OAc)2 (5.0 mol%), dcypt (10 mol%), CsF (2.0 equiv), toluene
(1.6 mL), 150 °C, 18 h. b MeOH (30 mol%) was added.
4-quinoline carboxylates, and other related (hetero)aromat-
ic esters resulted in poor reaction yields (see Supporting In-
formation).
In conclusion, we have developed a Pd-catalyzed decar-
bonylative α-arylation of (hetero)aromatic esters with ace-
tophenones.19 A ligand effect for this reaction was observed,
wherein our in-house diphosphine ligands could deliver the
Pd(OAc)2 (5.0 mol%)
dcypt (10 mol%)
CsF (2.0 equiv)
O
O
O
OMe
Ar
+
OMe
Ar
O
toluene (1.6 mL)
150 °C, 18 h
OPh
1 (0.40 mmol)
2a (2.0 equiv)
3
F
O
O
OMe
MeO
OMe
OMe
N
N
N
Ph
3Ba: 47%
3Ca: 63%
3Da: 65%
F3C
Scheme 3 Scope of aromatic esters. Reagents and conditions: 1 (0.40 mmol), 2a (2.0 equiv), Pd(OAc)2 (5.0 mol%), dcypt (10 mol%), CsF (2.0 equiv),
toluene (1.6 mL), 150 °C, 18 h.
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desired coupling product. Although this is the first example
of catalytic α-arylation using aromatic esters in a decarbon-
ylative manner, there is obviously room for improvement,
particularly regarding the scope of the ester. Further meth-
odology and a mechanistic study toward the development
of synthetically valuable ester-based coupling reaction are
ongoing in our laboratory.
Lett. 2016, 18, 5106. (f) Okita, T.; Kumazawa, K.; Takise, R.;
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(12) Representative examples from other groups. For esters, see:
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Halima, T.; Zhang, W.; Yalaoui, I.; Hong, X.; Yang, Y.-F.; Houk, K.
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Soc. Rev. 2017, 46, 5864. (b) Dander, J. E.; Garg, N. K. ACS Catal.
2017, 7, 1413. (c) Liu, C.; Szostak, M. Chem. Eur. J. 2017, 23,
7157. (d) Correa, A.; Cornella, J.; Martin, R. Angew. Chem. Int. Ed.
2013, 52, 1878.
Funding Information
This work was supported by JSPS KAKENHI Grant Number
JP16H01011, JP16H04148 (to J.Y.) and JP17K14453 (to K.M.), the ERA-
TO program from JST (to K.I.), the Early Bird Program of Waseda Uni-
versity (to K.M.), and a JSPS research fellowship for young scientists
(to R.T.). ITbM is supported by the World Premier International Re-
search Center (WPI) Initiative, Japan.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589120.
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References and Notes
(1) For selected reviews and accounts, see: (a) Bellina, F.; Rossi, R.
Chem. Rev. 2010, 110, 1082. (b) Johansson, C. C. C.; Colacot, T. J.
Angew. Chem. Int. Ed. 2010, 49, 676. (c) Noväk, P.; Martin, R.
Curr. Org. Chem. 2011, 15, 3233. (d) Culkin, D. A.; Hartwig, J. F.
Acc. Chem. Res. 2003, 36, 234.
(2) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1740.
(14) Representative examples of coupling reactions of aliphatic
esters, see: (a) Edwards, J. T.; Merchant, R. R.; McClymont, K. S.;
Knouse, K. W.; Qin, T.; Malins, L. R.; Vokits, B.; Shaw, S. A.; Bao,
D.-H.; Wei, F.-L.; Zhou, T.; Eastgate, M. D.; Baran, P. S. Nature
2017, 545, 213. (b) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.;
Edwards, J. T.; Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.;
Baran, P. S. Science 2016, 352, 801.
(15) Nakamura, K.; Tobisu, M.; Chatani, N. Org. Lett. 2015, 17, 6142.
(16) 3Aj was obtained as a mixture caused by ipso-substitution of
fluoride by phenoxide during the reaction. See Supporting
Information for details.
(3) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(4) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382.
(5) (a) Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 4,
4053. (b) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008,
130, 195.
(6) (a) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11818. (b) Hesp, K. D.; Lundgren, R. J.; Stradiotto, M.
J. Am. Chem. Soc. 2011, 133, 5194. (c) Ackermann, L.; Mehta, V. P.
Chem. Eur. J. 2012, 18, 10230. (d) Alsabeh, P. G.; Stradiotto, M.
Angew. Chem. Int. Ed. 2013, 52, 7242.
(17) (a) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.;
McCollum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006.
(b) Bordwell, F. G.; Cornforth, F. J. J. Org. Chem. 1978, 43, 1763.
(18) Zhang, J.; Bellomo, A.; Creamer, A. D.; Dreher, S. D.; Walsh, P. J.
J. Am. Chem. Soc. 2012, 134, 13765.
(19) Representative Experimental Procedure for Catalytic Decar-
bonylative α-Arylation of Ketones with Aromatic Esters
A 20 mL glass vessel equipped with J. Young® O-ring tap con-
taining a magnetic stirring bar and CsF (121.5 mg, 0.80 mmol,
2.0 equiv) was dried with a heatgun in vacuo and filled with N2
gas after cooling to room temperature. To this vessel were
added aromatic phenyl ester 1A (130.2 mg, 0.40 mmol, 1.0
equiv), aryl ketones 2 (120.1 mg, 0.80 mmol, 2.0 equiv),
Pd(OAc)2 (4.49 mg, 0.020 mmol, 5.0 mol%), and dcypt (19.1 mg,
0.040 mmol, 10 mol%). The vessel was vacuumed and refilled N2
gas three times. To this was added toluene (1.6 mL). The vessel
was sealed with O-ring tap and then heated at 150 °C for 18 h in
a 9-well aluminum reaction block with stirring. After cooling
(7) (a) Takise, R.; Muto, K.; Yamaguchi, J.; Itami, K. Angew. Chem. Int.
Ed. 2014, 53, 6791. (b) Koch, E.; Takise, R.; Studer, A.;
Yamaguchi, J.; Itami, K. Chem. Commun. 2015, 51, 855.
(8) (a) Muto, K.; Hatakeyama, T.; Yamaguchi, J.; Itami, K. Chem. Sci.
2015, 6, 6792. (b) Takise, R.; Itami, K.; Yamaguchi, J. Org. Lett.
2016, 18, 4428. (c) Steinberg, D. F.; Turk, M. C.; Kalyani, D. Tetra-
hedron 2017, 73, 2196.
(9) Dcypt is currently commercially available from KANTO Chemi-
cal Co. (Product No. 05806-65).
(10) Cornella, J.; Jackson, E. P.; Martin, R. Angew. Chem. Int. Ed. 2015,
54, 4075.
(11) For examples from our group, see: (a) Amaike, K.; Muto, K.;
Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 13573.
(b) Meng, L.; Kamada, Y.; Muto, K.; Yamaguchi, J.; Itami, K.
Angew. Chem. Int. Ed. 2013, 52, 10048. (c) Muto, K.; Yamaguchi,
J.; Musaev, D. G.; Itami, K. Nat. Commun. 2015, 6, 7508.
(d) Amaike, K.; Itami, K.; Yamaguchi, J. Chem. Eur. J. 2016, 22,
4384. (e) Muto, K.; Hatakeyama, T.; Itami, K.; Yamaguchi, J. Org.
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the reaction mixture to room temperature, the mixture was
passed through a short silica gel pad with EtOAc as an eluent.
The filtrate was concentrated and the residue was purified by
Isolera® (hexane/EtOAc = 5:1) afforded 3Aa as a white solid
(97.5 mg, 69% yield).
J = 8.8 Hz, 1 H), 7.73–7.67 (m, 2 H), 7.53–7.41 (m, 4 H), 6.95 (d, J
= 8.8 Hz, 2 H), 4.71 (s, 2 H), 3.86 (s, 3 H). 13C NMR (101 MHz,
CDCl3): δ = 194.7, 163.9, 157.0, 148.5, 142.0, 139.5, 130.8, 130.5,
129.4, 129.3, 129.2, 128.7, 127.5, 126.7, 126.5, 123.5, 120.7,
114.0, 55.5, 42.1. ESI-HRMS: m/z calcd for C24H20NO2 [M + H]+:
354.1489; found: 354.1487.
1
Compound 3Aa: H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 8.8
Hz, 1 H), 8.11 (d, J = 8.8 Hz, 2 H), 8.04 (d, J = 8.8 Hz, 2 H), 7.86 (d,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E