CuCl2-Mediated Oxidative Intramolecular α-Arylation of Ketones with Phenolic Nucleophiles via Oxy-Allyl Cation Intermediates

Article abstract of DOI:10.1002/asia.202001032

α-Functionalization of ketones in an umpolung fashion can be achieved by nucleophilic addition to the oxy-allyl cation intermediate. However, applicable carbon nucleophiles are limited to ones with high nucleophilicity. Additionally, introduction of a lea

Full text of DOI:10.1002/asia.202001032

CHEMISTRY
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Accepted Article
Title: CuCl2-Mediated Oxidative Intramolecular α-Arylation of Ketones
with Phenolic Nucleophiles via Oxy-Allyl Cation Intermediates
Authors: Takuto Mochimatsu, Yusuke Aota, Taichi Kano, and Keiji
Maruoka
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10.1002/asia.202001032
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CuCl2-Mediated Oxidative Intramolecular α-Arylation of Ketones
with Phenolic Nucleophiles via Oxy-Allyl Cation Intermediates
Takuto Mochimatsu,[a] Yusuke Aota,[a] Taichi Kano*[a] and Keiji Maruoka*[a,b,c]
[a]
T. Mochimatsu, Dr. Y. Aota, Prof. Dr. T. Kano
Department of Chemistry
Graduate School of Science
Kyoto University
Sakyo, Kyoto, 606-8502, Japan
E-mail: kano@kuchem.kyoto-u.ac.jp
Prof. Dr. K. Maruoka
Graduate School of Pharmaceutical Sciences
Kyoto University
Sakyo, Kyoto 606-8501, Japan
School of Chemical Engineering and Light Industry
Guangdong University of Technology
Guangzhou 510006, China
[b]
[c]
Supporting information for this article is given via a link at the end of the document.
Abstract: α-Functionalization of ketones in an umpolung fashion can
be achieved by nucleophilic addition to the oxy-allyl cation
intermediate. However, applicable carbon nucleophiles are limited to
ones with high nucleophilicity. Additionally, introduction of a leaving
group to the α-position of ketone substrates is required beforehand.
Herein, we report the CuCl2-mediated oxidative intramolecular α-
arylation of ketones with less nucleophilic phenolic moieties as carbon
nucleophiles via α-chlorination of ketones and the subsequent
generation of the oxy-allyl cation intermediates, giving ketones with a
quaternary carbon center at the α-position.
α-Arylated carbonyl compounds are found in natural products and
pharmaceuticals and considered as one of important building
blocks.1 Among them, ketones with a quaternary carbon center at
the α-position are valuable synthetic intermediates, while their
synthesis is quite difficult.2 To date, a number of synthetic
methods have been developed to prepare such motifs.3 In general,
α-arylketones are prepared from a nucleophilic enolate and an
electrophilic arylating agent (Scheme 1a, upper).4,5
In an umpolung strategy, on the other hand, addition of a
nucleophilic aromatic compound to an electrophilic α-carbon of
ketones has been significantly less investigated (Scheme 1a,
lower).6 Recently, a number of nucleophilic additions to the oxy-
allyl cation intermediates derived from ketones have been
investigated.7,8 In the presence of a base or an acid, ketones
having a leaving group at the α-position can be converted to highly
reactive electrophilic oxy-allyl cation intermediates, which are
known to react with various nucleophiles. However, less
nucleophilic aromatic compounds such as phenol derivatives are
not suitable nucleophiles for this type of reaction.
Scheme 1. Strategies for α-Arylation of Ketones via Oxy-allyl Cation
Intermediates.
1
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Recently, we have reported the Brønsted acid-catalyzed
intramolecular α-arylation of ketones with phenolic nucleophiles
via oxy-allyl cation intermediates (Scheme 1b).6k However, ketone
substrates require a hydroxy group as a leaving group at the α-
position to generate the oxy-allyl cation intermediate, and the
difficulty in their synthesis limits the synthetic utility of this
transformation. In this context, we became interested in
developing an intramolecular α-arylation of simpler ketones via
introduction of a leaving group in-situ and the subsequent
generation of the oxy-allyl cation intermediate. Since copper(II)
halides are known to be an α-halogenating agent of ketones as
well as a Lewis acid,9 such tandem sequence might be realized
(Scheme 1c). Herein, we describe CuCl2-mediated oxidative
intramolecular α-arylation of ketones with a tethered phenolic
nucleophile. In the present reaction, a chroman core with a
quaternary carbon center is constructed, which is an important
structural motif in bioactive molecules.10
We first investigated the oxidative intramolecular α-arylation of
cyclopentanone 1a bearing a tethered phenoxy group with 2.4
equiv of oxidant in trifluoroethanol (CF3CH2OH) and
dichloroethane (DCE) at 80 °C (Table 1). When halogenating
agents such as CuBr2, CuCl2, NCS, 2,3,4,5,6,6-hexachloro-2,4-
cyclohexadien-1-one (4) were employed as oxidant, respectively,
the desired spirocyclic ketone 2a was obtained in low to good
yields (entries 1–4). In these cases, formation of enone 3a was
observed. The reaction of 1a with CuCl2 in the presence of 1N
HCl gave 2a in a slightly decreased yield (entry 5). The addition
of 2,6-tBu2-pyridine completely shut down the reaction (entry 6).
Use of DCE as solvent resulted in no reaction, and the presence
of CF3CH2OH was shown to be crucial for the present reaction
(entries 7 and 8).11 When the reaction was performed under an
oxygen atmosphere with the expectation that the in-situ
generated CuCl would be reoxidized, 2a was obtained in a slightly
increased yield (entry 10).9d
10[f,g]
CuCl2
-
76
6
[a] All reactions were performed on a 0.1 mmol scale in 1.0 mL of solvent. [b]
Use of 2.4 eq. of additive. [c] Determined by 1H NMR analysis using 1,1,2,2-
tetrachloroethane as an internal standard.[d] CF3CH2OH as solvent. [e] DCE as
solvent. [f] CF3CH2OH/DCE (5:1) as solvent. [g] Performed under 1 atm of O2.
We next investigated the scope of cyclopentanones bearing a
variety of phenolic nucleophiles (Table 2).12 The reaction of
ketone having an electron-rich para-methylphenyl group afforded
2b in good yield. Introduction of a para-methoxy group led to a
significant decrease in yield (33%) because of the oxidation of the
product 2c. The shorter reaction time resulted in an increase in
yield (50%). When an electron withdrawing Br group was
introduced to the para-position, 2d was obtained in low yield
(11%) due to the undesired enone formation and the remaining α-
chloroketone. Interestingly, the addition of 1.2 equiv of ZnCl2 was
effective for increasing the yield of 2d (44%). The present α-
arylation was not applicable to a phenolic nucleophile having a
cyano group, probably because of the decreased electron density
of the aromatic ring and further deactivation by protonation (2e).
The meta-substitution led to the formation of single regioisomers
(2f–2i). The yield of 2i was drastically improved in the presence
of a catalytic amount of FeCl2. Incorporation of ortho-methyl group
proved to be slightly detrimental, giving 2j in 48% yield. When a
2-naphthoxy group was introduced, the reaction proceeded at the
sterically congested 1-position of the naphthyl group exclusively
(2k). The substrate having a branched tether gave 2l in low yield
as a mixture of diastereomers.
Table 1. Optimization of Reaction Conditions.[a]
Table 2. Substrate Scope of Phenolic Nucleophiles.[a]
Entry
1
Oxidant
CuBr2
CuCl2
NCS
Additive[b]
2a [%][c]
45
3a [%][c]
-
16
14
17
<1
7
2
-
72
3
-
14
4
4
-
25
5
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
1N HCl aq.
62
6
2,6-tBu2-pyridine
0
0
7[d]
8[e]
9[f]
-
-
-
59
7
0
2
72
8
2
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[a] All reactions were performed on a 0.1 mmol scale in 1.0 mL of solvent. [b]
Performed under 1 atm of O2. [c] Performed for 24 h. [d] ZnCl2 (1.2 eq.) was
added. [e] FeCl2 (20 mol%) was added. [f] NiCl2 (1.2 eq.) was added. [g] Using
a diastereomer mixture (1.1:1) as starting material.
3
4
5
6
5a
HCl
90
96
5b[c]
5b[c]
5b[c]
CuCl2
CuCl, HCl
HCl
94
99
We then investigated the substrate scope of ketone moiety
and the results are summarized in Table 3. A cyclic ketone having
a larger ring size was well tolerated (2m). While the reaction of 4-
piperidone derivatives did not proceed, the addition of 2.4 equiv
of FeCl2 led to the formation of the desired products 2n and 2o in
modelate yields. In the presence of 20 mol% of ZnCl2, an acyclic
ketone also provided the arylation product 2p, albeit in low yield.
[a] All ractions were performed on a 0.1 mmol scale in 1.0 mL of solvent. [b]
Determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as an internal
standard. [c] Using a mixture of 5b/5a (16:1) as starting material.
A plausible mechanism is illustrated in Scheme 2. In the
presence of copper(II) chloride, ketone 1m undergoes
chlorination to generate α-chloroketones 5a and 5b along with two
molecules of copper(I) chloride and an equivalent of HCl.9
Formation of the enol or the copper enolate and the acid-
mediated-elimiation of chloride ion generate the key oxy-allyl
cation intermediate. Finally, nucleophilic addition of the phenolic
moiety to the electrophilic α-carbon gives the spirocyclic ketone
2m.
Table 3. Substrate Scope of Ketones.[a]
[a] All reactions were performed on a 0.1 mmol scale in 1.0 mL of solvent. [b]
NiCl2 (20 mol%) was added. [c] FeCl2 (2.4 eq.) was added. [d] ZnCl2 (20 mol%)
was added.
To gain mechanistic insight into the present α-arylation of
ketones, arylation of α-chloroketones 5 was performed as shown
in Table 4. Under the standard reaction conditions using CuCl2,
the reaction of α-chloroketone 5a proceeded to afford the
arylation product 2m in excellent yield (entry 1). The reaction with
CuCl and HCl, which can be generated in the course of the
present reaction, also gave 2m in moderate yield (entry 2).
Without copper chloride, the reaction proceeded smoothly (entry
3). Use of α'-chloroketone 5b led to the formation of 2m under the
same conditions (entries 4–6). These results imply that the
identical oxy-allyl cation intermediate would be generated in-situ
from 5a and 5b as the electrophilic species before the nucleophilic
addition of the phenolic moiety and that the regioselectivity in the
chlorination does not affect the present intramolecular arylation.
Scheme 2. Proposed Mechanism.
In conclusion, we have developed the CuCl2-mediated
oxidative intramolecular α-arylation of ketones with the tethered
phenolic nucleophiles via α-chlorination and the subsequent
generation of the oxy-allyl cation intermediates. This study has
demonstrated that ketones having no leaving group can be
employed as the oxy-allyl cation precursors, expanding the utility
of the umpolung α-functionalization of ketones.
Table 4. α-Arylation of α-Chloroketones.[a]
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP26220803, JP18H01975, and JP20H04815 (Hybrid Catalysis).
Y.A. is grateful for Fellowships for Young Scientists from the
Japan Society for the Promotion of Science (JSPS).
Entry
5
Acid
Yield [%][b]
1
2
5a
5a
CuCl2
97
63
CuCl, HCl
3
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Conflict of Interest
The authors declare no conflict of interest.
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Keywords: umpolung • halogenation • arylation • quaternary
stereocenters • ketones
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4
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having a nitrogen tether instead of the oxygen linkage.
5
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10.1002/asia.202001032
Chemistry - An Asian Journal
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Intramolecular α-arylation of ketones in an umpolung fashion was achieved through the addition of tethered phenolic nucleophiles
to the electrophilic oxy-allyl cation intermediates which could be formed from the in-situ generated α-chloroketones, allowing the
formation of ketones bearing an all carbon quaternary center at the α-position.
6
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