Br?nsted Acid-Catalyzed Intramolecular α-Arylation of Ketones with Phenolic Nucleophiles via Oxy-Allyl Cation Intermediates

Article abstract of DOI:10.1002/ejoc.202000169

Nucleophilic addition to the oxy-allyl cation intermediate has emerged as a promising methodology for functionalization of the α-position of carbonyl compounds in an umpolung fashion. However, a structure of available carbon nucleophiles to trap the catal

Full text of DOI:10.1002/ejoc.202000169

A Journal of
Accepted Article
Title: Brønsted Acid-Catalyzed Intramolecular α-Arylation of Ketones
with Phenolic Nucleophiles via Oxy-Allyl Cation Intermediates
Authors: Yusuke Aota, Yuki Doko, Taichi Kano, and Keiji Maruoka
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10.1002/ejoc.202000169
European Journal of Organic Chemistry
COMMUNICATION
Brønsted Acid-Catalyzed Intramolecular α-Arylation of Ketones
with Phenolic Nucleophiles via Oxy-Allyl Cation Intermediates
Yusuke Aota,[a] Yuki Doko,[a] Taichi Kano*[a] and Keiji Maruoka*[a,b,c]
Abstract: Nucleophilic addition to the oxy-allyl cation intermediate
has been emerged as a promising methodology for functionalization
of the α-position of carbonyl compounds in an umpolung fashion.
However, a structure of available carbon nucleophiles to trap the
catalytically generated oxy-allyl cation has been limited to highly
nucleophilic ones. Herein, we report the Brønsted acid-catalyzed α-
arylation of ketones employing less explored phenolic nucleophiles as
carbon nucleophiles in the oxy-allyl cation catalysis, affording ketones
bearing an all carbon quaternary center at the α-position.
According to Mayr's nucleophilicity parameters (N), their N values
range from 7.26 to 2.83 and 10.38 to 5.21 for substituted indoles
and silyl enol ethers, respectively (Figure 1b).11 Additionally,
pyrrole (N = 4.63) and alkenyl- or alkynyl tetrafluoroborates have
been employed as the carbon nucleophile in the oxy-allyl cation
catalysis.10b–d,10g In contrast, development of catalytic α-
functionalization with less nucleophilic carbon nucleophiles still
remains a challenge. This limitation might be attributed to the low
concentration of the oxy-allyl cation intermediate under catalytic
conditions, and consequently, less reactive nucleophiles could
not trap the transient oxy-allyl cation intermediate effectively. In
this context, we have been interested in the possibility of using
phenol derivatives (N = –1.18) as the carbon nucleophile in the
oxy-allyl cation catalysis, to achieve the α-arylation of ketones.
This methodology would provide an alternative approach for the
Arylation at the α-position of carbonyl compounds is one of the
important transformations in synthetic chemistry since products
are valuable building blocks and represent a common structure in
natural products and pharmaceuticals.1 Among them, carbonyl
compounds having an all-carbon quaternary center at the α-
position are quite attractive, but still difficult to access.2 In order to
prepare such motifs, a variety of methodologies have been
developed to date.3 Generally, α-arylation of carbonyl compounds
mainly relies on the reaction between an electrophilic arylating
agent and a nucleophilic enolate or its equivalent (Figure 1a).4,5
On the other hand, α-arylation through nucleophilic addition of
aromatic nucleophiles to an electrophilic α-carbon of carbonyl
compounds has been less explored.6
Recently, a strategy based on nucleophilic addition to the oxy-
allyl cation intermediate has been emerged as an alternative
methodology for the functionalization of the α-position of ketones
in an umpolung fashion.7,8 The key oxy-allyl cation intermediate is
a transient electrophilic species, which can be generated from the
corresponding ketones bearing a leaving group at the α-position
with the assistance of an acid or a base and can be captured with
an appropriate nucleophile. Based on this strategy, in the
presence of a stoichiometric amount of an acid or a base, a broad
range of nucleophiles, including nitrogen-, oxygen-, sulfur- and
carbon-based ones, can be utilized for α-functionalization of
ketones.8,9 However, applicable carbon nucleophiles to trap the
catalytically generated oxy-allyl cation intermediates are limited to
highly nucleophilic ones such as indoles and silyl enol ethers.8i,10
[a]
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo, Kyoto 606-8502, Japan
E-mail: kano@kuchem.kyoto-u.ac.jp
http://kuchem.kyoto-u.ac.jp/yugo/.ac.jp
[b]
[c]
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
E-mail: maruoka@kuchem.kyoto-u.ac.jp
http://www.pharm.kyoto-u.ac.jp/orgcat/index.html
Supporting information for this article is given via a link at the end of
the document.
Figure 1. Strategies for α-arylation of ketones.
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10.1002/ejoc.202000169
European Journal of Organic Chemistry
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preparation of α-aryl ketones, which are important structural
motifs in synthetic chemistry. Herein, we describe Brønsted acid-
catalyzed intramolecular α-arylation of ketones with a tethered
phenolic nucleophile (Figure 1c). The resulting products have a
chroman skeleton, which is an important motif found in bioactive
compounds, bearing an all-carbon quaternary stereogenic
center.12
in high yields (2b and 2c). While the introduction of an electron
withdrawing group such as Br and CF3 at the para-position led to
low yield (46% and 11%, respectively) due to the undesired enone
formation, use of TfOH as catalyst in (CF3)2CHOH allowed the
formation of the desired products in moderate to good yields (2d
and 2e). On the other hand, in the presence of TfOH, reactions of
substrates bearing an ester or a sulfonamide group gave the
corresponding enones preferentially, presumably because
protonation of these groups by TfOH lowered the reactivity of the
corresponding phenolic nucleophiles. In these cases, use of less
acidic 4-NO2-C6H4-SO3H enabled the formation of the cyclized
products in moderate to good yields (2f and 2g). The present
method was not compatible with phenolic nucleophile bearing a
cyano group, probably due to its strong electron withdrawing
nature and further deactivation by protonation (2h). The meta-
substitution resulted in the formation of the corresponding
products 2i–2l in moderate to high yields. Remarkably, in these
cases, the reaction proceeded at the sterically less hindered
ortho-position, affording a single regioisomer. Incorporation of
ortho-methy group had no detrimental effect on the reactivity,
providing the desired product 2m in 89% yield. Despite its steric
hindrance, 2-naphthoxy group reacted at the more sterically
hindered position exclusively (2n).15 The practicability of the
present method was demonstrated with a 5 mmol scale of
reaction, giving 1.0 g of 2a in 91% yield.
We first examined the intramolecular α-arylation of α-hydroxy
cyclopentanone 1a, bearing a tethered phenoxy group in the
presence of 20 mol% of TsOH·H2O in various solvents at room
temperature (Table 1). The reactions in toluene, CH2Cl2 or MeCN
provided the desired spirocyclic ketone 2a in low yield, along with
the preferential formation of enone 3a probably due to instability
of the oxy-allyl cation intermediate in these solvents (entries 1–3).
When DMSO, THF or EtOH was used as solvent, the desired 2a
was not obtained (entries 4–6). To our delight, with a fluorinated
alcohol such as trifluoroethanol (CF3CH2OH), which is known to
be an effective solvent in nucleophilic functionalization of the oxy-
allyl cation intermediate, 2a was formed exclusively (entry 7).13,14
The conditions in entry 7 was applied to the reaction of the
independently synthesized enone 3a to investigate the possibility
of the formation of 2a from 3a, and consequently, no reaction was
observed. Use of less acidic CF3CO2H or (PhO)2PO2H as catalyst
in CF3CH2OH resulted in a significantly decreased yield (entries 8
and 9). Increasing the concentration (0.4 M) led to a similar yield
with lower catalyst loading (10 mol%) (entry 10).
Hexafluoroisopropanol ((CF3)2CHOH) was also found to be a
suitable solvent for the present α-arylation (entry 11).
Table 2. Intramolecular α-Arylation of cyclopentanones bearing various
phenolic nucleophiles.a
Table 1. Optimization of reaction conditions.[a]
Entry
Solvent
Catalyst
2a [%][b]
3a [%][b]
1
toluene
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
CF3CO2H
12
6
36
43
71
0
2
CH2Cl2
3
MeCN
15
0
4
DMSO
5
THF
0.
0
0.
43
1
6
EtOH
7
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
(CF3)2CHOH
98
17
0
8
0
9
(PhO)2PO2H
TsOH·H2O
TsOH·H2O
0
10[c]
11[c]
96
95
0
0
[a] Reactions were performed on a 0.1 mmol scale in 0.5 mL of solvent (0.2
M). [b] Determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as
an internal standard. [c] Reaction was performed at 0.4 M in the presence
of 10 mol% of TsOH·H2O.
[a] Reactions were performed on a 0.2 mmol scale in 0.5 mL of solvent (0.4
M). [b] TfOH as catalyst. [c] (CF3)2CHOH as solvent. [d] 4-NO2-C6H4-SO3H
as catalyst.
We next investigated the scope of α-hydroxy cyclopentanones
having a series of phenolic nucleophiles (Table 2). Reactions of
ketones bearing an electron-rich para-methylphenyl group or
para-methoxyphenyl group afforded the corresponding products
We next turned our attention toward substrate scope of ketone
moiety (Table 3). Cyclic α-hydroxy ketones having a larger ring
size were well tolerated (2o and 2p). Acyclic ketones were also
suitable substrates for the present α-arylation. The effect of a
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10.1002/ejoc.202000169
European Journal of Organic Chemistry
COMMUNICATION
carbon substituent (R2) at the carbonyl group on the reaction
efficiency was investigated using α-hydroxy ketones bearing a
methyl group at the α-position (R1 = Me). Introduction of a methyl
group on the carbonyl group (R2 = Me) led to no product formation
(2q). In contrast, replacement of the methyl group on the carbonyl
carbon with ethyl group (R2 = Et) resulted in the formation of the
desired product 2r in 72% yield. The yield of the reaction with
isopropyl-substituted ketone was diminished presumably due to
instability of the corresponding oxy-allyl cation intermediate by
steric congestion (2s). Introduction of benzyl group significantly
improved the yield, since the oxy-allyl cation intermediate can be
stabilized by conjugation with the π-system (2t).10b On the other
hand, reactions of 1u or 1v (R1 = Ph), which has a phenyl group
at the α-position, resulted in low to moderate yields (2u and 2v).
lactone 4 having a tetrasubstituted carbon center at δ-position in
91% yield. A cyclopentane 5 with two adjacent tetrasubstituted
carbon centers was obtained as a single diastereomer through a
nucleophilic addition of allylmagnesium bromide to the carbonyl
group of 2a.16 The ketone 2a was readily converted to the
corresponding enol triflate 6 in high yield by treating with Tf2O in
the presence of 2,6-di-tert-butylpyridine. The resulting 6 could be
transformed to a cyclopentene 7 with a 2-bromoethyl group and
an aryl group on the allylic position by BBr3-mediated ring-opening
reaction and the following introduction of trifluoromethanesulfonyl
group to the resulting phenolic hydroxy group. Finally, hydrolysis
of the enol triflate 7 mediated by a cobalt salt and triethylsilane
under oxygen atmosphere led to formation of the corresponding
cyclopentanone 8 bearing the all-carbon quaternary center at the
carbonyl α-position.17
Table 3. Substrate scope of ketones.a
To gain insight into the mechanism of the present α-arylation, we
performed some reactions as shown in Scheme 1. The present α-
arylation conditions were applied to the reaction of α-hydroxy
ketone 1w, which has two geminal methyl groups at α'-position,
and no reaction was observed (Scheme 1a). This result indicates
that the enolization of the α-hydroxy ketone would be necessary
to generate the oxy-allyl cation intermediate. We then employed
optically active 1a (99% ee) and quenched the reaction after 2 h.
The ketone 1a was recovered in 69% yield with 98% ee along with
the formation of racemic 2a in 28% yield, suggesting that the
stereochemical information of the α-position is lost during the
reaction and the α-position of the ketone is planarized before the
carbon-carbon bond forming step (Scheme 1b). Additionally,
utilizing 9 as a substrate led to the formation of 2s, which was
obtained in the reaction with 1s under the identical conditions
(Scheme 1c). This result implies that the same intermediate would
be generated from 9 and 1s before the carbon-carbon bond
forming step. These observations would support the presence of
the proposed oxy-allyl cation intermediate as the key electrophilic
species under the present conditions.8f
[a] Reactions were performed on a 0.2 mmol scale in 0.5 mL of solvent (0.4
M). [b] Reaction was performed at rt in the presence of 10 mol% of TfOH. [c]
(CF3)2CHOH as solvent. [d] Use of 20 mol% of TsOH•H2O. [e] Performed for
96 h. [f] Performed at 50 °C. [g] Performed at 40 °C.
The utility of this method was demonstrated through the
transformation of the obtained arylation product 2a (Figure 2).
Baeyer−Villiger oxidation with mCPBA afforded spirocyclic
Figure 2. Derivatization of arylation product 2a. amCPBA, Li2CO3, PhCH3.
ballylmagnesium bromide, THF. cTf2O, 2,6-di-tert-butylpyridine, CH2Cl2. dBBr3,
CH2Cl2, then Tf2O, pyridine, CH2Cl2. eCo(acac)2, Et3SiH, O2, iPrOH.
Scheme 1. Mechanistic investigation.
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Cossy, Synthesis 2019, 51, 178; g) Y.-J. Hao, X.-S. Hu, Y. Zhou, J. Zhou,
J.-S. Yu, ACS Catal. 2020, 10, 955.
Based on the above mechanistic investigation, a plausible
catalytic cycle for the present reaction is proposed in Figure 3.
Enolization of the α-hydroxy ketone 1a would be accelerated by
the Brønsted acid catalyst (HX). Subsequently, protonation of the
hydroxy group at the allylic position of the resulting enol would
allow the formation of the intermediate A, followed by the
generation of the key oxy-allyl cation intermediate B and water.
Then, nucleophilic addition of the tethered phenolic nucleophile to
the electrophilic α-position would afford the intermediate C. Finally,
deprotonation by the counteranion and rearomatization would
lead to the formation of the spirocyclic ketone 2a and regeneration
of the acid catalyst.
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Figure 3. Proposed mechanism.
In summary, we have developed the Brønsted acid-catalyzed
intramolecular α-arylation of ketones via the oxy-allyl cation
intermediate using the tethered phenolic nucleophiles. This study
has demonstrated that less nucleophilic phenols can be employed
as the carbon nucleophiles for the functionalization of the
catalytically generated oxy-allyl cation intermediate, expanding
the utility of that intermediate in the catalytic α-functionalization of
ketones.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP17H06450, JP26220803, and JP18H01975. Y.A. is grateful for
Fellowships for Young Scientists from the Japan Society for the
Promotion of Science (JSPS).
Keywords: umpolung • acid catalyst • arylation • quaternary
stereocenters • ketones
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[14] The structure of 2a was determined by single crystal X-ray diffraction
(CCDC-1971506).
[15] The structure of 2n was determined by single crystal X-ray diffraction
(CCDC-1971507).
[16] The relative configuration of 5 was determined by single crystal X-ray
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(CCDC-1971510).
[9]
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10.1002/ejoc.202000169
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Key Topic: Umpolung Arylation
COMMUNICATION
Yusuke Aota, Yuki Doko, Taichi Kano,*
Keiji Maruoka*
Page No. – Page No.
Brønsted Acid-Catalyzed
Intramolecular α-Arylation of Ketones
with Phenolic Nucleophiles via Oxy-
Allyl Cation Intermediates
Catalytic α-arylation of ketones in an umpolung fashion was demonstrated through
nucleophilic addition of phenol derivatives to the electrophilic oxy-allyl cation
intermediates, allowing the formation of ketones bearing an all carbon quaternary
center at the α-position.
This article is protected by copyright. All rights reserved.