Organocatalytic Arylation of α-Ketoesters Based on Umpolung Strategy: Phosphazene-Catalyzed SNAr Reaction Utilizing [1,2]-Phospha-Brook Rearrangement

Article abstract of DOI:10.1002/chem.201803218

An organocatalytic arylation of α-ketoesters was developed on the basis of umpolung strategy. Phosphazene P2-tBu efficiently catalyzes the three-component coupling reaction of α-ketoesters, a silylated secondary phosphite, and electron-deficient fluoroarenes to provide α-hydroxyester derivatives possessing an electron-deficient aryl group at the α-position. The reaction involves the catalytic generation of α-oxygenated ester enolates from α-ketoesters through the [1,2]-phospha-Brook rearrangement followed by the S_NAr reaction.

Full text of DOI:10.1002/chem.201803218

A Journal of
Accepted Article
Title: Organocatalytic Arylation of α-Ketoesters Based on Umpolung
Strategy: Phosphazene-Catalyzed SNAr Reaction Utilizing [1,2]-
Phospha-Brook Rearrangement
Authors: Azusa Kondoh, Takuma Aoki, and Masahiro Terada
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COMMUNICATION
Organocatalytic Arylation of α-Ketoesters Based on Umpolung
Strategy: Phosphazene-Catalyzed SNAr Reaction Utilizing [1,2]-
Phospha-Brook Rearrangement
Azusa Kondoh,[b] Takuma Aoki,[a] and Masahiro Terada*[a]
Abstract: An organocatalytic arylation of α-ketoesters was
developed on the basis of umpolung strategy. Phosphazene P2-tBu
efficiently catalyzes the three-component coupling reaction of α-
ketoesters, silylated secondary phosphite, and electron-deficient
fluoroarenes to provide α-hydroxyester derivatives possessing an
electron-deficient aryl group at the α-position. The reaction involves
the catalytic generation of α-oxygenated ester enolates from α-
ketoesters via the [1,2]-phospha-Brook rearrangement followed by
the SNAr reaction.
reaction generally requires a stoichiometric amount of a
Brønsted base for generating an anionic nucleophile, catalytic
variants have also been developed by using silylated
pronucleophiles with fluoroarenes as the electrophile under the
influence of a catalytic amount of a Lewis base.[6] Thus, we
designed a new catalytic system for the SNAr reaction of a
carbanion generated through the umpolung process by using a
silylated phosphite.[7] Specifically, we intended to develop a
reaction of ester enolates generated from α-ketoesters with
fluoroarenes, providing α-hydroxyester derivatives. Our
proposed reaction system is shown in Scheme 1.
The inversion of the inherent polarity of functional groups, the
so-called “umpolung”, is a useful strategy for designing and
developing new synthetic reactions including carbon-carbon
bond forming reactions.[1] We have been focusing on the
development of catalytic carbon-carbon bond forming reactions
that involve the catalytic generation of carbanions through the
formal umpolung process from corresponding carbonyl
compounds, that is, the addition of a secondary phosphite to a
keto
moiety,
followed
by
the
[1,2]-phospha-Brook
rearrangement[2] under the influence of a Brønsted base catalyst.
Specifically, we have successfully utilized the carbanions of less
acidic compounds, such as amide/ester enolates generated from
α-ketoamides/α-ketoesters,[3a-c] homoenolate equivalents from
chalcone derivatives,[3d] and benzyl anions from aromatic
aldehydes,[3e] in various types of catalytic nucleophilic addition
reactions under Brønsted base catalysis. Furthermore, we have
recently developed an “umpolung” intramolecular cyclization that
involves the catalytic generation of α-aminocarbanions from
imines.[4] The enantioselective addition reactions of enolates
derived from isatins and benzylidene pyruvates were developed
by groups of Johnson and Ooi, which also emphasized the
usability of the methodology.[2a,b] During the course of our
studies, we have envisioned the development of a catalytic
carbon-carbon bond forming reaction that differs from the
nucleophilic addition reaction, with the aim of expanding the
scope of the applicable transformation of carbanions generated
through the formal umpolung process. To this end, we have
focused our attention on the nucleophilic aromatic substitution
(SNAr) reaction, which is a conventional reaction for introducing
an aromatic group onto anionic nucleophiles.[5] Whereas the
Scheme 1. Designed reaction system.
First, silylated secondary phosphite 3 is activated by a Lewis
base catalyst and the following chemoselective 1,2-addition of
the resulting anion of phosphite proceeds to provide alkoxide A.
Subsequently, the migration of the dialkoxyphosphoryl moiety
from carbon to oxygen, that is, the [1,2]-phospha-Brook
rearrangement, proceeds to form α-oxygenated enolate B.
Finally, the SNAr reaction of B with fluoroarenes proceeds to
afford arylated α-hydroxyester derivative
4 along with a
generated fluoride, and the fluoride then regenerates the
catalyst or directly activate 3, completing the catalytic cycle.
Generally, the introduction of an aryl group to α-ketoesters is
accomplished by the 1,2-addition of aryl metal species, such as
aryl boronic acids, under the influence of a transition metal
catalyst including a rhodium catalyst based on the “normal”
reactivity considering the polarity of the keto moiety.[8] In contrast,
the intended reaction does not require such a precious transition
metal catalyst and the preparation of aryl metal species. More
importantly, the scope of introducible aryl groups in the intended
electrophilic arylation reaction is complementary to that of the
aforementioned conventional nucleophilic arylation. Thus, the
SNAr reaction enables the introduction of highly electron-
deficient aryl groups including polyfluorinated aryl groups. Based
on this concept and reaction design, we report herein an
organocatalytic arylation of α-ketoesters through the SNAr
reaction utilizing the [1,2]-phospha-Brook rearrangement. This
report also includes the catalytic substitution of difluorostyrene
[a]
[b]
T. Aoki, Prof. Dr. M. Terada
Department of Chemistry, Graduate School of Science
Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: mterada@m.tohoku.ac.jp
Dr. A. Kondoh
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201803218
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derivatives and a preliminary study of the enantioselective
arylation with an isatin derivative as the precursor of enolate.
We began our investigation by evaluating the viability of our
intended reaction. Treatment of ethyl phenylglyoxylate (1a) with
pentafluoropyridine (2a) and silylated diethylphosphite 3a in the
presence of 10 mol% TBAF at room temperature for 4 h gave
desired arylated α-hydroxyester derivative 4aa in 73% NMR
yield along with by-product 5a formed by the protonation of the
enolate intermediate instead of arylation (Table 1, entry 1).
Importantly, the reaction catalytically proceeded in a highly
chemoselective manner. Other by-products, such as arylated
phosphite 6a, which would be formed through the direct
substitution of 2a with 3a, were not observed in the initial
experiment. Then the screening for catalysts was conducted
(entries 2-6). Interestingly, some phosphazenes, which are
With the optimized reaction conditions in hand, the scope of the
substrates was investigated. First, the substituents on α-
ketoesters were screened with 2a as the electrophile (Scheme
2). 1b and 1c having a halogen moiety at the para position of a
phenyl ring provided corresponding products 4ba and 4ca in
good yields. In contrast, 1d having a para-methoxyphenyl group
provided 4da in moderate yield along with a significant amount
of 6a (25% yield) due to the low electrophilicity of 1d. In the case
of ortho-tolyl-substituted 1e, 4ea was obtained in 46% yield and
protonated by-product 5e was formed in 28% yield.[10] The
bulkiness around the reaction site of the enolate intermediate
would retard the SNAr reaction with 2a. α-Ketoesters 1f and 1g
possessing a meta-methoxyphenyl group and a 2-naphthyl
group, respectively, underwent the reaction without any problem
to provide 4fa and 4ga in high yields. Heteroaryl groups,
including the 2-benzothieny group and the 3-pyridyl group, were
compatible and corresponding products 4ha and 4ia were
obtained in good yields. Alkyl substituents were also examined;
however, almost no reaction occurred and the starting α-
ketoesters were recovered.
known as organosuperbases and generally utilized as
a
Brønsted base, showed good catalytic activity (entries 5 and
6).[9] In particular, P2-tBu gave the best result (entry 5). The
screening for solvents with P2-tBu as the catalyst revealed that
DMF was the solvent of choice, and 4aa was obtained in 90%
isolated yield (entry 12).
Table 1. Optimization of reaction conditions.[a]
yield[%][b]
entry
catalyst
solvent
4aa
5a
6a
1
TBAF
THF
73
43
5
11
24
43
43
3
<1
<1
<1
<1
<10
<5
4
2
CsF
THF
3
DABCO
P1-tBu
P2-tBu
P4-tBu
P2-tBu
P2-tBu
P2-tBu
P2-tBu
P2-tBu
P2-tBu
THF
4
THF
8
Scheme 2. Scope of α-ketoesters.[a] [a] Conditions: 1 (0.25 mmol), 2a (0.28
mmol), 3a (0.28 mmol), P2-tBu (0.025 mmol), DMF (1.0 mL), rt, 4 h. Yields are
isolated yields unless otherwise noted. [b] Yield determined by 1H NMR
analysis after column chromatography. See the Supporting Information for
details.
5
THF
87
52
86
90
90
82
89
94 (90)
6
THF
6
7
Et2O
5
Next the scope of fluoroarenes was investigated with 1a as the
precursor of enolate (Scheme 3). 1-Fluoro-2,4-dinitrobenzene
(2b) and 2-fluoro-5-nitropyridine (2c) provided corresponding
products 4ab and 4ac in good yields, respectively. The reaction
of pentafluoronitrobenzene (2d) resulted in the formation of
desired product 4ad in 71% yield along with a significant amount
of 6d and the isomer of 6d (13% combined yield). The reaction
of 2,4,6-trifluoropyrimidine (2e) proceeded at the 2-position in a
site-selective manner to provide 4ae in high yield. In the case of
2,6-difluoro-3-nitrobenzonitrile (2f), the substitution mainly
occurred at the 6-position to afford 4af as the major product and
a small amount of the isomer of 4af, which was formed through
the competing substitution at the 2-position. 1-Fluoro-4-
nitrobenzene (2g) was also applicable to this reaction to provide
8
toluene
CH2Cl2
AcOEt
CH3CN
DMF
4
<5
<1
6
9
1
10
11
12
7
4
2
1
<1
[a] Conditions: 1a (0.25 mmol), 2a (0.28 mmol), 3a (0.28 mmol) base (0.025
mmol), solvent (1.0 mL), rt, 4 h. [b] NMR yields. Isolated yield is shown in
parentheses.
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4ag in 69% yield. However, the reaction with less electrophilic 4-
fluorobenzonitrile (2h) did not proceed and only 5a was obtained.
Scheme 5. Enantioselective arylation of isatin derivative.
Finally, the derivatization of products was conducted (Scheme 6).
The diethoxyphosphoryloxy moiety of 4aa was an efficient
leaving group under acidic conditions and Friedel-Crafts-type
reactions proceeded with a variety of nucleophiles (Scheme 6a).
The use of anisole as the nucleophile provided triarylacetic acid
derivative 13 in high yield. Amination also proceeded by using
tosylamine as the nucleophile to afford α-amino acid derivative
14 in good yield. Furthermore, the conversion of the
Scheme 3. Scope of fluoroarenes.[a] [a] Conditions: 1a (0.25 mmol), 2 (0.28
mmol), 3a (0.28 mmol) P2-tBu (0.025 mmol), DMF (1.0 mL), rt, 4 h. Yields are
isolated yields unless otherwise noted. [b] Yield determined by 1H NMR
analysis after column chromatography. See the Supporting Information for
details. [c] Isomer of 4af was observed (in 4% NMR yield).
diethoxyphosphoryloxy moiety into
a hydroxyl group was
This umpolung strategy was further extended to the catalytic
substitution of difluorostyrene derivatives (Scheme 4). The
three-component reaction of α-ketoester 1a, silylated phosphite
3a and difluorostyrene derivatives 7 afforded monofluoroalkenes
8 in moderate to good yields with high Z selectivities.[11]
achieved by using H2O as the nucleophile, and 15a was
obtained in quantitative yield. As an alternative method for the
similar transformation, treatment of 4ag with sodium ethoxide in
ethanol provided 15b in good yield (Scheme 6b).
Scheme 4. Catalytic substitution of difluorostyrenes.
A preliminary study of the enantioselective arylation was carried
out (Scheme 5).[12] As a result, the reaction of isatin derivative 9
as the precursor of enolate with 1-fluoro-2,4-dinitrobenzene (2b)
proceeded in an enantioselective manner by using chiral
bis(guanidine)iminophosphorane 11, which was developed as a
chiral organosuperbase catalyst by our group,[13] to provide (+)-
10 in good yield with 66% ee. In addition, the use of chiral
bifunctional catalyst 12[14] afforded the opposite major
enantiomer of ()-10 with 88% ee albeit in moderate yield.
Scheme 6. Derivatization of products.
In conclusion, a novel organocatalytic method for the arylation of
α-ketoesters was developed based on the umpolung strategy.
P2-tBu efficiently catalyzes the three-component coupling
reaction of α-ketoesters, silylated secondary phosphite and
electron-deficient fluoroarenes to provide α-hydroxyester
derivatives possessing an electron-deficient aryl group at the α-
position. The reaction involves the catalytic generation of α-
oxygenated ester enolates from α-ketoesters via the [1,2]-
phospha-Brook rearrangement, followed by the SNAr reaction.
The newly developed methodology was further extended to the
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10.1002/chem.201803218
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COMMUNICATION
[4]
[5]
A. Kondoh, M. Terada, Chem. Eur. J. 2018, 24, 3998-4001.
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The reaction of 1a with 2a is representative (Table 1, entry 12). To a
solution of ethyl benzoylformate (1a, 40 μL, 0.25 mmol) and
pentafluoropyridine (2a, 30 μL, 0.28 mmol) in DMF (1.0 mL) were
sequentially added a solution of P2-tBu (2.0 M in THF, 13 μL, 0.025
mmol) and silylated phosphite (3a, 77 μL, 0.28 mmol) at room
temperature. The resulting mixture was then stirred at room temperature
for 4 h. The reaction was quenched with sat. aq. NH4Cl, and the product
was extracted with AcOEt. The combined organic layer was washed with
brine, dried over Na2SO4 and evaporated. The crude mixture was purified
by column chromatography (hexane/AcOEt = 3:1) to provide 4aa (0.11 g,
0.23 mmol, 90%) as a colorless oil.
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This research was supported by a Grant-in-Aid for Scientific
Research (S) (JP16H06354) and (C) (JP16K05680) from the
JSPS. We thank JSPS for a research fellowship for Young
Scientists (T. A.).
Keywords: base catalysis • SNAr reaction • umpolung • [1,2]-
phospha-Brook rearrangement • organocatalyst
[10] In the reactions of other α-ketoesters 1, the corresponding 5 was
formed in less than 6% yields.
[11] The configuration of the alkene moiety of 8 was determined by the
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COMMUNICATION
Azusa Kondoh, Takuma Aoki, Masahiro
Terada*
Page No. – Page No.
Organocatalytic Arylation of α-
Ketoesters Based on Umpolung
Strategy: Phosphazene-Catalyzed
SNAr Reaction Utilizing [1,2]-
Phospha-Brook Rearrangement
An organocatalytic arylation of α-ketoesters was developed on the basis of
umpolung strategy. Phosphazene P2-tBu efficiently catalyzes the three-component
coupling reaction of α-ketoesters, silylated secondary phosphite, and electron-
deficient fluoroarenes, which involves the catalytic generation of α-oxygenated
ester enolates from α-ketoesters via the [1,2]-phospha-Brook rearrangement
followed by the SNAr reaction.
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