Decarboxylative 1,4-Addition of α-Oxocarboxylic Acids with Michael Acceptors Enabled by Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.5b02392

Enabled by iridium photoredox catalysis, 2-oxo-2-(hetero)arylacetic acids were decarboxylatively added to various Michael acceptors including α,β-unsaturated ester, ketone, amide, aldehyde, nitrile, and sulfone at room temperature. The reaction presents a new type of acyl Michael addition using stable and easily accessible carboxylic acid to formally generate acyl anion through photoredox-catalyzed radical decarboxylation.

Full text of DOI:10.1021/acs.orglett.5b02392

Letter
pubs.acs.org/OrgLett
Decarboxylative 1,4-Addition of α‑Oxocarboxylic Acids with Michael
Acceptors Enabled by Photoredox Catalysis
Guang-Zu Wang, Rui Shang,* Wan-Min Cheng, and Yao Fu*
ChEM, CAS Key Laboratory of Urban Pollutant Conversion, Anhui Province Key Laboratory of Biomass Clean Energy, Department
of Chemistry, University of Science and Technology of China, Hefei 230026, P.R. China
S
* Supporting Information
ABSTRACT: Enabled by iridium photoredox catalysis, 2-oxo-2-(hetero)arylacetic acids were decarboxylatively added to various
Michael acceptors including α,β-unsaturated ester, ketone, amide, aldehyde, nitrile, and sulfone at room temperature. The
reaction presents a new type of acyl Michael addition using stable and easily accessible carboxylic acid to formally generate acyl
anion through photoredox-catalyzed radical decarboxylation.
ichael addition with acyl anion is a general way to
addition of α-oxocarboxylic acids through radical decarbox-
ylation under mild conditions. As depicted in Figure 1, a
M
construct γ-carbonyl compounds possessing a useful
electron-withdrawing functional group (Scheme 1).1 Classic
Scheme 1. Michael Addition with Acyl Anion Equivalent
methods to access such compounds include the Stetter reaction
through the unpolung Breslow intermediate from aldehyde.2 In
the interest of utilizing carboxylic acid to generate a nucleophile
in organic synthesis,3 we wondered whether such an acyl
nucleophile can be generated through decarboxylation of α-
oxocarboxylic acids in the Michael addition reaction.4,5b
Although α-oxocarboxylic acids have been successfully utilized
as acyl nucleophiles in transition-metal-catalyzed decarboxyla-
tive coupling reactions,5 their utilization as acyl nucleophiles in
addition to Michael acceptors remains underdeveloped,
possibly due to the thermo-instability that Michael acceptors6
incompatible with the harsh conditions often require for metal-
catalyzed redox neutral decarboxylation.7 Recently, we8 and
other groups9 discovered that α-oxocarboxylic acids can
decarboxylatively couple with electrophiles under mild
conditions though photoredox catalysis,10 and also inspired
by the recent works of photoredox catalyzed decarboxylative
1,4-addition of aliphatic carboxylic acids,11 we conjectured that
a photoredox catalyst may be suitable to catalyze Michael
Figure 1. Hypothesized mechanism of photoredox catalyzed
decarboxylative 1,4-addition of α-oxocarboxylic acid.
photoexcited photocatalyst *Mn+ can be reductively quenched
by α-oxocarboxylate to generate an acyl radical. The acyl radical
can be trapped by a Michael acceptor to generate an enolate
radical4b which may oxidize the reduced M(n−1)+ to regenerate
Mn+ and deliver the 1, 4-addition product after protonation.
Based on this hypothesis, we realized in this work that, when
enabled by a iridium photoredox catalyst, Ir[dF(CF3)-
ppy]2(phen)PF6, various 2-(hetero)aryl-2-oxocarboxylic acid
can proceed decarboxylative 1,4-addition with a series of
Michael acceptors, including unsaturated ester, ketone, amide,
nitrile, sulfone, and unsaturated aldehyde, which is a
challenging substrate in the Stetter reaction.2 This work offers
Received: August 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02392
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a new type of Michael addition with an acyl anion equivalent
that was generated through decarboxylation.
A typical example after optimization is demonstrated in
Table 1, entry 1. A transparent Schlenk tube charged with 2-
bases (see the Supporting Information for more information).
Although base can be used catalytically in principle for this
reaction, reducing base to catalytic amount significantly
decreased the yield (entry 8). The importance of base may
be ascribed to the effective generation of the carboxylate anion
for quenching the excited photoredox catalyst. Control
experiments revealed that the reaction absolutely needs the
photocatalyst and irradiation (entries 9 and 10). It should be
noted this reaction proceeds well under both air (92%) and
argon protection (90%) (Supporting Information).
Table 1. Study of Parameters for Decarboxylative 1,4-
a
Addition of 2-Oxophenylacetic Acid
Evaluation of the scope of Michael acceptors is summarized
in Scheme 2. α, β-Unsaturated ester, such as alkyl and aryl
a
Scheme 2. Scope with Respect to Michael Acceptors
b
entry
variations from the conditions in eq 1
none
yield (%)
c
1
2
92 (89 )
Ir-cat. 2 instead of Ir-cat. 1
[Ir(ppy)2(dtbbpy)]PF6 instead of Ir-cat. 1
[Ru(bpy)3]Cl2 instead of Ir-cat. 1
[Ru(bpz)3]Cl2 instead of Ir-cat. 1
without base
90
0
3
4
0
5
28
0
6
7
K2CO3 instead of K2HPO4
using 50 mol % of K2HPO4
without photoredox catalyst
without light
90
45
0
8
9
10
0
a
Reaction conditions: 1a (0.5 mmol), Michael acceptor (0.75 mmol),
catalyst (1 mol %), base (0.6 mmol), and CH2Cl2 (1 mL)/H2O (1
mL) at room temperature for 9 h under air. See the Supporting
b
Information for more details. GC yields using benzophenone as an
c
internal standard. Isolated yield.
oxo-2-phenylacetic acid (0.5 mmol), (E)-pent-3-en-2-one (0.75
mmol), K2HPO4 (0.6 mmol), and Ir[dF(CF3)ppy]2(phen)PF6
in a mixed solvent of dichloromethane and water (1 mL/1 mL)
was exposed under the irradiation of a 36 W blue LED at room
temperature. After 9 h irradiation, aqueous workup followed by
column chromatography gave the addition product, 2-methyl-1-
phenylpentane-1, 4-dione, in 89% isolated yield. Along with the
desired product, ∼10% of benzaldehyde was observed as a side
product. Table 1 summarizes several factors that affect the
reaction outcomes. Using a similar photoredox catalyst
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (Ir-cat. 2) [E1/2(M*/M−) =
1.21 V vs SCE, τ = 2300 ns]10g instead of Ir[dF(CF3)-
ppy]2(phen)PF6 (Ir-cat. 1) gave almost same yield (entry 2),
but using Ir(ppy)2(dtbbpy)PF6 [E1/2(M*/M−) = 0.66 V vs
SCE, τ = 557 ns]10g gave no product at all (entry 3).
Ruthenium-based photoredox catalyst [Ru(bpy)3]Cl2
[E1/2(M*/M−) = 0.77 V vs SCE, τ = 1100 ns]10g is totally
ineffective (entry 4). [Ru(bpz)3]Cl2 with a high oxidative
potential, but a relatively short excited-state lifetime [E1/2(M*/
M−) = 1.45 V vs SCE, τ = 740 ns],10g gave the desired product
in only 28% yield (entry 5).
a
Reaction conditions: 1a (0.5 mmol), Michael acceptors (0. 75
mmol), Ir-cat. 1 (1 mol %), K2HPO4 (0.6 mmol), and CH2Cl2/H2O =
1:1 (2 mL) under air.
acrylate are all good substrates (2b-2e). α, β-unsaturated
ketones are also amenable substrates (2f, 2a). Acrylamides gave
moderate yields (2g,h). α,β-Unsaturated aldehyde, which is
incompatible in the Stetter reaction, can also be successfully
used (2i). Acrylonitrile and α,β-unsaturated sulfone are also
suitable substrates (2j,k). Substituents on both the α-position
(2o) and β-position (2a,i) of the Michael acceptors are
The result of catalyst screen reveals that both the oxidative
potential [E1/2(M*/M−)] and the excited state lifetime are
crucial for the performance of the catalyst. The reaction cannot
proceed at all without a base (entry 6). Screening of base
revealed K2CO3 (entry 6) and K2HPO4 are the most suitable
B
DOI: 10.1021/acs.orglett.5b02392
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tolerated. β-CF3 substitution on acrylate is well tolerated, and a
1,4-dicarbonyl compound possessing a useful −CF3 substituent
was generated (2l). Alkylidenemalonate (2m) and diethyl
maleate (2n) are good substrates to generate the addition
product in high yields. Except for acyclic Michael acceptors,
cyclic Michael acceptors, such cyclopent-2-en-1-one, also work
well (2p). 1-(Cyclohex-2-en-1-yl)ethan-1-one gave the addition
product as a mixture of diastereomers in which the trans isomer
is the major product (trans/cis = 8:1). Several unsuccessful
substrates are also listed at the bottom of Scheme 2. Simple
acrylic acid (1) is ineffective, probably due to the competition
of reductive quenching with 2-oxocarboxylate. β-Dimethylated
(2) and β-phenyl-substituted (3) Michael acceptors are both
unreactive, which may be ascribed to the generation of a stable
tertiary and benzylic radical with relatively lower oxidation
potentials compared with α-carbonyl radical that is unable to
reoxidize IrII.12 Substrate 4, which can generate a stable tertiary
carbon radical, is unreactive. Styrene is unreactive.
A gram-scale reaction further demonstrated the applicability
of this photoredox-catalyzed acyl Michael addition (Scheme 4).
Scheme 4. Gram-Scale Reaction and Accessibly Further
Transformation to 2-Arylated Heterocycles
Subjecting 1.50 g of 2-oxo-2-phenylacetic acid yielded 1.61 g
(85% yield) of the desired addition product without decreasing
the yield compared with small-scale reaction. Furthermore, the
obtained 1,4-dicarbonyl compound can be easily transformed
into 2-arylated furan14 and pyrrole,15 which are of interest in
materials science and the pharmaceutical industry.
The generality of this reaction with regard to 2-oxo-2-
arylacetic acids is summarized in Scheme 3. 2-Oxo-2-phenyl-
A radical-trapping experiment was tested as shown in Scheme
5. It was found that adding 1,1-diphenylethylene or TEMPO
Scheme 3. Scope with Respect to 2-Oxo-2-(hetero)arylacetic
a
Acids
Scheme 5. Radical Trapping Experiment with TEMPO
(2,2,6,6-tetramethylpiperidinooxy) kills this reaction. The
suppressing effect of 1,1-diphenylethylene may be ascribed to
the generation of a stable tertiary benzylic radical by trapping
the benzoyl radical, thus ending the photoredox cycle. This
observation is in accordance with the substrate limitation
observed in Scheme 2. When 2.0 equiv of TEMPO was added
as an additive, 2,2,6,6-tetramethylpiperidin-1-yl benzoate was
observed in high yield (based on 1a). This observation revealed
TEMPO overwhelmingly traps the benzoyl radical in
preference to Michael acceptor and acts as oxidant to
regenerate the Ir(III) catalyst.4b These observations support
that the reaction proceeds through a radical decarboxylation,
and the poisoning effect of 1,1-diphenylethylene suggested that
the enolate radical generated is crucial for the regeneration of
the Ir(III) catalyst as proposed in Figure 1.11
a
Reaction conditions: 2-oxo-2-(hetero)arylacetic acids (0.5 mmol),
Michael acceptor (0. 75 mmol), Ir-cat. 1 (1 mol %), K2HPO4 (0.6
mmol), and CH2Cl2/H2O = 1:1 (2 mL) under air.
In summary, we have shown that when enabled by iridium
photoredox catalysis 2-oxocarboxylic acids can be used to
generate an acyl anion equivalent to add with various Michael
acceptors, including α, β-unsaturated ester, ketone, amide,
aldehyde, nitrile, and sulfone under mild conditions. The
reaction presents a new type of decarboxylative 1,4-addition
reaction utilizing stable and easily accessible 2-oxocarboxylic
acids and also demonstrates a new synthetic application of the
increasing repertoire of photoredox catalysis.
acetic acids with both electron-donating (3a) and electron-
withdrawing (3b) substituents on the phenyl ring are amenable
substrates. The electron-withdrawing substituent decreases the
conversion and the yield. This observation may be ascribed to
the reduced reductive quenching ability toward photoexcited
*Ir(III). Acetal functionality was well tolerated (3c). Aryl
iodide (3d) and aryl chloride (3e) turned out to be compatible.
No photoredox-catalyzed deiodination was observed.13 2-Oxo-
2-mesitylacetic acids worked well to deliver the product in high
yield (3f). Besides 2-phenyl substitution, 2-naphthyl- (3g) and
2-heteroaryl-substituted glyoxylic acids (3h,i) are all suitable
substrates, albeit in moderate yield. For reasons yet unclear, 2-
alkyl-2-oxoacetic acid and 2-amino-2-oxoacetic acid were
unsuccessful substrates with starting materials recovered
under the optimized reaction conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02392.
C
DOI: 10.1021/acs.orglett.5b02392
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Detailed experimental procedures and spectral data for
Letter
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21, 13191.
AUTHOR INFORMATION
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(c) Du, J.; Skubi, K. L.; Schultz, D. M.; Yoon, T. P. Science 2014, 344,
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■
Corresponding Authors
*E-mail: faint123@mail.ustc.edu.cn.
*E-mail: fuyao@ustc.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the 973 Program
(2012CB215306), NSFC (21325208, 21172209,
21361140372), IPDFHCPST (2014FXCX006), CAS
(KJCX2-EW-J02), FRFCU, and PCSIRT.
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DOI: 10.1021/acs.orglett.5b02392
Org. Lett. XXXX, XXX, XXX−XXX