An Ir-photoredox-catalyzed decarboxylative Michael addition of glyoxylic acid acetal as a formyl equivalent

Article abstract of DOI:10.1039/c7cc06252d

We reported herein an iridium-photoredox-catalyzed decarboxylative conjugated addition of glyoxylic acid acetals with various Michael acceptors, including unsaturated amide, ester, aldehyde, ketone, and nitrile under irradiation. Vinyl pyridine and α-aryl styrene are also suitable substrates. The reaction offers various types of acetal products, which are of synthetic significance as protected aldehydes.

Full text of DOI:10.1039/c7cc06252d

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Ir-Photoredox-Catalyzed Decarboxylative Michael Addition of
Glyoxylic Acid Acetal as Formyl Equivalent
Received 00th January 20xx,
Accepted 00th January 20xx
Sheng Zhang, Zhoumei Tan, Haonan Zhang, Juanli Liu, Wentao Xu and Kun Xu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We
reported
herein
an
iridium-photoredox-catalyzed catalyze decarboxylative Michael addition of glyoxylic acid
decarboxylative conjugated addition of glyoxylic acid acetals with acetal with a broad scope of Michael acceptors including α, β-
various Michael acceptors, including unsaturated amide, ester, unsaturated amide, ester, aldehyde, ketone, and nitrile at
aldehyde, ketone, and nitrile under irradiation. Vinyl pyridine and room temperature (Figure 1d). These Michael acceptors
α-aryl styrene are also suitable substrates. The reaction offers generally are less effective substrates for transition-metal-
various types of acetal products, which are of synthetic catalyzed hydroformylation using CO and H2 as syngas.10
significance as protected aldehydes.
Interestingly, vinyl pyridine and α-aryl styrene are also suitable
substrates for this transformation. The reaction directly
delivers acetals as protected aldehyde, which is more
synthetically useful because generally aldehyde is a reactive
functionality always needing protection against oxidation or
reduction in synthesis. The reaction described herein offers a
new pathway to synthesize functionalized acetals under mild
reaction conditions and also expands the synthetic power of
iridium photoredox catalysis in decarboxylative reactions.11,12
Introducion of a formyl group into an organic molecule via
formal addition of formyl anion equivalent onto an
unsaturated carbon-carbon bond is
a
very useful
transformation in organic synthesis.1 Because of the versatile
transformations of aldehyde functionality in organic synthesis,
2
extensive efforts have been devoted to synthesize aldehydes
from olefins via hydroformylation.3 These transformations
have
been
achieved
via
transition-metal-catalyzed
Figure 1 Formyl anion equivalent for conjugated additions
hydroformylation of styrenes and simple alkenes using syngas,
while for an electron-deficient alkene, conjugated addition of
an formyl anion equivalent with Michael acceptor is method of
choice.4-6 Literatures reported 4-isopropyl-2-oxazoli-5-one4
and formaldehyde N,N-dialkylhydrazone5 as convenient formyl
anion equivalents for conjugated additions with Michael
acceptors (Figure 1a and 1b). Chi et al. also revealed using
carbohydrates as formaldehyde equivalent for formyl 1,4-
additions by using N-heterocyclic carbene catalyst (Figure 1c).6
Recently, Wang and Mariano successfully applied glyoxylic acid
acetal as formyl anion equivalent to couple with aryl and
alkenyl electrophiles by applying organophotoredox/nickel
dual catalytic system7 and very recently they reported
organophotoredox catalyst, 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-
dicyanobenzene
(4CzIPN)
can
catalyze
formal
We commenced our experimentation by testing the
hydroformylation of styrenes with glyoxylic acid acetal with
high chemoselectivity and regioselectivity.8 We reported in
this work that an iridium photoredox catalyst9 is efficient to
decarboxylative addition of diethoxyacetic acid
ꢀwith N-
methyl-N-phenylacrylamide using a photoredox catalyst with
stoichiometric amount of base, because we believe that a
suitable photoredox catalyst may oxidize diethoxyacetate to
induce radical decarboxylation to deliver diethoxymethyl
radical that can be intercepted by the Michael acceptor. The
optimized reaction condition is shown in Table 1, equation 1.
Mixing diethoxyacetic acid (0.3 mmol), N-methyl-N-
phenylacrylamide (0.2 mmol), and K2HPO4 (0.24 mmol) with an
a.College of Chemistry and Pharmaceutical Engineering, Nanyang Normal
University, Nanyang, 473061 P. R. China.
b.Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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iridium photoredox catalyst, Ir[dF(CF3)ppy]2(dtbbpy)PF6
Journal Name
(
Ir- reactions give desired products in moderate to good yields (4-
cat.) in N,N-dimethylformamide (DMF) under irradiation at 10). The reaction is very efficient for diethyl 2-
room temperature afforded the desired conjugated addition ethylidenemalonate (11) and diethyl 2-benzylidenemalonate
product in 92% yield. The optimal iridium photoredox catalyst
(
13). Diethyl maleate as substrate gave the product 12 in high
(
Ir-cat.) is known for its long excitation life-time and high yield. For α, β-unsaturated esters, substituent at both α- and
*III/II
oxidative potential of excitation state (E
= +1.21 V vs β-positions are tolerable (13, 14, 15). Unsaturated ketone (16),
1/2
SCE)13 to oxidize carboxylate anion (Eox = +0.95 V vs SCE)7. aldehyde (17), and nitrile (18) are all amenable substrates
Other metallaphotoredox catalysts, such as Ir(bpy)3, showing broad substrate scope. The reaction can tolerate a
Ru(bpy)3Cl2•6H2O, and Ru(bpy)3 (PF6)2, were screened and series of functional groups such as aryl chloride, aryl fluoride,
were proved to be ineffective due to the short excitation aldehyde, boronate, and N-heteroarenes. Ethyl 3-
lifetime and low oxidative potential of excitation state (entries coumarincarboxylate, a natural product derived substrates
1-3). 4CzIPN is an effective catalyst while the yield is also works well giving desired product 19 in 54% yield. Besides
comparably lower than using the iridium catalyst (Ir-cat.
(entry 4). Ir(ppy)2(dtbbpy)PF6, a catalyst with lower excitation- 4,4,5,5-tetramethyl-1,3-dioxolane-2-carboxylic acid and 5,5-
state oxidative ability is much less effective compared with Ir- dimethyl-1,3-dioxane-2-carboxylic acid also reacted well (20
cat. (entry 5). The base also affects the reaction outcome, as 21 22).
)
2,2-diethoxyacetic acid, other glyoxylic acid acetals such as
,
,
among all the inorganic bases tested, K2HPO4 appeared to be
optimal, while KOAc gave comparable yield (entries 6-8).
Interestingly, though a base is required for this reaction to
deprotonate diethoxyacetic acid, direct use of sodium
diethoxyacetate or lithium diethoxyacetate as reactant gave
inferior results (entries 9 and 10). The salts have relatively
poor solubility compared with acid in DMF and solubility issue
may accounts for the reduced yield.
Scheme 1 Reaction scope regarding to Michael acceptors and different glyoxylic acid
acetalsa
Table 1 Studies of optimal reaction conditionsa
aReaction conditions: diethoxyacetic acid (0.3 mmol), N-methyl-N-
phenylacrylamide (0.2 mmol), Ir-cat. (0.004 mmol) and K2HPO4 (0.24 mmol) in
solvent (2 mL) irradiated by 36 W blue LEDs for 12 h under Ar. Isolated yields.
The reaction scope with respect to the Michael acceptors were
studied and demonstrated in Scheme 1. α, β-Unsaturated
amides including secondary and tertiary amides are amenable
substrates (
1,
2). N,N-diphenyl acrylamide works well to give
addition product
3
in 78% yield. For acrylate esters, the
2 | J. Name., 2012, 00, 1-3
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aReaction conditions: acid (0.3 mmol), Michael acceptor (0.2 mmol), Ir-cat. (0.004
mmol) and K2HPO4 (0.24 mmol) in DMF (2 mL) irradiated by 36 W blue LEDs for
12 h under Ar. Isolated yields. bNaOAc (0.3 mmol) was used as the base.
We further demonstrated the synthetic utility of this method
by conducting two gram-scale reactions. The yield of gram
scale reaction is comparable with small scale reaction. By
direct hydrolysis without isolating the acetal product, the
desired aldehyde product can be obtained in one pot. (Figure
Although the reaction does not work with simple styrene (23
)
or styrenes possessing electron-withdrawing substituents (see
SI for more information), we were delighted to find besides
Michael acceptors, 2-vinylpyridine and 4-vinylpyridine were all
reactive to give desired products in moderate to good yields
3).
Figure 3 Gram scale synthetic application and one-pot aldehyde synthesis
(Scheme 2, 24-26). Compared with the recent report by Wang
and Mariano where styrene can be used as amenable
substrate when 4CzlPN as photoredox catalyst was applied8,
the redox potential of the radical anion of 4CzlPN (
‐1.21 V vs
III/II
SCE) is higher than the potential of Ir-cat. (E1/2 = −1.37 V vs
SCE). Thus, from thermodynamic aspect we cannot explain
why styrene did not work using the iridium photoredox
catalyst. The failure may come from other side effects such as
energy transfer between iridium photoredox catalyst and
styrene or side reaction of oligomerization of styrene. α-Aryl
The reaction mechanism should be similar with recently
reported various photoredox catalyzed conjugated addition
reactions (Figure 4).14 First, the excited iridium photoredox
catalyst can oxidize 2,2-diethoxyacetate anion to induce
radical decarboxylation to generate diethoxymethyl radical.
The existence of radical intermediate in the reaction was
corroborated by a radial-trapping experiment using (2,2,6,6-
Tetramethylpiperidin-1-yl)oxy (TEMPO), which showed
complete suppression effect (see SI for more information). The
diethoxymethyl radical is intercepted by Michael acceptor to
generate a more stable radical with stronger oxidative ability
to reoxidize the reduced iridium photoredox catalyst back to
styrenes are suitable substrates (27, 28).
Scheme 2 Reaction scope regarding to styrene derivativesa
Ir(III). We cannot entirely exclude
a
pathway that
diethoxymethyl radical competes to oxidize Ir(II) catalyst to
generate diethoxymethyl anion to attack Michael acceptor.
Figure 4 Discussion of reaction mechanism
aReaction conditions: acid (0.3 mmol), Michael acceptor (0.2 mmol), Ir-cat. (0.004
mmol) and K2HPO4 (0.24 mmol) in DMF (2 mL) irradiated by 36 W blue LEDs for 12
h under Ar. Isolated yields. bNaOAc (0.3 mmol) was used as the base.
We observed an interesting intramolecular selectivity when N-
methyl-N-(4-vinylphenyl)acrylamide was used as substrate.
The decarboxylative addition selectively takes place at the
electron-deficient acrylamide moiety in 77% yield while leaving
the styrene moiety intact. Product of preferential reaction at
the styrene moiety of this substrate was not observed. (Figure
2).
In summary, we have developed an iridium-photoredox
catalyst catalyzed decarboxylative conjugated addition of
glyoxylic acid acetals with various Michael acceptors, including
unsaturated amide, ester, aldehyde, ketone, and nitrile at
room temperature under LED irradiation. Vinyl pyridine and α-
aryl styrene are also suitable substrates. The reaction offers a
new method to access various functionalized acetal products
that are of synthetic significance as protected aldehydes.
Figure 2 Selectivity between electron-deficient olefin and electron-rich olefin
We are greatful to the Natural Science Foundation of China
(21602119, U1504208 and 21702113).
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DOI: 10.1039/C7CC06252D
An iridium-photoredox-catalyzed decarboxylative conjugated addition of glyoxylic acid acetals
with various Michael acceptors was reported. The reaction offers various types of acetal products,
which are of synthetic significance as protected aldehydes.