Reductive Arylation of Arylidene Malonates Using Photoredox Catalysis

Article abstract of DOI:10.1021/acscatal.9b03608

A strategy with arylidene malonates provides access to β-umpolung single-electron species. Reported here is the utilization of these operators in intermolecular radical-radical arylations, while avoiding conjugate addition/dimerization reactivity that is

Full text of DOI:10.1021/acscatal.9b03608

Research Article
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2019, 9, 10350−10357
Reductive Arylation of Arylidene Malonates Using Photoredox
Catalysis
Rick C. Betori and Karl A. Scheidt*
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road,
Evanston, Illinois 60208, United States
S
* Supporting Information
ABSTRACT: A strategy with arylidene malonates provides access to β-umpolung
single-electron species. Reported here is the utilization of these operators in
intermolecular radical−radical arylations, while avoiding conjugate addition/
dimerization reactivity that is commonly encountered in enone-based photoredox
chemistry. This reactivity relies on tertiary amines that serve to both activate the
arylidene malonate for single-electron reduction by a proton-coupled electron transfer
mechanism as well as serve as a terminal reductant. This photoredox catalysis pathway
demonstrates the versatility of stabilized radicals for unique bond-forming reactions.
KEYWORDS: photoredox catalysis, arylation, proton coupled electron transfer, arylidene malonates, β-umpolung
he study of underexplored reactive intermediates has
Tdriven advances in carbon−carbon and carbon−heter-
oatom bond-forming reactions, leading to powerful trans-
formations that afford construction of both simple and
structurally complex molecular architectures.1 Among estab-
lished methods, disconnections utilizing inverse polarity
concepts, termed umpolung, have been a significant focus
and represent an appealing route for the preparation of chiral
molecules.2 N-heterocyclic carbenes (NHCs) have emerged as
unique catalysts for umpolung reactivity, where NHC-
homoenolate equivalents have been thoroughly explored as a
means of polarity-reversed reactivity of conjugate acceptors.3
More recently, the development of photoredox catalysis has
yielded new opportunities for the preparation of unconven-
tional operators under mild conditions.4 Lowest unoccupied
molecular orbital (LUMO)-lowering photoredox cooperative
catalysis, such as proton-coupled electron transfer (PCET)5
and Lewis acid/photoredox cooperative photoredox,6 has
facilitated the development of d1 (ketyl) and d3 (enone)
umpolung synthons previously inaccessible for single-electron
reduction by traditional visible light-absorbing photocatalysts
(Figure 1A). Recent reports utilizing bi-functional Lewis acid/
visible light catalysis7 and covalent interactions to facilitate
bathochromic activation and subsequent redox chemistry have
expanded this emerging field to access new chemical
Figure 1. Photoredox umpolung and arylations strategies.
reactivity.8
As part of our ongoing program to generate new
opportunities in β-umpolung reactivity, we recently reported
the exploitation of arylidene malonates as substrates in
photoredox/Lewis acid-cooperative catalysis to afford radi-
cal−radical cross-couplings, radical dimerizations, transfer
hydrogenations, and reductive annulations.9 These studies
focused on forming intermediates to access previously
unexplored chemical reactivities, namely, nondimerization/
cycloaddition reactions often seen with enone-derived radicals
(Figure 1A).6a−c,10 We demonstrated that arylidene malonates
[E1/2 red = −1.57 V for 1a vs saturated calomel electrode
(SCE)]11 demonstrate substantial capacity in LUMO-lowering
catalysis as shown by a dramatic change in reduction potential
Received: August 23, 2019
Revised: September 27, 2019
© XXXX American Chemical Society
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upon complexation with a Lewis acid (E1/2 red = −0.37 V vs
SCE, 1a + 100 mol % Sc(OTf)3). In particular, increased
resonance stabilization of the β-radical enolate intermediate
provides a versatile species that demonstrates reactivity
divergent from conventional β-enones.
photocatalyst concentration (3 mol %), and reaction
concentration (0.1 M) were held constant throughout.
Gratifyingly, the diaryl product 2a was formed with DPAIPN
and 2.5 equiv of NEt3 in CH3CN in 85% yield on 5 μmol scale
(see the Supporting Information for yields of all reactions in
96-well plate), where these results were validated on an initial
scale up to 0.2 mmol to provide 2a in 85% yield (see
Supporting Information for follow up optimization on isolable
scales).
We postulated that this stable β-radical enol would be able
undergo cross-coupling reactions with cyanoarene-derived
radicals, producing β-arylation products from the arylidene
malonate. Photoredox arylation using cyanoarenes has
attracted significant interest primarily because of the inherent
value of direct arene functionalization. In particular, MacMillan
and co-workers have demonstrated α-amino arylations,12
arylations of allylic sp3 C−H bonds,13 and β-arylation of
saturated aldehydes and ketones.14 Of note is the facile access
of these synthons using photoredox chemistry, enabling their
broad applicability (Figure 1B).15 Herein, we report the
utilization of these β-radical intermediates through a photo-
redox reductive arylation of arylidene malonates with
cyanoarenes to provide densely functionalized diarylmalonates
(Figure 1C).
To facilitate rapid reaction development, we utilized high-
throughput experimentation (HTE) to allow for the execution
of a large number of experiments to be conducted in parallel
while requiring less effort and cost per experiment when
compared to traditional means of experimentation (Scheme 1,
see Supporting Information for details).16 Variables that were
considered for optimization were as follows: photocatalyst,
terminal reductant, Lewis acid, and solvent, where equivalents
of cyanoarene (2.0 equiv), terminal reductant (2.5 equiv),
Observable trends demonstrate that a photocatalyst must be
both a capable oxidant and reductant (DPAIPN, Ir-
(ppy)2dtbpy), where catalysts that are strong oxidants/mild
reductants (Ph-MesAcr) provided no reactivity, and strong
reductants/mild oxidants (Ir(ppy)3) resulted in dimerization
of 1a.9a Evaluations of terminal reductants demonstrated that
tertiary amines were superior, where the Hantzsch ester (HE)
was only able to afford 2a in trace quantities. This highlights
the differences between tertiary amines and other terminal
reductants. Tertiary amines can, upon initial single-electron
reduction, result in the oxidized nitrogen atom forming a 2-
center/3-e− interaction17 or, after a [1,2]-H shift, serving as a
hydrogen-bond donor.18 This results in the oxidized amine
serving as both the terminal reductant and the Lewis acidic
intermediate necessary for activation of 1a.19 It is likely that
the [1,2]-H-shift to form a Brønsted acid is necessary, as
substitution of triethylamine for triphenylamine, a tertiary
amine unable to undergo a [1,2]-H-shift provided minimal
product either as the sole terminal reductant or used alongside
NEt3/NHEt3Cl (see Supporting Information).20 Because of
the dual terminal reductant/Lewis acid role of NEt3, inclusion
of an exogenous Lewis acid proved deleterious due to a more
complex reaction profile. A series of control experiments
demonstrated that the reaction did not take place in the
absence of photocatalyst or light (see the Supporting
Information for details). Moreover, we were pleased to find
that the optimized reaction conditions were not sensitive to
operational variations in reaction conditions, where differences
in temperature ( 15 °C), concentration (0.05−0.3 M), H2O
level (addition of desiccant10 equiv H2O), light intensity,
and O2 level all resulted in minimal changes in the observed
yield (Scheme 2, see Supporting Information).21
a
Scheme 1. Reaction Optimization Using HTE
With these optimized conditions, we investigated a variety of
substrates (Table 1). Generally, desired products were
obtained in good to excellent yields. Variations of the arylidene
malonate were well tolerated, where electron-rich and electron-
poor containing compounds were accessed in high yields
(Table 1, 2a−2m).
Diversity could be introduced into the dicarbonyl moiety to
tolerate a variety of diesters (Table 1, 2n−2p). A variety of
heteroaromatic systems were highly efficient in this reaction, as
pyridine, indole, furan, and pyrrole-containing arylidene
malonates afforded the diaryl species (Table 1, 2q−2t).
Unfortunately, alkylidene malonates are not successful with
these conditions (1u), presumably because of the increased
reduction potential relative to their arylidene malonate
counterparts (see the Supporting Information). Moreover,
substrates designed to afford quaternary centers were also
unsuccessful (1v). Unsubstituted pyridines and quinolones
only provided transfer hydrogenation products (1w−1aa).
Substrates derived from Meldrum’s acid showed no conversion
under the optimized conditions (1ab), presumably because of
an inability of 1ab to coordinate the NEt3 radical cation or
a
Reactions conducted on 5 μmol scale. Reactions were irradiated with
Lumidox 456 nm light-emitting diodes (LEDs) for 18 h. Yields
determined by ultra-performance liquid chromatography−mass
spectrometry (MS) using naphthalene as internal standard. See
Supporting Information.
+
NHEt3 to engage in PCET. Lastly, benzylidenepentane-2,4-
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a
a
Scheme 2. Reaction-Condition Sensitivity Assessment
Table 1. Arylidene Malonate Reaction Scope
a
Reaction conditions: constant: 1 (0.2 mmol), 4-CN-pyridine (0.4
mmol), NEt3 (0.5 mmol) DPAIPN (3 mol %). Reaction was
irradiated with Kessil PR160 456 nm LEDs for 18 h. Yields
determined by gas chromatography MS using biphenyl as internal
standard. See Supporting Information.
dione (1ac) provided a complex reaction mixture likely
because of ketyl radical formation, leading to undesired side
reactivity. Arene variation allowed for differentially substituted
pyridines, pyrmidines, pyrroles, and indoles (Table 2).
Attempts to utilize 1,4-dicyanobenzene (1,4-DCB) provided
no product, likely because of SET from DPAIPN to 1,4-DCB
(E1/2 red = −1.52 V vs SCE for DPAIPN radical anion) being
endergonic (E1/2 red = 1.67 V vs SCE for 1,4-DCB).
While this process affords similar connectivity compared to
transition-metal catalyzed conjugate arylations22 and organo-
metallic reagent conjugate additions,23 it is noteworthy that the
use of heteroaryl conjugate acceptors or heteroaryl nucleo-
philes is problematic, likely because of Lewis basic functionality
interacting with the metal catalysts.24
While the use of arylidene malonates as conjugate acceptors
in Friedel−Crafts arylation reactions is a well-established
paradigm,25 nearly all of the products prepared using this
method would not be possible using established methods,
highlighting the value of this method. To compare against
alternative approaches to afford diarylmalonates, we attempted
to prepare 2a through a Knoevenagel/hydrogenation or
organometallic addition into 1a and a Lewis-acid-catalyzed
dehydration coupling from diarylmethanol 5a using established
procedures (Scheme 3).26 Additionally, we tried a variety of
a
Reaction conditions: 1 (0.2 mmol), 4-CN-pyridine (0.4 mmol),
NEt3 (0.5 mmol) DPAIPN (3 mol %), CH3CN (2.0 mL) was
irradiated with Kessil PR160 456 nm LEDs for 18 h. Reported yields
are determined after isolation by chromatography. See Supporting
Information.
different organometallic and transition-metal catalyzed proce-
dures for conjugate addition into the arylidene malonate.
Lastly, a series of dehydrogenative coupling reactions from
diarylmethane 6a were also attempted.27 Unfortunately, all
conditions screened (see Supporting Information for details)
were unsuccessful either leading to no conversion of starting
material or decomposition under the reaction conditions,
highlighting the utility of this process.
To demonstrate utility of this methodology on a multigram
scale, we linearly scaled the reaction 1000-fold from the initial
screening conditions to access 2a in 85% yield. Additionally,
>90% of the DPAIPN photocatalyst was recovered via column
chromatography and was able to again reproduce the title
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a
Table 2. Arene Reaction Scope
Scheme 4. Gram-Scale Reaction and Telescope Process
a
Reaction conditions: 1a (0.2 mmol), arene (0.4 mmol), NEt3 (0.5
mmol) DPAIPN (3 mol %), CH3CN (2.0 mL) was irradiated with
Kessil PR160 456 nm LEDs for 18 h. Reported yields are determined
after isolation by chromatography. See the Supporting Information.
Scheme 3. Comparison to Known Methods
SCE).29 Notably, as both 1a and 4-CN pyridine are activated
for radical−radical coupling through single-electron reductions,
this likely indicates that the DPAIPN photocatalyst is going
through two separate redox cycles, both of which are initiated
by reductive quenching by NEt3. This observation is
corroborated by a lack of complete conversion of 1a when
fewer than 2 equivalents of NEt3 were employed (see
Supporting Information for details).
To determine if this process proceeds through a closed
photoredox cycle, we measured the quantum yield (Φ =
0.28).30 To verify that nonproductive relaxation pathways such
as phosphorescence or fluorescence were not impacting the
observed quantum yield measurement, we conducted simple
quenching experiments. Briefly, DPAIPN was irradiated and
the absolute fluorescence was measured. Subsequently, 83
equiv of NEt3 was added to a solution of DPAIPN (reflective
of equivalents of NEt3 under standard reaction conditions),
irradiated, and the absolute fluorescence was measured.
Minimal fluorescence was observed, indicating near-complete
quenching of the DPAIPN photocatalyst by NEt3 (quenching
fraction, Q = 0.94, Scheme 5B). Based on our proposed
mechanism that outlines the need for two photons required for
one molecule of the product being formed, an expected
quantum yield of <0.5 would be indicative of the reaction
potentially proceeding through a closed catalytic cycle. To
evaluate if isotope effects impacted the rate of 1a-radical
formation, we synthesized 1a-d1 and compared the rate of
consumption of 1a to 1a-d1 using initial rates. A slight
preference for 1a-d1 was measured (isolated: kH/kD = 0.92
reaction on gram scale without loss of yield (Scheme 4A). We
then evaluated a tandem one-pot Knoevenagel/arylation
process starting from benzaldehyde and dimethyl malonate,
where we were pleased to find that 2a could be accessed in
excellent yield after purification. Moreover, we found this
process could be telescoped further by concentration and
redissolution of the crude arylation reaction mixture in 1:9
H2O/dimethyl sulfoxide (DMSO) with LiCl to provide the
Krapcho product 7a in 64% yield over the three-transformation
process (Scheme 4B,C).
To study the mechanism of this process, we employed
fluorescence-quenching techniques with 1a and 4-CN pyridine
as model substrates (Scheme 5A).28 Stern−Volmer analysis
demonstrated that neither 1a nor 4-CN pyridine quench the
excited state of DPAIPN [E1/2 (DPAIPN*/DPAIPN•+) = 1.28
V vs SCE] in acetonitrile at 25 °C. However, addition of NEt3
resulted in a large decrease in the measured fluorescence,
indicating that this reaction proceeds through a reductive
quenching mechanism of DPAIPN [E1/2 (DPAIPN*/
DPAIPN•−) = 1.10 V vs SCE] by NEt3 (E1/2 ox = 0.83 V vs
0.03, competition kH/kD = 0.88
0.03). This rate of
consumption is likely due to the change in hybridization
from sp2 to sp3 upon reduction. Because of the in-plane bend
of an sp2 carbon being much stiffer than the out-of-plane bend
(where the in-plane and out-of-plane bends for sp3 carbons are
degenerate in energy), this results in a significant difference in
the zero-point energy of the two species, producing an inverse
secondary kinetic isotope effect (Scheme 5C).31
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SCE for 4-CN-pyridine).32 However, it is noteworthy that
NHEt3 , which is likely being formed under the reaction
Scheme 5. Mechanistic Experiments
+
conditions, (pKa = 9.00 in DMSO)33 is sufficiently acidic to
protonate 4-CN-pyridine, therefore allowing for a shift in the
reduction potential through Brønsted acid activation and
resulting in SET instead occurring on the 4-CN-pyridinium
ion.34 To investigate this, we conducted cyclic voltammetry
(CV) experiments with stoichiometric concentrations of
NHEt3Cl with 4-CN-pyridine, and found there was a notable
shift in reduction potential for the 4-CN-pyridinium species
(E1/2 red = −1.51 V), allowing for SET from the DPAIPN
radical anion to be slightly exergonic. Contrastingly, 1,4-DCB
showed minimal change in reduction potential upon titrating
NHEt3Cl (E1/2 red = −1.60 V vs SCE) which would result in
SET from the DPAIPN radical anion being endergonic,
thereby rationalizing the difference in reactivity observed
(Scheme 5D). No shift in reduction potential was observed
with either substrate upon addition of NEt3 (see Supporting
Information for details). These Brønsted acid activation
observations were corroborated by UV−vis studies, where 4-
CN-pyridine demonstrates both a noticeable change in the
absorption profile as well as an increase in absorption based on
stoichiometric addition of NHEt3Cl throughout the 250−300
nm range. However, 1,4-DCB shows a minimal change in the
UV absorption profile.35 No UV−vis change is observed with
either substrate upon addition of NEt3 (see Supporting
Information for details). In addition, UV−vis studies with 1a
demonstrated no shift upon addition of NEt3, but both a
change in the absorption profile and an absorbance increase
with NHEt3Cl throughout the 250−320 nm range.
A reasonable reaction pathway that accounts for the
observed data above begins with irradiation with visible light
that results in the formation of the excited DPAIPN
photocatalyst, a capable oxidant (Scheme 6). The reductive
quenching of the excited state of DPAIPN [E1/2 (DPAIPN*/
Scheme 6. Proposed Reaction Pathway
As aforementioned, 1,4-DCB is unreactive under these
reaction conditions, which was surprising because of the
potential difference between 1,4-DCB and 4-CN pyridine (E1/2
red = −1.67 V vs SCE for 1,4-DCB and E1/2 red = −1.87 V vs
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DPAIPN•−) = 1.10 V vs SCE]36 by SET with NEt3 (E1/2 ox =
0.83 V vs SCE) provides a strongly reducing DPAIPN radical
anion (E1/2 red = −1.52 V vs SCE). The NEt3 radical cation
exists in equilibrium via a 1,2 H-shift with the α-amino radical
cation and can be deprotonated by an additional molecule of
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.9b03608.
■
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Experimental procedures, characterization of products,
and spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: scheidt@northwestern.edu.
■
ORCID
Karl A. Scheidt: 0000-0003-4856-3569
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institute of General Medical Sciences
(R01GM073072, R01GM131431 to K.A.S. and
T32GM105538 to R.C.B.) for financial support. R.C.B. was
supported in part by the Chicago Cancer Baseball Charities at
the Lurie Comprehensive Cancer Center of Northwestern
University. The authors thank Mark Maskeri for plate
visualization assistance and Joshua Zhu for CV measurements.
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