Reductive annulations of arylidene malonates with unsaturated electrophiles using photoredox/Lewis acid cooperative catalysis

Article abstract of DOI:10.1039/C9SC00302A

A cooperative Lewis acid/photocatalytic reduction of salicylaldehyde-derived arylidene malonates provides access to a versatile, stabilized radical anion enolate. Using these unusual umpolung operators, we have developed a novel route to access densely fu

Full text of DOI:10.1039/C9SC00302A

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DOI: 10.1039/C9SC00302A
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Reductive Annulations of Arylidene Malonates With Unsaturated
Electrophiles Using Photoredox/Lewis Acid Cooperative Catalysis
Rick C. Betori, Benjamin R. McDonald, and Karl A. Scheidt*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
benzaldehydes)7, the development of cooperative catalytic
A
cooperative Lewis acid/photocatalytic reduction of
systems to effect said reduction potential have been highly
explored to afford annulations, reductive couplings and
radical-radical couplings.8
salicylaldehyde-derived arylidene malonates provides access to a
versatile, stabilized radical anion enolate. Using these unusual
Umpolung operators, we have developed a novel route to access
densely functionalized carbo- and heterocycles through a radical
annulation addition pathway.
Figure 1: Selected Annulation Strategies
The development of annulation strategies has proved
invaluable in organic synthesis, particularly for the
construction of complex natural products.1 In a broad sense,
annulation reactions can be divided into two electron and one
electron approaches, where two electron annulation tactics
include the venerable Diels-Alder, Michael and Dieckmann
reactions, as well as general nucleophilic additions and
alkylations. Conversely, one-electron annulation methods have
focused on using halogenated starting materials and tin
reagents, where seminal reports by Curran and Stork were
revolutionary for the advent of radical annulations.2 Despite
these elegant approaches, the use of stoichiometric tin
hydrides is problematic both due to toxicity and purification
problems, driving the need for the development of radical
annulation reactivity accessed through catalytic methods using
non-prefunctionalized starting materials.3 The development of
photoredox chemistry has rendered the catalytic generation of
open shell intermediates relatively facile due to the natural
abundance and ease of use of visible light, as well as the
superior chemoselectivity observed compared with traditional
methodologies for radical-based approaches.4
Along these lines, the use of photoredox chemistry to
access inverse polarity concepts, termed Umpolung, have
emerged as instrumental.5 Specifically, the generation of ketyl
radical species (e.g. d1 Umpolung operators) through the
reduction of carbonyl derivatives has been a major focus.6
Since carbonyls are typically characterized by strongly negative
Similarly, d3 Umpolung operators in photoredox have been
explored.9 Yoon et al. pioneered a cooperative catalytic
approach to enone -Umpolung reactivity using
a
photoredox/Lewis acid approach to afford [2+2], and [3+2]
cycloadditions.10 Following Yoon’s seminal work on enone -
Umpolung reactivity, recent reports have focused on using
bifunctional and cooperative catalytic approaches in
photoredox catalysis to access to new chemical reactivity.11
However, new directions and opportunities remain unexplored
in this area, primarily due to the inherent limitations of
bifunctional catalytic manifolds, which restrict reactivity and
generalizability as well.
redox potentials (E1/2 red
=
−1.93
V
vs. SCE for
a. Department of Chemistry, Center for Molecular Innovation and Drug Discovery,
Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United
States
† Email: Scheidt@northwestern.edu
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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activities in anti-cancer models.15 We envisioned that the
As part of our program to generate new opportunities in -
View Article Online
DOI: 10.1039/C9SC00302A
Umpolung chemistry, we recently reported the use of arylidene malonate-derived -Umpolung operator could grant
arylidene malonates as substrates in photoredox/Lewis acid access to previously unprepared derivatives. We initiated our
cooperative catalysis to afford radical-radical cross coupling, studies with 1a, which was readily accessible in 2 steps from
radical dimerizations, and transfer hydrogenations.12 As a salicylaldehyde, using a variety of photocatalysts and blue
major goal of this study, we focused on designing a stabilized LEDs, the results of which are summarized in Table 1.
Gratifyingly, we found that the desired chromane product was
formed with scandium triflate in acetonitrile using
photocatalyst dF-Ir and Hantzsch ester (HEH) in 81% yield with
a 1.2:1 dr. A variety of other bidentate Lewis acids were
investigated, all of which were capable of affording the title
reaction, albeit with decreased yield in comparison to
scandium triflate (entries 1-4). A survey of transition metal
photocatalysts identified dF-Ir as optimal. Interestingly,
organocatalysts of the dicyanobenzene family performed as
well as dF-Ir, with diphenyl aniline organocatalyst DPAIPN16
providing the desired product in comparable 85% yield and
diastereoselectivity. Solvent evaluation confirmed acetonitrile
to be the optimal solvent, whereas aprotic and protic (see
Supporting Information) were shown to be less successful.
Evaluations of alternative stoichiometric hydrogen atom
donors (DIPEA, NEt3, NBu3, BT) were capable of delivering 2a in
slightly decreased yields relative to the HEH; where a slight
increase in diastereoselectivity was observed (2:1 dr observed
with NEt3) at a precipitous loss of yield (entries 9-12). The
rationale for this observed increase in diastereoselectivity
could be due to coordination from the radical cation of NEt3
with the malonate, providing a facial selectivity to facilitate
increased diastereoselectivity, or that the C-C bond formation
is reversible and that the diastereoselectivity is determined, at
least in part, by the relative rates of hydrogen atom transfer.
As tertiary amines have been used previously for activation of
carbonyls for reduction, we evaluated DIPEA, NEt3 and NBu3 in
the absence of Sc(OTf)3, where drastically lower yields were
observed (entries 13-15). In this instance, it is believed that
upon initial single electron reduction, the oxidized nitrogen
atom in DIPEA, NEt3 or NBu3 can form a 2-center/3-e-
interaction,17 or after a [1,2]-H shift, can serve a hydrogen-
bond donor,18 which results in the oxidized amine serving as
both the terminal reductant and the Lewis acid necessary for
-Umpolung operator intermediate, with the hypothesis that a
more stabile radical anion would enable underexplored
chemical reactivity, namely intermolecular radical couplings,
rather than the dimerization reactions often seen with enone-
derived radical anions (e.g. cinnamates, E1/2 red = –2.3 V vs.
SCE)13. In this regard, we demonstrated that arylidene
malonates (E1/2 red = –1.57 V for phenyl arylidene malonate
vs. SCE)14, demonstrated a drastic shift in reduction potential
upon complexation with a Lewis acid (E1/2 red = –0.37 V for
phenyl arylidene malonate vs SCE). By utilizing arylidene
malonates, this cooperative catalytic approach afforded a
stabilized -radical enolate intermediate exhibiting reactivity
divergent from reductive species generated from conventional
enones, presumably due to greater persistence of the
resonance-stabilized radical anion. Herein we report
a
cooperative Lewis acid/photoredox reductive enolate
annulation strategy to provide densely functionalized carbo
and heterocycles.
Table 1: Optimization of the reaction conditions
activation of 1a.8d,8e
A series of control experiments
demonstrated that the reaction did not take place in the
absence of light, photocatalyst or Lewis acid (entries 16-18).
With these optimized conditions, we investigated a variety
of substrates (Table 2). Generally, the desired products were
obtained in good to excellent yields. Substrates bearing either
electron-rich and electron-poor substituents were well
tolerated; however, substrates with substitution at the 6-
position did not provide the desired product, presumably due
to reduced overlap between the enone and aryl -systems.
Diversity could be introduced into the dicarbonyl moiety to
tolerate a variety of diesters (2n-2o) in good to excellent
yields, albeit as a complex mixture of diastereomers. The
unsaturated electrophile could be varied to facilitate access to
benzyl (2p) and nitrile (2q) substituted chromanes in excellent
yields. Replacement of the olefin electrophile with alkyne
electrophiles proceeded with excellent yields (2t-2u), albeit as
a mixture of Z/E isomers.
aYield determined by GC with bibenzyl as internal standard. Product was observed in a
1.2:1 dr ratio. bYield of isolated product. cDIPEA used instead of HEH. dNet3 used instead
of HEH. eNBu3 used instead of HEH. fBT used instead of HEH. gno light. DIPEA =
diisopropylethylamine, NEt3 = triethylamine, BT = 2-phenyl-dihydrobenzothaizoline
Chroman and related heterocycles are a diverse class of
bioactive small molecules that our lab have previously
prepared and investigated for their wide range of biological
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successful, albeit with slightly diminished yields (2Vxi,ew72Ar%ticlyeiOenldlin)e,
Table 2: Reactions of salicylaldehyde derived arylidene malonates.
where the remaining mass balance is the saturated arylidene
DOI: 10.1039/C9SC00302A
O
O
O
O
HEH (1.5 equiv)
1 mol % DPAIPN
10 mol % Sc(OTf)3
malonate species. This is presumably due to the decreased
electrophilicity of the vinylogous carbonate starting material
due to hyperconjugation.19
R1
R2
R1
R2
R3
CH3CN (0.1 M)
blue LEDs, 5h
R3
O
O
1
2
Table 3: Reactions of arylidene malonates affording different core
scaffolds.
MeO2C
CO2Me
CO2Me
O
2a, 85%, 1.2:1
X-ray of trans 2a
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
O
O
2c, 70%, 1.2:1
Br
2b, 61%, 1.2:1
Cl
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
Reaction conditions: 1 (0.2 mmol), HEH (0.3 mmol), PC 7 (1 mol %), Sc(OTf)3 (10 mol %),
degassed CH3CN (2.0 mL) was irradiated with a blue LED (456 nm) for 5 h. Reported
yields are determined after isolation by column chromatography.
CO2Me
O
O
F
O
OMe
F
2f, 68%, 1.2:1
2e, 74%, 1.5:1
2d, 62%, 1.2:1
Unfortunately, substrates designed to allow access to
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
quaternary
centers
(either
derived
from
2’-
Me
hydroxyacetophenone or from senecioic acid) were not
successful in this reaction, presumably due to decreased
reactivity of the resulting -radical enolate intermediate and
decreasing electrophilicity of the tethered alkene respectively.
The importance of the dicarbonyl moiety was validated as a
means for Lewis acid coordination, as substrates derived from
Meldrum’s acid showed no conversion under the optimized
conditions. An intermolecular reductive coupling between 8
and methyl acrylate was unsuccessful, where only transfer
hydrogenation of to afford 9 was observed. This likely indicates
that reduction of the resulting radical anion proceeds more
rapidly than radical conjugate addition.
CO2Me
CO2Me
CO2Me
Br
F
O
Me
O
O
2g, 84%, 1.2:1
2h, 88%, 1.2:1
2i, 91%, 1.2:1
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
tBu
Cl
CO2Me
CO2Me
CO2Me
O
O
O
tBu
Cl
2j, 92%, 1.3:1
2l, 90%, 1.2:1
2k, 91%, 1.1:1
CO2Me
CO2Me
EtO2C
CO2Et
iPrO2C
CO2iPr
MeO2C
CO2Me
CO2Me
O
O
O
Figure 2: Reductive Annulation Reaction Extension
2m, 82%, 1.5:1
2n, 86%, 1.2:1
2o, 82%, 1.2:1
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
Ph
CN
CO2tBu
O
O
O
2p, 85%, 1.1:1
2q, 81%, 1.2:1
2r, 77%, 1.2:1
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
CO2Bn
Ph
CO2Et
O
O
O
2t, 71%, 1:1 Z:E
2u, 81%, 1:1 Z:E
2s, 88%, 1.2:1
Reaction conditions: 1 (0.2 mmol), HEH (0.3 mmol), PC 7 (1 mol %), Sc(OTf)3 (10 mol %),
degassed CH3CN (2.0 mL) was irradiated with a blue LED (456 nm) for 5 h. Reported
yields are determined after isolation by column chromatography.
Furthermore, we were pleased to find that modification of
the starting material to access tetrahydroquinolines (2v) and
tetrahydronapthalenes (2w) were also successful in high
yields, illustrating the capability of this methodology to access
a wide range of carbo and heterocyclic scaffolds in high
efficiency. Attempts to access dihydrobenzofuran was
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Notably, we were able to demonstrate this reaction on reaction does not propagate through a radical chain process
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multi-gram scale, where 2a was accessed in similar yields (See Supporting Information for details). DOI: 10.1039/C9SC00302A
under identical reaction conditions, further highlighting the
potential of this reaction. Additionally, the DPAIPN
photocatalyst was recovered after column chromatography in
80% yield. The recovered DPAIPN was subsequently used in a
multi-gram scale reaction without loss of yield, giving this
methodology additional utility due to the ability to recover and
reuse the catalyst.
To further study the mechanism of the -radical enolate
formation, we employed fluorescence quenching techniques
with 1a as a model substrate. A Stern-Volmer analysis revealed
that 1a does not quench the excited state of DPAIPN (E1/2 red =
-1.52 V vs. SCE) in acetonitrile at 25 °C (Figure 6). However,
inclusion of 100 mol % Sc(OTf)3 resulted in a large decrease in
the measured fluorescence. Notably, control experiments
demonstrated that Sc(OTf)3 itself does not quench the DPAIPN
excited state, indicating that pre-complexation of Sc(OTf)3 with
1a is necessary for generation of the radical anion.
Furthermore, variation of the stoichiometry of Sc(OTf)3 and 1a
revealed that the quenching process exhibits a first-order
dependence on each component (see Supporting Information).
Notably, these results only provide evidence that a Sc(OTf)3/1a
complex is necessary for arylidene malonate activation and is
not indicative of oxidative quenching of DPAIPN by
Figure 3: Gram-scale reaction
Sc(OTf)3/1a. To evaluate the possibility of
a reductive
A practical advantage of this strategy is the ease of
quenching mechanism, we conducted Stern-Volmer analysis
with the HEH, where quenching of DPAIPN fluorescence by the
HEH is observed. Both 1a and a 1a/100 mol % Sc(OTf)3
complex were also added to the HEH for Stern-Volmer
analysis, where minimal changes to the fluorescence
quenching profile were observed. This trend was evident
across 10, 25 and 50 mol % Sc(OTf)3 as well. This is likely
indicative that the HEH is responsible for quenching the photo-
excited DPAIPN, not the Sc(OTf)3/1a complex. Fluorescence
quenching experiments with NBu3 was also evaluated, where
the inclusion of 1a and a 1a/100 mol % Sc(OTf)3 complex
resulted in no change to the quenching profile of DPAIPN by
NBu3 (see Supporting Information).
synthetically elaborating these products.
A
one-pot
Krapcho/Dieckmann/Krapcho sequence with cis-2a proceeded
in 85% yield, affording an interesting [6,6,5] fused ring system.
Figure 4: Krapcho/Dieckmann Synthesis of Fused Ring System
To probe the mechanism of this process, we investigated
whether this photoredox process can propagate through a
chain process rather than the presumed closed-catalytic
photoredox cycle.20 We were pleased to find that upon using a
“light/dark” experiment21 that product formation was only
observed during periods of irradiation (Figure 5). While
supporting our mechanistic hypothesis, “light/dark”
experiments are typically not sufficient to fully elucidate
whether a process proceeds through a closed-catalytic cycle as
opposed to a propagating chain process.22
Figure 6: Stern-Volmer Fluorescence Quenching Analysis
3.0
2.5
AM (no Sc(OTf)3)
2.0
1.5
1.0
0.5
AM (0.1 M Sc(OTf)3)
HEH
HEH (0.1 M AM/Sc(OTf)3)
HEH (0.1 M AM)
Figure 5: Light/dark experiments
0.00
0.02
0.04
0.06
0.08
0.10
Concentration / M
While both processes are thermodynamically comparable,
it is unlikely that an oxidative quenching mechanism
predominates, primarily because of the decreased possibility
of finding a Sc(OTf)3/1a complex due to catalytic Sc(OTf)3
relative to superstoichiometric HEH. We investigated the
transformation of 1a to 2a using stoichiometric Sc(OTf)3 and
found no significant difference in the reactivity profile or yield
between using 10 and 100 mol % Sc(OTf)3. We found that
using stoichiometric NBu3 was able to provide 2a without the
presence of Sc(OTf)3 in 35% yield, indicating that reductive
quenching of the photocatalyst is likely the initial step of this
mechanism, where oxidative quenching is thermodynamically
unfavourable (Table 1, entry 15). Moreover, as with transition
metal photocatalysts, reductive quenching of DPAIPN is
kinetically favourable relative to oxidative quenching, leading
us to believe that a reductive quenching pathway is the
As a follow up to these studies, we demonstrated that this
reaction has a quantum yield of 1.0, indicating that the
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primary pathway.23 Furthermore, Ir(ppy)3 , which would only
be viable in an oxidative quenching cycle, only yielded trace
product (Table 1, entry 5).
HEH
HEH
View Article Online
DOI: 10.1039/C9SC00302A
SET
PC*
To further understand the nature of the Sc(OTf)3/1a
complex, UV-Vis spectroscopic characterization was carried
out. Interestingly, the Sc(OTf)3/1a complex demonstrated a
considerable difference in the UV-Vis spectrum relative to 1a
alone, where there is an additional shoulder peak around 380-
410 nm. While this demonstrates that the Sc(OTf)3/1a complex
can absorb blue LED light, no reactivity is observed without the
DPAIPN photocatalyst present, indicating that it is unlikely that
the Sc(OTf)3/1a complex can generate any intermediates that
result in consumption of 1a. To confirm that the Sc(OTf)3/1a
complex does not undergo productive photoredox reaction
pathways in the absence of DPAIPN, we irradiated 1a with 10
mol % Sc(OTf)3 and superstoichiometric DIPEA, NEt3, NBu3 and
HEH. No conversion of 1a was observed in any case. Finally,
the UV-Vis profile of 1a showed no change in the presence of
either DIPEA, NEt3 or NBu3 (100 mol %), indicating that the
amines themselves are not interacting with 1a, but instead
need to undergo a single electron reduction to complex with
1a (See Supporting Information for details).
PC
Sc
PC
O
O
1
MeO
OMe
SET
Sc
O
O
MeO
OMe
O
CO2Me
Sc(OTf)3
2
O
CO2Me
Sc
Sc
O
O
HEH
O
O
MeO
OMe
CO2Me
MeO
OMe
CO2Me
HAT
O
O
With this data in hand and in line with our previous work
on photoredox/Lewis acid cooperative catalysis, we propose
the following mechanism for the observed reactivity (Figure 7):
Irradiation with visible light results in the formation of excited
DPAIPN photocatalyst, a capable oxidant (E1/2 ox = 1.10 V vs.
SCE). Reduction of the resulting DPAIPN excited state by HEH
(E1/2 ox = 0.89 V vs. SCE) furnishes a strongly reducing DPAIPN
catalyst (E1/2 red = –1.52 V vs. SCE). Subsequently, the reduced
DPAIPN species transfers an electron to the Lewis acid-
arylidene malonate complex, producing the nucleophilic
radical anion and regenerating the ground state DPAIPN
catalyst. The radical anion is able to add into the unsaturated
bond, forming the chromane ring and a stabilized radical,
which upon hydrogen atom transfer from the corresponding
HEH radical cation, leads to the enolate complex. Subsequent
proton transfer from the protonated HEH leads to the desired
product.
HEH
HEH
Conclusions
A Lewis acid/photoredox cooperative catalytic manifold is
capable of generating stabilized radical anion species from
salicylaldehyde-derived arylidene malonates has been
developed.
This
reactive
intermediate
undergoes
intramolecular conjugate addition with pendent unsaturated
electrophiles to afford structurally diverse chromanes. This
platform sets the stage for further development of -
Umpolung reactivity via photoredox catalysis, which is
currently underway in our laboratory.
Notes and references
We thank the National Institute of General Medical
Sciences (F31GM116532 to B.R.M. 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 Cancer
Center of Northwestern University. The authors declare no
competing financial interests.
Figure 7: Proposed pathway
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