A General Organocatalytic System for Electron Donor-Acceptor Complex Photoactivation and Its Use in Radical Processes

Article abstract of DOI:10.1021/jacs.1c05607

We report herein a modular class of organic catalysts that, acting as donors, can readily form photoactive electron donor-acceptor (EDA) complexes with a variety of radical precursors. Excitation with visible light generates open-shell intermediates under mild conditions, including nonstabilized carbon radicals and nitrogen-centered radicals. The modular nature of the commercially available xanthogenate and dithiocarbamate anion organocatalysts offers a versatile EDA complex catalytic platform for developing mechanistically distinct radical reactions, encompassing redox-neutral and net-reductive processes. Mechanistic investigations, by means of quantum yield determination, established that a closed catalytic cycle is operational for all of the developed radical processes, highlighting the ability of the organic catalysts to turn over and iteratively drive every catalytic cycle. We also demonstrate how the catalysts' stability and the method's high functional group tolerance could be advantageous for the direct radical functionalization of abundant functional groups, including aliphatic carboxylic acids and amines, and for applications in the late-stage elaboration of biorelevant compounds and enantioselective radical catalysis.

Full text of DOI:10.1021/jacs.1c05607

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Article
A General Organocatalytic System for Electron Donor−Acceptor
Complex Photoactivation and Its Use in Radical Processes
Eduardo de Pedro Beato, Davide Spinnato, Wei Zhou, and Paolo Melchiorre*
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ABSTRACT: We report herein a modular class of organic
catalysts that, acting as donors, can readily form photoactive
electron donor−acceptor (EDA) complexes with a variety of
radical precursors. Excitation with visible light generates open-shell
intermediates under mild conditions, including nonstabilized
carbon radicals and nitrogen-centered radicals. The modular nature
of the commercially available xanthogenate and dithiocarbamate
anion organocatalysts offers a versatile EDA complex catalytic
platform for developing mechanistically distinct radical reactions,
encompassing redox-neutral and net-reductive processes. Mecha-
nistic investigations, by means of quantum yield determination,
established that a closed catalytic cycle is operational for all of the developed radical processes, highlighting the ability of the organic
catalysts to turn over and iteratively drive every catalytic cycle. We also demonstrate how the catalysts’ stability and the method’s
high functional group tolerance could be advantageous for the direct radical functionalization of abundant functional groups,
including aliphatic carboxylic acids and amines, and for applications in the late-stage elaboration of biorelevant compounds and
enantioselective radical catalysis.
catalytic regime would significantly expand its efficiency and
synthetic applicability.
INTRODUCTION
■
The photochemistry of electron donor−acceptor (EDA)
complexes1 is a powerful approach to generating radicals
under mild conditions, providing fresh opportunities in
synthetic chemistry.2 The strategy exploits the association of
an electron acceptor substrate A and a donor molecule D to
form a new molecular aggregate in the ground state (Figure
1a). Although the two components A and D may not absorb
visible light themselves, the resulting EDA complex generally
does. Visible-light excitation then triggers an intramolecular
single-electron transfer (SET), leading to a radical ion pair
([D+•, A−•]). When a suitable leaving group (LG) is present,
an irreversible fragmentation productively renders two reactive
open-shell intermediates, which can engage in synthetically
useful radical processes.2
EDA complex photochemistry has attracted the interest of
chemists because of the ease of operation, the unique ability to
use visible light to activate colorless substances, and the
possibility of generating radicals without exogenous photo-
redox catalysts.3 There are, however, aspects that lower the
generality and versatility of this radical generation strategy. For
example, the most straightforward synthetic application of
EDA complex activation is based on the light-driven coupling
of two stoichiometric donor and acceptor substrates.4 The
moieties of the substrates will eventually end up in the core of
the products, thus restricting their structural diversity.
Implementing the EDA complex activation strategy within a
Moving away from stoichiometric reactivity would require
the use of an electron-rich catalyst that could trigger the EDA
complex formation upon aggregation with an electron-poor
substrate (Figure 1b). A photoinduced SET would then lead to
radicals, which could be intercepted by an external trap to form
a product. The most problematic yet essential step of this
catalytic plan is the effective turnover of the catalyst, which
requires SET reduction of the catalyst radical cation, arising
from the photoactivity of the progenitor EDA complex. So far,
few reported protocols could address this requirement and
develop a catalytic EDA complex strategy.5 Our group
demonstrated that some chiral organocatalytic intermediates,
including enamines,6a−c iminium ions,6d,e and enolates,7 could
serve as catalytic donors in EDA complex formation to trigger
photochemical radical formation while stereoselectively trap-
ping the ensuing open-shell intermediates. One limitation of
this approach was the inability to turn over the catalyst: in fact,
the EDA complex photoactivity served as an initiation step to
Received: June 1, 2021
© XXXX The Authors. Published by
American Chemical Society
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established that a closed catalytic cycle is operational for all
the developed reactions, thus highlighting the ability of the
catalysts to turn over and iteratively drive every catalytic cycle.
Overall, this organocatalytic system offers a simple, general way
to promote a variety of synthetically useful and mechanistically
distinct radical processes.11
RESULTS AND DISCUSSION
■
Background and Design Plan. The present study was
motivated by our interest in developing photochemical
catalytic methods for generating radicals under mild con-
ditions. Recently, we reported that commercially available
nucleophilic organic catalysts, including the dithiocarbamate
anion catalyst A, adorned with an indole chromophoric unit,12
and potassium ethyl xanthate catalyst B,13 can activate alkyl
and acyl electrophiles, including chlorides, via an SN2 pathway
(Figure 2a). Visible-light excitation of the resulting photon-
Figure 1. (a) Photochemistry of stoichiometric EDA complexes for
radical generation. (b) Moving the EDA complex activation strategy
into a catalytic regime: previous examples of catalytic donors. (c) A
new modular class of donor organocatalysts for catalytic EDA
complex photochemistry and their use in radical processes.
feed radicals in a self-propagating chain process.6b−d Bosque
and Bach8 and Stephenson and co-workers9 recently reported
different strategies that could effectively turn over catalytic
electron-donors. These catalytic platforms were unfortunately
limited to the activation of specific radical precursors, which
intrinsically narrowed their synthetic applicability and general-
ity. A more flexible EDA complex catalytic approach was
disclosed by Shang and Fu and their co-workers, who
described how a combination of triphenylphosphine (Ph3P)
and sodium iodide (NaI) could catalyze synthetically useful
radical reactions.10 This catalytic platform could trigger the
formation of photoactive three-component EDA complexes
with a variety of radical precursors. However, all these previous
strategies were limited to the development of redox-neutral
radical processes only.
Figure 2. (a) Our recently developed SN2-based radical generation
method using nucleophilic organocatalysts A and B and the key
turnover event, based on the reduction of the persistent radical II via
either SET or HAT. (b) Translating the potential of catalysts A and B
into an EDA complex photoactivation strategy: their use as catalytic
donors to generate nonstabilized radicals. RA: redox auxiliary, which
drives EDA complex formation and acts as a fragmenting group.
Herein, we report a general and modular class of electron-
donor organocatalysts that, although they cannot absorb visible
light themselves, can readily form photoactive EDA complexes
with different radical precursors (Figure 1c). Specifically,
commercially available dithiocarbamate anion and xanthogen-
ate catalysts A and B can generate a variety of radicals under
blue-light excitation, including nonstabilized primary carbon
radicals and nitrogen-centered radicals. The modular nature of
these organic catalysts allowed us to tune their properties,
including stability toward acidic conditions, thus offering a
versatile and robust EDA catalytic strategy. This flexibility
secured the development of both redox neutral and net-
reductive photoinduced radical processes. Mechanistic inves-
tigations, by means of quantum yield determination,
absorbing intermediates I afforded radicals upon homolytic
cleavage of the weak C−S bond. A merit of this SN2-based
catalytic platform is that, by relying solely on the electrophilic
properties of the precursors, it could grant access to open-shell
intermediates from substrates that would be inert to classical
radical-generating strategies. Its underlying mechanism, how-
ever, also limited the approach, since only substrates amenable
to an SN2 displacement could be used. In addition, only
stabilized radicals (including benzyl, allyl, and radicals bearing
either a heteroatom or an electron-withdrawing moiety at the
α-position) could be effectively generated and used in a variety
of C−C12−14 and C−B bond-forming processes.14c
B
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Extensive mechanistic studies13 allowed us to elucidate a
crucial aspect of this system, namely, the mechanism of catalyst
turnover. Specifically, we found that the sulfur radical II, which
emerges from the photolytic cleavage of intermediate I, can
dimerize to form III.13,14a Dimer III, which can absorb in the
visible region, is in a light-regulated equilibrium with the
progenitor sulfur-centered radical II. This dimerization
manifold, by conferring a longer lifetime to radical II,15
enables an effective catalyst turnover. We demonstrated that
the sulfur-centered radical II, which has a persistent character,
can be effectively reduced and turned over by an SET event or
by a hydrogen atom transfer (HAT) process.13
The versatile mechanism underpinning catalyst turnover,
along with the electron-rich nature of A and B, made us
wonder if these organic catalysts could be successfully used as
catalytic donors for EDA complex photoactivation (Figure 2b).
We were motivated by the following considerations: (i) it is
synthetically appealing to develop a general EDA complex
catalytic strategy based on commercially available organic
catalysts and use it to generate a variety of radicals. (ii) Our
understanding of the sulfur-centered radical II behavior, which
would be generated upon EDA complex formation and
photoinduced SET, may help in the design of photoinduced
radical processes. By ensuring that different paths are available
for turning over the catalyst, the relative kinetic stability of II
could be used to develop mechanistically distinct radical
transformations, including net-reductive processes that are not
accessible via previously reported EDA complex catalytic
platforms.8−10 (iii) Using A and B as catalytic EDA donors
would significantly expand the synthetic potential and
applicability of this family of organocatalysts beyond the
SN2-based catalytic platform.12−14 This is because radical
precursors not prone to an SN2 displacement could also
become competent substrates. For example, using reaction
partners decorated with a purposely installed electron-poor
activating group, which serves as both a redox-auxiliary (RA,
blue circle in Figure 2b, which triggers EDA complex
formation) and leaving group, would allow the generation of
previously inaccessible nonstabilized carbon radicals, including
primary ones, and nitrogen-centered radicals.
Developing a Net-Reductive Process. To test the
feasibility of our EDA complex catalytic strategy, we
investigated the reaction of cyclohexyl N-(acyloxy)-
phthalimide16 1a and vinyl sulfone 2a catalyzed by the organic
catalysts A and B. We selected this process as a testbed because
it would require the photochemical formation of a non-
stabilized cyclohexyl radical IV, which could not be generated
using our previous SN2-based catalytic strategy.12−14 Mecha-
nistically, the resulting Giese-type addition17 of the cyclohexyl
radical IV to the electron-poor olefin 2a would require a net-
reductive pathway in order to proceed. Figure 3 details the
proposed mechanism of the overall process. The ground-state
association between the electron-rich donor catalyst (A or B)
and the electron-poor substrate 1a would lead to a visible-light-
absorbing EDA complex. The formation of the EDA complex
is feasible considering the tendency of stoichiometric thiolates
and dithiocarbonyl anions to serve as donor partners for EDA
complexes.18 A photoinduced SET would then generate the
cyclohexyl radical IV along with the sulfur-centered radical II.
Upon interception of radical IV by 2a to forge a new C−C
bond, the emerging electrophilic radical V would abstract a
hydrogen atom from γ-terpinene (a H donor). This reductive
step leads to product 3a and to the cyclohexadienyl radical VI.
Figure 3. Mechanistic plan for a net-reductive Giese-type addition
manifold catalyzed by the excitation of a catalytic EDA complex.
NPhth: phthalimide.
Overall, this sequence, which requires reduction of both the
radical precursor 1a (via an SET) and intermediate V (via
HAT), characterizes a net-reductive process. Crucial for
catalyst turnover would be the reduction of the dithiocarbonyl
radical II (Eox = 0.45−0.75 V vs SCE), which our previous
studies established could proceed via an SET event from the
cyclohexadienyl radical VI (Ered = −0.1 V vs SCE)12 or via an
HAT pathway from γ-terpinene.13 Both reductive steps would
eventually close the catalytic cycle by returning the organic
catalysts. Importantly, the fact that catalyst turnover can be
realized by simply using an external reductant (e.g., γ-terpinene),
thus avoiding any specific interaction with a radical
intermediate that is a progenitor to the reaction product,
increases the versatility of this EDA catalytic system.
We conducted initial experiments reacting substrates 1a and
2a at 40 °C in dimethylacetamide (DMA) using a blue light-
emitting diode (LED) strip emitting at 465 nm, γ-terpinene as
the H donor (4 equiv), and 10 mol % of the donor catalyst
(Table 1). The commercially available indole-containing
dithiocarbonyl anion catalyst A and potassium ethyl xanthate
catalyst B both provided the target Giese addition product 3a
with high chemical yield (entries 1 and 2). Sodium
diethyldithiocarbamate C was also a suitable catalyst for this
transformation (entry 3). These results established that
catalysts with different properties can be used as suitable
EDA donors; for example, the dithiocarbonyl catalyst A
possesses a higher electron-donor ability than B, as inferred by
their redox properties,19 and it is more stable under acidic
conditions (see section D1.4 in Supporting Information for
details). The modular nature of these catalysts can therefore
offer a versatile EDA complex catalytic platform. Further
investigations were conducted using the inexpensive catalyst B.
Interestingly, the reaction was also promoted by green light
(λmax = 520 nm, entry 4), while the presence of air was
deleterious for reactivity (entries 5). Control experiments
showed the need for light and for the donor catalyst (entries 6
and 7). In addition, the reactivity was completely inhibited
(entry 8) in the presence of a radical scavenger (TEMPO;
interception of the cyclohexyl radical was observed and results
are detailed in section D1.3 of the Supporting Information).
C
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a
Table 1. Optimization Studies
b
entry
catalyst
deviation
yield (%)
1
2
3
4
5
6
7
8
A
B
C
B
B
B
none
B
none
none
none
81
95 (86)
85
95
0
0
0
0
c
Figure 5. Absorption at 620 nm of the transient xanthyl radical IIa
generated upon 355 nm laser excitation of a 1:1 mixture of 1a and
catalyst B (30 mM) in DMA.
green LED (520 nm)
under air
no light
none
0.01 ms), consistent with the characteristic line shape of
xanthyl radical IIa.13 This observation corroborates the idea
that the key event for radical generation is the photoinduced
intracomplex SET within the EDA complex, formed between
1a and B.
TEMPO (1.5 equiv)
a
Reactions were performed under inert atmosphere on a 0.1 mmol
scale at 40 °C for 16 h under illumination by a blue LED strip (λmax
465 nm, 14 W) using 1.5 equiv of 2a and 4 equiv of γ-terpinene.
Redox potentials of the catalysts were measured in CH3CN vs Ag/
AgCl; see section D4 in the SI for details. Cy: cyclohexyl. NPhth:
phthalimide. Yield determined by H NMR analysis of the crude
mixture using trimethoxybenzene as the internal standard. Yield of
=
To gain further insight into the mechanism, we measure the
quantum yield (Φ) of the overall model reaction of 1a and 2a
catalyzed by B, which was as low as 0.01 (λ = 460 nm, using
potassium ferrioxalate as the actinometer; see section D.5 in
Supporting Information for details). This information, which is
not consonant with a radical chain propagation manifold,
corroborates the mechanistic scenario depicted in Figure 3: it
supports our original plan that the donor B serves as an actual
EDA catalyst, since it can effectively turn over while iteratively
driving the formation of radicals in every catalytic cycle.
To increase the synthetic utility of our approach, we sought
to implement a two-step telescoped sequence to form the
redox-active radical precursor 1a in situ and use it without
further purification (Scheme 1a). This one-pot procedure
granted access to product 3a from readily available cyclo-
hexanecarboxylic acid upon simple treatment with N-
(hydroxy)phthalimide (NHPI). In addition, catalyst B proved
compatible with a direct domino protocol, where all the
reagents were added together at the onset of the reaction
(Scheme 1b). These methods add a synthetically useful
b
1
c
the isolated product 3a.
We then performed additional mechanistically diagnostic
investigations. The formation of an EDA complex under the
reaction conditions was confirmed through UV/vis spectro-
scopic analysis (Figure 4). Immediately after mixing catalyst B
Scheme 1. (a) One-Pot Two-Step Telescoped Procedure to
a
Functionalize the Carboxylic Acid and (b) Domino
Procedure, Where All Reagents Were Added at the Same
b c
,
Time
Figure 4. Optical absorption spectra, recorded in DMA in 1 mm path
length quartz cuvettes using a Shimadzu 2401PC UV/vis spectropho-
tometer, and visual appearance of the separate reaction components
and of the colored EDA complex between catalyst B and 1a. [1a] =
0.10 M, [B] = 0.01 M.
with the phthalimide ester substrate 1a, the solution developed
a marked yellow color, while its optical absorption spectrum
showed a bathochromic displacement in the visible spectral
region, diagnostic of a new EDA molecular aggregation in the
ground state.
In addition, we detected the formation of the xanthyl radical
IIa by means of laser flash photolysis (Figure 5). Accordingly,
when a 1:1 mixture of 1a and catalyst B was excited with a laser
beam centered at 355 nm, we observed the formation of a
transient species absorbing at 620 nm (half lifetime = 0.1
a
b
The solvent was evaporated between the two steps. Yields refer to
c
the isolated product 3a. Abbreviations: DIC, N,N′-diisopropylcarbo-
diimide; NHPI, N-(hydroxy)phthalimide; DCM, dichloromethane.
D
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Figure 6. EDA complex catalytic strategy for the generation of alkyl radicals from carboxylic acids and their use in decarboxylative Giese addition
processes. Reactions were performed on a 0.2 mmol scale using 1 equiv of acid 1. Yields of products refer to isolated products 3 after purification.
The bold orange bond denotes the newly formed C−C bonds. Unless otherwise indicated, all entries were performed using a telescoped sequence
a
without isolation of the phthalimide ester 1 by simply evaporating the solvent (DCM) after completion of the first step. Notes: Using the
b
preformed phthalimide ester 1 as the radical precursor. One-pot domino procedure according to the conditions in Scheme 1b. Abbreviations:
NHPI, N-hydroxyphthalimide; DIC, N,N′-diisopropylcarbodiimide; Cy, cyclohexyl; Pr, propyl; Boc, tert-butyloxycarbonyl; Cbz, carboxybenzyl; Bn,
benzyl; Ts, tosyl; EWG, electron-withdrawing group.
dimension to the EDA complex catalytic platform, since
abundant aliphatic carboxylic acids can be directly function-
alized and used as radical precursors without the need to
isolate complex phthalimide esters.
We then used the telescoped procedure to evaluate the
scope of the decarboxylative Giese-type addition protocol
catalyzed by the EDA donor B (Figure 6). A variety of
carboxylic acids could be directly functionalized. Primary
(products 3b and 3e), secondary (3c), and tertiary (3d)
radicals were generated efficiently and trapped with different
electron-poor olefins in good to excellent yields. The protocol
tolerated a variety of functional groups. For example, amino
acids could be used as radical precursors (adducts 3f−i), while
a precursor bearing a chloride substituent selectively reacted at
the carboxylic moiety under the optimized conditions (3e).
We also demonstrated that this method is suitable for the
direct functionalization of biorelevant compounds bearing
unprotected polar functional groups. For example, oleanolic
acid (3j), which contains a free hydroxyl group, dehydrocholic
Figure 7. (a) EDA complex catalytic strategy for the deaminative
Giese-type addition processes. Note: Product 3m was formed in a
3.8:1 ratio with the regioisomeric five-member ring adduct; see the
a
acid (3k), and biotin (3l) could all be efficiently functionalized.
We finally demonstrated that the one-pot domino procedure
detailed in Scheme 1b could be applied to directly function-
alize complex carboxylic acid substrates (adducts 3g, 3j, and
3l).
To further explore the potential of our photochemical
catalytic radical generation method, we investigated the
activation of pyridinium salts 4. Substrates 4 are prone to
EDA complex formation, acting as acceptors, and can provide
alkyl radicals upon SET activation.19 The indole-based
dithiocarbamate catalyst A proved more effective than catalyst
B for the EDA complex activation of pyridinium salts 4 (see
sections D1.2 and D1.4 in Supporting Information for details).
This result highlights how the modular nature of these donor
catalysts can be leveraged to optimize the activation of
electronically different radical precursors.20
Supporting Information for details. (b) One-pot telescoped procedure
for functionalized amines. Reactions were performed on a 0.2 mmol
scale.
approach to the decarboxylative Giese-type addition protocol,
since radical precursors 4 can be readily synthesized from
amines. The applicability of the method was also showcased by
developing a one-pot telescoped procedure where the primary
amine 5 could be directly converted to product 3n through the
in situ formation of the corresponding pyridinium salt 4
(Figure 7b). This telescoped procedure did not require any
evaporation of the solvent and could be performed by simply
adding the reagents sequentially.
We then envisaged that the same catalytic protocol used for
the Giese-type addition could be successfully translated to
perform a Barton decarboxylation process.21 When conducted
in the absence of an olefin trap 2, the EDA-complex-based
catalytic system would provide an alkyl radical prone to
hydrogen atom abstraction (via HAT) from γ-terpinene,
delivering the decarboxylation reductive product 6. We
We therefore used catalyst A (20 mol %) to trigger the
formation of nonstabilized secondary carbon radicals from 4,
which were readily intercepted by electron-poor olefins (Figure
7a). This deamination strategy offers a complementary
E
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demonstrated the feasibility of this idea by applying a one-pot
domino process, which allowed the direct reduction of
carboxylic acids (Figure 8).
Scheme 2. EDA Complex Catalysis for Deaminative
Reduction
chain process is highly unlikely, confirming the ability of the
EDA catalytic donor to turn over and repeatedly trigger radical
formation.
Developing a Redox-Neutral Process. The Giese
addition and the Barton decarboxylation processes developed
so far proceed via a net-reductive mechanism. One of our
targets was to identify a versatile EDA complex catalytic
platform suitable for the design of radical processes based on
mechanistically divergent mechanisms. We considered the
radical α-alkylation of silyl enol ethers 7 as a suitable test
reaction to implement a redox-neutral process. We envisaged a
catalytic cycle (Figure 9) where the excitation of the catalytic
Figure 8. EDA complex catalysis for the Barton decarboxylation.
Reactions were performed on a 0.2 mmol scale using a one-pot
domino process. Yields refer to isolated products 6 after purification.
The bold orange bond denotes the newly formed bonds.
Abbreviations: NHPI, N-hydroxyphthalimide; DIC, N,N′-diisopro-
pylcarbodiimide; Boc, tert-butyloxycarbonyl; Bn, benzyl.
The xanthogenate catalyst B (10 mol %) secured an effective
activation of the phthalimide ester substrate generated in
situ.20 Primary (adduct 6a), secondary (6b), and tertiary (6c)
acids were all competent substrates in this experimentally
simple protocol. The Barton decarboxylation has found broad
application in total synthesis.22 We therefore tested our
methodology in the reduction of complex biologically relevant
carboxylic acid-containing molecules, including gibberellic acid
(6f) and a baclofen derivative (product 6g). The functionaliza-
tion of dehydrocholic acid, leading to product 6d, was
efficiently performed on a 4 mmol scale, demonstrating that
this method is amenable to synthetically useful applications.
Finally, this catalytic process could be extended to include a
deaminative reduction path, since pyridinium salts 4 were used
as radical precursors, leading to products 6 (Scheme 2). Here,
too, the indole-based catalyst A was the donor catalyst of
choice for the activation of 4.
Mechanistically, we propose that this process proceeds via a
net-reductive manifold resembling the general catalytic cycle
depicted in Figure 3. The radical of type IV emerging from the
EDA complex photoactivity is quenched by γ-terpinene to
afford the reduced product 6, while the dithiocarbonyl radical
II can be reduced by a SET (from the cyclohexadienyl radical
VI) or HAT manifold (from γ-terpinene). To corroborate this
scenario, we measured the quantum yield of the Barton
decarboxylation leading to product 6b using the corresponding
preformed phthalimide ester radical precursor. The quantum
yield Φ was found to be 0.01 (λ = 460 nm, using potassium
ferrioxalate as the actinometer). This indicates that a radical-
Figure 9. Mechanistic plan for a redox-neutral transformation
catalyzed by the excitation of a catalytic EDA complex.
EDA complex, formed upon association of the donor catalyst
with a radical precursor, such as the pyridinium salts 4, forms
the target radical IV. The silyl enol ether 7 would then
intercept IV, leading to the α-oxo radical VII. SET between
VII and the sulfur-centered radical II, which is stabilized by a
dimerization mechanism, would regenerate the EDA catalytic
donor and form the oxocarbenium ion VIII, which can
hydrolyze to afford the final α-alkylation ketone product 8. The
overall sequence requires reduction of the radical precursor 4
and oxidation of intermediate VII, therefore constituting a
redox-neutral process. In contrast to previous processes, an
effective catalyst turnover would here require an SET between
the sulfur radical II and a radical intermediate progenitor of the
reaction product VII.
Our catalytic platform was flexible enough to accommodate
this mechanistic requirement. Both EDA catalysts A and B
could effectively trigger the photochemical radical alkylation of
silyl enol ethers (see section D1.2 in the Supporting
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Figure 10. Redox-neutral addition of alkyl radicals to silyl enol ethers under EDA complex catalysis. Reactions were performed on a 0.2 mmol scale
using 2.0 mL of DMSO. Yields refer to isolated products 8 after purification. The bold orange bond denotes the newly formed C−C bond. Unless
otherwise indicated, all entries were performed at 25 °C. Notes: a40 °C; b60 °C; c1:1 mixture of DMSO/DCE used as solvent; ein the absence of
f
water; using alkyl N-(acyloxy)phthalimides 1 as radical precursors. TBS: tert-butyldimethylsilyl.
Information for a comparison of the catalysts’ performance).
Since the indole-based dithiocarbamate catalyst A offered
better and more consistent results, it was selected to evaluate
the generality of the process (Figure 10). A broad range of
pyridinium salts 4 could be used as precursors of electrophilic
radicals, which were trapped by 7. Both primary radicals
(product 8a), including benzylic ones (8b), and secondary
carbon radicals (adducts 8c,d) could be generated and
intercepted. The approach displayed a good tolerance toward
heterocycles containing nitrogen atoms (adducts 8e,f). We
then demonstrated that silyl enol ethers 7 derived from both
aliphatic (product 8g) and aromatic ketones could intercept an
electrophilic α-ester radical. A variety of substitution patterns
on the aryl ring, with different electronic or steric profiles (8h−
k), could be easily accommodated. An easily oxidizable
heterocyclic substrate (8i) was tolerated. In addition, a
substrate derived from azaperone, containing an aminopyridine
and a piperazine moiety, could be alkylated in moderate yield
(8m). Last, nonstabilized secondary and primary radicals could
be effectively generated from phthalimide esters 1 and
successfully intercepted, providing products 8n and 8o in
moderate yield.23
Figure 11. Three-component process under EDA complex catalysis.
NPhth: phthalimide.
Given the different underlying mechanism of this redox-
neutral process with respect to previously studied net-reductive
transformations, we considered it pertinent to determine the
quantum yield of the reaction leading to product 8h. The very
low quantum yield (Φ = 0.02, λ = 460 nm) supports the
mechanism depicted in Figure 9, where the EDA donor
catalyst A is responsible for the formation of every radical and
can effectively turn over by engaging in both a reduction and
an oxidation process.
We then set out to develop a three-component reaction
under EDA complex catalysis that combined a Giese addition
with the radical trap by silyl enol ethers 7 (Figure 11).
Specifically, we used phthalimide ester substrates 1 to generate
nucleophilic radicals. Capitalizing upon the mismatched
polarity between the photogenerated radical and the
electron-rich silyl enol ether 7, we first favored the selective
radical trap by an electron-poor olefin 2. The electron-deficient
secondary radical emerging from this Giese-addition manifold
had the right polarity to rapidly react with 7, affording the
complex cascade products 9. This cascade sequence, which is
reported here for the first time, was efficiently catalyzed by the
xanthate catalyst B,20 providing rapid access to structurally
complex products 9 from readily available substrates and using
an experimentally simple protocol.
We then wondered if this EDA complex catalytic platform
could be applied to develop another redox-neutral process,
G
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namely, the radical C-alkylation of heteroarenes. The Minisci
reaction involves the addition of a nucleophilic carbon-
centered radical onto a protonated heteroaromatic compound.
It is widely used in organic synthesis since it offers a direct way
to functionalize heterocycles.24 Different variants of this
transformation have been reported using a variety of alkyl
radical precursors.25 These methods require a rearomatization
of the radical cation IX, generated upon radical addition to the
protonated heteroarene, which proceeds via an SET oxidation
using either a stoichiometric oxidant or photoredox catalysis
(Figure 12). We surmised that our EDA catalysts can first
Remarkable functional group tolerance was observed, since the
reaction conditions tolerate protected amines (11g) and
unprotected alcohols (11h−j). To demonstrate the synthetic
utility of the method, we successfully performed the alkylation
of an intermediate used in the synthesis of the HIF protyl-
hydroxylase inhibitor roxadustat (products 11h−i), the
anticancer agent camptothecin (11j), and the neuroleptic
drug azaperone (11k). Importantly, this catalytic method
could be applied for the direct methylation of heterocycles
(adducts 11c, 11g, and 11i), a useful process given the unique
pharmacokinetic properties inferred by the methyl substituent
to medicinally relevant azine derivatives.28 Finally, we
demonstrated that a variety of primary, secondary, and tertiary
carbon-centered radicals could be generated from phthalimide
ester precursors 1 and installed within 2-methylquinoline
(products 11l−p). A list of unsuccessful substrates for all the
reactions discussed in this study is reported in section C9 of
the Supporting Information.
Figure 12. Common mechanistic pathway in Minisci-type reactions
and its integration with our EDA complex catalytic strategy.
We measured the quantum yield of the Minisci reaction
leading to product 11b, which was <0.01 (λ = 460 nm, using
potassium ferrioxalate as the actinometer; see section D.5 in
Supporting Information for details). This experiment further
supports the ability of donor A to catalyze the photochemical
generation of alkyl radicals while triggering the overall Minisci
process in the absence of external oxidants.
Finally, we envisioned that our EDA catalytic platform could
be compatible with the enantioselective Minisci protocol
recently reported by Phipps and co-workers,29 who used a
chiral phosphoric acid [(R)-TRIP, Scheme 3] to direct the
stereoselective addition of prochiral radicals, generated using
an external iridium-based photocatalyst, to heteroarenes. The
EDA donor catalyst A was successfully applied in this
generate the carbon radicals and then oxidize intermediate IX
(Ered = −1.01 V vs SCE),26 capitalizing on the kinetic stability
of the sulfur-centered radical IIa (Eox = 0.45 V vs SCE, Table
1). The last step would provide the Minisci product while
returning the EDA donor catalyst.20
This idea was successfully realized using the indole-based
catalyst A (10 mol %), which offered a better stability than
catalyst B under the acidic conditions20,27 required for the
Minisci process (Figure 13). Using preformed substrates 1 as
radical precursors, we first explored the scope of the
heterocycles amenable to this Minisci-type catalytic protocol.
Quinolines (products 11a−c), isoquinolines (11d), and
pyridine (11e) derivatives were all competent substrates.
Figure 13. Photochemical catalytic generation of alkyl radicals and their addition to heterocycles. Reactions were performed on a 0.2 mmol scale
using 2.0 mL of DMSO. Yields refer to isolated products 11 after purification. The bold orange bond denotes the newly formed C−C bond. Notes:
b
c
aperformed in NMP as solvent; 3 equiv of TfOH; performed at 60 °C. Abbreviations: Cy, cyclohexyl; Ts, tosyl; NPhth, phthalimide.
H
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Article
modular nature of the commercially available organocatalysts
served to develop mechanistically distinct photoinduced redox-
neutral and net-reductive radical transformations. For all the
developed processes, we established, by means of quantum
yield determination, that a closed catalytic cycle is operational,
highlighting the ability of the EDA catalysts to turn over and
iteratively drive every catalytic cycle. We also highlighted how
the catalysts’ stability and the method’s high functional group
tolerance could be advantageous for the direct radical
functionalization of abundant functional groups, including
aliphatic carboxylic acids and amines, and for applications in
the late-stage elaboration of biorelevant compounds and
enantioselective radical catalysis. All these features showcase
the versatility of this EDA complex catalytic platform, which
may be useful for developing further radical processes.
Scheme 3. Application in Enantioselective Radical
Catalysis
a
a
Abbreviations: Ac, acetyl; NPhth, phthalimide.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05607.
■
asymmetric radical process, affording the chiral products 11q
and 11r in high yield and stereocontrol.
sı
Further Synthetic Applications of the EDA Catalytic
System. The general applicability of a chemical strategy is a
suitable parameter for evaluating its usefulness. To further
explore the potential of our EDA catalytic radical generation
approach, we investigated the activation of other radical
precursors that can form an EDA complex. For example, we
found that catalyst A can effectively promote the formation of a
trifluoromethyl radical upon EDA complex activation of the
Togni reagent 12 (Scheme 4).30 An effective radical trap by
silyl enol ether 7a afforded the α-trifluoromethyl ketone
product 13.
Details of experimental procedures and full character-
ization data and copies of NMR and HPLC spectra for
synthesized compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Paolo Melchiorre − ICIQInstitute of Chemical Research of
Catalonia, the Barcelona Institute of Science and Technology,
43007 Tarragona, Spain; ICREACatalan Institution for
Research and Advanced Studies, 08010 Barcelona, Spain;
orcid.org/0000-0001-8722-4602; Email: pmelchiorre@
iciq.es
Scheme 4. Trifluoromethylation of Ketones via EDA
Complex Catalysis
Authors
Eduardo de Pedro Beato − ICIQInstitute of Chemical
Research of Catalonia, the Barcelona Institute of Science and
Technology, 43007 Tarragona, Spain
Davide Spinnato − ICIQInstitute of Chemical Research of
Catalonia, the Barcelona Institute of Science and Technology,
43007 Tarragona, Spain
Wei Zhou − ICIQInstitute of Chemical Research of
Catalonia, the Barcelona Institute of Science and Technology,
43007 Tarragona, Spain
We also used the xanthate catalyst B to generate an amidyl
radical upon EDA complex activation of the dinitrophenoxy
amide 14 (Scheme 5).31 Radical cyclization afforded the
lactam product 15 in high yield.
Scheme 5. Amidyl Radical Formation and Cyclization
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05607
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Agencia Estatal de
Investigación (PID2019-106278GB-I00), the AGAUR (Grant
2017 SGR 981), and the European Research Council (ERC-
2015-CoG 681840-CATA-LUX). E.P.B. thanks MINECO
(CTQ2016-75520-P) for a predoctoral fellowship. W.Z. thanks
the China Scholarship Council (CSC201908310093) for a
predoctoral fellowship.
CONCLUSION
■
In summary, we have reported a modular class of organic
catalysts that, acting as donors, can readily form photoactive
electron donor−acceptor (EDA) complexes with a wide variety
of radical precursors. Excitation with weak visible light grants
access to stabilized and nonstabilized alkyl radicals under mild
experimental conditions. The generated radicals were then
leveraged to design synthetically useful transformations. The
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