General access to C-centered radicals: Combining a bioinspired photocatalyst with boronic acids in aqueous media

Article abstract of DOI:10.1021/acscatal.0c03422

Carbon-centered radicals are indispensable building blocks for modern synthetic chemistry. In recent years, visible light photoredox catalysis has become a promising avenue to access C-centered radicals from a broad array of latent functional groups, including boronic acids. Herein, we present an aqueous protocol wherein water features a starring role to help transform aliphatic, aromatic, and heteroaromatic boronic acids to C-centered radicals with a bioinspired flavin photocatalyst. These radicals are used to deliver a diverse pool of alkylated products, including three pharmaceutically relevant compounds, via open-shell conjugate addition to disparate Michael acceptors. The mechanism of the reaction is investigated by computational studies, deuterium labeling, radical-trapping experiments, and spectroscopic analysis.

Full text of DOI:10.1021/acscatal.0c03422

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Research Article
General Access to C‑Centered Radicals: Combining a Bioinspired
Photocatalyst with Boronic Acids in Aqueous Media
Maheshwerreddy Chilamari, Jacob R. Immel, and Steven Bloom*
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ABSTRACT: Carbon-centered radicals are indispensable building blocks for modern synthetic chemistry. In recent years, visible
light photoredox catalysis has become a promising avenue to access C-centered radicals from a broad array of latent functional
groups, including boronic acids. Herein, we present an aqueous protocol wherein water features a starring role to help transform
aliphatic, aromatic, and heteroaromatic boronic acids to C-centered radicals with a bioinspired flavin photocatalyst. These radicals
are used to deliver a diverse pool of alkylated products, including three pharmaceutically relevant compounds, via open-shell
conjugate addition to disparate Michael acceptors. The mechanism of the reaction is investigated by computational studies,
deuterium labeling, radical-trapping experiments, and spectroscopic analysis.
KEYWORDS: radical, biocompatible, photoredox catalysis, flavin, boronic acid
C-centered radicals (namely, sp2C• and sp3C•) are useful
intermediates in the preparation of natural products,
pharmaceuticals, and agrochemicals.1 Owing to their broad
utility, a number of powerful photocatalytic platforms
including C−H or C−halogen abstraction, single-electron
oxidation or reduction, and energy transferhave evolved to
convert molecules containing both innate (i.e., carboxylic
acids, alkenes, alcohols, halides, and C−H bonds) and
synthetic (i.e., phthalimides, oxalates, diazonium salts, and
silicates) functional groups into chemically reactive C-centered
radicals.2 In many instances, these photocatalytic paradigms
offer a milder and more sustainable route to C-centered
radicals3 as compared to complementary procedures employ-
ing stoichiometric reagents (e.g., tin hydrides,4 manganese(III)
acyloxy derivatives,5 trialkylboranes,6 and borohydrides7 or
other metal salts8). Furthermore, use of photocatalysts enables
C-centered radicals to be parlayed with a more diverse pool of
acceptor molecules through redox-neutral processes, thereby
expanding their applications in chemical synthesis.9 For these
reasons, development of photocatalytic strategies to access C-
centered radicals from commercially available or easily installed
functional groups has become an active area of research.
Recently, use of photocatalysts for controlled oxidation of
boronic acids (ubiquitous reagents in organic synthesis10 and
substituents in many biologically active molecules11) and
trifluoroborates12 to yield C-centered radicals has been
explored. In the case of boronic acids, coordinately saturated
iridium photocatalysts (i.e., (Ir[dF(CF3)ppy]2(dtbpy))PF6))13
and organic photocatalysts (i.e., 10-(3,5-dimethoxyphenyl)-9-
mesityl-1,3,6,8-tetramethoxyacridin-10-ium BF4 and phenan-
threne)14 are employed in place of standard metal salts (Mn3+,
Ag1+, Fe2+/3+, Ni2+, Bi3+)15 to facilitate formation of aryl and
alkyl radicals, which can be subsequently captured by an array
of Michael acceptors to afford C−C coupled products.
Unfortunately, these photocatalysts are only mildly effective
on their own and call for addition of strong ionic bases
(NaOH)14b or Lewis bases (DMAP)16 to assist boronic acid
oxidation through formation of labile boronate or amino−
boryl complexes, respectively. These additives can potentially
hinder the scope of boronic acids. In alkaline media (pH 11−
13), many boronic acids, including several classes of hetero-
cycles, are prone to protodeboronation by Kuivila (base-
catalyzed) and Perrin (specific-base catalyzed) mechanisms.
Base-mediated protodeboronation can likewise occur via
concentration-dependent autocatalysis or by a direct reaction
with water (often with more basic heterocycles).17 These
Received: August 5, 2020
Revised: October 6, 2020
https://dx.doi.org/10.1021/acscatal.0c03422
© XXXX American Chemical Society
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mechanisms can be accelerated in the presence of UV−vis
light.18 Lewis bases can compete with the oxidation of
electron-deficient boronic acids by reductively quenching the
photocatalyst.19 Whether by these constraints or others,
established photocatalytic methods have yet to demonstrate
wide success with heteroaromatic boronic acids (i.e., N-, O-,
and S-containing).20 Discovery of a more comprehensive
method might well enhance the utility of boronic acids in
chemical synthesis and drug development.
With a focus on the present conundrum of generality, we
gathered that a photocatalyzed method that avoids the use of
exogenous activating reagents could minimize boronic acid
decomposition or undesirable side reactions and permit mild
access to C-centered radicals. To this end, boronic acids are
known to form Lewis base adducts with water and/or low
concentrations of boronate salts at physiological pH.21 These
electron-rich intermediates should be more susceptible to
single-electron oxidation. A catalytic system that leverages
water as a primary solvent might, therefore, obviate the need
for ionic- or amine-base activation altogether (Figure 1).
Furthermore, by generating C-centered radicals in aqueous
formation of C-centered radicals is deemed essential to our
design plan. Initially, we found inspiration from nature in the
way of flavin monooxygenases. This family of flavoenzymes
houses a conserved flavin cofactor which is able to transform
aromatic boronic acids to aromatic alcohols harnessing
molecular O2.25 As photocatalysts, flavin cofactors have also
been shown to act as single-electron photo-oxidants26 or
reductants27 in deaerated water under visible light irradiation.
Intrigued by their open-shell reactivity and ability to oxidize
boronic acids under biocompatible conditions, we postulated
that a flavin-derived cofactor might be an ideal photocatalyst to
access radicals in a highly general manner. Once formed, we
surmised that the radicals could engage a Michael acceptor to
furnish a stable conjugate addition product, an overall process
hereafter referred to as deborylative−alkylation. Now, we
disclose our recent findings in which a flavin-based photo-
catalyst, lumiflavin (LF), can be used to convert an array of
commercially available heteroaromatic, aromatic, and aliphatic
boronic acids to valuable alkylated products under innocuous,
biocompatible, and general conditions with visible light.
To begin our investigations, we examined heteroaromatic
(N-containing) boronic acids, being less explored in previous
reports. We selected pyridine-3-boronic acid (stable to
protodeboronation; t0.5 > 1 week, pH 12, 70 °C)17 as a
prototypical heterocycle and diethyl ethylidenemalonate
(DEEM) as a Michael acceptor. Accordingly, a mixture of
Michael acceptor and excess pyridine-3-boronic acid was
irradiated in the presence of various flavin photocatalysts using
10 mM phosphate buffer with 5% (v:v) DMF as solvent. In the
case of lumiflavin, we observed small quantities of the desired
3-alkylpyridine product following 16 h of irradiation (40W
blue LED). We also observed formation of 3-hydroxypyridine
as a minor byproduct along with large amounts of unaltered
pyridine-3-boronic acid. Anodic substitution reactions of
aromatic organoboron compounds have previously been
documented.28 In the absence of any residual oxygen, the
propensity for flavin photocatalysts to perform two sequential
single-electron oxidation events29 might well lead to an aryl
cation which can be trapped by water or OH− under our
reaction conditions. Interestingly, increased amounts of 3-
hydroxypyridine were found in the case of less effective flavin
photocatalysts. In line with these results, we suspected that 3-
hydroxypyridine might act as a poison through competitive
oxidation (Epox ≈ 0.9 V vs SCE in H2O pH 7.4)30 in lieu of the
less readily oxidized 3-pyridineboronic acid (for reference,
ox
phenylboronic acid is Ep = 2.55 V vs SCE and potassium
phenyltrifluoroborate is Ep = 1.95 V vs SCE).31 Indeed,
ox
adding 10 mol % or 1 equiv of 3-hydroxypyrdine to our
standard reaction mixture resulted in no product formation
and no consumption of pyridine-3-boronic acid. At this point,
we gathered that modifying the pH of the reaction and
changing the organic cosolvent could ameliorate background
aryl−alcohol formation and enhance reaction efficiency. By
adjusting the reaction to pH 7.8 with ammonium formate
buffer and using methyl acetate (5% v:v), formation of alcohol
could be substantially diminished and the yield of alkylated
pyridine improved to 11%. Sufficient quantities of pyridine-3-
boronic acid still remained. Increasing the amount of organic
cosolvent beyond 5% (v:v) or using pure organic solvents with
extensively dried boronic acids and ammonium formate gave
considerably lower yields, identifying the essential role of water
as a solvent. Use of (Ir[dF(CF3)ppy]2(dtbpy)PF6) or 9-
mesityl-10-methylacridinium perchlorate as alternative photo-
Figure 1. General access to C-centered radicals using a bioinspired
flavin photocatalyst and boronic acids in water.
media, hydrogen-atom abstraction from solvent (BDE of H2O
= 119 kcal mol−1)22a prevalent background reaction of C-
centered radicals in organic solvents such as MeCN (BDE = 97
kcal mol−1)23 and THF (BDE = 92 kcal mol−1)24might also
be deterred. To test our proposed strategy, identification of a
photocatalyst that is both suitably oxidizing and water
compatible along with a reactive probe molecule to quantify
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a
Table 1. Boronic Acid Scope for Flavin-Catalyzed Deborylative−Alkylation
a
All reactions were performed using 0.026 mmol of boronic acid, 30 mol % of lumiflavin, and 10 equiv of diethyl ethylidenemalonate. Reactions
were degassed with N2 and irradiated for 16 h with four, 40 W blue LEDs in a solution of pH 7.8 (ammonium formate) H2O and MeOAc (95:5, 10
mM overall concentration). Isolated yields are in parentheses. See Supporting Information for full experimental details and additional substrates.
b
c
d
Isolated yield using 3 equiv of Michael acceptor. Reactions were performed at 0.63 mmol scale with respect to boronic acid. Yield reported by
1
crude H NMR using dibromomethane (1 equiv) as an internal standard.
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a
a
Table 2. Scope of Michael Acceptors
Scheme 1. Drug Synthesis
a
For products 50−53 and 55−59, the reactions were performed using
0.026 mmol of boronic acid, 30 mol % of lumiflavin, and 10 equiv of
Michael acceptor. The reactions were degassed with N2 and irradiated
for 16 h with four, 40 W blue LEDs in a solution of pH 7.8
(ammonium formate) H2O and MeOAc (95:5, 10 mM overall
b
concentration). The reaction was performed using 0.026 mmol of
54, 30 mol % of lumiflavin, and 2 equiv of boronic acid. Isolated yields
are in parentheses.
catalysts gave only trace amounts of alkylated product under
our optimized conditions (a similar result was found for other
heteroaromatic boronic acids). Despite our best efforts to
improve this reaction further, we were unable to increase the
yield of 3-alkylpyridine. We hypothesized that the diminished
yield could be due to the limited nucleophilicity of the 3-
pyridyl radical. To examine this theory, we subjected the more
readily oxidized sodium trihydoxy(pyridine-3-yl)borate salt to
our reaction conditions.28,31 The yield of the reaction was
comparable. Employing the more nucleophilic radical
precursor, 6-methoxy-3-pyridineboronic acid (1), afforded a
significant increase in reaction efficiency to 26% yield. Use of
excess Michael reagent (10 equiv) improved the reaction of 1
to an optimal 61% isolated yield.
Considering the importance of electronics to boronic acid
reactivity, we decided to explore the scope of our reaction to a
myriad of heterocyclic boronic acids (Table 1). (It is important
to note that in some cases the boronic acid was not
commercial; in these instances, the trifluoroborate derivative
was used insteadcompounds 18, 20, 46, 47, and 49.) Among
those surveyed, fluoro-, ether-, and thioether-containing
pyridine boronic acids were efficient substrates for debor-
ylative−alkylation (compounds 1−6, yields 41−80%). Our
methodology was likewise successful with other nitrogenous
heterocycles including quinolines, isoquinolines, pyrimidines,
indoles, indazoles, benzimidazoles, and pyrazoles (compounds
9−17 and 19−21, yields 28−68%). In all cases, increased
amounts of Michael acceptor (10 equiv) afforded optimal
yields for heteroaromatic boronic acids, likely proceeding
through highly reactive sp2 radicals. On scale (0.63 mmol), the
a
For the synthesis of 63, the reaction was performed using 0.026
mmol of Michael acceptor (60), 30 mol % of lumiflavin, and 2 equiv
of boronic acid (33). For product 65, the reaction was performed
using 0.0026 mmol of boronic acid, 30 mol % of lumiflavin, and 10
equiv of Michael acceptor. For the synthesis of 67, the reaction was
performed using 0.026 mmol of boronic acid (66), 30 mol % of
lumiflavin, and 2 equiv of Michael acceptor (62). All of the reactions
were degassed with N2 and irradiated for 16 h with four, 40 W blue
LEDs in a solutions of pH 7.8 (ammonium formate) H2O and
MeOAc (95:5, 10 mM overall concentration). Isolated yields are in
parentheses.
reaction performed well as demonstrated by 2, 8, 13, 28, 41,
and 46.
Satisfied by the generality of our method to nitrogenous
heterocycles, we next assessed a series of boronic acids derived
from common therapeutic scaffolds, e.g., benzothiazoles
(compound 18, antitumor, antimicrobial, and antidiabetic),32
dibenzothiophenes (compound 26, keratolytic),33 and diben-
zofurans (compound 27, anti-inflammatory).34 In all cases,
alkylated products were obtained in moderate yields (51−
59%) and with excellent chemoselectivity. Finally, we
examined aromatic and aliphatic boronic acids (Table 1). To
our delight, aromatic systems proved competent substrates,
affording yields of alkylated products between 36% and 80%
yield, including an ortho-substituted boronic acid 31 and a
well-established anticancer warhead 36.35 Electron-deficient
phenylboronic acids (4-CF3, 4-F, 4-CN, and 4-COCH3) gave
lower yields (5−26% 1H NMR yields data not shown),
presumably being less nucleophilic and harder to oxidize. In
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Scheme 2. Photocatalyzed Oxidation of Boronic Acids
Figure 2. Computational and experimental studies into the open-shell
mechanism.
the case of aliphatic boronic acidscyclic, linear, and
heteroatom containingeach proved to be viable substrates
for deborylative−alkylation. Unlike aromatic systems, we
found that 3 equiv of Michael acceptor gave comparable
yields to the use of 10 equivalents, a result consistent with the
greater nucleophilicity of sp3 radicals. To our surprise,
methylboronic acid 43 was a promising candidate for
conjugate addition. Access to methyl radicals represents a
particularly attractive avenue for introducing methyl groups
into drug molecules,36 and its direct generation from a boronic
acid has not been achieved prior to our report.
Concluding our survey of disparate boronic acids, we turned
our attention to the use of alternative Michael acceptors in our
reaction (Table 2). Conjugated esters, ketones, and amides
worked well in addition to a vinyl sulfone, acrylonitrile, and
vinylphosponate using 2 as the radical precursor (compounds
50−59, yields 28−71%). No polymerization was observed for
these Michael acceptors. Styrenes, propiolates, vinyl boronates,
and vinylsilanes were not effective. The poor efficiency of these
alkenes is attributed to the inability of lumiflavin to reduce the
radicals formed in these systems following open-shell conjugate
addition.37 Nevertheless, by employing N-methylmaleimide 60
as a Michael acceptor, we successfully prepared the
anticonvulsant drug phensuximide 63 (44% yield) in one
step from phenylboronic acid 33. By employing the
commercially available boronic acid 64 and N-Boc-3-
pyrrolin-2-one 61, we synthesized the FDA-approved
phosphodiesterase-4 (PDE4) inhibitor rolipram 65 in 43%
yield. Finally, starting from 2-N-Boc-aminopyridine-5-boronic
acid 66 and the phthalimide Michael acceptor 62, we prepared
the thrombin inhibitor 67 in 51% yield.38 These results
highlight the application of our methodology to prepare three
medicinally significant compounds (Scheme 1).
To provide some insight into the mechanism of our reaction,
we undertook preliminary computational experiments. As
evidenced by Figure 2, the nucleophilicity of the proposed
radical intermediate, obtained from optimized open-shell
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structures at B3LYP/6-311G+*39 and corrected using
weighted averages from neutral and protonated states of
heterocycles in water, agreed with the observed efficiency of
1
the reaction (by H NMR analyses). Radical intermediates
with electron affinities of ≤2.0 eV are suitable substrates for
alkylation under our optimized reaction conditions. This trend
only provides a first approximation as other factors such as (i)
partial acid-catalyzed protolysis via a Kuivila mechanism,40 (ii)
specific-base-mediated protolysis through a Perrin mecha-
nism,41 or (iii) additional protolysis and disproportionation
processes as summarized by Lloyd−Jones17 may well influence
the yields for unique heteroaromatic boronic acids. However,
our analysis does correctly account for substrates that
performed less admirably, including pyridine-3-boronic acid,
which computationally gives rise to a highly electrophilic
radical (2.48 eV) following oxidative deborylation.42 In all, this
computational model not only provides a convenient tool for
predicting substrate competence but also garners initial
support for the existence of radical intermediates in our
reaction.
To further explore the intermediacy of radicals, we
performed a radical-trapping experiment in the presence of
TEMPO and a deuterium-labeling study in D2O. Reaction of 2
in the absence of diethyl ethylidenemalonate and with 2 equiv
of TEMPO afforded 11% of the O-pyridyl-TEMPO coupling
product 68 (Figure 2A). This result indicates that a free
heteroaromatic radical is oxidatively generated by the
lumiflavin photocatalyst. To probe the involvement of this
radical in the C−C bond-forming event, we reacted 2 with
diethyl ethylidenemalonate using our optimized procedure and
D2O as solvent (Figure 2B). If the heteroaryl radical engages
with our Michael acceptor via single-electron conjugate
addition, we anticipate formation of a stabilized α-malonyl
radical. This radical is easily reduced to the corresponding
anion by single-electron reduction (E°′ ≈ 0.7 V vs SCE),43 an
achievable potential from the reduced state of the lumiflavin
photocatalyst (E°′ ≈ −0.46 V vs SCE at pH 7 for flavins).44
The resultant anion would be protonated by solvent to
complete the catalytic cycle. Delivery of a proton from reduced
lumiflavin semiquinone may also be possible and cannot be
excluded. If solvent is involved in the final protonation event,
replacing H2O with D2O should lead to the α-deuterated
product 69. As expected, we found that reaction of 2 in D2O
produced deuterium-enriched 69 in 66% yield (98% d-
content). To dismiss any chance that 69 was formed by
keto−enol tautomerization from the protonated congener, we
subjected H-69 to a pH 7.8 D2O solution for 16 h with blue
light irradiation. No deuterium incorporation was observed.
1
Figure 3. Low-temperature H NMR and Stern−Volmer studies.
Finally, we explored the radical formation step. We used 11
B
NMR to determine the identity of the boronic acid species
formed during the reaction (Scheme 2). For this series of
studies 3-thiopheneboronic acid was employed due to its
greater solubility in D2O. Performing our standard reaction in
the absence of light gave only a single peak centered at 27 ppm,
corresponding to monomeric 3-thiopheneboronic acid. No
boronate was evident after 16 h of stirring in the dark. An
identical observation was found for other heteroaromatic
boronic acids (compounds 2, 9, 15, and 21) despite their
limited solubility in D2O. The absence of any conjugate
1
addition product was also noted by H NMR. When the
Figure 4. Proposed mechanism for the flavin-catalyzed deborylative−
alkylation of boronic acids.
reaction was irradiated with 440 nm light, a new peak at 19
ppm formed, identified as boric acid. This signal could be
recapitulated by the combination of boronic acid, lumiflavin,
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and 440 nm irradiation in D2O. Addition of diethyl
ethylidenemalonate to the irradiated mixture afforded the α-
deuterated conjugate addition product. Inclusion of TEMPO
(2 equiv) gave a TEMPO-trapped adduct, identified by mass
spectrometry. In accordance with these findings we find the
following. (1) Formation of an oxidatively labile boronate salt
is unlikely, at least on the 11B NMR time scale. Thus, the C-
centered radical does not appear to be generated through an
intermediate boronate. (2) Formation of a discrete Lewis base
adduct between lumiflavin and the boronic acid is unlikely, not
bond (86 kcal mol−1 compared to 116 kcal mol−1 for
uncomplexed H2O by ab initio calculations), enabling H-
atom abstraction. The derived CS-symmetric radical readily
dissociates to form an alkyl radical and Alkyl2BOH. Use of
aqueous solvent in our reaction may therefore entice the
coordination of water to the Lewis acidic boronic acid,
promoting H-atom abstraction or PCET by singlet lumiflavin.
A HAT mechanism is less feasible due to an inherent
electronic mismatch between the electrophilic N-centered
radical of photoexcited lumiflavin and the O−H bond of water,
favoring the PCET mechanism. Abstraction of a single electron
from the aqua−boryl complex would increase the acidity of the
O−H bond of the coordinated water, allowing for deprotona-
tion by the reduced lumiflavin semiquinone (pKa ≈ 8.4).53 The
resulting boronyl radical fragments to give the reactive C-
centered radical and boric acid (Scheme 2, vi, −15 kcal mol−1).
To probe formation of an aqua−boryl complex, we
1
having been observed by 11B NMR or H NMR. To further
rule out formation of a photocatalyst−boronic acid complex,
we used UV−vis spectroscopy. No change in the UV−vis
spectrum of lumiflavin was observed upon titration with the
boronic acid in water. Previous work by Wolf45 and
Fukuzumi46 showed that coordination of Lewis acids to flavins
results in a characteristic blue shift of the flavin absorption and
fluorescence maximum. The absence of any distinct shift in our
reaction argues against complex formation and indicates that
this adduct is not responsible for generating the C-centered
radical (Figure S6).
1
performed low-temperature 11B NMR and H NMR experi-
ments. In cooling a solution of 3-thiopheneboronic acid in
D2O from 25 to 0 °C, the boronic acid was found to retain its
monomeric form (Figure 3). The 11B spectra revealed
considerable broadening of the boronic acid signal but afforded
no new signals. Temperatures below 0 °C gave similar results.
A slight upfield shift of the boronic acid aromatic protons was
also observed upon cooling. Weak coordination of a water
molecule to the boronic acid could stabilize the boronic acid
monomer at low temperatures and cause a buildup of electron
density on the Lewis acidic boronic acid. This weak dative
interaction is expected to be in rapid equilibrium and could
contribute to 11B peak broadening.21 In contrast, solvation of
the boronic acid in a less coordinating solvent, d6-acetone,
resulted in extensive aggregate formation at low temperatures
and a general deshielding of the aromatic and boronic acid
proton signals. While these experiments do not provide
definitive evidence for water coordination, they do indicate
that water significantly affects the boronic acid coordination
sphere.
In hopes to elucidate a potential PCET mechanism involving
an aqua−boryl complex, we performed a Stern−Volmer
quenching experiment and a deuterium-labeling experiment.
Excitation of lumiflavin in an aqueous solution of 3-
thiopheneboronic acid resulted in considerable quenching of
lumiflavin (Figure 3), indicating that a favorable electron
transfer between the boronic acid and the photocatalyst is
possible in water. Direct quenching from water was not
observed by Stern−Volmer, relegating a mechanism based on
the intermediacy of hydroxy radicals formed by water
oxidation. Quenching of 3-pyridineboronic acid by lumiflavin
was also observed by Stern−Volmer (Figure S7), suggesting
that formation of N-heterocyclic radicals occurs through a
similar mechanism. To examine proton transfer we prepared
d2-phenylboronic acid−PhB(OD)2. If proton transfer occurs
from a coordinated water molecule, reaction of d2-phenyl-
boronic acid with lumiflavin in H2O should afford BO3D2H
and N5-H-lumiflavin semiquinone. Unfortunately, rapid
exchange of water with the boronic acid caused significant
scrambling of the deuterium atoms. While this innate exchange
did limit our ability to probe proton transfer from a
coordinated water molecule, we were able to study deuterium
transfer between ground state lumiflavin and d2-phenylboronic
acid in anhydrous solvents (CHCl3, CH3CN, dioxane, DCM,
acetone). Deuteration of the basic N-5 nitrogen was not
observed. A mechanism involving deprotonation of the boronic
Finding no evidence for the formation of a discrete boronate
or photocatalyst−boronic acid complex to assist radical
formation, we examined the direct oxidation of 3-thiophene-
boronic acid by photoexcited lumiflavin using computations.
Thermodynamic energies for triplet lumiflavin, lumiflavin
radical anion, and 5H-lumiflavin radical were taken from
previous work by Platz.47 First, we envisioned that the reaction
could proceed through a boronyl radical formed via direct
hydrogen-atom abstraction from the boronic acid and/or
proton-coupled electron transfer (PCET) by triplet lumiflavin
(Scheme 2, i). Alternatively, we imagined electron transfer
(Scheme 2, ii) followed by deprotonation. The resultant
boronyl radical could fragment to give a C-centered radical and
BO2H, which hydrolyzes to boric acid (Scheme 2, iii). HAT or
PCET (+14 kcal mol−1) and SET (+121 kcal mol−1) were
predicted to be unfavorable. Fragmentation of the boronyl
radical was also predicted to be unfavorable (+26 kcal mol−1).
To offset the unfavorable reactivity of triplet lumiflavin, we
postulated the involvement of singlet photoexcited lumiflavin.
Experimental measurements by Muller48 determined an energy
difference of 2.79 eV between the ground and the singlet
excited state of lumiflavin in water. A similar value (ca. 3.05
eV) was obtained by quantum chemical calculations as
summarized by Schapiro.49,50 Considering the singlet excited
state, direct oxidation of the boronic acid is still predicted to be
unfavorable (+102 kcal mol−1). Singlet lumiflavin has been
shown to oxidize aromatic compounds ≤2.0 V vs SCE via
SET.51 Aromatic, heteroaromatic, and aliphatic boronic acids
often have potentials ≥ 2.0 V vs SCE, leading to an unfavorable
electron tranfer.31 Interestingly, exothermic coordination of a
molecule of water to the boronic acid (Scheme 2, iv, −2.7 kcal
mol−1) is predicted to facilitate a favorable PCET or HAT
event, but not SET, from singlet lumiflavin (Scheme 2, v, −18
kcal mol−1). These mechanisms are unfavorable in the case of
triplet lumiflavin (+7.4 kcal mol−1). (Even though PCET, SET,
and HAT from triplet lumiflavin may be endothermic,
generation of the C-centered radical is still a favorable process
overall (−10.3 kcal/mol−1), suggesting that catalysis through
the triplet state may still occur.) Formation of C-centered
radicals from trisubstituted borane−water complexes was
originally proposed by Wood.52 Complexation of H2O to
trialkylboranes results in substantial weakening of the O−H
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acid by ground state lumiflavin followed by photocatalyzed
oxidation is therefore improbable.
Douglas for help recording low-temperature 11B and 1H
NMR spectra.
From our collective data, we propose the following
mechanism for deborylative−alkylation: (1) coordination of
water to the boronic acid, (2) photoexcitation of the lumiflavin
photocatalyst by 440 nm light gives rise to excited lumiflavin
which abstracts an electron and a proton from the aqua−boryl
complex, (3) fragmentation of the resulting open-shell
intermediate releases the heteroaryl radical, (4) expedient
capture of the heteroaryl radical via open-shell conjugate
addition (1.8 × 108 M−1 s−1 for phenyl radical)54 to diethyl
ethylidenemalonate, and (5) reduction of the α-malonyl radical
by SET, HAT, or PCET from LFH• forges the desired
alkylated product and regenerates the ground state photo-
catalyst (Figure 4).
In conclusion, we present a general catalytic platform to
access diverse heteroaromatic radicals as well as aromatic and
aliphatic radicals from commercial boronic acids using an
under-explored and cofactor-derived flavin photocatalyst in
aqueous media. We demonstrate the ability of these radicals to
engage Michael acceptors via single-electron conjugate
addition. Finally, we show that water acts as a key solvent
and potential reagent for radical generation and open-shell
alkylation. Further investigations to harness the aqueous
compatibility of this reaction and the unique properties of
flavin photocatalysts for applications to more biologically
relevant substrates (i.e., peptides and proteins) are presently
underway and forthcoming.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c03422.
■
sı
Experimental procedures and compound characteriza-
tion (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Steven Bloom − Department of Medicinal Chemistry, University
of Kansas, Lawrence, Kansas 66045, United States;
orcid.org/0000-0002-4205-4459; Email: spbloom@
ku.edu
́
Williams, J. D.; Rincon, J. A.; de Frutos, O.; Mateos, C.; Kappe, C. O.
Authors
Implementing Hydrogen Atom Transfer (HAT) Catalysis for Rapid
and Selective Reductive Photoredox Transformations in Continuous
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Complexity. Chem. Sci. 2020, 11, 4051−4064. (p) Yeston, J. Amines
as a Gateway to Alkyl Radicals. Science 2020, 367, 995−996.
Maheshwerreddy Chilamari − Department of Medicinal
Chemistry, University of Kansas, Lawrence, Kansas 66045,
United States
Jacob R. Immel − Department of Medicinal Chemistry,
University of Kansas, Lawrence, Kansas 66045, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c03422
́
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was performed in the Department of Medicinal
Chemistry at the University of Kansas and supported by the
School of Pharmacy, University of Kansas, and the Chemical
Biology of Infectious Disease COBRE (KU-Lawrence). The
authors thank Dr. Travis Witte for his assistance with
collecting Stern−Volmer measurements and Dr. Justin
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