Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
Key words Minisci reaction - photoredox catalysis - visible light - radical alkylation - late-stage
functionalization - heteroarenes
1
Introduction
Nitrogen-containing heterocycles constitute the backbone of natural products, medicinally
valuable small molecules, and agrochemicals (Scheme [1 ]A).[1 ]
[2 ] Methodologies for the direct C–H alkylation and perfluoroalkylation of N -heteroarenes enable both the late-stage modification of clinical leads and rapid
diversification of drug-like libraries.[3,4 ] These strategies allow for expedient access to unexplored chemical space and circumvent
conventional de novo chemical syntheses.[5 ] Notably, the medicinal chemistry community has placed growing interest on late-stage
functionalization technologies, as they allow for rapid modulation of drug metabolism
and pharmacokinetic profiles of lead compounds.[3 ]
[4 ]
[5 ] Thus, synthetic approaches that are not dependent on strong oxidants/reductants,
high reaction temperatures, or pre-functionalized substrates are of high-value to
both academic and industrial sectors.
Corey R. J. Stephenson was born in Collingwood, Ontario, Canada and received his undergraduate degree from
the University of Waterloo in 1998. He completed graduate studies under the direction
of Professor Peter Wipf at the University of Pittsburgh before joining the lab of
Professor Erick M. Carreira at ETH Zürich. In September 2007, he joined the Department
of Chemistry at Boston University as an Assistant Professor and was granted tenure
and promoted to Associate Professor in February, 2013. In July 2013, he joined the
Department of Chemistry at the University of Michigan as Associate Professor of Chemistry.
In September 2015, Corey was promoted to full Professor.Alexandra C. Sun was born in Boston, Massachusetts, USA in 1993. She received her B.S. degree (Chemistry)
in 2015 from Brandeis University, where she conducted undergraduate research with
Professor Christine Thomas. Alexandra is now pursuing her Ph.D. studies in the group
of Professor Corey Stephenson at the University of Michigan, where she is currently
working on the development of new photoredox catalysis methodology and continuous
flow technology.Rory C. McAtee was born in Phillipsburg, New Jersey, USA in 1992. He received his B.S. (Chemistry)
from Lycoming College in 2015 performing undergraduate research with Professors Holly
Bendorf and Charles Mahler. Rory then joined the group of Professor Corey Stephenson
at the University of Michigan, where he is currently a Ph.D. candidate studying photoredox
catalysis in organic synthesis.Edward J. McClain was born in Pittsburgh, Pennsylvania, USA in 1993. He attended West Virginia University
for undergraduate studies, performing undergraduate research with Professors Xiaodong
Shi and Brian V. Popp. Upon graduating from WVU in 2016, Edward joined the group of
Professor Corey Stephenson at the University of Michigan, where he is currently a
Ph.D. candidate studying photoredox catalysis in organic synthesis.
The addition of open-shell alkyl and perfluoroalkyl radical intermediates to heteroarenes
is referred to as the Minisci reaction (Scheme [1 ]B).[6 ]
[7 ]
[8 ]
[9 ] Minisci’s original protocol relied on free radical formation from carboxylic acids
via formation of their corresponding silver salts, followed by oxidative decarboxylation
upon treatment with a persulfate oxidizing agent. Addition of an alkyl radical intermediate
onto a protonated heteroarene, followed by rearomatization, yields the desired alkylated
heterocyclic product (Scheme [1 ]C). Based on Studer and Curran’s mechanistic studies, rearomatization is proposed
to occur via deprotonation and sequential single electron oxidation of the functionalized
heteroarene upon radical addition.[10 ] Since Minisci’s seminal contributions, this reactive paradigm for the alkylation
of (hetero)arenes has been a stalwart foundation for modern drug discovery and development.[11 ] Furthermore, renewed interest in the mild and operationally simple generation of
radical intermediates has spurred rapid evolution in the area of (hetero)arene alkylation.[12 ]
[13 ]
[14 ] In part, the driving inertia for this interest has been the emergence of visible-light-mediated
photoredox catalysis, which facilitates exceptionally mild single-electron-transfer
(SET) events with organic substrates.[15 ]
[16 ]
[17 ] Importantly, the pharmaceutical industry has recognized the transformative impact
of photoredox catalysis,[18 ]
[19 ] as it has far-reaching implications in harnessing sustainable energy sources, reducing
waste streams, and avoiding hazardous and/or toxic reagents classically employed for
carbon-centered radical formation (e.g., Bu3 SnH, BEt3 /O2 ). Given that state-of-the-art photochemical methods are already employed in drug
development (e.g., elbasvir[20 ] and artemisinin[21 ]), we anticipate that the photoredox radical (perfluoro)alkylation of (hetero)arenes
will be an invaluable synthetic technology for years to come.
Scheme 1 The Minisci alkylation of N -heteroarenes
In light of the importance of such transformations, we have decided to summarize recently
reported methods for visible-light-enabled radical C(sp2 )–H alkylations and perfluoroalkylations of medicinally relevant (hetero)arenes. The
sections to follow are organized based on radical precursor reagents. When appropriate,
the discussions will aim to highlight the unique selectivity outcomes dictated by
the electronic properties of alkyl and perfluoroalkyl radicals. This short review
is not intended to be comprehensive and is aimed at emphasizing novel photoredox catalysis
technologies for the radical alkylation of (hetero)arenes, which we anticipate will
have an enduring impact in academic and industrial settings.
Alkyl Carboxylic Acids and Carboxylic Acid Derivatives
2
Alkyl Carboxylic Acids and Carboxylic Acid Derivatives
Alkyl carboxylic acids are versatile feedstock chemicals that are ubiquitous throughout
nature and have been widely used as chemical building blocks.[22 ]
[23 ] Owing to their low cost, stability, minimal toxicity, and commercial availability,
alkyl carboxylic acids have been widely utilized across a variety of synthetic transformations
and represent preeminent building blocks for combinatorial chemistry (e.g., amide
bond formation). In recent years, the radical decarboxylation of aliphatic carboxylic
acids and their activated derivatives has emerged as a powerful strategy for the Minisci
functionalization of bioactive organic molecules.
A broad selection of methods have been developed to promote the decarboxylation of
alkyl carboxylic acid derivatives through a reductive pathway. In the context of photoredox
catalysis, the formation of alkyl radicals via a reductive pathway would enable a
net redox neutral catalytic cycle, thereby eliminating the need for a terminal oxidant.
At the same time, a reductive alkylation strategy has the potential to expand upon
the scope of alkylating reagents, allowing access to compounds with significantly
higher oxidation potentials.[24 ] Pioneering studies on the reductive decarboxylative generation of alkyl radicals
were conducted by Barton and co-workers in the 1960s.[22 ] Barton and co-workers utilized N- hydroxypyridine-2-thione in the reductive activation of carboxylic acids for applications
such as carbonyl reduction and reductive halogenation.[25 ]
[26 ] In 1991, Oda, Okada, and co-workers disclosed the use of N -(acyloxy)phthalimides (NAP) as redox auxiliaries to enable the decarboxylative generation
of alkyl radicals upon single electron reductive fragmentation (E
1/2 = –1.26 to –1.39 V vs. SCE), using visible-light-mediated photoredox catalysis.[27 ]
Since 2017, NAP esters have been employed in several visible-light-driven Minisci
alkylation protocols to promote reductive alkyl radical generation.[28 ]
[29 ]
[30 ]
[31 ]
[32 ] Notably, Phipps and co-workers have reported an enantioselective variant of the
Minisci reaction (Scheme [2 ]) that utilizes a combination of asymmetric Brønsted acid catalysis and photoredox
catalysis.[30 ] The use of a chiral phosphoric acid catalyst provides both stereo- and regiocontrol
in the direct addition of prochiral α-amino alkyl radicals to the 2-position of a
variety of pyridine and quinoline-based substrates. This strategy elegantly facilitates
the synthesis of enantioenriched α-heterocyclic amines through an efficient late-stage
functionalization approach. Jiang and co-workers have also designed an alternative,
organocatalytic approach for constructing α-isoquinoline-substituted secondary amines
in an enantioselective manner.[31 ] Nonetheless, the use of NAP esters for photoredox Minisci alkylations typically
necessitates a separate isolation step following ester formation, resulting in an
overall two-step procedure. In 2018, Sherwood and co-workers at Bristol-Meyers Squibb
developed an operationally simple, one-pot protocol for the in situ generation of NAP esters, which obviates the need for isolating the pre-functionalized
alkyl partner and facilitates the rapid generation of analogue libraries.[32 ]
Scheme 2 Enantioselective synthesis of α-heterocyclic amines using a Brønsted acid/photoredox
catalytic platform
In 2015, the Stephenson group developed a novel strategy for the visible-light-driven
trifluoromethylation of electron-rich (hetero)arenes (Scheme [3 ]), by using pyridine N -oxide to induce reductive radical generation from trifluoroacetic anhydride (TFAA).[24 ] With respect to considerations including safety, material availability, and reagent
price (TFAA $35 per kg at 1,000 kg), trifluoroacetic acid (TFA) and its derivatives
represent highly attractive sources of CF3 . Given the prohibitively high oxidation potential of the TFA anion (F3 CCO2 Na E
p/2
ox > +2.4 V vs. SCE), the authors were able to promote a mild reductive decarboxylation
of a TFAA/pyridine N -oxide adduct (E
p/2
red = –1.10 V vs. SCE) to access the trifluoromethyl radical within the electrochemical
window of [Ru(bpy)3 ]Cl2 . Notably, following reductive cleavage of the weak N–O bond and CO2 extrusion, the generation of pyridine as a byproduct resolves the need for an exogenous
base. Furthermore, TFAA and pyridine N -oxide are used in equal stoichiometry with respect to the substrate, and this reagent
combination is sufficiently inexpensive for large-scale operations (pyridine N -oxide $40–$70 per kg at 1,000 kg). The authors have demonstrated the efficacy of
this design in the C–H trifluoromethylation of a number of electron-rich heterocyclic
and aromatic substrates, including medicinally important MIDA boronates. Through a
collaboration with Eli Lilly, the trifluoromethylation of a Boc-protected pyrrole
substrate was carried out on 1.2 kg scale in a continuous flow system, which produced
the trifluoromethylated product in 50% yield at production rates of 87.2 mmol per
hour (approx. 0.5 kg per day).[33 ]
Scheme 3 Reductive decarboxylative (perfluoro)alkylation of heteroarenes using pyridine N -oxides
The Stephenson group has further expanded upon this methodology to achieve the radical
perfluoroalkylation of a variety of electron-rich (hetero)arene substrates.[33 ] In particular, they have designed a radical chlorodifluoromethylation strategy that
provides a valuable synthetic entryway to accessing electron-rich difluoromethylated
(hetero)arenes.[34 ] Moreover, chlorodifluoromethylation, followed by hydrogenolysis, of 6-methoxyquinoline
was demonstrated to furnish the 7-difluoromethylated product. This electronically
mismatched product is otherwise inaccessible via the nucleophilic difluoromethyl radical,
which is selective for the electrophilic 2- and 4-positions of the quinoline core.
An orthogonal, fragment coupling approach (Scheme [3 ]) has been developed by the Stephenson group for the addition of electron-rich (fluoro)alkyl
radicals onto electron-deficient heteroarenes.[35 ] Notably, this fragment coupling manifold minimizes chemical waste production, since
the dual role of the heterocyclic N -oxide as both a redox auxiliary and a coupling partner avoids the use of stoichiometric
additives. This methodology enables access to a wide range of alkyl coupling partners,
including medicinally relevant motifs such as tertiary azetidines, fluorinated cyclopropyl
groups, and a norbornene bicyclic scaffold. A variety of pharmaceutically important
heterocyclic N -oxides derived from pyridine, quinoline, and azaindole cores were reported to undergo
successful alkylation in modest to good yields. By using pyridine N -oxide as a sacrificial redox auxiliary, the authors were able to further expand upon
their scope of heteroarene substrates to access electron-deficient heteroarenes, such
as quinoxaline, as well as more complex pharmaceutical scaffolds.
With the goal of designing a Minisci alkylation strategy for the late-stage functionalization
of advanced pharmaceutical intermediates, DiRocco and co-workers at Merck disclosed
the innovative use of stable organic peroxides as alkylating reagents under photoredox
conditions (Scheme [4 ]).[36 ] Reaction parameters were optimized using a high-throughput experimentation platform,
and the use of cyclometallated Ir(III)+ photocatalysts [Ir{dF(CF3 )ppy}2 (dtbbpy)]PF6 and [Ir(ppy)2 (dtbbpy)]PF6 provided access to methyl, ethyl, and cyclopropyl radical intermediates from bench-stable
and inexpensive alkyl peracetates. The methodology was shown to be amenable to the
late-stage alkylation of an array of complex medicinal and agrochemical agents bearing
both 6- and 5-membered heterocyclic scaffolds. Most importantly, the transformation
proceeded smoothly in the presence of functionalities such as basic amines, alcohols,
amides, and esters, without the need for protecting groups. With respect to methyl
radical generation, the authors propose a mechanistic pathway involving the activation
of tert -butyl hydroperoxide through a reductive proton-coupled electron transfer (PCET) process.
The resulting α-peroxy radical subsequently undergoes homolytic O–O bond cleavage
to afford acetic acid and a tert -butoxy radical species. The authors hypothesize that methyl radical formation arises
from β-scission of the tert -butoxy radical, thereby producing acetone as a byproduct.
Scheme 4 Late-stage functionalization of biologically active heterocycles using alkyl peracetates
In 2014, the MacMillan group reported the first use of photoredox catalysis for the
oxidative decarboxylation of alkyl carboxylic acids in the arylation of α-amino acids.[37 ] In 2017, Glorius and co-workers disclosed a Minisci alkylation strategy that enables
access to alkyl radical intermediates through the oxidative decarboxylation of carboxylic
acids.[38 ] Sodium persulfate is used as an external oxidant to mediate alkyl radical formation,
as well as facilitate photocatalyst turnover. The authors propose that the generation
of desired alkyl radicals occurs through a hydrogen-atom transfer (HAT) event between
a reduced sulfate radical anion species and a carboxylic acid precursor, resulting
in oxidative decarboxylation. This reaction manifold enables the expedient functionalization
of heterocyclic scaffolds, including pyridine, quinoline, and quinazoline cores. A
range of primary, secondary, and tertiary alkyl radicals could be accessed from their
corresponding alkyl carboxylic acid and amino acid precursors. In 2018, Genovino,
Frenette, and co-workers disclosed a separate visible-light-driven Minisci alkylation
protocol using hypervalent iodine reagents and organophotocatalysis to facilitate
alkyl radical generation from carboxylic acids.[39 ]
3
Alkylboronic Acids
Since 2000, aryl/alkylboron reagents have been identified to serve as radical precursors
for C–C bond forming processes via oxidative C–B bond cleavage.[40 ]
[41 ]
[42 ]
[43 ]
[44 ]
[45 ]
[46 ]
[47 ] In 2016, Chen, Liu, and co-workers disclosed the Minisci C–H alkylation of N -heteroarenes with primary and secondary alkylboronic acids using the photocatalyst
Ru(bpy)3 Cl2 and acetoxybenziodoxole (BI-OAc) as a sacrificial oxidant (Scheme [5 ]).[48 ] Diversely substituted primary and secondary boronic acids (e.g., alkyl bromide,
aryl iodide, ester, amide, carbamate, terminal alkyne, and benzyl chloride) were well
tolerated. Pyridines, pyrimidines, and a purine riboside substrate were all efficiently
functionalized. It should be noted that more electron-rich heteroarenes, including
benzothiazole and benzimidazole, could also be successfully alkylated. The authors
propose that the reaction is initiated by a single-electron reduction from the photoexcited
Ru(II)* to acetoxybenziodoxole, providing an oxygen-centered radical intermediate.
This radical species is then proposed to react with the alkylboronic acid reagent
to form the desired alkyl radical via a radical ‘ate’ transition state. DFT calculations
support that this is a facile and highly exothermic process at room temperature.
Scheme 5 Photoredox Minisci alkylation using boronic acid alkylating reagents
Potassium Alkyl- and Alkoxymethyltrifluoroborates
4
Potassium Alkyl- and Alkoxymethyltrifluoroborates
Potassium organotrifluoroborates are considerably more attractive radical precursors
than their corresponding boronic acids, given their lack of an empty p-orbital, which
increases their overall stability and robustness toward harsh reaction conditions.[49 ] In 2011–2013, Molander and co-workers reported the first use of potassium alkyl-
and alkoxymethyltrifluoroborates as radical precursors in the direct C–H alkylation
of (hetero)arenes employing manganese(III) acetate as an oxidant in the presence of
trifluoroacetic acid.[50 ]
[51 ] Under the optimized reaction conditions, the authors were able to functionalize
several nitrogen-containing heterocycles all in good to excellent yields.
In 2017, Molander and co-workers reported an impressive advance from their earlier
manganese(III) acetate mediated Minisci chemistry by showcasing that alkyltrifluoroborates
(many of which are commercially available) can be activated by an inexpensive, sustainable
organophotocatalyst (Scheme [6 ]).[52 ] Following reaction optimization, the authors found the utility of a mesitylacridinium
photocatalyst (MesAcr), potassium persulfate (as a sacrificial oxidant), and trifluoroacetic
acid to be the optimal reagent combination for the C–H functionalization of heteroarenes.
Under these reaction conditions, medicinally important cores including quinolines,
isoquinolines, indazoles, pyridines, and quinazolinones, could all be functionalized
with an impressive scope of primary, secondary, and tertiary alkyltrifluoroborates
in good to excellent yields. As expected, electron-rich cores such as benzimidazole,
were unreactive toward these Minisci alkylation conditions. These conditions proved
tolerant of a diverse array of functional groups including aryl halides, unprotected
amines, thioethers, and amides. Notably, quinine, which features a free alcohol, terminal
alkene, and a tertiary amine (which has a known propensity for competitive photocatalytic
oxidation) was efficiently (54% yield) and selectively (C2) functionalized. To showcase
the late-stage functionalization utility of their developed protocol, the authors
successfully functionalized camptothecin, an anticancer drug candidate, at the C7-position.
Mechanistically, the authors propose single electron oxidation of the alkyltrifluoroborate
reagent, which leads to generation of the desired alkyl radical intermediate and BF3 .
Scheme 6 Organophotocatalytic Minisci alkylation using alkyltrifluoroborate radical precursors
5
Alkyl Halides
Alkyl halides are among the most widely used materials in organic chemistry. However,
their application as radical precursors has been hindered because of the harsh conditions
required for radical generation, such as the use of highly toxic trialkyltin hydrides.[53 ] The advent of modern photoredox catalysis provided a solution to this problem, as
photoredox catalysts can be readily employed for the reductive dehalogenation of alkyl
halides, resulting in the formation of free alkyl radicals. In 2010, the Stephenson
group reported the seminal application of photoredox catalysis for the intramolecular
alkylation of heteroarenes through reductive dehalogenation of activated alkyl bromides
(Scheme [7 ]A).[54 ] This report represented a significant milestone, as it was the first Minisci alkylation
that was promoted by photoredox catalysis. The authors’ proposed mechanism involved
generation of a Ru(I) species through reductive quenching of the excited state photocatalyst.
This Ru(I) species could then reduce malonyl bromides to produce a carbon-centered
radical; subsequent trapping of the radical intermediate by electron-rich indoles
and pyrroles afforded the functionalized products. Following this initial report,
the Stephenson group extended this methodology to access intermolecular C–H alkylations
(Scheme [7 ]B),[55 ] as well as the intermolecular construction of quaternary centers.[56 ]
Scheme 7 Visible-light-driven dehalogenative alkylation of heteroarenes
Two reports in 2018 have highlighted the continued expansion of Minisci protocols
featuring dehalogenative radical generation. First, a group at Vertex Pharmaceuticals
demonstrated the ability to predictably access C3- and C5-functionalized products
by performing the Minisci reaction under basic conditions.[57 ] This report featured the reductive dehalogenation of unactivated alkyl iodides and
demonstrated the ability to predict the site of alkylation based upon the electronics
of a heteroaryl substrate. Additionally, the Wang group reported a separate Minisci
alkylation protocol which utilizes a halogen atom abstraction event to promote radical
generation.[58 ] This work was enabled through the adaptation of conditions concurrently reported
by the Stephenson[59 ] and MacMillan[60 ] groups for visible-light-mediated bromide atom abstraction from alkyl and aryl bromides,
facilitated by a tris(trimethylsilyl)silane radical [(Me3 Si)3 Si• ] species generated in situ. The use of a halogen atom abstraction approach allowed
the Wang group to access a diverse scope of alkyl halides and heteroarenes.
The incorporation of trifluoromethyl groups onto (hetero)arenes represents an important
transformation in medicinal chemistry applications. As such, dehalogenative Minisci
alkylations have also been expanded upon to include the trifluoromethylation of heteroarenes.
In 2011, the MacMillan group developed the first reported method for the visible-light-driven
radical trifluoromethylation of (hetero)arenes (Scheme [8 ]).[61 ] In this report, reduction of trifluoromethanesulfonyl chloride by a ruthenium photocatalyst
induced the loss of sulfur dioxide, affording the reactive trifluoromethyl radical
species. This species could be effectively trapped by a number of (hetero)arenes,
resulting in C–H trifluoromethylation. This method demonstrated the applicability
of photoredox catalysis in medicinal chemistry, as a number of trifluoromethylated
pharmacophores could be easily accessed. Following this report, a collaborative effort
by the Fukuzumi, Cho, and You groups described the use of a platinum(II) acetylacetonate
(acac) photosensitizer for the reduction of trifluoromethyl iodide. The resultant
trifluoromethyl radical was utilized in the subsequent C–H trifluoromethylation of
heteroarenes.[62 ]
Scheme 8 Photoredox trifluoromethylation of unactivated (hetero)arenes
In the aforementioned examples, catalysis is promoted by engaging the photosensitizer
in outer-sphere electron transfer events. At the same time, dehalogenative radical
generation has also been demonstrated to be driven by non-canonical photocatalysts
that engage the halide substrate through inner-sphere electron transfer or direct
halogen atom abstraction events. In 2015, the Barriault group described the use of
gold photoredox catalysis for the application of unactivated alkyl bromides to the
alkylation of N -heteroarenes through an intramolecular cyclization (Scheme [9 ]).[63 ] This methodology was extended to intermolecular radical additions in 2016. In this
more recent study, the Barriault group proposed a mechanistic pathway involving an
excited state exciplex that could undergo an inner-sphere electron transfer to furnish
the alkyl radical species (Scheme [9 ]).[64 ] The development of these methods has provided mild conditions for accessing primary
alkyl radical fragments. In 2017, a group from Pfizer reported the use of manganese
decacarbonyl (Mn2 CO10 ) for the alkylation of heteroarenes utilizing simple alkyl iodides as substrates.[65 ] The authors proposed that the Mn2 CO10 catalyst undergoes Mn–Mn bond homolysis upon irradiated with blue light. The resultant
(CO)5 Mn• radical species can then abstract an iodine atom from the alkyl iodide reagent to
enable alkyl radical generation.
Scheme 9 Dehalogenative alkylation using gold photoredox catalysis
6
Alcohols and Ethers
The late-stage incorporation of oxygenated functionality into complex molecules can
have a significant impact on the physical properties (e.g., solubility) of a compound.
For drug discovery, the optimization of these properties for a lead compound is vital
to the development of clinical candidates.[66 ] Thus, the development of methods for the installation of simple oxygenated fragments,
such as those derived from alcohols and ethers, is an important point of development
for the Minisci reaction.
The application of alcohols in the visible-light-driven Minisci alkylation of heteroarenes
was first reported in 2015 by the MacMillan group (Scheme [10 ]).[67 ] The authors proposed that the methylation of heteroarenes could be achieved through
the initial addition of a carbon-centered hydroxymethyl radical onto a heteroarene
substrate. The hydroxymethyl group could then be converted into the desired methyl
fragment through a spin-center shift induced by the concomitant loss of water. The
subsequent benzylic radical species was proposed to be reduced and protonated to furnish
the final methylated product. Importantly, the proposed hydroxymethyl radical intermediate
in this report was generated through C–H abstraction of methanol with a thiol co-catalyst.
This method provided a general manifold for accessing Minisci reactivity, as a variety
of alcohols, pyridines, quinolines, and isoquinolines were amenable to these alkylation
conditions. Following this report, in 2016, DiRocco and co-workers utilized a radical
relay reaction to promote the visible-light-mediated hydroxymethylation of heteroarenes
with methanol.[68 ] This reaction was proposed to proceed through the generation of a phenyl radical
species from the Ir(III)-catalyzed reductive decomposition of benzoyl peroxide. The
phenyl radical intermediate then undergoes hydrogen atom abstraction from methanol,
thereby generating the active hydroxymethyl radical species, which could be trapped
by a variety of heteroarenes. This hydroxymethylation protocol allows for the late-stage
functionalization of an array of pharmacophores. While the above two examples utilize
iridium photocatalysts to promote reactivity, Minisci reactions featuring alkyl alcohol
reagents have also been reported in the absence of photocatalysts. In 2017, the groups
of Li[69 ] and Barriault[70 ] independently reported the application of near UV irradiation to promote the methylation
of heteroarenes.
Scheme 10 Visible-light-driven Minisci alkylation reaction using alcohols as alkylating agents
In 2014, the MacMillan group reported the first application of ethers in conjunction
with photoredox catalysis for Minisci reactivity.[71 ] The developed method utilized persulfate salts as both an oxidant and C–H abstraction
reagent. From a mechanistic standpoint, oxidative quenching of the photocatalyst by
the persulfate salt generates an equivalent of sulfate radical anion, which readily
abstracts a hydrogen atom from the ethereal substrate. This seminal report demonstrates
the impact of photoredox catalysis on broadening the scope of Minisci reaction protocols,
as both cyclic and acyclic ethers could be innovatively used as radical alkylating
reagents under mild conditions. In 2017, the Ryu group described the use of a polyoxometalate
photocatalyst tetrabutylammonium decatungstate (TBADT) for a visible-light-driven
Minisci alkylation reaction.[72 ] In its excited state, the TBADT photocatalyst enabled the selective, oxidative generation
of radical intermediates through the direct abstraction of electron-rich hydrogen
atoms present across ether, alkane, and amide substrates. It is noteworthy that Minisci
reactions enabled by the C–H abstraction of saturated molecules are not limited to
oxygenated substrates, as this mechanistic paradigm has also been reported with the
employment of protected amines[73 ] and alkanes.[72 ]
[74 ]
7
Conclusion
As exemplified in this short review, the utility of photoredox catalysis for the Minisci
alkylation reaction provides synthetic chemists with a myriad of opportunities to
utilize inexpensive, commercially abundant alkylating reagents (e.g., carboxylic acids,
alcohols, alkyltrifluoroborates, alkyl halides, etc.) for the direct, C–H alkylation
of heteroarenes. Notably, visible-light-driven Minisci alkylation reactions have been
demonstrated to proceed under mild reaction conditions and are tolerant of a variety
of complex functionalities. In particular, these strategies have been shown to hold
significant value for late-stage functionalization efforts in drug discovery. The
continued development of photoredox Minisci alkylation reactions that are amenable
to a broader scope of complex heterocyclic compounds, while providing improved regioselectivity,
is vital to enhancing the synthetic utility and impact of this transformation. Furthermore,
demonstrating the scalability of photoredox Minisci alkylation protocols (e.g., using
continuous flow systems) may offer valuable opportunities for bridging drug discovery
efforts with process development needs.
