Site-selective direct C-H pyridylation of unactivated alkanes by triplet excited anthraquinone

Article abstract of DOI:10.1021/jacs.1c00549

Site-selective C-H functionalization in chemical feedstocks is a challenging and useful reaction in the broad field of chemical research. Here, we report a modular photochemical platform for the site-selective C-H pyridylation of unactivated hydrocarbons via the unique synergistic effects of triplet excited anthraquinone and an amidyl radical-based reverse hydrogen atom transfer (RHAT) agent. The selective pyridylation of tertiary and secondary C(sp³)-H bonds in abundant chemical feedstocks was achieved by employing various N-aminopyridinium salts in a highly selective fashion, thus providing a new catalytic system for the direct construction of high-value-added compounds under ambient reaction conditions. Moreover, this operationally simple protocol is applicable to a variety of linear-, branched-, and cyclo-alkanes and more complex molecules with high degrees of site selectivity under visible-light conditions, which provides rapid and straightforward access to versatile synthons for upgrading feedstocks under mild, metal-free reaction conditions.

Full text of DOI:10.1021/jacs.1c00549

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Site-Selective Direct C−H Pyridylation of Unactivated Alkanes by
Triplet Excited Anthraquinone
Wooseok Lee, Sungwoo Jung, Minseok Kim, and Sungwoo Hong*
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ABSTRACT: Site-selective C−H functionalization in chemical
feedstocks is a challenging and useful reaction in the broad field of
chemical research. Here, we report a modular photochemical platform
for the site-selective C−H pyridylation of unactivated hydrocarbons
via the unique synergistic effects of triplet excited anthraquinone and
an amidyl radical-based reverse hydrogen atom transfer (RHAT)
agent. The selective pyridylation of tertiary and secondary C(sp3)−H
bonds in abundant chemical feedstocks was achieved by employing
various N-aminopyridinium salts in a highly selective fashion, thus
providing a new catalytic system for the direct construction of high-
value-added compounds under ambient reaction conditions. More-
over, this operationally simple protocol is applicable to a variety of
linear-, branched-, and cyclo-alkanes and more complex molecules with high degrees of site selectivity under visible-light conditions,
which provides rapid and straightforward access to versatile synthons for upgrading feedstocks under mild, metal-free reaction
conditions.
bonds.39 The Zuo group reported that the Ce-catalyzed C−H
INTRODUCTION
■
functionalization of hydrocarbons could be achieved by
The direct conversion of pure hydrocarbons into value-added
utilizing various alkoxy radicals as HAT agents.21 The Wu
group achieved photoinduced alkylation and amination of
unactivated C−H bonds by using bromine radicals as highly
efficient and selective HAT agents.38
organic compounds is a long-standing goal in organic synthesis
and catalysis. Chemical methods to achieve this goal could
have broad application potential in synthetic organic
chemistry, considering the reduction in the number of
synthetic steps and the abundance of inexpensive starting
feedstocks.1−12 To achieve high regioselectivity, strategies that
use directing groups in substrates and the intramolecular
hydrogen atom transfer (HAT) process have been frequently
used to activate inert C(sp3)−H bonds.13−18 The intrinsic
chemical inertness and the subtle difference in electronic and
steric properties of the ubiquitous aliphatic C−H bonds among
common feedstock alkanes, however, have posed formidable
challenges for achieving useful reactivity and selectivity. Since
radicals can differentiate aliphatic C−H bonds based on
differences in their bond dissociation energies and polarity,
radical-mediated reaction systems have been widely explored
for the selective C−H functionalization of unactivated alkanes.
In this context, diversified applications of photocatalysis have
recently emerged as a powerful tool for previously inaccessible
site-selective functionalization of C−H bonds in abundant
chemical feedstocks (Scheme 1a).19−40 For example, the
Glorius group demonstrated a benzoyloxy radical-mediated
HAT process for the C−H activation of alkanes using an Ir-
based photocatalyst, where electron-rich methine C−H bonds
were selectively activated.32 Aggarwal and colleagues disclosed
an elegant strategy that takes advantage of the steric bulkiness
of boronate radicals to selectively activate primary C−H
Despite these advances in photochemical processes, there
remains high demand for the development of a mild and
general platform for the direct conversion of readily accessible
feedstocks into valuable heteroarene-containing molecules in a
convenient and sustainable manner. In line with our ongoing
interest in visible-light-induced C−H pyridylation,41−56 we
hope to develop an approach for the highly selective C−H
heteroarylation of unactivated alkanes. Recently, Lakhdar’s
research group has demonstrated Ir-catalyzed C−H alkylation
of pyridine derivatives, which relies on photoredox-induced
methoxy radicals as HAT agents.52 However, as this method is
limited to symmetrical cycloalkanes, expansion of the
boundaries of unactivated hydrocarbon scope is required.
When our group investigated a similar approach, we discovered
that both the reactivity and selectivity were disappointingly low
Received: January 16, 2021
Published: February 8, 2021
https://dx.doi.org/10.1021/jacs.1c00549
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© 2021 American Chemical Society
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Article
of the previous report, we speculated that suitable HAT
catalysts such as triplet excited anthraquinone (AQ) could
trigger a site-selective HAT process involving a specific C−H
bond to promote the efficient generation of a C-centered
radical.57,58 Moreover, in contrast to what is typically seen with
amidyl radicals as HAT agents,59−62 we considered that this
class of radicals generated in situ from N-aminopyridinium
salts is highly energetic and can readily abstract a hydrogen
atom from AQ−H as an effective RHAT agent, thereby rapidly
turning over the AQ HAT catalyst. Although an amidyl radical
has not previously been used as an RHAT agent or merged
with a HAT catalyst for photocatalytic C−H functionalization,
our initial computational investigations revealed that the
RHAT process between AQ−H and an amidyl radical is
thermodynamically favorable. We expect that if this strategy is
successful, it will be possible to upgrade a wide range of
abundant hydrocarbon feedstocks directly into valuable
pyridine-containing alkane building blocks. Herein, we report
the successful implementation of this modular photochemical
platform for the site-selective C−H pyridylation of a diverse set
of hydrocarbon frameworks via the synergistic effects of an AQ
photocatalyst and an amidyl radical-based RHAT agent
(Scheme 1b). This reaction manifold is applicable to a wide
range of C−H bonds, including complex molecules, under
ambient reaction conditions with excellent selectivity for more
hindered aliphatic sites, such as tertiary and secondary C−H
bonds in hydrocarbon chains. Significantly, in all cases,
reactions took place selectively at the C4 position of the
pyridine rings driven by the N-methyl sulfonyl group on
pyridinium salts.
Scheme 1. Design Plan: Site-Selective Direct C−H
Pyridylation of Unactivated Hydrocarbons Using
Anthraquinone and N-Aminopyridinium Salts
when alkane substrates with two different reaction sites (i.e.,
acyclic hydrocarbons) were used, which indicates that an
alkoxy radical-mediated HAT approach is less effective in this
system. The Inoue group reported direct C−H pyridination of
aryl-substituted alkanes by employing benzophenone and 4-
cyanopyridine.49 Despite significant improvement in the
synthesis of pyridine-containing molecules, this method is
mostly limited to reactive benzylic C−H bonds and 4-
cyanopyridine as a coupling partner. In this context, the site-
selective conversion of unactivated alkane feedstocks into
structurally diverse heteroarene-containing molecules remains
a highly unmet need for the chemistry community.
We proposed that the following requirements should be met
to achieve this goal: (i) when combined with pyridinium salts,
photoinduced direct HAT catalysis is preferred to overcome
the limitation of redox potentials, thereby preventing
deleterious photoreduction of pyridinium substrates during
the reactions; (ii) the preference of the HAT catalyst for H-
abstraction should be well-matched with the targeted reaction
site to acquire a high level of reactivity and site-selectivity; (iii)
in order to achieve high catalytic turnover, the HAT catalyst
must rapidly be regenerated prior to side reactions, such as
dimerization. For example, a reverse hydrogen atom transfer
(RHAT)30 agent must be able to quickly abstract a hydrogen
atom from the HAT catalyst−hydrogen adduct; (iv) the cross-
coupling of the specific C−H bonds in the pyridine moiety is
very desirable to avoid the regioselectivity issue (C2 vs C4).
On the basis of the consideration of these issues, we wondered
whether a synergistic catalytic system consisting of a direct
HAT photocatalyst and an RHAT agent would provide precise
regional recognition of the specific C−H bonds in a catalytic
fashion, thus enabling the highly selective C−H functionaliza-
tion of unactivated alkanes under mild conditions. On the basis
RESULTS AND DISCUSSION
■
To explore both the reactivity and site selectivity of the
proposed photoinduced transformation, 2,5-dimethylhexane
(1a) was selected as the initial standard alkane substrate, and
pyridinium salt 2 was used as the reaction partner under
irradiation with blue LEDs (Table 1). Our initial attempts to
use N-methoxypyridinium salt 2a under previously reported
reaction conditions52 failed to produce any product, and 2-
phenylpyridine was observed as a major byproduct (entry 1),
which indicates that the effective HAT process between the
methoxy radical and 1a is less likely to occur in this system.
Therefore, the success of the proposed transformation requires
a more efficient HAT catalyst that can readily abstract a H
atom from 1a. Among possible candidates, eosin Y,
tetrabutylammonium decatungstate (TBADT), and aryl
ketones were considered as suitable HAT photocatalysts for
this purpose. After screening of reaction parameters, the
reaction occurred predominantly at the tertiary C−H bond
(>20:1) when eosin Y was used as a photocatalyst63−65 to
deliver the product 3a in 39% yield at room temperature (entry
2). However, eosin Y was somewhat involved in the
photoreduction of N-aminopyridinium salt 2b through a single
electron transfer (SET) pathway,43,44 leading to the decom-
position of 2b. To overcome the drawback of eosin Y, we
sought to design other catalytic systems that utilize a more
efficient HAT catalytic cycle. Recently, the MacMillan group
developed a strategy for the C−H arylation of unactivated
alkanes with aryl bromides under a dual-catalytic manifold
consisting of TBADT and Ni catalysts using near-UV light
(390 nm LEDs).66 Interestingly, when TBADT was used as a
HAT photocatalyst in our system, the selectivity between
tertiary and secondary C−H bonds in 1a decreased to 9:1,
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a
detected when 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)
was added to the reaction mixtures (entry 11).
Table 1. Optimization of the Reaction Conditions
After robust optimization of the reaction conditions, we next
investigated the scope of various unactivated hydrocarbons to
evaluate the generality of this selective C−H pyridylation
(Table 2). First, we evaluated the broadly available feedstock
alkane family in terms of site selectivity and reactivity.
Pleasingly, the current method proceeded selectively at the
tertiary C−H bonds among multiple hydridic protons (>20:1
r.r. if not denoted otherwise) in various linear alkane chains,
such as 2,5-dimethylhexane (3a), 2,3-dimethylbutane (3b),
2,4-dimethylpentane (3c), 2,2,5-trimethylhexane (3d), iso-
pentane (3e), and 2-methylpentane (3f). Notably, this
protocol tolerated versatile functional groups such as
phthalimide (3i), benzoate (3j and 3k), ester (3l), bromide
(3g), and chloride (3h), and the intriguing synthetic value of
this transformation was further demonstrated by its excellent
site- and chemoselectivity for methine positions (bond
dissociation energy (BDE) = 96.5 kcal/mol)80 over the α-
position of heteroatoms in alkane substrates. Remarkably, for
substrates bearing more than one tertiary C−H bond with
subtle differences in terms of steric effects and BDEs, this
catalytic system has a marked preference for the abstraction of
slightly more electron-rich methine C−H bonds, yielding
targeted products 3m and 3n. Next, the pivotal importance of
small feedstock alkanes prompted us to evaluate the
applicability of this method to more challenging gaseous n-
butane. Gratifyingly, we observed that this protocol enables the
efficient functionalization of n-butane to afford synthetically
useful building blocks (3q) with excellent selectivity despite
the small difference in BDEs between secondary (BDE = 98.6
kcal/mol) and primary hydrogens (BDE = 101.1 kcal/mol).
Likewise, n-pentane and n-hexane were successfully trans-
formed, and trapping of the pyridyl group with two competing
methylene C−H bonds resulted in two isomeric mixtures (3r
and 3s). Employing a substituted cyclic alkane resulted in the
formation of the corresponding product 3o with excellent
selectivity for the tertiary C−H bond. Similarly, the
adamantane derivative was amenable to the standard
conditions with an excellent degree of selectivity at the
methine position (3p). The current method can be extended
to norbornane and oxabicycloheptane, and methylene C−H
bonds on the ethylene bridge were selectively activated,
demonstrating an excellent level of regio- and diastereose-
lectivity (3t and 3u). Expanding the scope from electronically
neutral hydrocarbons to a diverse range of heteroatom-
containing substrates, such as methanol, 1,4-dioxane, thioether,
and aliphatic amides, was possible to successfully afford the
coupling products (3v−3z) with the incorporation of pyridine
exclusively at the carbon adjacent to the heteroatom. To
establish the broad utility of the unified protocol, substrates
bearing different classes of hydrogen donors (aldehyde, amide,
phosphine oxide, and alkylsilane units) were further examined.
Under the same reaction conditions, the phosphorus group
was compatible with the current conditions to afford 3aa and
3ab. Alkyl silane can also be utilized as a building block for this
protocol to insert a pyridine moiety (3ac). In addition,
aldehydes and amides can be successfully applied to achieve
umpolung reactivity exclusively at the acyl C−H bonds over
the tertiary and alpha positions of heteroatoms, accessing
diverse acylation-type products (3ad−3ai). Similarly, cyclic
alkanes were also competent substrates, which were efficiently
converted to the desired products with excellent yield
b
c
entry
salt
PC (1.0 mol%)
yield (%)
selectivity (C2/C3)
d
1
2a
2b
2b
2b
2b
2c
2d
2a
2c
2c
2c
fac-Ir(ppy)3
eosin Y
TBADT
benzophenone
AQ
AQ
AQ
AQ
AQ
trace
39
23
44
67
78
46
15
2
>20:1
9:1
>20:1
>20:1
>20:1
18:1
e
3
e
4
5
6
7
d
8
f
>20:1
9
n.d.
n.d.
n.d.
10
11
g
AQ
a
Reaction conditions: 1a (0.5 mmol), 2 (0.1 mmol), and catalyst (1.0
mol%) in acetonitrile (1.0 mL) under irradiation using blue LEDs
(440 nm) at rt for 48 h under N2. Yields were determined by H
b
1
c
1
NMR spectroscopy. The ratio of selectivity was determined by H
d
NMR spectroscopy and GC-MS. NaHCO3 (1.2 equiv) was added.
e
Without NaHCO3, no product was detected. A 390 nm Kessil LED
f
g
was used. Reaction was carried out in the dark. TEMPO (2.0 equiv)
was added. TBADT = tetrabutylammonium decatungstate. 1,2-DCE =
1,2-dichloroethane. DCM = dichloromethane. n.d. = not detected.
accompanied by a decrease in reactivity (entry 3). Next, we
considered the use of aryl ketones and quinones that have been
reported as useful visible-light HAT photocatalysts by merging
with Ni or Cu catalysts to achieve promising potential in the
catalytic activation of inert C−H bonds.67−79 For example,
Martin and co-workers reported C−H arylation and alkylation
under dual diaryl ketone HAT/Ni catalysis.69 In addition, the
Gong group achieved stereoselective C−H functionalization of
hydrocarbons under dual pentacenetetrone HAT/Cu catal-
ysis.70 Our evaluation of various members of this class of HAT
photocatalysts revealed that AQ derivatives improved the
product yield and selectivity (see the SI for details). Notably,
we found that the employment of AQ as the HAT catalyst
resulted in increased reactivity. Under this HAT/RHAT
catalytic system, an external base was not required. Solvent
screening experiments revealed that reaction was best
conducted in acetonitrile and that the C−H bond in
acetonitrile is inert under the given HAT catalytic systems
(see the SI for details). The effect of the sulfonamide group on
the N-aminopyridinium salt was next investigated by tuning its
electronic effect (entries 5−8). Replacing the p-tolyl group
with a more electron-deficient 4-trifluoromethyl phenyl moiety
(2c) further increased the yield (entry 6, 78%), probably
because the generated alkyl radical is more favorably
intercepted by electron-deficient salt. We carried out control
experiments to confirm the critical role of light and the
photocatalyst (entries 9 and 10). As anticipated, 3a was not
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a
Table 2. Site-Selective Direct C−H Pyridylation of Alkanes
a
Reaction conditions: 1 (0.5 mmol), 2c (0.1 mmol), and AQ (1.0 mol%) in acetonitrile (1.0 mL) under irradiation using blue LEDs (440 nm) at rt
b
for 48 h under N2. Isolated yields. Regioisomeric ratios were determined by GC-MS and 1H NMR (>20:1 r.r. if not denoted otherwise). 10 equiv
of 1 was used. NaOAc (2.0 equiv) was added as a base, and the ratios (product/decarbonylated product) are given in parentheses.
c
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regardless of ring size (3aj−3an). Thus, this catalytic system
consisting of an AQ HAT photocatalyst and an amidyl RHAT
agent serves as a powerful tool to functionalize a wide range of
linear, branched, and cyclized hydrocarbons with high degrees
of site-selectivity by overcoming the redox limitation associated
with the SET process.
Table 4. Late-Stage Site-Selective C−H Pyridylation of
Biorelevant Compoundsa
To further demonstrate the versatility of the current method,
we subsequently surveyed the scope of the reactions with
respect to the pyridine unit by using cyclohexane (1ak) as a
coupling partner. As illustrated in Table 3, this exploration
Table 3. C4-Selective Alkylation on Various Pyridine
a
Cores
Subsequently, several control experiments were conducted
to examine the reaction pathway, as shown in Scheme 2. First,
to compare the influence of the sulfonamide group on the
reaction rate, mixtures of salts 2c and 2b-D were subjected to
Scheme 2. Control Experiments
a
Reaction conditions: 1ak (0.5 mmol), 2 (0.1 mmol), and AQ (1.0
mol%) in acetonitrile (1.0 mL) under irradiation using blue LEDs
b
(440 nm) at rt for 24 h under N2. Isolated yields. 10 equiv of 1ak
was used.
revealed that cyclohexane could be readily functionalized with
a broad range of functionally diverse pyridyl groups with
excellent C4 selectivity. Variation in the pyridine unit with a
variety of substitution patterns at either the C2 or C3 position
had little influence on the overall reaction efficiency, and a
broad range of groups, such as methyl (4b), methoxy (4c and
4h), trifluoromethyl (4d and 4k), heteroarene (4f and 4g), p-
bromo phenyl (4e), bromo (4i), and ester (4j) groups were
viable under the optimized conditions. In addition, a
cyclopentyl-fused pyridinium salt was an effective substrate
to afford 4l.
Because N-aminopyridinium salts are readily prepared from
the corresponding pyridines, the value of this protocol was
further demonstrated by its applicability to the late-stage
functionalization of more structurally complex molecules, as
illustrated in Table 4. Pleasingly, we were able to perform site-
selective insertion of 2,5-dimethylhexane (1a) into pyridine-
based drugs, such as bisacodyl and vismodegib, to generate the
corresponding alkylated products 5a and 5b with excellent
selectivity at the tertiary C−H bond. Moreover, this strategy
could be applied to the selective functionalization of an alkane
complex molecule with structurally diverse C−H nucleophiles
such as aniracetam (5d) at the α-position of the heteroatom.
Leucine and memantine derivatives were effectively engaged in
this selective pyridylation at the tertiary carbon (5d and 5e),
thus significantly expanding the utility of this transformation
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Figure 1. (a) Free energy profile of C−H pyridylation of alkanes. (b) Reactions with an amidyl radical. (c) Proposed reaction pathway.
the optimized reaction conditions (Scheme 2a). We observed
that higher reactivity was observed for the more electron-
deficient CF3 group on the sulfonamide group. To determine
whether the alkyl radical reacts with the pyridinium salt rather
than with pyridine, mixtures of 2e and 2-phenylpyridine (3ak′)
were employed (Scheme 2b). The reaction was successful only
with pyridinium salt 2e, while 3ak′ was not involved as an alkyl
radical acceptor. Next, we compared the amount of 3ak′
formed by salt decomposition to better understand the
deleterious photolysis process of 2c (Scheme 2c). To this
end, we conducted control experiments using 1.0 mol% of Q1,
TBAB, and AQ. Notably, the use of AQ maximized the
efficiency of the desired cross-coupling and resulted in only
trace amounts of pyridine byproduct. Next, we noticed that the
exclusion of oxygen was critical to the success of the reaction
(Scheme 2d). In contrast, the reaction was shown to be
insensitive to moisture. We next tested the reactions with
unactivated alkanes employing TsNHMe and PIFA as an
oxidant in the absence of AQ, where an amidyl radical
generated from TsNHMe could be used as a HAT agent
(Scheme 2e).54 We observed that the reactions with simple
alkanes, such as isopentane and 2,5-dimethylhexane, led to a
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lower selectivity between tertiary and secondary C−H bonds
with a significant decrease in reactivity. These results support
that our HAT/RHAT catalytic system is highly efficient for the
site-selective C−H pyridylation.
in Figure 1b, our calculations suggest that the RHAT process
that abstracts a hydrogen atom from AQ−H is a favorable
pathway because the step barrier of direct HAT (TS-B) was
13.4 kcal/mol, whereas the energy of the corresponding
transition state TS-A for RHAT was 11.2 kcal/mol. The
measured reaction quantum yield was Φ = 0.009 (see the SI
for details). Despite the higher barrier of a direct HAT event,
once an amidyl radical is generated, a chain pathway involving
the intermolecular HAT process of an amidyl radical is likely to
contribute to this transformation in a significant way because
the direct hydrogen abstraction from alkanes can benefit from
the statistical effect of a high concentration of alkane substrates
to form an alkyl radical species (Figure 1c). In this process, the
amidyl radical-mediated HAT process still favors the formation
of a tertiary alkyl radical over a secondary radical. As shown in
Figure 1b, the C−H abstraction of the tertiary carbon by an
amidyl radical shows a 3.8 kcal/mol preference over the
secondary carbon.
We next turned our attention to understand the mode of
action of AQ, and three conceivable reaction pathways can be
envisioned (Scheme S2 in the SI): (i) photoreduction of a
pyridinium salt through SET by AQ followed by a radical chain
pathway with an amidyl radical; (ii) photolysis of a pyridinium
salt through triplet−triplet energy transfer (EnT) from an AQ
sensitizer; (iii) direct HAT process induced by a triplet excited
AQ photocatalyst. First, the comparison of the redox potential
of the excited-state AQ* (E(AQ•+/AQ*) > 1.7 V vs SCE)81
and the pyridinium salt (−0.77 V peak potential vs SCE, see
Figure S3 in the SI) revealed that AQ has a much higher
oxidation potential than the pyridinium salt; thus, the
photoreduction of the pyridinium salt via a SET process by
AQ is thermodynamically unfavorable. Next, we examined the
possibility of triplet−triplet EnT. The energy of the triplet state
of AQ* was 62.9 kcal/mol,82 which is not congruent with the
calculated triplet energy of the 2-methyl N-aminopyridinium
salt (ET = 88.7 kcal/mol) (Figure S13 in the SI). Considering
the reaction efficiency with AQ (4b: 90% yield in Table 3), it is
therefore less likely that an EnT pathway is involved in the
reaction mechanism (for UV light-induced catalyst-free
setup,83,84 see the SI for details). Putting these observations
into perspective, we speculated that the triplet excited state of
AQ is likely to serve as a direct HAT catalyst to generate alkyl
radicals, which is consistent with the previously observed mode
of action.
To gain deeper insights into the mechanism and the site-
selectivity, we performed density functional theory (DFT)
calculations, and the reaction energy profiles are shown in
Figure 1a. The reaction begins with photoexcitation of AQ to
triplet excited AQ* upon absorption of visible light. Two alkyl
radicals II and II′ can be obtained depending on which C−H
bond in 1a is abstracted by a triplet excited AQ. Hydrogen
atom abstraction from the tertiary carbon occurs via TS-I with
a barrier of 3.4 kcal/mol to form tertiary alkyl radical II,
whereas the generation of the secondary alkyl radical II′ is
associated with transition state TS-I′ at 5.3 kcal/mol, thereby
enriching tertiary alkyl radical II. Nucleophilic alkyl radical II is
then poised for radical addition to the C4-position of salt 2c.85
Our calculations suggest that the radical addition step
determines regioselectivity, leading to the formation of two
possible isomers. Although radical coupling between alkyl
radical II′ and pyridinium salt 2c can be considered, this
pathway associated with the transition state TS-II′ is 5.5 kcal/
mol higher than TS-II. Therefore, the generated secondary
radical II turns over at a much slower rate. To push the process
forward, intermediate III undergoes facile deprotonation
followed by homolytic N−N bond cleavage through TS-IV
to ultimately form desired product 3a. Collectively, we found
that the regioselectivity for major product 3a is governed at the
radical addition step and that the H-abstraction step is partially
responsible for the observed high regioselectivity via enrich-
ment of tertiary alkyl radical II.
CONCLUSIONS
■
In summary, we have developed a visible-light-mediated
catalytic platform for the C−H pyridylation of unactivated
hydrocarbons with a high level of reactivity and site selectivity
under mild, metal-free reaction conditions. The generated
amidyl radicals can serve as highly efficient dual RHAT and
HAT agents, which is the key to the success of this
transformation. This catalytic system enables the selective
generation of tertiary or secondary alkyl radicals in chemical
feedstocks, allowing facile access to high-value-added C4-
alkylated pyridine building blocks. Moreover, this operationally
simple protocol is applicable to a variety of linear, branched,
and cycloalkanes and more complex biologically relevant
molecules with high degrees of site selectivity. We expect that
the ability of this catalytic system to directly engage abundant
unactivated alkanes as coupling partners will streamline
feedstock upgrading processes in synthetic chemistry.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00549.
■
sı
Experimental procedure and characterization of new
1
compounds (1H and C NMR spectra) (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Sungwoo Hong − Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science (IBS), Daejeon
34141, Korea; Department of Chemistry, Korea Advanced
Institute of Science and Technology (KAIST), Daejeon
34141, Korea; orcid.org/0000-0001-9371-1730;
Email: hongorg@kaist.ac.kr
Authors
Wooseok Lee − Department of Chemistry, Korea Advanced
Institute of Science and Technology (KAIST), Daejeon
34141, Korea; Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science (IBS), Daejeon
34141, Korea; orcid.org/0000-0003-0982-106X
Sungwoo Jung − Department of Chemistry, Korea Advanced
Institute of Science and Technology (KAIST), Daejeon
34141, Korea; Center for Catalytic Hydrocarbon
Next, we sought to elucidate the mode of action of the
amidyl radical species produced from the pyridinium salt in
this transformation by means of DFT calculations. Specifically,
we questioned whether an amidyl radical could undergo a
direct HAT process from alkane C−H bonds or RHAT to
regenerate the AQ catalyst from the AQ−H species. As shown
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Article
(16) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q.
Transition Metal-Catalyzed C-H Activation Reactions: Diastereose-
lectivity and enantionselectivity. Chem. Soc. Rev. 2009, 38, 3242−
3272.
Functionalizations, Institute for Basic Science (IBS), Daejeon
34141, Korea; orcid.org/0000-0003-3692-4961
Minseok Kim − Department of Chemistry, Korea Advanced
Institute of Science and Technology (KAIST), Daejeon
34141, Korea; Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science (IBS), Daejeon
34141, Korea; orcid.org/0000-0002-2924-9614
(17) Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed Ligand-
Directed C-H Functionalization Reactions. Chem. Rev. 2010, 110,
1147−1169.
(18) Rouquet, G.; Chatani, N. Catalytic Functionalization of C(sp2)-
H and C(sp3)-H Bonds by Using Bidentate Directing Groups. Angew.
Chem., Int. Ed. 2013, 52, 11726−11743.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00549
(19) Capaldo, L.; Ravelli, D. Hydrogen Atom Transfer (HAT): A
Versatile Strategy for Substrate Activation in Photocatalyzed Organic
Synthesis. Eur. J. Org. Chem. 2017, 2017, 2056−2071.
(20) Le, C.; Liang, Y.; Evans, R. W.; Li, X.; MacMillan, D. W. C.
Selective sp3 C-H Alkylation via Polarity-Match-Based Cross-
Coupling. Nature 2017, 547, 79−83.
(21) An, Q.; Wang, Z.; Chen, Y.; Wang, X.; Zhang, K.; Pan, H.; Liu,
W.; Zuo, Z. Cerium-Catalyzed C-H Functionalizations of Alkanes
Utilizing Alcohols as Hydrogen Atom Transfer Agents. J. Am. Chem.
Soc. 2020, 142, 6216−6226.
(22) Capaldo, L.; Quadri, L. L.; Ravelli, D. Photocatalytic Hydrogen
Atom Transfer: The Philosopher’s Stone for Late-Stage Functional-
ization? Green Chem. 2020, 22, 3376−3396.
(23) Dai, Z. Y.; Nong, Z. S.; Wang, P. S. Light-Mediated Asymmetric
Aliphatic C-H Alkylation with Hydrogen Atom Transfer Catalyst and
Chiral Phosphoric Acid. ACS Catal. 2020, 10, 4786−4790.
(24) Ghorbani, F.; Harry, S. A.; Capilato, J. N.; Pitts, C. R.; Joram, J.;
Peters, G. N.; Tovar, J. D.; Smajlagic, I.; Siegler, M. A.; Dudding, T.;
Lectka, T. Carbonyl-Directed Aliphatic Fluorination: A Special Type
of Hydrogen Atom Transfer Beats out Norrish II. J. Am. Chem. Soc.
2020, 142, 14710−14724.
(25) Kawasaki, T.; Ishida, N.; Murakami, M. Dehydrogenative
Coupling of Benzylic and Aldehydic C-H Bonds. J. Am. Chem. Soc.
2020, 142, 3366−3370.
(26) Laudadio, G.; Deng, Y.; van der Wal, K.; Ravelli, D.; Nuno, M.;
Fagnoni, M.; Guthrie, D.; Sun, Y.; Noel, T. C(sp3)-H Functionaliza-
tions of Light Hydrocarbons Using Decatungstate Photocatalysis in
Flow. Science 2020, 369, 92−96.
(27) Sarver, P. J.; Bacauanu, V.; Schultz, D. M.; DiRocco, D. A.;
Lam, Y. H.; Sherer, E. C.; MacMillan, D. W. C. The Merger of
Decatungstate and Copper Catalysis to Enable Aliphatic C(sp3)-H
Trifluoromethylation. Nat. Chem. 2020, 12, 459−467.
(28) Zheng, Y. W.; Narobe, R.; Donabauer, K.; Yakubov, S.; Konig,
B. Copper(II)-Photocatalyzed N-H Alkylation with Alkanes. ACS
Catal. 2020, 10, 8582−8589.
(29) Morton, C. M.; Zhu, Q.; Ripberger, H.; Troian-Gautier, L.;
Toa, Z. S. D.; Knowles, R. R.; Alexanian, E. J. C-H Alkylation via
Multisite-Proton-Coupled Electron Transfer of an Aliphatic C-H
Bond. J. Am. Chem. Soc. 2019, 141, 13253−13260.
(30) Ueda, M.; Maeda, A.; Hamaoka, K.; Sasano, M.; Fukuyama, T.;
Ryu, I. Bromine-Radical-Mediated Site-Selective Allylation of C(sp3)-
H Bonds. Synthesis 2019, 51, 1171−1177.
(31) Antonchick, A. P.; Burgmann, L. Direct Selective Oxidative
Cross-Coupling of Simple Alkanes with Heteroarenes. Angew. Chem.,
Int. Ed. 2013, 52, 3267−3271.
(32) Mukherjee, S.; Maji, B.; Tlahuext-Aca, A.; Glorius, F. Visible-
Light-Promoted Activation of Unactivated C(sp3)-H Bonds and Their
Selective Trifluoromethylthiolation. J. Am. Chem. Soc. 2016, 138,
16200−16203.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dedicated to Professor Kyo Han Ahn on the occasion of his
retirement. This research was supported financially by Institute
for Basic Science (IBS-R010-A2).
REFERENCES
■
(1) Tran, B. L.; Li, B.; Driess, M.; Hartwig, J. F. Copper-Catalyzed
Intermolecular Amidation and Imidation of Unactivated Alkanes. J.
Am. Chem. Soc. 2014, 136, 2555−2563.
(2) Cuthbertson, J. D.; MacMillan, D. W. C. The Direct Arylation of
Allylic sp3 C-H Bonds via Organic and Photoredox Catalysis. Nature
2015, 519, 74−77.
(3) Sharma, A.; Hartwig, J. F. Metal-Catalysed Azidation of Tertiary
C-H Bonds Suitable for Late-Stage Functionalization. Nature 2015,
517, 600−604.
(4) Cook, A. K.; Schimler, S. D.; Matzger, A. J.; Sanford, M. S.
Catalyst-Controlled Selectivity in the C-H Borylation of Methane and
Ethane. Science 2016, 351, 1421−1424.
(5) Tang, S.; Wang, P.; Li, H.; Lei, A. Multimetallic Catalysed
Radical Oxidative C(sp3)-H/C(sp)-H Cross-Coupling between
Unactivated Alkanes and Terminal Alkynes. Nat. Commun. 2016, 7,
11676.
(6) Hu, A.; Guo, J. J.; Pan, H.; Zuo, Z. Selective Functionalization of
Methane, Ethane, and Higher Alkanes by Cerium Photocatalysis.
Science 2018, 361, 668−672.
(7) Margrey, K. A.; Czaplyski, W. L.; Nicewicz, D. A.; Alexanian, E.
J. A General Strategy for Aliphatic C-H Functionalization Enabled by
Organic Photoredox Catalysis. J. Am. Chem. Soc. 2018, 140, 4213−
4217.
(8) Chu, J. C. K.; Rovis, T. Complementary Strategies for Directed
C(sp3)-H Functionalization: A Comparison of Transition-Metal-
Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/
Nitrene Transfer. Angew. Chem., Int. Ed. 2018, 57, 62−101.
(9) Michaudel, Q. M.; Thevenet, D.; Baran, P. S. Intermolecular
Ritter-Type C-H Amination of Unactivated sp3 Carbons. J. Am. Chem.
Soc. 2012, 134, 2547−2550.
(10) Bergman, R. G. C-H activation. Nature 2007, 446, 391−393.
(11) Chen, X.; Engle, K. M.; Wang, D.-H; Yu, J.-Q. Palladium(II)-
Catalyzed C-H Activation/C-C Cross Coupling Reactions: Versatility
and Practicality. Angew. Chem., Int. Ed. 2009, 48, 5094−5115.
(12) Waele, V. D.; Poizat, O.; Fagnoni, M.; Bagno, A.; Ravelli, D.
Unraveling the Key Features of the Reactive State of Decatungstate
Anion in Hydrogen Atom Transfer (HAT) Photocatalysis. ACS Catal.
2016, 6, 7174−7182.
(33) Liao, K.; Pickel, T. C.; Boyarskikh, V.; Bacsa, J.; Musaev, D. G.;
Davies, H. M. L. Site-Selective and Stereoselective Functionalization
of Non-Activated Tertiary C-H Bonds. Nature 2017, 551, 609−613.
(34) Ravelli, D.; Fagnoni, M.; Fukuyama, T.; Nishikawa, T.; Ryu, I.
Site-Selective C-H Functionalization by Decatungstate Anion Photo-
catalysis: Synergistic Control by Polar and Steric Effects Expands the
Reaction Scope. ACS Catal. 2018, 8, 701−713.
(35) Li, G. X.; Hu, X. F.; He, G.; Chen, G. Photoredox-Mediated
Minisci-Type Alkylation of N-Heteroarenes with Alkanes with High
Methylene Selectivity. ACS Catal. 2018, 8, 11847−11853.
(13) Stateman, L. M.; Nakafuku, K. M.; Nagib, D. A. Remote C-H
Functionalization via Selective Hydrogen Atom Transfer. Synthesis
2018, 50, 1569−1586.
(14) Nechab, M.; Mondal, S.; Bertrand, M. P. 1,n-Hydrogen-Atom
Transfer (HAT) Reactions in Which n≠5: An Updated Inventory.
Chem. - Eur. J. 2014, 20, 16034−16059.
(15) Sarkar, S.; Cheung, K. P. S.; Gevorgyan, V. C-H
Functionalization Reactions Enabled By Hydrogen Atom Transfer
To Carbon-Centered Radicals. Chem. Sci. 2020, 11, 12974.
3010
https://dx.doi.org/10.1021/jacs.1c00549
J. Am. Chem. Soc. 2021, 143, 3003−3012

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(36) Yang, H. B.; Feceu, A.; Martin, D. B. C. Catalyst-Controlled C-
H Functionalization of Adamantanes Using Selective H-Atom
Transfer. ACS Catal. 2019, 9, 5708−5715.
(37) Cao, H.; Kuang, Y.; Shi, X.; Wong, K. L.; Tan, B. B.; Kwan, J.
M. C.; Liu, X.; Wu, J. Photoinduced Site-Selective Alkenylation of
Alkanes and Aldehydes with Aryl Alkenes. Nat. Commun. 2020, 11,
1956.
(56) Xu, P.; Chen, P. Y.; Xu, H. C. Scalable Photoelectrochemical
Dehydrogenative Cross-Coupling of Heteroarenes with Aliphatic C-H
Bonds. Angew. Chem., Int. Ed. 2020, 59, 14275−14280.
́
(57) Cervantes-Gonzalez, J.; Vosburg, D. A.; Mora-Rodriguez, S. E.;
́
Vazquez, M. A.; Zepeda, L. G.; Villegas Gómez, C.; Lagunas-Rivera, S.
Anthraquinones: Versatile Organic Photocatalysts. ChemCatChem
2020, 12, 3811−3827.
(38) Jia, P.; Li, Q.; Poh, W. C.; Jiang, H.; Liu, H.; Deng, H.; Wu, J.
Light-Promoted Bromine-Radical-Mediated Selective Alkylation and
Amination of Unactivated C(sp3)-H Bonds. Chem. 2020, 6, 1766−
1776.
(58) Wang, L.; Wang, T.; Cheng, G.-J.; Li, X.; Wei, J.-J.; Guo, B.;
Zheng, C.; Chen, G.; Ran, C.; Zheng, C. Direct C-H Arylation of
Aldehydes by Merging Photocatalyzed Hydrogen Atom Transfer with
Palladium Catalysis. ACS Catal. 2020, 10, 7543−7551.
(59) Carestia, A. M.; Ravelli, D.; Alexanian, E. J. Reagent-Dictated
Site Selectivity in Intermolecular Aliphatic C-H Functionalizations
Using Nitrogen-Centered Radicals. Chem. Sci. 2018, 9, 5360−5365.
(60) Tanaka, H.; Sakai, K.; Kawamura, A.; Oisaki, K.; Kanai, M.
Sulfonamides as New Hydrogen Atom Transfer (HAT) Catalysts for
Photoredox Allylic and Benzylic C-H Arylations. Chem. Commun.
2018, 54, 3215−3218.
(39) Shu, C.; Noble, A.; Aggarwal, V. K. Metal-Free Photoinduced
C(sp3)-H Borylation of Alkanes. Nature 2020, 586, 714−719.
(40) Weigel, W. K., III; Dang, H. T.; Yang, H. B.; Martin, D. B. C.
Synthesis of Amino-Diamondoid Pharmacophores via Photocatalytic
C-H Aminoalkylation. Chem. Commun. 2020, 56, 9699−9702.
(41) Kim, I.; Kang, G.; Lee, K.; Park, B.; Kang, D.; Jung, H.; He, Y.-
T.; Baik, M.-H.; Hong, S. Site-Selective Functionalization of
Pyridinium Derivatives via Visible-Light-Driven Photocatalysis with
Quinolinone. J. Am. Chem. Soc. 2019, 141, 9239−9248.
(42) Kim, N.; Lee, C.; Kim, T.; Hong, S. Visible-Light-Induced
Remote C(sp3)-H Pyridylation of Sulfonamides and Carboxamides.
Org. Lett. 2019, 21, 9719−9723.
(43) Moon, Y.; Park, B.; Kim, I.; Kang, G.; Shin, S.; Kang, D.; Baik,
M.-H.; Hong, S. Visible Light Induced Alkene Aminopyridylation
Using N-Aminopyridinium Salts as Bifunctional Reagents. Nat.
Commun. 2019, 10, 4117.
(44) Jeon, J.; He, Y. T.; Shin, S.; Hong, S. Visible-Light-Induced
ortho-Selective Migration on Pyridyl Ring: Trifluoromethylative
Pyridylation of Unactivated Alkenes. Angew. Chem., Int. Ed. 2020,
59, 281−285.
(45) Jung, S.; Shin, S.; Park, S.; Hong, S. Visible-Light-Driven C4-
Selective Alkylation of Pyridinium Derivatives with Alkyl Bromides. J.
Am. Chem. Soc. 2020, 142, 11370−11375.
(46) Lee, K.; Lee, S.; Kim, N.; Kim, S.; Hong, S. Visible-Light-
Enabled Trifluoromethylative Pyridylation of Alkenes from Pyridines
and Triflic Anhydride. Angew. Chem., Int. Ed. 2020, 59, 13379−13384.
(47) Mathi, G. R.; Jeong, Y.; Moon, Y.; Hong, S. Photochemical
Carbopyridylation of Alkenes Using N-Alkenoxypyridinium Salts as
Bifunctional Reagents. Angew. Chem., Int. Ed. 2020, 59, 2049−2054.
(48) Moon, Y.; Lee, W.; Hong, S. Visible-Light-Enabled ortho-
Selective Aminopyridylation of Alkenes with N-Aminopyridinium
Ylides. J. Am. Chem. Soc. 2020, 142, 12420−12429.
(49) Hoshikawa, T.; Inoue, M. Photoinduced Direct 4-Pyridination
of C(sp3)-H Bonds. Chem. Sci. 2013, 4, 3118−3123.
(50) Quattrini, M. C.; Fujii, S.; Yamada, K.; Fukuyama, T.; Ravelli,
D.; Fagnoni, M.; Ryu, I. Versatile Cross-Dehydrogenative Coupling of
Heteroaromatics and Hydrogen Donors via Decatungstate Photo-
catalysis. Chem. Commun. 2017, 53, 2335−2338.
(51) Ikarashi, G.; Morofuji, T.; Kano, N. Terminal-Oxidant-Free
Photocatalytic C-H Alkylations of Heteroarenes with Alkylsilicates as
Alkyl Radical Precursors. Chem. Commun. 2020, 56, 10006−10009.
(52) Rammal, F.; Gao, D.; Boujnah, S.; Gaumont, A. C.; Hussein, A.
A.; Lakhdar, S. Visible-Light-Mediated C-H Alkylation of Pyridine
Derivatives. Org. Lett. 2020, 22, 7671−7675.
(53) Rammal, F.; Gao, D.; Boujnah, S.; Hussein, A. A.; Lalevée, J.;
Gaumont, A.-C.; Morlet-Savary, F.; Lakhdar, S. Photochemical C-H
Silylation and Hydroxymethylation of Pyridines and Related
Structures: Synthetic Scope and Mechanisms. ACS Catal. 2020, 10
(22), 13710−13717.
(54) Shao, X.; Wu, X.; Wu, S.; Zhu, C. Metal-Free Radical-Mediated
C(sp3)-H Heteroarylation of Alkanes. Org. Lett. 2020, 22, 7450−
7454.
(61) Ganley, J. M.; Murray, P. R. D.; Knowles, R. R. Photocatalytic
Generation of Aminium Radical Cations for C-N Bond Formation.
ACS Catal. 2020, 10, 11712−11738.
̈
(62) Rossler, S. L.; Jelier, B. J.; Magnier, E.; Dagousset, G.; Carreira,
E. M.; Togni, A. Pyridinium Salts as Redox-Active Functional Group
Transfer Reagents. Angew. Chem., Int. Ed. 2020, 59, 9264−9280.
(63) Fan, X. Z.; Rong, J. W.; Wu, H. L.; Zhou, Q.; Deng, H. P.; Tan,
J. D.; Xue, C. W.; Wu, L. Z.; Tao, H. R.; Wu, J. Eosin Y as a Direct
Hydrogen-Atom Transfer Photocatalyst for the Functionalization of
C-H Bonds. Angew. Chem., Int. Ed. 2018, 57, 8514−8518.
(64) Srivastava, V.; Singh, P. K.; Singh, P. P. Photocatalysed Eosin Y
Mediated C(sp3)-H Alkylation of Amine Substrates via Direct HAT.
Tetrahedron Lett. 2019, 60, 1333−1336.
(65) Yan, J.; Cheo, H. W.; Teo, W. K.; Shi, X.; Wu, H.; Idres, S. B.;
Deng, L. W.; Wu, J. A Radical Smiles Rearrangement Promoted by
Neutral Eosin Y as a Direct Hydrogen Atom Transfer Photocatalyst. J.
Am. Chem. Soc. 2020, 142, 11357−11362.
(66) Perry, I. B.; Brewer, T. F.; Sarver, P. J.; Schultz, D. M.;
DiRocco, D. A.; MacMillan, D. W. C. Direct Arylation of Strong
Aliphatic C-H Bonds. Nature 2018, 560, 70−75.
(67) Xia, J. B.; Zhu, C.; Chen, C. Visible Light-Promoted Metal-Free
C-H Activation: Diarylketone-Catalyzed Selective Benzylic Mono-
and Difluorination. J. Am. Chem. Soc. 2013, 135, 17494−17500.
(68) Xia, J. B.; Zhu, C.; Chen, C. Visible Light-Promoted Metal-Free
sp3 C-H Fluorination. Chem. Commun. 2014, 50, 11701−11704.
(69) Shen, Y.; Gu, Y.; Martin, R. sp3 C-H Arylation and Alkylation
Enabled by the Synergy of Triplet Excited Ketones and Nickel
Catalysts. J. Am. Chem. Soc. 2018, 140, 12200−12209.
(70) Li, Y.; Lei, M.; Gong, L. Photocatalytic Regio- and
Stereoselective C(sp3)-H Functionalization of Benzylic and Allylic
Hydrocarbons as Well as Unactivated Alkanes. Nat. Catal. 2019, 2,
1016−1026.
(71) Ishida, N.; Masuda, Y.; Imamura, Y.; Yamazaki, K.; Murakami,
M. Carboxylation of Benzylic and Aliphatic C-H Bonds with CO2
Induced by Light/Ketone/Nickel. J. Am. Chem. Soc. 2019, 141,
19611−19615.
(72) Masuda, Y.; Tsuda, H.; Murakami, M. C1 Oxidation/C2
Reduction Isomerization of Unprotected Aldoses Induced by Light/
Ketone. Angew. Chem., Int. Ed. 2020, 59, 2755−2759.
(73) Dewanji, A.; Krach, P. E.; Rueping, M. The Dual Role of
Benzophenone in Visible-Light/Nickel Photoredox-Catalyzed C-H
Arylations: Hydrogen-Atom Transfer and Energy Transfer. Angew.
Chem., Int. Ed. 2019, 58, 3566−3570.
(74) Li, L.; Mu, X.; Liu, W.; Wang, Y.; Mi, Z.; Li, C.-J. Simple and
Clean Photoinduced Aromatic Trifluoromethylation Reaction. J. Am.
Chem. Soc. 2016, 138, 5809−5812.
(75) Amaoka, Y.; Nagatomo, M.; Watanabe, M.; Tao, K.; Kamijo, S.;
Inoue, M. Photochemically Induced Radical Alkenylation of C(sp3)-H
Bonds. Chem. Sci. 2014, 5, 4339−4345.
(55) Tian, H.; Yang, H.; Tian, C.; An, G.; Li, G. Cross-
Dehydrogenative Coupling of Strong C(sp3)-H with N-Heteroarenes
through Visible-Light-Induced Energy Transfer. Org. Lett. 2020, 22,
7709−7715.
3011
https://dx.doi.org/10.1021/jacs.1c00549
J. Am. Chem. Soc. 2021, 143, 3003−3012

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(76) Kamijo, S.; Hoshikawa, T.; Inoue, M. Photochemically Induced
Radical Transformation of C(sp3)-H Bonds to C(sp3)-CN Bonds.
Org. Lett. 2011, 13, 5928−5931.
(77) Hoshikawa, T.; Kamijo, S.; Inoue, M. Photochemically Induced
Radical Alkynylation of C(sp3)-H Bonds. Org. Biomol. Chem. 2013,
11, 164−169.
(78) Paul, S.; Guin, J. Radical C(sp3)-H Alkenylation, Alkynylation
And Allylation of Ethers And Amides Enabled By Photocatalysis.
Green Chem. 2017, 19, 2530−2534.
(79) Nagatomo, M.; Yoshioka, S.; Inoue, M. Enantioselective
Radical Alkynylation of C(sp3)-H Bonds Using Sulfoximine as a
Traceless Chiral Auxiliary. Chem. - Asian J. 2015, 10, 120−123.
(80) Blanksby, S. J.; Ellison, G. B. Bond Dissociation Energies of
Organic Molecules. Acc. Chem. Res. 2003, 36, 255−263.
(81) Bachman, J. E.; Curtiss, L. A.; Assary, R. S. Investigation of the
Redox Chemistry of Anthraquinone Derivatives Using Density
Functional Theory. J. Phys. Chem. A 2014, 118, 8852−8860.
(82) Wilkinson, F. Transfer of Triplet State Energy and the
Chemistry of Excited States. J. Phys. Chem. 1962, 66, 2569−2574.
(83) Gadde, K.; Mampuys, P.; Guidetti, A.; Ching, H. Y. V.;
Herrebout, W. A.; Van Doorslaer, S.; Abbaspour Tehrani, K.; Maes, B.
U. W. Thiosulfonylation of Unactivated Alkenes with Visible-Light
Organic Photocatalysis. ACS Catal. 2020, 10, 8765−8779.
(84) Strieth-Kalthoff, F.; Glorius, F. Triplet Energy Transfer
Photocatalysis: Unlocking the Next Level. Chem. 2020, 6, 1888−
1903.
(85) Kim, I.; Park, S.; Hong, S. Functionalization of Pyridinium
Derivatives with 1,4-Dihydropyridines Enabled by Photoinduced
Charge Transfer. Org. Lett. 2020, 22, 8730−8734.
3012
https://dx.doi.org/10.1021/jacs.1c00549
J. Am. Chem. Soc. 2021, 143, 3003−3012