Phenylglyoxylic Acid: An Efficient Initiator for the Photochemical Hydrogen Atom Transfer C?H Functionalization of Heterocycles

Article abstract of DOI:10.1002/cssc.202001892

C?H functionalization at the α-position of heterocycles has become a rapidly growing area of research. Herein, a cheap and efficient photochemical method was developed for the C?H functionalization of heterocycles. Phenylglyoxylic acid (PhCOCOOH) could behave as an alternative to metal-based catalysts and organic dyes and provided a very general and wide array of photochemical C?H alkylation, alkenylation, and alkynylation, as well as C?N bond forming reaction methodologies. This novel, mild, and metal-free protocol was successfully employed in the functionalization of a wide range of C?H bonds, utilizing not only O- or N-heterocycles, but also the less studied S-heterocycles.

Full text of DOI:10.1002/cssc.202001892

Chemistry–Sustainability–Energy–Materials
Accepted Article
Title: Phenylglyoxylic Acid: An Efficient Initiator for the Photochemical
Hydrogen Atom Transfer (HAT) C-H Functionalization of
Heterocycles
Authors: Giorgos N Papadopoulos, Maroula G. Kokotou, Nikoleta
Spiliopoulou, Nikolaos F. Nikitas, Errika Voutyritsa, Dimitrios
Ioannis Tzaras, Nikolaos Kaplaneris, and Christoforos G.
Kokotos
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To be cited as: ChemSusChem 10.1002/cssc.202001892
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01/2020

10.1002/cssc.202001892
ChemSusChem
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Phenylglyoxylic Acid: An Efficient Initiator for the Photochemical
Hydrogen Atom Transfer (HAT) C-H Functionalization of
Heterocycles
Giorgos N. Papadopoulos,[a] Maroula G. Kokotou,[a] Nikoleta Spiliopoulou,[a] Nikolaos F. Nikitas,[a]
Errika Voutyritsa,[a] Dimitrios Ioannis Tzaras,[a] Nikolaos Kaplaneris[a] and Christoforos G. Kokotos*[a]
Abstract: C-H functionalization at the α position of heterocycles
has become a rapidly growing area of research. Herein, we report
a
cheap and efficient photochemical method for the C-H
functionalization of heterocycles. PhCOCOOH can behave as an
alternative to metal-based catalysts and organic dyes and provides
a very general and wide array of photochemical C-H alkylation,
alkenylation and alkynylation, as well as C-N bond forming
reaction methodologies. This novel, mild and metal-free protocol is
successfully employed in the functionalization of a wide range of
C-H bonds, utilizing not only O- or N-heterocycles, but also the
less studied S-heterocycles.
Introduction
The introduction of novel reactivities and new platforms of
activation is the ultimate goal in organic synthesis.[1]
Photochemistry, the use of light to promote organic
transformations, is a concept introduced in literature in 1912
and provides access to alternative activations compared to
polar chemistry.[2] In recent years, photoredox catalysis has
become a powerful strategy for the activation of small
molecules.[3,4] Most examples rely on the use of metal-based
catalysts (mainly Ru or Ir), having the advantage of tuning their
electronic properties via ligand manipulation. Unfortunately,
these complexes can be expensive, and some are not
commercially-available. To address this problem, a number of
organic dyes have been employed as photocatalysts, which in
many cases provide similar reactivities. Photoorganocatalysis
is a low-cost and environmentally friendly alternative.[5,6]
However, each of these catalysts has certain limitations. For
example, benzophenones have a long-lived triplet state, which
allows a hydrogen atom transfer (HAT) process to occur.
Nevertheless, a reverse hydrogen atom transfer (RHAT) is
required, in order, for the catalyst, to be regenerated. Since
this is usually a slow procedure, a faster dimerization of
benzophenone to benzopinacol is usually observed. Quinones
constitute an important category of photoinitiators, when
Scheme 1. Approaches for the selective photochemical C-H
functionalization of heterocycles.
irradiated in the near UV. This family of catalysts is scarcely
reported in photochemical reactions, while in the case of
polyoxometalates, the use of toxic transition metals cannot be
avoided. In addition, organic dyes, like Eosin Y,[7] are shown to
be competent visible-light absorbing photochemical catalysts.
The direct transformation of C-H to C-C or C-N bonds is one of
the most ideal methodologies for constructing complex
molecules with various potential applications in medicinal and
bioorganic chemistry.[8] Heterocycles are present in
[a]
Dr. Giorgos N. Papadopoulos, Dr. Maroula G. Kokotou, Nikoleta
Spiliopoulou, Nikolaos F. Nikitas, Dr. Errika Voutyritsa, Dimitrios
Ioannis Tzaras, Nikolaos Kaplaneris and Prof. Dr. C. G. Kokotos
Laboratory of Organic Chemistry, Department of Chemistry,
National and Kapodistrian University of Athens, Panepistimiopolis
15771, Athens, Greece. E-mail: ckokotos@chem.uoa.gr
Supporting information for this article is given via a link at the end
of the document.
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10.1002/cssc.202001892
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FULL PAPER
pharmaceuticals and bioactive molecules (35% of drugs
feature a heterocycle). Also, heterocyclic scaffolds are found in
plant-derived natural products and are ubiquitous in biological
processes. Thus, researchers are constantly searching for
novel functionalization methods.[9] Most of them are metal-
catalyzed processes, while a handful of examples refer to
metal-free C-H transformations. Although significant advances
have been made, direct metal-catalyzed functionalization of
heterocycles is still confronted by several challenges. For
example, heteroatoms including N, S, and O can potentially
coordinate strongly to transition metal catalysts, which can
ultimately lead to catalyst poisoning/deactivation or C-H
functionalization at undesired positions via chelation.
Dialkyl azodicarboxylates have been recognized as extremely
useful electrophiles, due to their strong electron-withdrawing
character and their vacant orbital.[10a-c] Early literature refers to
scarce examples of reactions of dialkyl azodicarboxylates with
ethers in various metal-catalyzed, radical-initiated or
photochemical reactions.[10-12] In these reports, only N-
heterocycles[11] (Scheme 1, A), and two examples with O-
heterocycles[12] were presented (Scheme 1, B). Unfortunately,
no S-heterocycles have been reported, while a unified solution
is still absent.
Barriault reported the photoredox-mediated catalytic
generation of chlorine atoms and their ability to undergo
hydrogen atom transfer reactions with a variety of cyclic and
not cyclic alkanes and their addition to activated alkenes using
an iridium-based catalyst.[18] Also, Nicewicz presented the
alkylation of carbamate-protected amines, using an organic
acridinium photoredox catalyst and 445 nm LEDs as the
irradiation source (Scheme 1, F).[19] Finally, Vincent reported
the benzophenone photocatalyzed Giese-type alkylations of C-
H bonds using unsubstituted acrylates, acrylonitrile and methyl
vinyl ketones as acceptors, in the presence of a catalytic
amount of Cu(OAc)2.[20]
We have recently developed a photochemical protocol that is
easy to operate, employing cheap household lamps as the
irradiation source and phenylglyoxylic acid, a cheap, organic,
and commercially available molecule, as the initiator for the
functionalization of aldehydes or alcohols (Scheme 2, A).[21]
A
fast and efficient visible-light metal-free hydroacylation of
dialkyl azodicarboxylates, was developed,[21a] and extended in
the synthesis of hydroxamic acids[21b] and amides,[21c] finding
application in the synthesis of the drugs Vorinostat and
Moclobemide. Then, a green and easy reproducible selective
hydroacylation of both electron poor and electron rich alkenes
was presented[21f, 21g] and an efficient photochemical protocol
for the synthesis of γ-lactones,[21e] starting from diesters of
maleic acid and alcohols.
Except from the C-N functionalization of heterocycles on the α
position, the direct C-H alkenylation of heterocycles is also an
important area of research. A number of protocols have been
reported, based on peroxides/UV light, generation of radicals,
aerobic/autooxidation
Bis(phenylsulfonyl)ethylene is
and
photoinitiation.[13]
commercially available
1,2-
a
reagent, which has been used for the addition of alkenyl
functional groups.[14] A limited number of approaches for the
functionalization of C-H bonds of heterocycles employing
sulfones have been reported. Initially, Fuchs introduced
alkynyl triflone reagents for the thermally-induced or
photochemical
(UV-light)
radical
alkynylation
of
tetrahydrofuranyl derivatives.[15a] The same year, Fuchs
extended their method by incorporation of vinyl triflones as the
alkenylation reagent via an AIBN-catalyzed process.[15b] Later,
Inoue introduced
a stoichiometric photocatalytic method
employing benzophenone for the direct alkynylation[15c] and
alkenylation[15d] of 2-pyrrolidinone (Scheme 1, C). Very recently,
Paul and Guin took advantage of the main activation mode of
benzophenone-derived triplets, in order to initiate a hydrogen
atom transfer (HAT) process (Scheme 1, D).[15e] This method,
although elegant and green is limited by the slow reverse HAT
or reverse electron transfer/proton transfer, which has as an
outcome the poor turnover of the photocatalyst, requiring high
catalyst loadings and long reaction time.
In addition to the C-H alkenylation of heterocycles, the C-H
alkylation has also received some attention. In 2005, Ochiai
reported the alkylation of O-heterocycles, using tert-
butylperoxy-1,2-benziodoxol-3(1H)-one.[16] Recently,
Wu
reported a method using a wide range of electron-
deficient alkenes to afford the alkylation product of
heterocycles.[17] The generation of the α-ethereal carbon
radicals was achieved by a HAT process between excited
Eosin Y, which was used as the photocatalyst, and THF,
Scheme 2. HAT catalysis for the C-H functionalization mediated by
phenylglyoxylic acid.
under white LED irradiation (Scheme 1, E) [17]
Very recently,
.
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10.1002/cssc.202001892
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Our aim is to achieve the direct photochemical C-H
functionalization of heterocycles as a promising approach with
high atom- and step-economy (Scheme 2, B). Herein, we
report our results on the mild alkenylation of C-H bonds, using
phenylglyoxylic acid as the photoinitiator and cis-1,2-
bis(phenylsulfonyl)ethylene (Scheme 2, B, i). In order to
expand the potential of our protocol, we tested our
photochemical protocol, not only in the reaction between a
range of olefins and various heterocycles (Scheme 2, B, ii),
but also in the successful formation of C-N bonds (Scheme 2,
B, iii). In general, herein, we demonstrate that not only O- or
N-, but also S-heterocycles can be activated via sustainable
and green photochemistry, using a low-cost setup and
providing comparable or better results to metal photocatalysis.
Results and Discussion
We initially investigated the reaction between THF (1a) and
diisopropyl azodicarboxylate (DIAD, 2a) (Scheme 3). A variety
of aryl ketones (3a-f) were employed, and PhCOCOOH (3a)
outperformed all, providing 4 in quantitative yield in short
reaction time (4 h). In the absence of either the initiator or light,
the reaction did not proceed. THF is used as the reagent and
the solvent, since attempts to employ other solvents, in order
to reduce the amount of THF, led to lower yields.[22] However,
extending the reaction time, efficient yields of the product
could be obtained, reducing the amount of THF (5 equivalents
in Pet. Ether for 48 h, 83% yield or 3 equivalents in Pet. Ether
for 96 h, 58% yield), providing a useful alternative for late-
stage functionalization.[22] The reaction can also be driven by
sunlight (25 September 2019, 10:00-14:00, Athens, Greece,
37.97° N, 23.72° E). No special precautions were taken to
exclude air or moisture and reagent-grade THF was employed.
Having established the optimum reaction conditions, we turned
our attention into the exploration of the substrate scope
(Scheme 4). First, a series of dialkyl azodicarboxylates were
tested, affording products 4-7 in excellent yields (Scheme 4,
A). Monosubstituted tetrahydrofurans at the α position led to a
mixture of regioisomers (products 8-10, Scheme 4, B). Moving
from five-membered to six-membered ring O-heterocycles or
using linear aliphatic ethers led to products 11-18 (Scheme 4,
Scheme 4. Substrate scope of the photochemical C-H functionalization
leading to a new C-N bond.
C). Then, S-heterocycles were successfully employed (19 and
20, Scheme 4, D). N-Heterocycles, which are present in drugs
or are important for industrial processes, reacted smoothly
leading to 21-24 in high yields, making this method suitable for
late-stage functionalization of drugs (like the anti-diabetic
Galvus[23a]) or enzyme inhibitors (like indolizidine 235b[23b]
)
containing heterocycles (Scheme 4, E). This constitutes, in our
knowledge, the first successful unified solution for the
introduction of C-N bonds to O-, N- and S-heterocycles.
These results gave us the opportunity to further try other types
of radical acceptors. Initially, the photochemical reaction
between THF (1a) and 1,2-bis(phenylsulfonyl)ethylene (25)
was studied (Scheme 5). Among the promoters tested,
PhCOCOOH provided the best results in short reaction time.
Common catalysts, like Eosin Y or Ru(bpy)3Cl2 did not afford
the product in high yields.[22] As before, attempts to employ
other solvents and reduce the amount of THF as being simply
the reagent led to lower yields.[22] However, as before, in
substrates that are more precious, lower amount of
heterocycles can be employed and similar yields can be
Scheme 3. Catalyst screening for the photochemical synthesis of 4.
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10.1002/cssc.202001892
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Scheme 5. Catalyst screening for the photochemical C-H alkenylation of
THF.
obtained by extending the reaction time. The reaction can also
be performed under sunlight.
After establishing the optimum reaction conditions,[22] we
explored the substrate scope (Scheme 6). Other
tetrahydrofuranyl adducts, like 2-methyl-THF or dioxolane,
reacted well leading to two regioisomers (9:1), in favor of the
expected
tertiary-substituted
product
in
excellent
diastereoselectivity. Moving from five-membered to six-
membered heterocycles led to 28-30 (Scheme 6, A). Acyclic
ethers were also functionalized in good to excellent yields (32-
36). The only exception was diethoxyethane, which led to a
3:1 mixture of regioisomers (34:35) (Scheme 6, B). S-
Heterocycles that are scarcely employed in C-H
functionalization methods reacted smoothly leading to 37 and
38 (Scheme 6, C). Finally, this protocol can be extended to N-
heterocycles (39-43), leaving open the potential of late-stage
functionalization of drugs (Scheme 6, D).[23] Finally, we turned
our attention into the alkene partner (44-46). Interestingly, this
method can be extended to C-H alkynylation reaction (47)
(Scheme 6, E).
Being successful in the C-H alkenylation of heterocycles, we
moved on the C-H alkylation. We initially investigated the
reaction between THF (1a) and diethyl maleate (48a) (Scheme
7). A variety of (activated) ketones were employed, and
PhCOCOOH (3a) proved to be the best promoter, leading to
the formation of 49 in 93% yield in short reaction time (4 h).
Extending the reaction time, efficient yields of the product
could be obtained, reducing the amount of THF (5 equivalents
in H2O for 48 h, 85% yield or 3 equivalents in H2O for 96 h,
84% yield), providing a useful alternative for late-stage
functionalization.[22]
Scheme 6. Substrate scope of the photochemical C-H alkenylation of
heterocycles.
A variety of substituted electron-deficient olefins were tested
and in all cases the products were isolated as mixture of
diastereomers (Scheme 8). Alkyl-substituted electron-deficient
olefins reacted smoothly leading to 49-55 in high yields
(Scheme 8, A). This method can be extended to benzyl-
substituted electron-deficient olefins (56-59) (Scheme 8, B).
Finally, a range of different Michael acceptors were employed
successfully, affording the desired products in good to
excellent yields (60-62) (Scheme 8, C). Acrylate-type
substrates (esters, amides or aldehydes) were also tested,
Scheme 7. Catalyst screening for the photochemical synthesis of 49.
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however only polymerization products were observed.
Next, we turned our attention into the heterocyclic partner
(Scheme 9). 2-Methyl-THF reacted well leading to two
regioisomers (63). Six-membered heterocycles and were
successfully employed in the reaction, affording 64-67 in
excellent yields (Scheme 9, A). The reaction was also carried
out efficiently, when acyclic ethers were tested, leading to 68
and 69 (Scheme 9, B). S-Heterocycles were also successfully
tested, affording 70 and 71 in high yields (Scheme 9, C).
Finally, as before, N-heterocycles were functionalized
successfully, affording the desired products in good yields (72
and 73) (Scheme 9, D).
N,O-Acetals are useful building blocks for further synthetic
manipulations, for example via reactions with various ylides.[24]
Nucleophilic substitution reaction at the α position of 4 by
benzyl alcohol, in the presence of BF3.Et2O, led to protected
alcohol 74 (Scheme 10).
Scheme 10. Example of further functionalization of addition product.
Scheme 8. Substrate scope of the photochemical alkylation of THF.
In an attempt to further enhance the applicability of our
protocol, we employed it to the synthesis of addition products
bearing natural abudant moieties and nitrogen bearing
scaffolds, which are common in pharmaceutical products
(Scheme 11). Initially, the reaction between dioxane and the
fumarate esters of cholesterol and citronellol were performed
leading to 75 and 76. Also, a cyclic acetal derived from 3-
phenyl-propanal led to 77 in high yield and excellent E/Z-
selectivity. In order to expand the protocol on the use of N-
containing heterocycles, which are more frequently
encountered in pharmaceuticals, we employed the late-stage
Scheme 11. Examples with life abundant molecules, mixed heteroatom
heterocycles and nitrogen containing heterocycles.
Scheme 9. Substrate scope of the photochemical alkylation of heterocycles.
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functionalization conditions (N-heterocycle 5.0 equivalents, 48
h), leading to products 78-80 in excellent yields.
Mechanistic studies
Mechanistic experiments were performed to elucidate the
reaction mechanism. In all three cases, our major target was to
understand the type of interaction between phenylglyoxylic
acid and the rest of the mixture, THF and the radical trap.
Starting from fluorescence quenching studies.[22] After
irradiation of phenylglyoxylic acid (1 mM in MeCN) at 360 nm,
its fluorescence was measured at 402 nm and in all cases the
quenching of phenylglyoxylic acid by increasing amounts of
added THF and radical traps are both trivial, except for the
case of diethyl maleate (48a), where the quenching is due to
the Z/E isomerization of the double bond, induced by the
excited keto acid. All these indicate that the initial radical is not
formed by the excited phenylglyoxylic acid, but by another
radical species which is not yet present.
Intens.
x10
Intens.
x10
4
5
4
4
3
2
1
3
2
1
0
0
5
10
15 Time [min]
0
5
10
15 Time [min]
Intens.
Intens.
6
5
x10
x10
5
4
3
2
1
0
Next, UV-Vis experiments were performed.[22] The association
of an electron-rich molecule with an electron-acceptor can lead
to the formation of an aggregate, called electron donor-
acceptor (EDA) complex. EDA complexes are known in
literature since the 1950s,[25] but only recently Melchiorre and
others have identified them as active species in photochemical
reactions.[5d] An EDA complex is usually recognized, when
upon addition of the two components, an increase in the UV
absorbance of the mixture is observed. Upon mixing
phenylglyoxylic acid, with DIAD in THF or with 25 in THF or
with 48a in THF, no noticeable increase in the UV absorbance
was observed, excluding the possibility of an EDA complex
formation, in all three cases.[22]
5
4
3
2
1
0
0
5
10
15 Time [min]
0
5
10
15 Time [min]
Extracted Ion Chromatograms at A) m/z 305.1923, B) m/z 304.1860,
C) m/z 297.1421 and D) 298.1484
Figure 1. KIE of the C-N bond forming methodology.
Next, we studied the photochemical reaction by NMR
spectroscopy. Previous studies on the photochemistry of
phenylglyoxylic acid propose that excited triplet state of
phenylglyoxylic acid in iPrOH decomposes upon irradiation to
the dimerization product (diphenyltartaric acid),[26a] whereas in
water the photodecomposition leads to benzaldehyde.[21g,26b-d]
The process was monitored by 13C- and 1H-NMR spectroscopy
and our observations state that excited phenylglyoxylic acid, in
THF, photodecomposes both to benzaldehyde and to
Intens.
x10
3.0
Intens.
x10
6
5
5
2.5
2.0
1.5
1.0
0.5
0.0
4
3
2
1
diphenyltartaric
acid.[22]
The
products
of
the
photodecomposition are observed both in the spectra from the
irradiation of phenylglyoxylic alone and of the reaction
mixture.[22] According to literature precedents[26] and our own
observations,[21g] this means that excited PhCOCO2H is
decomposing both to benzoyl radical and ketyl radical, which
are responsible for the initiation of the process.
The radical nature of the reaction was also confirmed with the
use of radical traps (BHT and TEMPO), where no product was
formed.[22] More specifically, when the reaction mixture with
TEMPO was irradiated, in the presence of phenylglyoxylic acid
in THF, an adduct (THF-TEMPO) was identified, which
confirms the generation of the α-THF radical.[22]
0
0
5
10
15 Time [min]
0
5
10
15 Time [min]
Intens.
Intens.
5
x10
6
x10
5
3
2
1
0
4
3
2
1
0
0
5
10
15 Time [min]
0
5
10
15 Time [min]
Extracted Ion Chromatograms at A) m/z 239.0736, B) m/z 246.1176,
C) m/z 261.0556 and D) 268.0995
Moreover, in order to shed more light in the reaction
mechanism, a kinetic isotope effect (KIE) experiment was
performed (Figure 1). Since we have a long interest in
Figure 2. KIE of the C-H alkenylation methodology.
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studying reaction mechanisms with the use of High Resolution
Mass Spectrometry (HRMS),[27] the KIE was measured both by
NMR and HRMS.[22] Treatment of DIAD with THF and d8-THF,
provided products 4-d0, 4-d1, 4-d7 and 4-d8. Also, treatment
of 26 with THF and d8-THF, led to sulfonyl alkenes 27-d0 and
27-d7. The KIE was determined, (Figure 2).
simple, photoorganocatalytic protocol for the C-H activation of
O-, S- and N-heterocycles was demonstrated, leading to
products in good to high yields. These results can offer a new
and alternative route in Photocatalysis.
In
a recent report, Yoon employed the quantum yield
Experimental Section
measurement as a mechanistic tool.[28] Using potassium
ferrioxalate as the actinometer,[28,29] we calculated the quantum
yield for all the cases, more specifically, THF and DIAD (Φ =
44), THF and 25 (Φ = 39), THF and 48a (Φ = 85), indicating a
chain propagation mechanism in all cases.
In a glass vial with a screw cap, phenylglyoxylic acid (15 mg,
0.10 mmol) and dialkyl azodicarboxylate (0.50 mmol) or 1,2-
bis(phenylsulfonyl)ethylene (26) (154 mg, 0.50 mmol) or
Michael acceptor (0.50 mmol) were dissolved in
ether/heterocycle (1 mL). The vial was sealed with a screw cap
and left stirring under household bulb irradiation (2 x 85W
household lamps) for 2-96 hours. After completion of the
reaction, the solvent was removed in vacuo and the product
was purified by flash silica chromatography
Taking all these data into account, a mechanism is proposed
(Scheme 12). In THF, phenylglyoxylic acid (3a) is excited to
singlet state I and via intersystem crossing (ISC) to triplet state
II and is photodecomposed to both phenyltartaric acid and
benzoyl radical III via homolytic cleavage of the activated C-C
bond of triplet excited form.[21g,22,26] When a HAT donor is
present (THF), ketyl (IV) or benzoyl (III) radical abstracts a
hydrogen atom from THF, leading to the first alpha
tetrahydrofuranyl (α-THF) radical V, which initiates the process.
Addition of this initial α-THF radical V to the radical acceptor,
affords new radical species, which via a radical propagation
mechanism (quantum yield measurement) affords the desired
product. In the case of the C-H alkenylation, the propagation
occurs from the phenylsulfonyl radical, generated after the
elimination. This reaction does not require any precaution from
air, since the energy transfer quenching from oxygen of the
radicals generated by PhCOCOOH is a slower process from
the HAT process.[21g,22]
Acknowledgements
The authors gratefully acknowledge the Hellenic Foundation
for Research and Innovation (HFRI) for financial support
through a grant, which is financed by 1st Call for H.F.R.I.
Research Projects to Support Faculty Members
&
Researchers and the procurement of high-cost research
equipment grant (grant number 655). M. G. K. would like to
thank the State Scholarships Foundation (IKY) for financial
support through a post-doctoral research scholarship funded
by the “Supporting Post-Doctoral Researchers-Call B” (MIS
5033021), action of the Operational Programme “Human
Resources Development, Education and Lifelong Learning”
and co-funded by the European Social Fund (ESF) and Greek
National Resources. N. S. would like to thank the Hellenic
Foundation for Research and Innovation (HFRI) for financial
support through a doctoral by the Hellenic Foundation for
Research and Innovation (HFRI) under PhD Fellowship grant
(Fellowship Number: 721). N. F. N. would like to thank the
State Scholarships Foundation (IKY) for financial support
through a doctoral fellowship, which is co-financed by Greece
and the European Union (European Social Fund-ESF) through
the Operational Programme “Human Resources Development,
Education and Lifelong Learning” in the context of the project
“Strengthening Human Resources Research Potential via
Doctorate Research” (MIS-5000432), implemented by the
State Scholarships Foundation (IKY)”. E. V. would like to thank
the State Scholarship Foundation (IKY) for financial support
through a doctoral fellowship. The authors would like to thank
Prof. V. Constantinou from the Agricultural University of
Athens for access to the fluorescence spectrometer and Dr. D.
Limnios, I. K. Sideri, P. Bampilis and M. Alefanti for initial
experiments. Also, COST Action C-H Activation in organic
synthesis (CHAOS) CA15106 is acknowledged for helpful
discussions.
Scheme 12. Proposed reaction mechanism.
Conclusions
In conclusion,
a novel, metal-free photochemical C-H
functionalization of heterocycles was developed. This method
relies on a small organic molecule (phenylglyoxylic acid) and
cheap household lamps or sunlight. Herein, a unified fast,
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products, see: b) M.-J. Zhang, G. M. Schroeder, Y.-H. He, Z. Guan,
RSC Adv. 2016, 6, 96693-96699.
Keywords: Photochemistry • Phenylglyoxilic acid • Hydrogen
Atom Transfer • C-H activation • Metal-free processes
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10.1002/cssc.202001892
ChemSusChem
FULL PAPER
FULL PAPER
Giorgos N. Papadopoulos, Maroula G.
Kokotou, Nikoleta Spiliopoulou, Nikolaos F.
Nikitas, Errika Voutyritsa, Dimitrios Ioannis
Tzaras, Nikolaos Kaplaneris and
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Page No. – Page No.
Phenylglyoxylic Acid: An Efficient
Initiator for the Photochemical
Hydrogen Atom Transfer (HAT) C-
H Functionalization of
Photochemistry. A mild, metal-free and easy-to-execute protocol for the C-H
functionalization of O-, S- and N-heterocycles.
Heterocycles
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