Copper catalyzed photoredox synthesis of α-keto esters, quinoxaline, and naphthoquinone: Controlled oxidation of terminal alkynes to glyoxals

Article abstract of DOI:10.1039/c8sc03447h

Herein, we report a facile visible light induced copper catalyzed controlled oxidation of terminal CC alkynes to α-keto esters and quinoxalines via formation of phenylglyoxals as stable intermediates, under mild conditions by using molecular O₂ as a sustainable oxidant. The current copper catalysed photoredox method is simple, highly functional group compatible with a broad range of electron rich and electron poor aromatic alkynes as well as aliphatic alcohols (1°, 2° and 3° alcohols), providing an efficient route for the preparation of α-keto esters (43 examples), quinoxaline and naphthoquinone with higher yields than those in the literature reported thermal processes. Furthermore, the synthetic utility of the products has been demonstrated in the synthesis of two biologically active molecules, an E. coli DHPS inhibitor and CFTR activator, using the current photoredox process. In addition, we applied this methodology to the one-pot synthesis of a heterocyclic compound (quinoxaline, an FLT3 inhibitor) by trapping the intermediate phenylglyoxal with O-phenylenediamine. The intermediate phenylglyoxal can also be isolated and further reacted with an internal alkyne to form naphthoquinone. This process can be readily scaled up to the gram scale.

Full text of DOI:10.1039/c8sc03447h

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Copper Catalyzed Photoredox Synthesis of α-Keto Esters,
Quinoxaline, Naphthoquinone: Controlled Oxidation of Terminal
Alkynes to Glyoxals
Deb Kumar Das,‡ V. Kishore Kumar Pampana‡ and Kuo Chu Hwang*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan, Republic of China.
E-mail: kchwang@mx.nthu.edu.tw; Fax: (+886) 35711082.
‡These authors contributed equally.
KEYWORDS: photoredox catalysis, copper, single electron transfer, controlled oxidation,
molecular oxygen
ABSTRACT:
Herein, we report a facile visible light induced copper catalyzed controlled oxidation of terminal
C≡C alkynes to α-keto esters and quinoxalines via formation of phenylglyoxals as stable
intermediate, under mild conditions by using molecular O2 as a sustainable oxidant. The current
copper catalysed photoredox method is simple, highly functional group compatible with a broad
range of electron rich, electron poor aromatic alkynes as well as aliphatic alcohols (1º, 2º and 3º
alcohols), providing an efficient route for preparation of α-keto esters (43 examples), quinoxaline
as well as naphthoquinone with higher yields than literature reported thermal
processes.Furthermore, the synthetic utility of the products has been depicted by the synthesis of
two biologically active molecules, i.e., E-coli DHPS inhibitor, and CFTR activator using the
current photoredox process. In addition, we applied this methodology for one pot synthesis of a
heterocyclic compound (quinoxaline, an FLT3 inhibitor) by trapping the intermediate
phenylglyoxal with O-phenylenediamine. The intermediate phenylglyoxal can also be isolated
and further react with an internal alkyne to form naphthoquinone. This process can be readily
scaled up to a gram scale.

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INTRODUCTION
Photoredox catalysis has proven to be a powerful tool for the construction of new chemical
bonds that has attracted research attention from all around the world.1 Photoredox copper-based
complexes have been shown to be an inexpensive, potent catalytic system for various organic
transformations.2 In recent years, the direct introduction of two vicinal functional groups into
terminal alkynes via activation of C≡C triple bond becomes a very attractive process to achieve
valuable synthons, bioactive natural products, and their synthetic analogues.3,4 In particular,
catalyzed oxidation of C≡C triple bonds by transition metal complexes in the presence of
molecular O2 plays an important role in chemical industry.5 However, it remains very
challenging to avoid over oxidation of C≡C triple bonds to generate over-oxidized products.6 Our
group has recently reported various visible light-mediated copper(I)-catalysed cross-coupling,
and C-H annulations reactions.7 It has been demonstrated that copper(I) phenylacetylide is the
key photo catalyst involved in this visible light induced coupling reactions.7 It was shown that
photo-irradiation of copper(I) phenylacetylide in presence of molecular oxygen can generate
Cu(II)-phenylacetylide and superoxide radical anion via single electron transfer (SET) process.7d
The generated superoxide radical anion coordinates to copper ligand complex, and is responsible
for controlled oxidation of C≡C triple bond of terminal alkyne.7dSimilarly, we envisaged that a
terminal alkyne can be transformed into valuable α-keto esters via controlled oxidation. α-Keto
ester analogues are considered to be valuable precursors and intermediates for various
pharmaceuticals and bioactive molecules.8 Due to their vast potential,8 many research groups
have put significant efforts into the synthesis of these compounds in recent years.9 Recently, Jiao
et al. reported photoredox catalyzed synthesis of α-keto esters via oxidation of α-aryl halo
derivatives using expensive ruthenium catalyst under sunlight irradiation (Scheme 1a).10a

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Thereafter, the same group described aerobic oxidative esterification reaction of 1,3-diones via
C-C bond cleavage at high temperatures (Scheme 1b)10b that results in unwanted esters as
byproducts. Later on, Song et al. demonstrated oxidative esterification of acetophenones at high
temperatures.11 Despite significant progress, common major limitations of literature strategies
include the use of expensive catalysts9a,d,f,11 pre-synthesized starting substrates,9b,h,11the need of
additives or base,9d-g,10a,11 requirement of stoichiometric amounts of oxidants,9a formation of ester
byproducts,10b harsh reaction conditions, 9 b-c,e-g,10b,11 poor or no yield of product when 2º or 3º
alcohols were used.9a-e,10b,11Therefore, there is a strong need to develop an efficient modality for
the construction of α-keto esters that can conquer the above-mentioned limitations. In this
communication, we report a visible-light-induced copper catalyzed synthesis of α-keto esters
from reaction of a variety of alkynes and aliphatic alcohols under mild conditions using O2 as
oxidant (Scheme1c).
(Scheme 1)
The significance of the present work includes: (a) this is the first example of oxidation of
terminal alkynes to α-keto esters under visible light at room temperature under mild condition;
(b) low toxic, inexpensive CuI was used as catalyst and abundant O2 as an oxidant, (c) controlled
oxidation of C≡C triple bond to phenylglyoxals, thus no formation of ester or homo-coupling
byproducts, and (d) broad substrate scope and compatibility with a wide range of aromatic
alkynes and 1º, 2º, or 3º alcohols. To the best of our knowledge, the use of terminal alkynes as a
key starting material for the synthesis of α-keto esters under visible light has yet to be reported.

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RESULTS AND DISCUSSION
When a mixture of phenyl acetylene 1a (0.5mmol), MeOH 2a (2 mL), copper iodide (CuI, 5
mol%), and 2-picolinic acid (1.0 equiv.) as a ligand in CH3CN (4 mL) in presence of molecular
O2 was irradiated under blue LEDs at room temperature for 12h, it furnished the desired α-keto
ester (3a) with a yield of 86% (Table 1, entry 1). When CuI was replaced by other CuX catalysts
(X=Cl, Br), the desired product, 3a, was not formed (Table 1, entry 2). The halide anion effect
was attributed to the larger size and polarizability and better leaving ability of iodide ion in
organic solvents as compared to other halide anions that facilitates easy formation of copper
complex for this reaction. Removal of copper catalyst or ligand failed to produce 3a (Table 1,
entries 3 & 4). When the amount of ligand loading was decreased to 5 or 10 mol%, the
conversion of phenyl acetylene to desired α-keto ester (3a) was low and either reaction failed or
gave very trace amount of desired product (Table 1, entries 5 & 6). Reaction with 50 mol % of 2-
picolinic acid as ligand provided the product 3a in 71% yield (Table 1, entry 7). Whereas,
increasing the amount of ligand to 2.0 equivalents gave α-keto ester in 85% yield (Table 1, entry
8). The yield was similar when 1.0 equivalent of ligand was used (Table 1, entry 1). Increasing
or decreasing the amount of ligand failed to increase the yield of the desired product, thus it can
be concluded that optimal amount of the 2-picolinic acid ligand is 1.0 equiv. Replacing the
ligand with di-picolinic acid does not affect the yield of 3a (Table 1, entry 9), whereas in case of
2-amino pyridine as ligand, we observed a complete inhibition of 3a (Table 1, entry 10). Yield of
3a remains the same in neat MeOH, but tends to decrease in THF and toluene (Table 1, entries
11-13). Reactions under ambient white light irradiation produced 3a with 82% yield (Table 1,
entry 15). Removal of either O2 or either light leads to no product formation, indicating their
crucial roles in the current protocol (Table 1, entries 16 & 17).
(Table 1)
Having established the optimal reaction conditions, we then investigated the scope and
applicability of this reaction using different 1º, 2º and 3º alcohols as substrates for the synthesis
of substituted α-keto esters (Table 2). Reactions were performed with various primary alcohols
like ethanol (2b), n-propanol (2c), n-butanol (2d) and 2-methylpropan-1-ol (2e), and the desired
product (3b-e) was obtained in good yields at room temperature (Table 2). The current
photochemical process also works well for primary alcohol like 2-methoxyethanol (2f) and
benzyl alcohol (2g) providing α-keto esters (3f and 3g) in good to excellent to yields under
similar reaction conditions (Table 2).
(Table 2)
Interestingly, cyclopropanemethanol (2h) and tetrahydrofurfuryl alcohol (2i) reacted well with
1a to produce 3h, and 3i in 84% and 68% yields, respectively, without cyclic ring opening. Next,
1a reacts with 2o alcohols (2j-2l) smoothly to afford corresponding α-keto esters (3j-3l) in good
yields. Slightly strained or labile alcohols (2h, 2i, 2k, 2l) worked well in this protocol, without

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producing any cleavage products, which are not possible using earlier thermal processes. Besides,
1a reacts with alicyclic 2o alcohols (2m-2o) to afford desired products (3m–3o) in good yields
(Table 2). Unfortunately, this protocol does not work for the aromatic alcohols, such as phenol,
which was attributed to the fact that phenol was oxidized to p-benzoquinones in the presence of
copper and O2.7a,12 Reaction of 1a with tertiary butanol (2p), provided α-keto ester 3p in 70%
yield (Table 2). It is worth to note that transformation of terminal alkynes to α-keto esters using
tertiary alcohols has no precedent literature reports. Unfortunately, this protocol does not work for
the aliphatic amines. Both primary and secondary amines, such as n-propyl amine and piperidine, were
used as nucleophiles for the present system, but no α-ketoamide product was observed. Next, a
competitive reaction of phenyl acetylene (1a) with equal moles of 1º, 2º and 3º alcohols, such as
MeOH (2a), isopropanol (2j) and tertiary butanol (2p) under standard conditions was surveyed,
which afforded α-keto ester 3a as major product in 73% yield derived from 1º alcohol i.e.,
MeOH. Product 3j derived from 2º alcohol was formed in trace quantity with no any α-keto ester
3p resulting from tertiary butanol. From nucleophilic attach to the glyoxal aldehyde, 3º alcohol
is expected to be better than 2º alcohol, and then 1º alcohol. This observed result clearly
indicates that steric hindrance plays a more important role than electronic factor, which leads to
predominance of primary alcohol in the coupling reaction.
Next, the substrate scope of aryl alkynes was examined with different aliphatic alcohols under
the standard conditions (Table 3). The electron neutral and halo-(Cl, F, and I) substituted phenyl
acetylenes readily react with aliphatic alcohols to afford corresponding α-keto esters (4b–4j)
with good to excellent yields as depicted in Table 3. Aryl alkynes with strong electron
withdrawing and donating (CF3, CN, nitro, acetyl, ester, sulfone, methoxy) groups showed
excellent tolerance in the current photoredox protocol to give corresponding α-keto esters
(4k−4t) in good yields (Table 3). Copper-catalyzed aerobic oxidative coupling reactions
involving electron rich substituted terminal alkynes suffer from homo-coupling as
byproduct.7dHowever, in the current process no homo-coupling product was observed. Notably,
the present photoredox process works well for reaction of 1,3-dialkynes to generate 1,3-α-diketo
ester products 4u and 4v in good yields when using methanol as the solvent. The synthesis of
1,3-diketo esters is either difficult8b,d,13 or not achievable by previously reported thermal
processes. However, in contrast, it was easily achieved with the current photoredox process.

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(Table 3)
Note that when tertiary butanol was coupled with 1,3-dialkyne, only mono α-keto ester 4w was
obtained in 81% yield, where the absence of di-substituted α-keto ester might be due to steric
hindrance effect from the bulky tertiary butyl group in the SN2 reaction. Notably heterocyclic
alkynes 2-ethynylthiophenes, 3-ethynylthiophenes and 3-ethynylpyridine, which are usually
sensitive to oxidative conditions, also effectively react with 1o, 2o and 3o alcohols to generate the
desired α-keto esters (4x-4z, 4va) in moderate to good yields. However, heterocyclic alkynes
ethynyl indole and ethynyl pyrimidine failed to give desired α-keto esters under the current
protocol. This protocol was successful in producing α-keto ester, 4wa, in 83% yield when
heteroaryl alkyne 5-ethynyl-1,3-benzodioxole was used under similar conditions. Unfortunately,
aliphatic terminal alkynes did not work for this protocol and failed to produce corresponding α-
keto ester as products. The reason for the failure of aliphatic alkynes is most probably due to the
lower acidity of aliphatic terminal alkynes as compared to aromatic ones, thus making the step of
formation of copper phenylacetylide from aliphatic alkynes slower than aromatic alkynes.
Finally, the application of the current visible light-initiated Cu(I)-catalyzed strategy was
demonstrated for the expedient synthesis of compounds with biological activity, such as 1-
benzyl-3-(3-nitrophenyl)quinoxalin-2(1H)-one 6n (a CFTR activator)8a and bis oxime ester 5t
(an E-coli DHPS inhibitor)8c. Phenylquinoxalinone6n could be synthesized in 3 steps in 44%
overall yield (Scheme 2), which is greener and better than the literature reported method (4 steps
with overall yields of 32%). (Scheme S1 and S2, ESI†).8a
(Scheme 2)
Next, bis oxime ester 5t was prepared in 2 steps in 60% overall yield (Scheme 2), which is also
better and greener than literature reported process (4 steps, 25% overall yield) using pre-
synthesized starting substrates.8c In addition, the current process can be readily scaled up to a
gram scale (1.029 g of 3-Nitro phenyl acetylene); 1.16 g of 4n was obtained (79% yield) after
irradiation with blue LEDs for 12 h at room temperature (ESI†) and further we have evaluated
and compared green chemistry metrics (Fig. S5 and S6, ESI†).7d The structures of 4n and 6n
were confirmed by single-crystal X-ray diffraction (Fig. S7 and S8, ESI†). In addition,
compounds 4u, 4v, and 4x can be used as precursors for synthesizing biologically active
molecules (Scheme S7, ESI†).

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Synthesis of Quinoxaline via double condensation of 1,2-phenylenediamines with
phenylglyoxals in the presence of catalyst is a well-established concept in organic synthesis.14a
Hashmi et al. reported gold and silver bi-metal co-catalyzed synthesis of quinoxaline derivatives
from terminal alkynes which involved oxidation of phenyl acetylene to phenyl glyoxals using
external oxidant pyridine N-oxide (4 equiv.)14b (Scheme S6, ESI†). Recently, it was shown
quinoxaline derivatives can be synthesized by copper-catalyzed oxidative reaction of
phenylglyoxal with o-phenylenediamines.14c Inspired by the above literature reports, we
hypothesized controlled oxidation of phenyl acetylene will generate phenylglyoxal as a possible
intermediate in the present copper catalyzed photoredox process. Thus trapping of phenylglyoxal
intermediate with 1,2-phenylenediamines may lead to one-pot synthesis of pharmacologically
active 2-phenyl quinoxaline by using cheaper Cu catalyst and abundant molecular O2 as an
oxidant. So, under the same reaction condition, we added 1.0 equiv. of 4,5-dimethylbenzene-1,2-
diamine (7) to the reaction solution and irradiated with visible light for 12h at room temperature
(Scheme 3). Not surprisingly, we obtained the corresponding 6,7-dimethyl-2-phenylquinoxaline
(8), which is a biologically active FLT3 inhibitor),15 in 65% yield as a product in this
unprecedented photoredox copper catalyzed one pot process (Scheme 3). We did not observe
formation of 3-phenylquinoxalin-2-ol as a product in the current photoredox method, which was
previously reported as a key product under a strong basic condition.7g The difference in the
formation of products was attributed to the differences in the reaction condition and thus
different reaction mechanisms (Mechanistic comparison, Scheme S7, ESI†).
(Scheme 3)
To provide detail insights regarding the reaction mechanism, we carried out several control
experiments, as shown in Scheme 4. First, pre-synthesized copper(I)-phenylacetylide1a′ was
used to react with MeOH, in the absence of CuI under similar reaction condition, which
produced the desired α-keto ester (3a) with 40% yield after 12 h of irradiation (eq 1, Scheme 4).
(Scheme 4)
The reduced yield can be attributed to the fact that the isolated Cu(I)-phenylacetylide powder
exists in highly aggregated forms.7d,16 The result implies that in situ-generated Cu(I)-
phenylacetylide is most probably the key light-absorbing photocatalyst involved in this oxidative
coupling reaction. Next, we performed a short-time reaction of 3 h, under the optimal condition,

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and we were delighted to isolate phenylglyoxal13 as a stable intermediate in 62% yield (eq 2,
Scheme 4). Phenylglyoxals are important precursors in organic synthesis, and can be used to
construct various biologically active heterocyclic compounds.14b,17In the literature, very few
methods are available for the synthesis of glyoxal derivatives.14b The most common method for
the synthesis of phenylgloxal involves SeO2 mediated oxidation of substituted methyl ketones
under harsh reaction conditions.18 Recently, photoredox oxidation of brominated acetophenones
to phenylglyoxal was reported using expensive ruthenium photocatalyst.19 That method, however,
cannot use commercially available phenylacetylene as the starting substrate. In contrast,
synthesis of phenylglyoxal was easily achieved in short time in our current study under mild
reaction conditions using inexpensive copper to catalyze photoredox process and commercially
available arylalkynes as starting substrates. After isolation of phenylglyoxal, we conducted some
key control experiments with 13 for better understanding of the reaction mechanism. First,
reaction of phenylglyoxal with MeOH was carried out in the presence of light and O2, but in the
absence of CuI catalyst, which leads to no formation of α-keto ester 3a (eq 3, Scheme 4). When
phenylglyoxal reacts with the solvent MeOH in the presence of 5mol% CuI catalyst, light and
O2, but the absence of the 2-picolinic acid ligand, only a trace amount of 3a was formed (eq 4,
Scheme 4). When the control reaction was performed in the presence of CuI catalyst, 2-picolinic
acid, O2, and blue light irradiation, 3a was produced in 90% yield (eq 5, Scheme 4). If the same
reaction was carried out in a N2 atmosphere, no formation of 3a was observed (eq. 6, Scheme 4).
From the above control experiments (eq 3-6, Scheme 4), it is very clear that CuI catalyst, 2-
picolinic acid ligand, O2, and blue light irradiation all are very crucial factors for the formation of
the α-keto ester product 3a.
Selective oxidation of terminal alkynes to glyoxal, free from the subsequent over oxidation to
glyoxalic acid, is a very challenging reaction in synthetic chemistry.6 In our current protocol,
selective oxidation of phenyl acetylene to phenyl glyoxal was achieved successfully and no
phenyl glyoxalic acid resulting from over oxidation was observed. Thus, when phenyl glyoxalic
acid 15 was used to react with MeOH under the same condition, we did not observe the product
3a, which clearly suggests that over oxidization of glyoxal to glyoxalic acid20 did not occur in the
current reaction condition (eq 7, Scheme 4). 2-Picolinic acid plays a crucial role in avoiding the
formation of homocoupling product from copper phenylacetylide (which is a common side
product in reaction involving terminal alkynes in presence of copper catalyst) and it directs the

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system to activate terminal C≡C bond via controlled oxidation to phenylglyoxal. It is
documented in the literature that nitrogen containing ligands can reduce the formation of
polymeric byproducts and Glaser alkyne-alkyne homocoupling products.21a Hence the optimal
amount of ligand is found to be 1.0 equivalent due to the above mentioned facts. Formation of
polymeric form of Cu(II) bis-picolinate (single crystal X-ray Fig. S9, ESI†) might be one of the
reason for the decrease in the yield when reaction was carried out with 5 and 10 mol% of 2-
picolinic acid as ligand. Also due to amphoteric nature of 2-picolinic acid21b, it can help maintain the
acidic pH of the reaction mixture, thus avoiding the over-oxidation of phenyl glyoxal to glyoxalic acid.
Therefore, excess amount of 2-picolinic acid (i.e., 1 eqv.) ligand, instead of catalytical amount, is required
to achieve optimal product yield. Next, phenylglyoxal 13, isolated from the current photoredox
process could readily react with internal alkyne for the synthesis of 1,2-naphthoquinone 16, via
oxidative annulation reaction22 (eq 8, Scheme 4). Further, reaction of phenylglyoxal 13 with
MeOH was carried out under O2 in the absence of light i.e., dark condition, which leads to no
formation of α-keto ester 3a (eqns 9 & 10, Scheme 4). This result clearly demonstrates that light
irradiation is required for the transformation of phenyl glyoxal to α-keto ester product. Most
probably, the transformation of phenyl glyoxal to α-keto ester product requires the help of copper
superoxide radical, which cannot be generated in the absence of light irradiation. The superoxide
radical anion was generated under visible light irradiation of Cu(I)-phenylacetylide, and is
responsible for controlled aerobic oxidation of phenyl glyoxal to α-ketoesters.
Finally, isotopic labeling experiment was carried out in presence of 18O2 (98%), instead of
16O2 air, under the standard conditions (Scheme 5). O labeled α-keto esters 3f were obtained,
18
with a ratio of 18O18O-3f: 18O16O-3f: 16O16O-3f = 63.4: 26.4: 10.2 (Scheme S9 ESI†). These
results unambiguously indicate that the oxygen atoms in the α-keto ester products mainly
18
originate from the molecular O2. The O16O-3f product was most probably formed via a partial
exchange with moisture in air or during the silica gel column purification process.19 It should be
noted that the compounds containing 1,2-diketo groups are active, and the oxygen of carbonyl
can be exchanged via hemiketal with the oxygen of water in air.5b,23
(Scheme 5)
Based on the above control experiments and our previous studies,7c,d a plausible mechanism was
proposed and shown in Scheme 6. Photoexcitation of in situ-generated Cu(I)-phenylacetylide
(1a’) (UV-visible spectrum, Fig. S6, ESI†) generates a long lived (τ= 15.9 ꢀs) triplet excited

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state Cu(I)-phenylacetylide (9)7c,d with partial charge separation occurring via ligand to metal
charge transfer (LMCT).7c-d Thus photoexcited Cu(I)-phenylacetylide then donates an electron to
•−
molecular O2 (i.e., a SET process) to generate a superoxide radical anion (O2 ) and an electron
deficient Cu(II)-phenylacetylide (10),7c,d which was confirmed by EPR measurements by using
5,5-dimethyl-1-pyrrolineN-oxide (DMPO) as a selective superoxide spin trapping reagent (Fig.
S2, ESI†). Next, coordination of 2-picolinic acid (L) to Cu(II)-phenylacetylide and subsequent
reaction to molecular O2 results in the formation of copper(III)-superoxo complex 11.7c,24
Isomerization rearrangement of the resulting Cu(III)-peroxo complex (11)occurs with concurrent
formation of a C–O bond to form the intermediate (12),23 Subsequent O–O bond cleavage of the
intermediate (12)produces 2-oxo-2-phenylacetaldehyde (13) and CuII(pic)2 was eliminated as a
blue ppt (Fig. S1 & S9, ESI†).25 Further, a nucleophilic attack on (13) by alcohol (2) on electron
deficient carbonyl group affords hemiacetal intermediate (14),9c,11 which further undergoes
copper catalysed aerobic oxidation26 to produce α-keto esters (3). When 4,5-dimethylbenzene-
1,2-diamine (7) was present in the reaction mixture, it traps the in situ-generated
phenylglyoxal13via intermolecular double condensation reaction to produce 6,7-dimethyl-2-
phenylquinoxaline (8) in a one-pot manner, as shown in Scheme 6.
(Scheme 6)
In the presence of 4,5-dimethylbenzene-1,2-diamine, formation of α-keto esters was suppressed,
due to the fact that o-phenylene diamine acts as a better nucleophile (N is less electronegative
than O) to phenylglyoxal than alcohol (2), thus favouring the formation of 2-phenyl quinoxaline
(8), instead of formation of hemiacetal (14).
CONCLUSION
In summary, we have developed an unprecedented visible light induced copper catalyzed process
for the controlled aerobic oxidation of terminal C≡C triple bond to phenylglyoxal at room
temperature, followed by esterification, for the synthesis of α-keto esters that evades the need of
base, expensive catalyst, strong oxidants, elevated temperatures and other harsh reaction
conditions. The reaction proceeds easily with excellent functional group tolerance towards
electron donating and withdrawing terminal alkynes. Moreover, it is compatible with 1o, 2o, 3o
alcohols and slightly strained or labile alcohols, which is not possible or difficult in thermal
processes. The utility of this protocol has also been successfully applied for the synthesize two

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biologically active molecules, i.e., 1-benzyl-3-(3-nitrophenyl) quinoxalin-2(1H)-one (a CFTR
activator) and bis oxime ester (an E-coli DHPS inhibitor) in a gram scale with fewer steps and
higher total yields than the literature reported processes. We have also demonstrated one pot
synthesis of pharmacologically active heterocyclic compound i.e., 2-phenyl quinoxaline (a FLT3
inhibitor) via an unprecedented photoredox copper catalyzed process, as well as synthesis of
naphthoquinone using phenylglyoxal isolated from the current photoredox process.
AUTHOR INFORMATION
Corresponding Author
* Email: kchwang@mx.nthu.edu.tw
Author Contributions
‡ D.K.D and V.K.K.P contributed equally for this work.
Conflicts of interest
There are no conflicts to declare.
ACKNOWLEDGMENT
This work was supported by the Ministry of Science & Technology, Taiwan.
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Scheme 1.Different synthetic approaches toward α-keto esters.
Previous Work
a) Ru(bpy)3Cl2 catalyzed oxidation of -aryl halogen derivatives under sunlight
O
Br
Ru-photocat.
OR
Ph
co-catalyst
Ph
CO2R
O
Li2CO3, sunlight
b) Cu-catalyzed aerobic oxidative esterification reaction of 1,3-diones
O
O
CuBr/Py
O
O
OR
ROH
Ph
Ph
OR
O2, Toluene, 90 oC
Ph
Ph
O
byproduct
Previous reports failed with 3o alcohols and gave poor yields with 2o alcohols.
Visible light initiates the reaction
Current work
c) Photoredox copper catalyzed synthesis of -keto esters under blue light
O
R1-OH
CuI (5mol%)
O-R1
R
2-picolinic acid(1.0 equiv.)
O
O2
CH3CN, RT
R
blue light
43 examples
Controlled oxidation of terminal C C triple bond. O2 (1 atm) as oxidant
Works very well with 1o, 2o & 3o alcohols at RT with excellent yields.
No formation of byproducts with broad substrate scope

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Table 1. Optimization of reaction conditiona
aReaction conditions: 1a (0.50 mmol), MeOH (2 mL), CH3CN (4 mL), ligand (0.5 mmol) and
catalyst (0.05 mmol), the reaction mixture was irradiated with blue LEDs (40 mW/cm2 at 460
b
c
nm) at RT for 12h under O2 (1atm). Isolatedyields. Other copper salts such as CuX (X = Cl,
Br). d5 mol % of 2-picolinic acid was used. e10 mol% of 2-picolinic acid were used. f50 mol % of
g
2-picolinic acid was used. 2.0 equiv. of 2-picolinic acid were used. MeOH (4 mL) was used
h
i
both as reactant and solvent. Under 1 atm. air. Under ambient white light irradiation (12h, 8
j
k
l
mW/cm2 at 460 nm). At room temperature and in the dark. Under N2 atmosphere. n.r. = no
reaction.

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Table 2. Substrate scope of alcoholsa
O
OR
CuI (5 mol%)
Ph
R-OH
Ph
1a
2-picolinic acid (1 equiv.)
CH3CN, O2, 12 h
O
2a-p
3a-p
RT, blue-LEDs
O
O
O
O
O
O
OMe
O
O
Ph
Ph
Ph
O
Ph
Ph
Ph
O
O
O
3db, 79%
3c, 79%
3b, 85%
3a, 86%
O
O
O
O
O
O
O
Ph
OMe
Ph
O
Ph
O
O
O
3gb, 71%
3f, 90%
3hb,
84%
3e, 65%
O
O
O
O
O
O
O
O
O
Ph
O
3ib, 64%
Ph
Ph
Ph
Ph
O
O
O
O
O
3kb, 79%
3l, 84%
3j, 90%
O
O
O
O
O
O
O
O
Ph
Ph
Ph
tBu
O
O
O
O
3nb, 81%
3ob, 82%
3m, 83%
3p,
70%
aStandard conditions. b2 mmol of ROH in 4 mL of CH3CN, isolated yields.

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Table 3. Substrate scope of aryl terminal alkynesa
O
CuI (5 mol%)
O
R2
R2-OH
2a-p
O
R1
Ph
2-picolinic acid (1 equiv.)
CH3CN, O2
R1
O
O
1b-v
4b-z, 4va, 4wa
RT, blue-LEDs
O
O
OR2
O
O
OEt
O
O
O
O
tBu
nBu
Me
4cb,
2
4e,
4f,
R = Me, 90%, 12h
4db,
4b,
4g,
87%, 12h
86%, 12h
74%, 12h
2
t
R = Bu, 70%, 12h
OMe
O
O
Cl
CF3
O
O
OPr
O
OMe
I
O
R1
O
O
O
O
1
2
4hb,
4j, 84%, 12h
R =4-Cl, R = Cy,78%,12h
77%,12h
4kb,
72%, 12h
4ib, R1=4-F, R2 = Cy 72%,12h
O
O
O
O
O
O
OR2
OMe
NC
O
O2N
O
O
86 %, 9h
O
O
O
NC
2
4n,
4o,
R = Me, 84%, 9h
4l,
4m,
4p,
82%, 9h
O
84%, 9h
O
2
t
R = Bu, 61%, 9h
OMe
OMe
O
O
MeO
O
O
MeO
O
O
O
S
CO2Me
O
O
4sb,
4q,
4r,
4t,
78%, 12h
84%, 12h
92%, 12h
88%, 12h
O
OMe
O
O
O
O
OMe
OtBu
MeO
OMe
MeO
O
O
O
O
O
O
4u, 93%, 12h
4v,
4w,
94%, 12h
81%, 12h
O
O
OMe
O
OR2
OMe
O
O
OMe
S
O
O
O
S
O
N
2
4y,
R =i-Pr, 78%, 12h
4x,
89%, 12h
4va, 80%, 12h
4wa, 83%, 12h
4z, R2=tBu, 40%, 12h
aStandard conditions. b2 mmol of R-OH in 4 mL of CH3CN.

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Scheme 2. Synthesis of biologically active phenylquinoxalinone, 6n (CFTR activator) and bis
oxime ester, 5t (DHPS inhibitor).
NO2
N
CuI
O
OMe
O
ref. 8a
2-picolinic acid
O2N
N
O
O2N
MeOH, RT
O2
6n
blue-LEDs
4n, 84%, 9h
overall yield= 44.1%
CFTR activator
HO
OH
CuI
O
O
N
N
2-picolinic acid
MeOH, RT
O2
NH OH.HCl
OMe
MeO
2
MeO
OMe
ne
ridi
py
overnight
O
O
O
O
5t, 64%
blue-LEDs
4u, 93%, 12h
overall yield = 60%
DHPS inhibitor
Scheme 3. One pot synthesis of 2-phenyl quinoxaline (a FLT3 inhibitor) by in-situ trapping
phenylglyoxal using commercially available substrate, 1,2-phenylenediamine.

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Scheme 4. Mechanistic control studies.
O2, 2-picolinic acid
+
Ph
Cu MeOH
3a, 40%
(1)
(2)
RT, 12 h, blue-LEDs
tion
di
on
al c
tim
op
+
13, 62%
Ph
MeOH
blue LEDs, 3 h
CuI (5 mol%)
2-picolinic acid (1 equiv.)
MeOH, O2
MeOH, O2
3a
90%
(5)
(6)
n.r.
H2O
(3)
(4)
O
RT, 12h
blue LEDs
H
RT, 12h, blue LEDs
O
CuI (5 mol%)
CuI(5 mol%)
2-picolinic acid (1 equiv.)
(intermediate)
isolated
13
n.r.
3a
trace
MeOH, N2
RT, 12h, blue LEDs
MeOH, O2
RT, 12h, blue LEDs
MeOH
optimal conditions
O
OH
Ph
(7)
(8)
3a, 0%
O
blue LEDs
15
O
O
Ph
O
FeCl3
H
16, 42%
Ph
13
DCE, RT
1 h
Ph
Ph
O
Ph
H2O
H
O
MeOH, RT
n.r.
Optimal condition
(9)
n.r.
(10)
O
Dark
Dark
13
Scheme 5. Isotopic labelling experiment.

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Scheme 6.Plausible mechanism for the formation of α-keto esters.
1
CuI
Ph
CuI
*
Ph
O2
SET
Ph
+
CuI
1a'
9
blue-LEDs
O2 + H2O2
H2O O2
O2
Ph
CuII
10
O2
OH
N
L
O
O
O
R
[LCu-O-O]
Ph
Ph
OH
N
O
3
O
III
Me
Me
N
N
Ph
Cu
O
11
8
O
H2O
[LCu-O-O]
Me
Me
NH2
7
NH2
2H2O
(glyoxal trapped
in situ)
R-OH
H
O
O
CuIIL2
(blue ppt)
O
Ph
H
H
2
Ph
Ph
13
O O
12
O
OR
-H2O
14

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Table of Content