Carbamoyl Radicals via Photoredox Decarboxylation of Oxamic Acids in Aqueous Media: Access to 3,4-Dihydroquinolin-2(1 H)-ones

Article abstract of DOI:10.1021/acs.orglett.8b00449

The first visible-light-mediated photoredox oxidative approach for generating carbamoyl radicals from oxamic acids is disclosed. Reaction of the generated carbamoyl radicals with electron-deficient alkenes opens efficient access to 3,4-dihydroquinolin-2(1H)-ones under mild conditions through a sequence of intermolecular radical addition, cyclization, and aromatization. The process is compatible with a variety of oxamic acids and electron-deficient alkenes, and a wide variety of 3,4-dihydroquinolin-2(1H)-ones were prepared.

Full text of DOI:10.1021/acs.orglett.8b00449

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Carbamoyl Radicals via Photoredox Decarboxylation of Oxamic
Acids in Aqueous Media: Access to 3,4-Dihydroquinolin-2(1H)‑ones
Qi-Fan Bai, Chengan Jin, Jing-Yao He, and Gaofeng Feng*
Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Shaoxing University, Shaoxing, 312000, People’s
Republic of China
S
* Supporting Information
ABSTRACT: The first visible-light-mediated photoredox
oxidative approach for generating carbamoyl radicals from
oxamic acids is disclosed. Reaction of the generated carbamoyl
radicals with electron-deficient alkenes opens efficient access to
3,4-dihydroquinolin-2(1H)-ones under mild conditions
through a sequence of intermolecular radical addition,
cyclization, and aromatization. The process is compatible with a variety of oxamic acids and electron-deficient alkenes, and a
wide variety of 3,4-dihydroquinolin-2(1H)-ones were prepared.
Scheme 1. Methods for Generation of Carbamoyl Radicals
isible-light photoredox catalysis has emerged as a
Vpowerful, eco-friendly synthetic platform for forming
carbon−carbon or carbon-heteroatom bonds by employing
ruthenium/iridium polypyridyl complexes or organic dyes as
photoredox catalysts.1 Excited with visible light, photoredox
catalysts could act as both excellent one-electron reductants and
oxidants, which react with organic or organometallic molecules
to generate reactive alkyl, aryl, and acyl radicals to engage in
reaction process, enabling a wide array of previously
inaccessible transformations could be accomplished under
extraordinary mild conditions. In this context, photoredox
decarboxylative functionalization of carboxylic acids have
attracted significant attention.2 Many types of acids, such as
α-oxocarboxylic acids,3 α-amino acids,4 and α-oxy acids5 could
undergo direct decarboxylation to afford the corresponding
radicals under photoredox conditions. In particular, conversion
of carboxylic acid to the corresponding N-hydroxyphthalimide
(NHPI) ester has been wide explored and demonstrated as a
versatile and powerful tool for site-specific decarboxylation to
afford alkyl or acyl radicals,6 as N-hydroxyphthalimide motif
could easily undergo single-electron reduction by the excited
photocatalyst, followed by rapid decarboxylative fragmentation
weight (formula weight (FW) = 146) becomes part of waste
after the reaction.
From the viewpoint of atom-economy, preparation handling,
and stability, direct conversion of readily available oxamic acid
to a carbamoyl radical, although challenging, would be much
more appealing. Existing methods for carbamoyl radical
generation from oxamic acid usually employ stoichiometric
K2S2O8 or H2O2 as an oxidant, along with Pd or Ag as a
catalyst9 (see Scheme 1b). To the best of our knowledge,
photoredox catalysis for the generation of carbamoyl radicals
from oxamic acids has not been reported yet.
Herein, we report a visible-light-mediated approach for
generating a carbamoyl radical from oxamic acid and its
reaction with alkenes to afford 3,4-dihydroquinolin-2(1H)-
ones, which is a privileged structure subunit existing in many
biologically active natural products and pharmaceuticals,10 via a
7
−
to liberate 1 equiv of CO2 and NPhth as byproducts.
A carbamoyl radical is a versatile reaction intermediate for
synthesizing molecules with amide functionality and nitrogen-
containing heterocycles. Thus, development of novel strategies
for generation of carbamoyl radicals is highly desirable. Very
recently, employing N-hydroxylphthalimide as decarboxylative
auxiliary, Petersen and co-workers8 disclosed a photoredox-
neutral approach for generation of carbamoyl radicals from N-
hydroxyphthalimido oxamides using Ir(ppy)3 as a catalyst
(Scheme 1a). Although this method was shown to possess a
wide substrate scope, the starting N-hydroxyphthalimido
oxamides must be prepared under relative harsh conditions
(low temperature, dry solvent), stored in darkness, and the
phthalimide subunit, containing around half of the molecular
Received: February 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
sequence of intermolecular radical addition, intramolecular
cyclization, and aromatization.
A gram-scale synthesis of oxamic acids was carried out
through an operating-simple sequence:
according to 1H NMR analysis, and isolated in 64% yield (entry
1 in Table 1). PC-1 is crucial for the transformation, as much
lower yields were observed when PC-2, Eosin Y, and 2,4,6-
triphenylpyrylium fluoroborate were employed as photo-
catalysts (entries 2−4 in Table 1). Increasing the amount of
ethyl acrylate 2a to 5 equiv could improve neither reaction
efficiency nor yield (entry 5 in Table 1). Elevating the reaction
temperature to 55 °C resulted in a decreased yield of 24%,
which is due to the formation of N-methyl-N-phenylformamide
(entry 6 in Table 1). Solvent screening indicated that aqueous
CH2Cl2 was optimal, and the addition of H2O had a beneficial
effect (entries 7−13 in Table 1). It was found that basic
additives had a deleterious effect, as lower yields were observed,
ranging from 35% to 42% (entries 14−16 in Table 1). On the
other hand, the addition of acetic acid could also achieve the
comparable yields with those adding base (entry 17 in Table 1).
Interestingly, the amount of oxygen seemed important for
achieving high yield, as lower yields were observed under both
O2 and N2 atmosphere (entries 18 and 20 in Table 1) and
comparable yield was achieved without N2 bubbling (entry 19
in Table 1). The presence of more O2 was prone to
demethylation of the target 3a to form 4-ethoxycarbonyl-3,4-
dihydroquinolin-2(1H)-one (entry 18 in Table 1). Control
experiments confirmed that both photocatalyst and visible light
were essential for significant conversion to the product (entries
21 and 22 in Table 1), as no product was observed in the
absence of both light and photocatalyst.
(1) reaction of N-alkylaniline with methyl 2-chloro-2-
oxoacetate at room temperature in the presence of
NaHCO3;
(2) hydrolysis of the resulting methyl ester in THF with
aqueous KOH; and
(3) acidification of the aqueous layer with HCl, followed by
filtration and extraction.
The reaction conditions for the synthesis of 3,4-dihydroqui-
nolin-2(1H)-ones were then optimized using N-methyl-N-
phenyloxamic acid 1a and ethyl acrylate 2a as model substrates.
Some selected examples are listed in Table 1. Gratifyingly, by
irradiating the mixture of N-methyl-N-phenyloxamic acid 1a
and 3 equiv of ethyl acrylate 2a in CH2Cl2−H2O (v/v = 2:1)
with 36 W blue LEDs, in the presence of 2 mol % of PC-1 as
photocatalyst at 30 °C for 40 h, the desired 3,4-
dihydroquinolin-2(1H)-one 3a was observed in 68% yield,
a
Table 1. Optimization of Reaction Conditions
With the optimized conditions in hand, we next sought to
investigate the substrate scope of both alkenes and oxamic acids
in this new photoredox carbamoyl radical generation, radical
addition, and cyclization process. To simplify operation,
reactions were carried out without N2 bubbling and the results
are summarized in Scheme 2. A wide array of monosubstituted
electron-deficient alkenes, such as n-butyl acrylate, t-butyl
acrylate, N,N-dimethylacrylamide, ethyl vinyl ketone, phenyl
vinyl sulfone, and acrylonitrile were first subjected to the
reaction with N-methyl-N-phenyloxamic acid under the stand-
ard conditions, affording the corresponding 3,4-dihydroquino-
lin-2(1H)-ones 3b−3g in 31%−60% yields. Moreover, 1,1-
disubstituted alkenes was also compatible with the process.
Particularly, the reaction of α-methylene-γ-butyrolactone with
N-methyl-N-phenyloxamic acid proceeded smoothly to provide
the spirocyclic lactone lactam 3i in 41% yield, which was
slightly lower than that of Donald’s, using N-hydroxyphthali-
mido oxamide as the carbamoyl radical precursor. A series of
oxamic acids with different substitutions on the phenyl subunit
was then investigated. To our delight, the oxamic acids with
both electron-withdrawing (−Cl, −F, and −CF3) and electron-
donating (−Me and −OMe) groups could provide the desired
3,4-dihydroquinolin-2(1H)-ones 3j−3o in moderate yields,
ranging from 41% to 56%. Finally, two types of oxamic acids
with different groups on the N atom were investigated.
Pleasingly, both N-benzyl- and N-allyl-substituted oxamic
acids could undergo a similar process smoothly, providing the
desired products 3p−3s in 50%−74% yields, although they
have potential reactions on both the benzyl and allyl motifs.
Mechanism studies were then carried out. In the reaction of
N-methyl-N-phenyloxamic acid with ethyl acrylate under the
standard conditions, a trace amount of N-methyl-N-phenyl-
formamide was isolated.11 Moreover, when a radical scavenger
(TEMPO) was added to the same reaction, only a trace amount
of 3a was detected. Both results indicated that the reaction
probably proceeded via the formation of a carbamoyl radical. A
b
entry
variation from the standard conditions
yield (%)
1
2
none
68 (64)
38
PC-2 instead of PC-1
c
3
PC-3 instead of PC-1
trace
trace
65
4
PC-4 instead of PC-1
5
with 5 equiv of 2a
d
6
performed at 55 °C
24
7
H2O instead of CH2Cl2−H2O
CH2Cl2 instead of CH2Cl2−H2O
acetone-H2O instead of CH2Cl2−H2O
CH3CN−H2O instead of CH2Cl2−H2O
DMSO-H2O instead of CH2Cl2−H2O
THF-H2O instead of CH2Cl2−H2O
EtOH-H2O instead of CH2Cl2−H2O
with 1.5 equiv of KH2PO4
with 1.5 equiv of K3PO4.3H2O
with 1.5 equiv of K2CO3
trace
18
8
9
22
10
11
12
13
14
15
16
17
18
19
20
21
22
16
trace
13
12
39
35
42
with 1.5 equiv of CH3COOH
under O2 atmosphere
44
e
(34)
without N2 bubbling
62 (60)
N2 through “freeze-pump-thaw” cycle
no blue light
(35)
0
0
no PC-1
a
Reaction conditions: N-methyl-N-phenyloxamic acid 1a (0.3 mmol),
ethyl acrylate 2a (0.9 mmol), photocatalyst (2 mol %), organic solvent
(4 mL), H2O (2 mL), N2(bubbling for 5 min), 36 W blue LEDs, 30
b
°C, 40 h. Determined by 1H NMR spectroscopy with 1,3,5-
trimethoxybenzene as internal standard. The value given in the
parentheses is the isolated yield. Irradiating with 36 W green LEDs.
N-methyl-N-phenylformamide was observed in 10% yield. 4-
Ethoxycarbonyl-3,4-dihydroquinolin-2(1H)-one was isolated in 10%
c
d
e
yield.
B
DOI: 10.1021/acs.orglett.8b00449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope Investigation
plausible mechanism is illustrated in Scheme 3. Irradiation of
IrIII with blue light generated long-lived photoexcited catalyst
In conclusion, we have disclosed a new visible-light-mediated
decarboxylative approach toward a carbamoyl radical from
oxamic acid. As an example for application of the present
methodology, the generated carbamoyl radical was subjected to
the reaction with electron-deficient alkenes, enabling efficient
access to 3,4-dihydroquinolin-2(1H)-ones via a sequence of
intermolecular radical addition, intramolecular cyclization, and
aromatization. The process is compatible with a variety of
oxamic acids and electron-deficient alkenes. Moreover,
comparing with N-hydroxyphthalimido oxamide as the
reductive carbamoyl radical precursor, oxamic acid is not only
more atom-economical, stable, and easily prepared, but it also
undergoes the reaction in an oxidative manner under
photoredox catalysis, thus providing a basis for the develop-
ment of carbamoyl radical chemistry. Synthesis of other
heterocycles via visible-light-mediated decarboxylative gener-
ation of carbamoyl radical from oxamic acid is under
investigation.
Scheme 3. Proposed Reaction Mechanism
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00449.
IrIII*, which was then reductively quenched with oxamic acid to
afford IrII, carbamoyl radical intermediate A, and CO2.
Intermolecular nucleophilic addition of the carbamoyl radical
to electron-deficient alkene then occurred to generate new
radical B, which could then engage in intramolecular homolytic
aromatic substitution to deliver cyclohexadienyl radical C. The
reduced IrII was then oxidized by the residue oxygen in the
reaction tube to regenerate the ground state IrIII to complete
the catalytic cycle. Meanwhile, the generated oxygen radical
anion abstracted a hydrogen atom from cyclohexadienyl radical
C to provide the desired 3,4-dihydroquinolin-2(1H)-one 3 and
Experimental procedures and compound characterization
data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chfeng@usx.edu.cn
ORCID
−
−
HO2 . Finally, HO2 anion was protonated to form H2O2.
Gaofeng Feng: 0000-0001-8521-8305
C
DOI: 10.1021/acs.orglett.8b00449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. Soc. 2017, 139, 15632. (m) Zhao, Y.; Chen, J.-R.; Xiao, W.-J.
Org. Lett. 2018, 20, 224. (n) Kong, W.; Yu, C.; An, H.; Song, Q. Org.
Lett. 2018, 20, 349. (o) Yang, J.-C.; Zhang, J.-Y.; Zhang, J.-J.; Duan, X.-
H.; Guo, L.-N. J. Org. Chem. 2018, 83, 1598.
Notes
The authors declare no competing financial interest.
(7) Examples for utilizing −NPhth byproduct for amine synthesis
through photoredox catalysis, see: (a) Allen, L. J.; Cabrera, P. C.; Lee,
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ACKNOWLEDGMENTS
■
Financial support by Shaoxing University for supporting the
National Natural Science Foundation of China (No. 21302130)
is acknowledged with thanks. We thank Prof. Jian Jin (Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences)
for discussions and help.
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D
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Org. Lett. XXXX, XXX, XXX−XXX