Visible-Light-Promoted Oxidative Amidation of Bromoalkynes with Anilines: An Approach to α-Ketoamides

Article abstract of DOI:10.1021/acs.orglett.8b00586

A convenient and practical synthetic route to α-ketoamides from bromoalkynes and anilines through phototriggered organic transformations via a C-N cross-coupling and an oxidation of Ca‰?C was developed. The reaction could be furnished without an external photocatalyst at ambient conditions, and a wide range of α-ketoamides were obtained in good yields.

Full text of DOI:10.1021/acs.orglett.8b00586

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Promoted Oxidative Amidation of Bromoalkynes with
Anilines: An Approach to α‑Ketoamides
Ke Ni,† Ling-Guo Meng,*,† Kuai Wang,† and Lei Wang*,†,‡
†Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: A convenient and practical synthetic route to α-ketoamides
from bromoalkynes and anilines through phototriggered organic trans-
formations via a C−N cross-coupling and an oxidation of CC was
developed. The reaction could be furnished without an external
photocatalyst at ambient conditions, and a wide range of α-ketoamides
were obtained in good yields.
he pursuit of a facile and practical platform for the
Scheme 1. Different Routes to α-Ketoamides
T
synthesis of α-ketoamides has attracted the attention of
synthetic chemists,1 because these structural units exist in
bioactive molecules, such as BMS190914 and SNJ-1945, which
are used as a calpain inhibitor and retinoic acid receptor
selective ligand, respectively (Figure 1).2 Furthermore, the α-
Recently, visible-light-initiated organic reactions as the most
important and novel platform for chemical transformations
have received much attention due to exhibition of synthetic
efficiency and practicability.10 In general, occurrence of a
photoreaction relies on metal complexes or organic dyes used
as intermediates to transfer the luminous energy into a chemical
reaction.11 Although some photoreactions proceeded without
photosensitizers, those reactions occurred with an oxidant,12
additive,13 or ultraviolet light14 irradiation.15 Therefore, the
development of more feasible and practical visible-light-induced
organic transformations has great value. Very recently, we have
discovered that simple alkenes and alkynes could be used as
good photoreaction substrates for the construction of
complicated molecules using organic dye as a photocatalyst
under visible light irradiation.16 After further investigation, we
are delighted to find that bromoacetylenes exhibit more
reactivity in the presence O2 under visible light irradiation
and reacted with anilines smoothly to afford α-ketoamides
(Scheme 1, eq 2). Obviously, this synthetic method supplies a
direct and practical platform to α-ketoamides, compared with
the previous reports, as shown in Scheme 1. Herein, we report a
visible-light-promoted directly oxidative amidation of bromoal-
Figure 1. Biological molecules containing α-ketoamide moiety.
ketoamide structure was also found in an analytical reagent that
acts as a fluorescent probe candidate for H2O2.3 The general
preparation route to α-ketoamides is the condensation of
amines with α-keto acids (α-keto acyl halides).4 In addition,
other synthetic reactions, such as transition-metal catalyzed
double carbonylation,5 peroxide oxidation reaction,6 and so
on,7 have been developed for the formation of α-ketoamides.
Interestingly, Jiao employed terminal alkynes as the precursor
for the preparation of α-ketoamides in the presence of a Cu-
catalyst and O2,8 and a similar transformation also could be
achieved under metal-free conditions (Scheme 1, eq 1).9
However, prominent deficiencies of the above methods require
a transition-metal catalyst, or harsh and complicated reaction
conditions. Accordingly, the development of a more convenient
and practical approach for these classic molecules remains a
challenge for chemists.
Received: February 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00586
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Organic Letters
Letter
ab
,
kynes with anilines in the presence of O2 under ambient
conditions without any photosensitizers and additives.
Scheme 2. Scope of Bromoalkynes
We commenced our study by using 2,4-dibromo-6-fluoro-
aniline (1a) and phenylethynyl bromide (2a) as the model
substrates for optimizing the reaction conditions, and the
results are shown in Table 1. The reaction of 1a with 2a in the
a
Table 1. Optimization of the Reaction Conditions
b
entry
light source
solvent
yield (%)
c
1
blue LED
blue LED

DCE
37
2
DCE
64
<5
3
DCE
d
4
blue LED
blue LED
blue LED
blue LED
blue LED
blue LED
blue LED
blue LED
blue LED
blue LED
blue LED
purple LED
green LED
red LED
DCE
<5
5
toluene
EtOAc
CH3CN
CH2Cl2
CHCl3
THF
82
69
61
54
52
30
28
21
<10
<10
68
65
66
6
7
8
9
10
11
12
13
14
15
16
17
acetone
EtOH
DMF
a
Reaction conditions: 1a (0.20 mmol), 2 (0.30 mmol), blue LED,
b
c
toluene (2.0 mL), rt, in O2 atmosphere, for 12 h. Isolated yield. 0.50
mmol of iodoalkynes was used.
DMSO
toluene
toluene
toluene
substrates 2 with a halogen group (F, Cl, or Br) on the para-
position of benzene rings generated the products (3ag−ai) in
62−70% yields. The reactions of substrates 2 with a substituted
group, including CH3, F, or Cl, on the meta-position of the
phenyl rings with 1a produced the desired products (3aj−al) in
73−80% yields. When a CH3 or Cl group was located at the
ortho-position of the benzene rings in substrates 2, the
corresponding products 3am and 3an were obtained in 60%
and 63% yields, respectively, exhibiting a slightly steric
hindrance. On the other hand, when phenylethynyl chloride
or phenylethynyl iodide was used instead of phenylethynyl
bromide to react with 1a, the reaction also occurred and
generated the desired product 3aa in 15% and 79% yields,
respectively. Only a trace amount of the desired product was
observed when benzylacetylene bromide was used in the
reaction.
To further evaluate the scope of this amidation reaction,
different anilines were examined under the optimized
conditions, as shown in Scheme 3. Trihalogen substituted
anilines, including 2-bromo-4,6-difluoro-, 2,4,6-tribromo-, and
4-bromo-2,6-difluoro-anilines, proceeded well in the reaction
with 2a, providing the desired products (3ba−da) in 64−75%
yields. The reactions of a variety of dihalogen substituted
anilines, such as 2-bromo-4-fluoro-, 2,4-dibromo-, 3,5-dibro-
mo-, 2,6-difluoro-, 3,5-difluoro-, 2-iodo-4-fluoro-, 2-iodo-4-
bromo-, 2,6-dichloro-, 3,5-dichloro-, 3,4-dichloro-, and 2-
bromo-4-chloro-anilines, with 2a were also converted to the
corresponding α-ketoamides (3ea−oa) in 61−83% yields.
Meanwhile, 2-bromo-5-(trifluoromethyl)aniline reacted with
2a, providing 3pa in 81% yield. Subsequently, monohalogen
substituted anilines with F, Cl, Br, and I at the ortho- or meta-
position of the phenyl rings reacted with 2a to afford the
corresponding products (3qa−ua) in 62−68% yields. Anilines
containing a CN group located on the ortho-, para-, or meta-
a
Reaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), light source,
b
c
solvent (2.0 mL), rt, in O2 atmosphere, for 12 h. Isolated yield. In
air. Under N2.
d
presence of air under blue LED irradiation for 12 h afforded N-
(2,4-dibromo-6-fluorophenyl)-2-oxo-2-phenylacetamide (3aa)
in 37% yield (Table 1, entry 1). The yield was improved to
64% when the reaction was carried out in the presence of O2
(Table 1, entry 2). This transformation was almost halted
without light or under N2 (Table 1, entries 3 and 4). After
investigating the effect of the solvent on this coupling reaction,
toluene was found to be the best solvent (Table 1, entry 5);
poor yields (21−69%) of α-ketoamide 3aa were obtained when
EtOAc, CH3CN, CH2Cl2, CHCl3, THF, acetone, and EtOH
were used as the solvent (Table 1, entries 6−12). With further
utilization of polar solvents (DMF and DMSO), much lower
yields were observed (Table 1, entries 13 and 14). On the other
hand, when the reaction was performed under the irradiation of
different light sources, including purple LED, green LED, and
red LED, the desired product was also obtained with slightly
less efficiency (Table 1, entries 15−17).
With the optimized conditions in hand, a variety of
bromoacetylenes were used to react with 2,4-dibromo-6-
fluoroaniline 1a to explore the substrate scope of the
photoinduced oxidative amidation, and the results are
presented in Scheme 2. It was found that 1-bromo-2-
arylacetylenes 2 with different substituents on the phenyl
rings could react with 1a well and provide the corresponding α-
ketoamides in satisfactory yields. 1-Bromo-2-arylacetylenes 2
with an electron-donating group, such as CH3O, CH3, Et, Pr, or
tBu, on the para-position of the phenyl rings reacted with 1a to
afford the desired products (3ab−af) in 70−82% yields, while
B
DOI: 10.1021/acs.orglett.8b00586
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 3. Scope of Anilines
Scheme 4. Control Experiments
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added to
the reaction system, this oxidative amidation was almost
inhibited (Scheme 4e). In order to obtain evidence that this
reaction was triggered by either substrate 1a or 2a, more in-
depth control experiments were performed. The results
indicated that no reaction of 1a was observed in the absence
of 2a under the optimized conditions (Scheme 4f), but the
reaction of substrate 2a without 1a led to the disappearance of
2a and the observation of a complicated reaction (Scheme 4g).
Meanwhile, 1,4-diphenyl-1,3-butadiyne was detected by GC-
MS when the reaction of 2a was stirred under N2 (Scheme 4h).
The above-mentioned facts imply that the C−Br bond
homolytic cleavage in bromoalkynes occurred under visible-
light irradiation conditions and subsequently triggered the
amidation reaction with amines.
Based on the obtained results in the control experiments, the
reaction mechanism is shown in Scheme 5. The C(sp)−Br
Scheme 5. Proposed Mechanism
a
Reaction conditions: 1 (0.20 mmol), 2a (0.30 mmol), blue LED,
b
toluene (2.0 mL), rt, in O2 atmosphere, for 12 h. Isolated yield.
c
Mixed solvent (1 mL toluene and 1 mL EtOAc) was used.
position of the benzene rings could react with 2a to produce
the anticipated products (3va−xa) in satisfactory yields.
Furthermore, CF3-substitued anilines also proceeded in the
reaction and were converted to the desired products (3ya−za)
in good yields. Notably, aromatic secondary amines were also
transformed into the corresponding products (3αa−γa) in 65−
85% yields. However, the reaction failed when electron-rich
aniline (p-methoxyaniline and p-methylaniline), butyl amine, or
p-methylbenzenesulfonamide was used in the reaction.
To elaborate the reaction clearly and ascertain oxygen atoms
in the products 3, which come from O2 or H2O, several control
experiments were conducted, as depicted in Scheme 4. When
the model reaction was carried out in the absence of O2 and
H2O, or in the presence of 2.0 equiv of H2O, only a trace
amount of 3aa was observed (Scheme 4a and 4b). It was
further confirmed that the oxygen element in the product 3aa is
all from O2, but not from H2O through the control
experiments, Scheme 4c and 4d. When a radical scavenger
bond homolytic cleavage of 2a is triggered under visible-light
irradiation to generate alkynyl radical A and a Br• radical.
Meanwhile, an electron-donor−acceptor complex was not
observed (SI for detail). Alkynyl radical A reacted with O2 to
1
give intermediate B (no signal showed the existence of O2 by
electron spin resonance (ESR); see SI for detail).17 Meanwhile
Br• abstracted hydrogen from 1a to give intermediate C,18
which then coupled with B to afford D. Next, the formed D
underwent the rearrangement process to afford the desired
product 3aa. It is should be noted that the generation of
intermediate A and B during the reaction can be confirmed by
C
DOI: 10.1021/acs.orglett.8b00586
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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the GC-MS and HRMS analysis of control experiments in
Scheme 4g−h, respectively (SI).
In conclusion, we have developed a convenient and practical
synthetic route to α-ketoamides through a visible-light-
triggered tandem oxidative amidation of bromoalkynes with
anilines under transition-metal-free, photocatalyst-free, and
additive-free conditions. This amidation reaction tolerated a
broad range of substrate scopes and produced a variety of α-
ketoamides in good yields. Further efforts on the development
of a novel visible-light-induced synthetic platform are currently
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
(11) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322. (b) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016,
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6828.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00586.
(12) (a) Zhao, Y.; Huang, B.; Yang, C.; Xia, W. Org. Lett. 2016, 18,
3326. (b) Tan, H.; Li, H.; Ji, W.; Wang, L. Angew. Chem., Int. Ed. 2015,
54, 8374. (c) Yang, S.; Li, P.; Wang, L. Org. Lett. 2017, 19, 3386. (d) Ji,
W.; Li, P.; Yang, S.; Wang, L. Chem. Commun. 2017, 53, 8482. (e) Zhu,
X.; Li, P.; Shi, Q.; Wang, L. Green Chem. 2016, 18, 6373.
Full experimental details and characterization data for all
products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(13) (a) O’broin, C. Q.; Fernandez, P.; Martínez, C.; Muniz, K. Org.
́
̃
Lett. 2016, 18, 436. (b) Barham, J. P.; Coulthard, G.; Emery, K. J.;
Doni, E.; Cumine, F.; Nocera, G.; John, M. P.; Berlouis, L. E. A.;
McGuire, T.; Tuttle, T.; Murphy, J. A. J. Am. Chem. Soc. 2016, 138,
7402. (c) Torti, E.; Protti, S.; Merli, D.; Dondi, D.; Fagnoni, M. Chem.
- Eur. J. 2016, 22, 16998. (d) Li, L.; Liu, W.; Mu, X.; Mi, Z.; Li, C.-J.
Nat. Protoc. 2016, 11, 1948.
*E-mail: milig@126.com.
*E-mail: leiwang88@hotmail.com
ORCID
Lei Wang: 0000-0001-6580-7671
Notes
(14) (a) Arceo, E.; Montroni, E.; Melchiorre, P. Angew. Chem., Int.
Ed. 2014, 53, 12064. (b) Dell’Amico, L.; Vega-Penaloza, A.; Cuadros,
̃
The authors declare no competing financial interest.
S.; Melchiorre, P. Angew. Chem., Int. Ed. 2016, 55, 3313. (c) Li, L.; Mu,
X.; Liu, W.; Wang, Y.; Mi, Z.; Li, C.-J. J. Am. Chem. Soc. 2016, 138,
5809. (d) Sato, Y.; Kawaguchi, S.-I.; Nomoto, A.; Ogawa, A. Angew.
Chem., Int. Ed. 2016, 55, 9700.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21772062, 21572078 and 21402061),
the Young Talent Key Project of Anhui Province
(gxyqZD2016411), and the Natural Science Foundation of
Anhui (No. 1708085MB45) for financial support of this work.
(15) (a) Murphy, J. J.; Bastida, D.; Paria, S.; Fagnoni, M.; Melchiorre,
́
P. Nature 2016, 532, 218. (b) Arceo, E.; Jurberg, I. D.; Alvarez-
Fernandez, A.; Melchiorre, P. Nat. Chem. 2013, 5, 750.
́
(16) (a) Wang, K.; Meng, L.-G.; Wang, L. Org. Lett. 2017, 19, 1958.
(b) Wang, K.; Meng, L.-G.; Zhang, Q.; Wang, L. Green Chem. 2016,
18, 2864.
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D
DOI: 10.1021/acs.orglett.8b00586
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