G Model
CCLET 4595 No. of Pages 4
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C. Zhou et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
To confirm whether diverse α-ketoamides could be synthesized
through the optimized method, the scope of the substrates was
investigated. As summarized in Fig. 1, the reaction showed good
compatibility and proved to be a general method to construct
diverse α-ketoamides. Aniline containing both electron-donating
and electron-withdrawing groups reacted with benzoylacetoni-
trile to afford the desired products in moderate to good yields (3a-
3n). The substituents at different positions did not greatly affect
the yield (3b-3e, 68%–78%). Aniline bearing electron-neutral (H, 4-
Me, Et) and electron-donating (OMe and t-Bu) groups resulted in
successful conversion to the corresponding products in moderate
to good yields (3a and 3f–3 h, 64%–79%). The scope of the
substrates was further extended to various electron-withdrawing
halogenated substrate (F, CF3, Cl), giving the corresponding
products with 54%–60% yields (3i-3k) successfully. A satisfactory
yield was also achieved using secondary amines as the products (3
l, 83%). Additionally, 1-naphthylamine also proceeded smoothly to
generate the corresponding product 3n with a 60% yield under the
standard reaction conditions. Moreover, benzoylacetonitrile bear-
ing electron-neutral and electron-withdrawing groups or aliphatic
acyl acetonitrile reacted well with aniline (3o-3q, 68%–78%).
When using 1, 2-diaminobenzene to replace aniline, the
experimental products were quite different from our expected
results (Scheme S1 in Supporting information). We synthesized
quinoxalines from 1, 2-diaminobenzene and benzoylacetonitrile
under our optimized reaction conditions with 76% yield and
without by-product. We then expanded the scope of benzoylace-
tonitrile. As shown in Fig. 2, the reactions were also highly efficient
and smooth with yields of 63% to 72% (5b-5d), both electron-
withdrawing and electron-donating groups have a relatively low
impact on the reaction rate and yield. 2-Thenoylacetonitrile can
also give the corresponding product with 50% yield (5f). We also
scope the 1,2-diaminobenzene with electron-withdrawing and
electron-donating groups, to our satisfactory, the substituted 1,2-
diaminobenzene also proceed smoothly with benzoylacetonitrile.
It is noteworthy that under the circumstances of single substituted
1,2-diaminobenzene, two regioisomers were obtained due to the
unsymmetric nature of single substituted 1,2-diaminobenzene
(5g-5i), which react equally well to the C–O double bond. While the
symmetric substituted 1,2-diaminobenzene only give one product
(5 j). Importantly, the present method for generating quinoxalines
proceeds without the use of a metal or an extra oxidant.
Scheme 1. Synthesis of α-ketoamides and quinoxalines.
Table 1
Optimization of reaction conditions.a.
Entry
Solvent
Amine
Time (h)
Yield (%)b
1
THF
THF
0.5
0.5
8
8
52
0
2c
3
THF
THF
THF
THF
THF
THF
THF
THF
DMSO
DMF
NMP
DCM
PhCH3
CH3CN
0.5
0.5
0.5
0.75
0.75
0.75
1.0
4
21
59
59
61
72
72
72
72
55
4
4
5
6
7
8
9
10
11
12
13
14
15
16
12
20
8
12
20
12
12
12
12
12
12
12
12
1.5
0.75
0.75
0.75
0.75
0.75
0.75
21
34
16
51
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5–1.5 mmol), solvent (2 mL), room
In order to further explore the active site of the reaction, we
conducted the following control experiments (Scheme 2). When
we converted the carbonyl to sulfone, no reaction was detected, so
carbonyl is important in the reaction. At the same time, neither
benzoylcyanide nor benzonitrile was found to react with aniline
under this condition, indicating that the cyanogroup and methy-
lene were equally important.
Although we knew that visible light and O2 were necessary for
the success of the reaction, we wondered what is the key factor
enabled this catalyst-free process. One possibility is that singlet
oxygen is produced and responsible for the oxidative coupling
process under our standard conditions. Experiments to determine
the presence of photoexcited singlet oxygen in the reaction system
were performed (Scheme S2 in Supporting information). Trapping
experiments were carried under irradiation using 1,3-diphenyli-
sobenzofuran [12] produced the desired product 1,2-phenylenebis
(phenylmethanone), however, the corresponding product was not
acquired in the dark, which suggested that under our reaction
conditions, visible-light promoted the generation of singlet
oxygen. Quenching experiments were conducted, using 1,4-
diazabicyclo[2.2.2]octane (DABCO) [13], a common quencher of
1O2, only a trace amount of 3a was produced in the reaction. These
quenching and trapping experiments clearly indicated that 1O2
temperature.
b
c
Isolated yield.
No visible light.
decreased to 21% while increasing the reaction time to 12 h, which
was increased to 59% (Table 1, entries 3 and 4). However, an
additional increase in the reaction time did not produce the higher
yield (Table 1, entry 5). Then the diverse molar ratio of benzoyl
acetonitrile and aniline was studied under the same conditions
except reaction time. First, we studied the reaction at different
reaction time under the molar ratio is 1:1.5, interestingly, the
product yield increased from 61% to 72% and did not change with
the time extending to 20 h, which indicate that 12 h may be enough
for the substrate to react with each other (Table 1, entries 6–8). No
significant improvement of yield was observed when increase the
molar ratio above 1:1.5 (Table 1, entries 9 and 10). To further
enhance the α-ketoamide yield, an extensive screening of solvents
was tested. Among various tested solvents, including DMSO, DMF,
DCM, NMP, MeCN, toluene, the yield of 3a was lower than in THF
(Table 1, entry 7 and entries 11–16), which indicates that the
reaction is sensitive to reaction media. THF was the best solvent in
terms of the reaction yield, hence it was used throughout the
present work.
Please cite this article in press as: C. Zhou, et al., Facile photochemical synthesis of α-ketoamides and quinoxalines from amines and