Organic Letters
Letter
the Michael acceptor was investigated. Different substituted 2-
arylidenemalonate bearing aromatic groups with different
electronic and steric properties were tested in the reaction
with 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1), and the
corresponding addition products 3−7 could be obtained with
excellent yields. 2-Arylidenemalonitriles and 2-arylidene-1,3-
diketones bearing different substituents in the aromatic ring
were also investigated obtaining the corresponding products 8−
10 and 11−15, respectively, with good to excellent yields (51−
99%). Interestingly, methyl 2-oxo-2H-chromene-3-carboxylate
could be used as a radical acceptor obtaining the corresponding
product 16 in 64% yield and 1:1 dr. Later, we tested other α,β-
unsaturated compounds such as chalcones and other enones as
radical acceptors obtaining the corresponding products 17−32
with good yields. Remarkably, a wide range of substituents are
tolerated at the β-position of the double bond such as aryl, alkyl,
CF3, SiMe3, ester, or ketones. α,β-Unsaturated N-acylpyrazoles
could be used as radical acceptors, although the corresponding
product 32 is obtained with moderate yield (52%). Simpler
Michael acceptors such as acrolein, methyl vinyl ketone, or
acrylophenone as well as other cyclic enones such as chromone
could be used, although the corresponding chromanone 36 was
obtained with low yield (25%). Next, we demonstrate the
synthetic potential of this methodology for the late-stage
functionalization of natural products or structurally diverse
pharmaceutically relevant substances, including oleic acid and
indomethacin, which were well-tolerated (80% and 79% yield,
respectively). We next explored the Giese reaction with other
1,4-dihydroquinoxalin-2-ones. For example, 1,4-dibenzyl-3,4-
dihydroquinoxalin-2-one could be used under the optimized
reaction conditions, although the Giese product 39 was obtained
with moderate yield (48%). 3,4-Dihydroquinoxalin-2-one
bearing electron-donating (Me, MeO) or electron-withdrawing
(Br, F) groups at different positions on the aromatic ring
furnished the corresponding products 40−44 in good yields
(66−99%), regardless of the position or the electronic character
of the substituents. Finally, the reaction tolerates different
benzylic substituents, affording the corresponding alkylated
quinoxalines 45 and 46 from moderate to good yields. These
results are remarkable, because only the oxidation of the
endocyclic CH2 was observed.
To further showcase the practicability and scalability of this
protocol, we performed the radical conjugate addition at the
gram scale using sunlight irradiation (Scheme 2B). Under these
conditions, the results were similar, in terms of yield, to those
obtained on the small scale (97% yield), although we observed
an enhancement on the diastereoselectivity from 1.6:1 dr, in the
small scale, to 3.8:1 dr, in a gram scale. Furthermore, we have
applied several chemical transformations for the synthesis of
interesting dihidroquinoxaline derivatives. For example, decar-
boxylation of 43 gave the corresponding product 47 smoothly in
54% yield (Scheme 2C). Taking into consideration that the
presence of multiple nitrogen heterocycles is very important for
drug discovery and medicinal chemistry, we perform several
transformations taking advantage of the 1,3-dicarbonyl and 1,4-
dicarbonyl obtained products. Compound 11 was treated with
methylhydrazine in the presence of AcOH in dioxane at 110 °C,
obtaining the corresponding pyrazole functionalized with a
quinoxaline moiety (Scheme 2D). Finally, compound 28 was
used for the preparation of two substituted pyrroles (49 and 50)
by the Paal−Knorr reaction,24 with good yields (82% and 61%,
respectively) in both cases (Scheme 2E).
Scheme 1. (A) Oxidative α-Functionalization of Amines, (B)
Addition of α-Amino Radicals to Michael Acceptors, and (C)
Examples of Biologically Active Dihydroquinoxalin-2-ones
conditions, due to their inherent structure. Moreover, 1,4-
dihydroquinoxalinones constitute a prevalent skeleton fre-
quently found in many biologically active compounds (Scheme
1C). Many examples are used as pharmaceuticals, including
antiviral compounds used for the treatment of HIV,18 anticancer
compounds,19 cholesteryl ester transfer protein inhibitors,20 and
anti-inflammatory compounds.21 Therefore, continuing with
our interest in the oxidative functionalization of cyclic amines,22
we described the radical addition of 1,4-dihydroquinoxalin-2-
ones to a wide range of electron-deficient olefins using a catalytic
system formed by Ru(bpy)3Cl2 and (PhO)2PO2H under blue
LED irradiation.
The Giese reaction between 4-benzyl-3,4-dihydroquinoxalin-
2(1H)-one (1) and dimethyl 2-benzylidenemalonate (2) was
selected as the model reaction (Table S1).23 Compound 1 is a
challenging substrate due to the possible formation of two α-
amino radicals, in the benzylic position or at the α-position to
the amide. The initial reaction using 1 mol % Ru(bpy)3Cl2 under
irradiation of 5 W white LEDs did not give the corresponding
addition product 3 (entry 1); instead, we observed the
dimerization of 1. In order to gain more reactivity, we decided
to use diphenyl hydrogen phosphate (A1) as a Brønsted acid
additive as Yoon described.8 To our surprise, 78% yield of the
product 3 was obtained after 48 h (entry 2). Under blue LED
irradiation, the reaction was faster, and the radical addition
product was obtained with higher yield (82%, entry 12).23
Increasing the amount of 3,4-dihydroquinoxalinone from 1.15
to 1.3 equiv was beneficial for the speed of the Giese reaction (6
h), and product 3 was isolated with 92% yield (entry 13).
After identifying the optimized reaction conditions, we set to
explore the scope of the radical addition of dihydroquinoxalin-2-
ones to Michael acceptors (Scheme 2A). First, the versatility of
B
Org. Lett. XXXX, XXX, XXX−XXX