Metal-Free C(sp2)-H/N-H Cross-Dehydrogenative Coupling of Quinoxalinones with Aliphatic Amines under Visible-Light Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b03079

A novel and efficient visible-light-induced C(sp²)-H/N-H cross-dehydrogenative coupling (CDC)-amination with both primary and secondary aliphatic amines at room temperature in air is developed. This photocatalytic reaction allows the direct formation of 3-aminoquinoxalin-2(1H)-ones via CDC-amination in the absence of any external oxidant added from outside. Preliminary mechanistic studies reveal that the present reaction proceeds through a radical process.

Full text of DOI:10.1021/acs.orglett.8b03079

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free C(sp2)−H/N−H Cross-Dehydrogenative Coupling of
Quinoxalinones with Aliphatic Amines under Visible-Light
Photoredox Catalysis
Wei Wei,*,†,‡,§ Leilei Wang,† Pengli Bao,† Yun Shao,‡ Huilan Yue,‡ Daoshan Yang,†,§
Xiaobo Yang,∥ Xiaohui Zhao,*,‡ and Hua Wang†
†School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong, China
‡Qinghai Provincial Key Laboratory of Tibetan Medicine Research and Key Laboratory of Tibetan Medicine Research, Northwest
Institute of Plateau Biology, Chinese Academy of Sciences, Qinghai 810008, China
§College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao, 266042, P. R. China
∥College of Chemistry & Chemical Engineering, Shenyang Normal University, Shenyang, Liaoning 110034, P. R. China
S
* Supporting Information
ABSTRACT: A novel and efficient visible-light-induced
C(sp2)−H/N−H cross-dehydrogenative coupling (CDC)-
amination with both primary and secondary aliphatic amines
at room temperature in air is developed. This photocatalytic
reaction allows the direct formation of 3-aminoquinoxalin-
2(1H)-ones via CDC-amination in the absence of any external
oxidant added from outside. Preliminary mechanistic studies
reveal that the present reaction proceeds through a radical
process.
Scheme 1. Visible-Light-Induced C−H Amination Using
he construction of the C−N bond has long been a
Tfundamentally important pursuit in the synthetic
community.1 Recent decades have witnessed considerable
progress in this field, with a rapid emergence of numerous
elegant amination strategies, including transition-metal-cata-
lyzed Buchwald−Hartwig amination and Ullman amination for
building C−N bonds.2 From a synthetic point of view, C−H/
N−H cross-dehydrogenative coupling (CDC) amination
represents one of the most straightforward and efficient
approaches for the construction of the C−N bond due to its
high atom and step economy.3 In this context, the visible-light-
photoredox catalysis has recently been developed as a
fascinating technique for C−H/N−H CDC-amination via an
aminium radical cation process under mild conditions.4 Among
the well-established photocatalytic CDC-aminations, nitrogen
coupling partners are generally limited to aromatic amines,5
azoles,6 and electron-poor species7 such as carbamates,
sulfonamides, amides, and imides. Aliphatic amines are
extremely valuable structural features in natural products and
biologically active molecules. Nevertheless, direct C−H/N−H
amination with aliphatic amines still remains challenging since
many methods for their functionalizations lead to carbon−
carbon bond formation adjacent to the nitrogen atom.8
Hitherto, only scarce photocatalytic amination examples have
been realized using aliphatic amines as coupling partners.9,10 In
2017, Knowles’ group reported an elegant photodriven
protocol for hydroaminations of unactivated olefins with
secondary aliphatic amines (Scheme 1a).9 The same year,
Aliphatic Amines
Nicewicz’s research group also presented an efficient photo-
catalytic C−H/N−H amination of activated arenes with
primary aliphatic amines (Scheme 1b).10 These two well
developed photocatalytic C−H amination methods only
involved the utilization of a single type of aliphatic amines
(secondary or primary aliphatic amines) as the amination
source. Therefore, it is highly desirable to explore a new
Received: September 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03079
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Organic Letters
Letter
a
photocatalytic C−H/N−H amination system applied to both
secondary and primary aliphatic amines. With our continuous
efforts devoted to photochemical reactions and green organic
synthesis,11 herein, we wish to report a new and efficient metal-
free visible-light-induced, Eosin Y-catalyzed direct C(sp2)−H/
N−H CDC-amination with both aliphatic primary and
secondary amines leading to 3-aminoquinoxalin-2(1H)-ones
(Scheme 1c).
Table 1. Optimization of the Reaction Conditions
As a vital class of heterocyclic units, quinoxalin-2(1H)-ones
are frequently found in many natural products, pharmaceutical
agents, and functionalized materials.12 In particular, 3-amino-
quinoxalin-2(1H)-ones are an important subfamily with
diverse biological and pharmacological activities such as
anticancer,13 antimicrobial,14 antiviral,15 anti-inflammatory,16
antidiabetic,17 and antihypertensive18 properties. Driven by
their significant biological activity and pharmacological value,
various synthetic approaches have been developed for the
synthesis of 3-aminoquinoxalin-2(1H)-ones. Traditional syn-
thetic methods are mainly focused on the assembly of the
quinoxalin-2(1H)-one rings and the nucleophilic substitution
of halo or other leaving group substituted quinoxalin-2(1H)-
ones with amines.19 Alternative metal-catalyzed or strong
oxidant mediated methods for cross-coupling of quinoxalin-2-
ones with amines have also been developed.20 Nevertheless, all
of these established reactions encountered certain drawbacks,
such as the need for extra steps to prepare prefunctionalized
starting materials, high reaction temperature, the use of
transition metal reagents, or a stoichiometric amount of strong
oxidants. Thus, there is still great demand for the development
of a simple, mild, convenient, economic, and environmentally
friendly strategy to construct 3-aminoquinoxalin-2(1H)-ones.
The present metal-free photocatalytic C−H/N−H amina-
tion reaction, which can be performed at room temperature in
air to give various 3-aminoquinoxalin-2(1H)-ones with
moderate to good yields, does not require the use of any
transition-metal catalyst and a stoichiometric amount of strong
oxidants (Scheme 1c). Contrary to the known 3-amino-
quinoxalin-2(1H)-one syntheses, our preliminary mechanistic
studies suggest an alternative radical reaction pathway.
Our study commenced with the model reaction of 1-
methylquinoxalin-2(1H)-one (1a) and morpholine (2a) by the
use of Ru(bpy)2Cl2 (2 mol %) as a catalyst in DMSO at room
temperature under air (Table 1, entry 1). The reaction was
carried out under irradiation with 3 W blue LED lamps. To our
delight, the desired product 3aa was obtained in 51% yield
after 12 h (Table 1, entry 1). Furthermore, other metal-free
photocatalysts such as Na2-Eosin Y, Eosin B, Rhodamine B,
Acridine Red, Bengal Rose, and Eosin Y were also examined.
Among these photocatalysts examined, Eosin Y was demon-
strated to be the most effective one to give the desired product
3aa in 81% yield (Table 1, entry 7). Only a trace amount of the
desired product was detected in the absence of photocatalyst
(Table 1, entry 8). Next, a range of solvents were screened by
use of Eosin Y as the catalyst. Among various organic solvents,
THF emerged as the most suitable solvent for the reaction,
producing the desired product in 82% yield (Table 1, entry
15). Other solvents such as DCE, MeCN, DMF, EtOH, and
DME lead to a relatively lower reaction efficiency (Table 1,
entries 9−14). Only a trace amount of product was detected
when the reaction was carried out in water (Table 1, entry 16).
The reaction efficiency was not improved by increasing the
amount of Eosin Y to 5 mol % (Table 1, entry 17). Notably,
the desired product 3aa was still obtained in 82% yield when
b
entry
photocatalyst (mol %)
solvent
DMSO
yield (%)
1
2
3
4
5
6
7
8
Ru(bpy)2Cl2 (2)
Eosin B (2)
Rhodamine B (2)
Acridine Red (2)
Rose Bengal (2)
Na2-Eosin Y (2)
Eosin Y (2)
−
Eosin Y (2)
Eosin Y (2)
Eosin Y (2)
Eosin Y (2)
Eosin Y (2)
Eosin Y (2)
Eosin Y (2)
Eosin Y (2)
Eosin Y (5)
Eosin Y (1)
Eosin Y (1)
Eosin Y (1)
Eosin Y (1)
Eosin Y (1)
Eosin Y (1)
Eosin Y (1)
51
<10
38
25
57
74
81
trace
10
33
28
53
22
64
82
trace
72
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
1,4-dioxane
DCE
DMF
EtOH
DME
THF
H2O
THF
THF
THF
THF
THF
THF
THF
THF
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
82
c
59
d
80
e
47
f
57
g
63
h
0
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), photocatalyst
(1−5 mol %), solvent (2 mL), 3 W blue LEDs (460−480 nm), air, rt,
12 h. Isolated yields based on 1. 2a (0.24 mmol). 2a (0.6 mmol).
b
c
d
e
f
g
h
Under O2. 3 W green LEDs. 3 W white LEDs. Without light
irradiation.
the loading of catalyst was reduced to 1 mol % (Table 1, entry
18). Moreover, the relatively lower yield was obtained along
with the reduced loading of 2a (Table 1, entries 19 and 20).
Only a 47% yield of 3aa was obtained when the model reaction
was carried out under dioxygen (Table 1, entry 21). In
addition, the desired product 3aa was also obtained in 57% or
63% yield when the reaction was conducted under irradiation
with 3 W green or white LED lamps, respectively (Table 1,
entries 22 and 23). No transformation was observed when the
reaction was carried out in the dark (Table 1, entry 24).
With the optimized reaction conditions in hand, we then
evaluated the scope of this reaction using different quinox-
B
DOI: 10.1021/acs.orglett.8b03079
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Letter
alinone derivatives and aliphatic amines (Scheme 2). The
compatibility with N-substituted quinoxalinones was first
free protected quinoxalin-2(1H)-ones also worked well and
afforded the corresponding product 3la in 81% yield.
Unfortunately, when an electron-withdrawing substituent
such as the N-acetyl group protected substrate was used in
this reaction, none of the desired product 3ma was detected.
Furthermore, a series of substituted quinoxalin-2-ones with
halo and CN groups at the phenyl ring reacted smoothly to
produce the corresponding products 3na−3sa, which provided
a handle for further functionalization. Finally, a series of
aliphatic amines were attempted under the standard con-
ditions. In addition to morpholine, secondary aliphatic amines
such as pyrrolidine, piperidine, 4-methylpiperidine, cis-2,6-
dimethylmorpholine, and dimethylamine were all compatible
with the reaction to give the desired products 3ab−3ag. In
addition, various primary aliphatic amines containing an
aromatic ring group or long aliphatic chains were also suitable
substrates, and the corresponding products 3ah−3am were
obtained in moderate to good yields. Nevertheless, none of
desired product was detected when arylamines such as aniline
and N-methylaniline were employed in the present reaction
system. In addition, no transformation was observed when the
reactions of morpholine with simple arenes (i.e., 1,3,5-
trimethoxybenzene and 1,2,3-trimethoxybenzene) or other
heteroaromatic substrates (i.e., pyridine and indole) were
conducted under the standard conditions.
Scheme 2. Results for Visible-Light-Promoted C−H/N−H
CDC Amination of Quinoxalinones with Aliphatic
a b
,
Amines
Several control experiments were performed to elucidate the
possible reaction mechanism. When TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy) or DMPO (5,5-dimethyl-1-pyr-
roline-N-oxide) was added into the reaction system under the
standard conditions, the present transformation was com-
pletely inhibited, suggesting that this transformation might
involve a radical process (Scheme 3a). Furthermore, DMPO
Scheme 3. Control Experiments
was employed as a capture reagent to trap the possible
nitrogen radical in this reaction by electron spin resonance
(ESR) (Scheme 3b). As shown in Figure 1, no obvious signal
of the nitrogen radical spin adduct was observed when
morpholine (2a) was treated with Eosin Y (1 mol %) in the
presence of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) at
room temperature in the dark. To our delight, an ESR signal of
the nitrogen radical spin adduct emerged after the reaction
mixture was irradiated by 3 W blue LED lamps after 2 min in
an ESR tube, which obviously strengthened in the following 14
min (g = 2.006, AN = 1.379 mT, AH = 1.588 mT, ANβ = 0.22
mT). The above results suggested that a nitrogen radical
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Eosin Y (1 mol
b
%), THF (2 mL), 3 W blue LEDs, air, rt, 12−24 h. Isolated yields
based on 1.
examined. Various N-protected aliphatic groups such as N-
methyl, N-ethyl, N-propyl, N-butyl, N-benzyl, N-2-oxo-2-
phenylethyl, N-esteryl, N-allylic, and N-propynyl groups were
all well tolerated in this reaction system to give the desired
products in good yields (3aa−3ia). Substrates including N-
aromatic groups were also suitable for this reaction, providing
the desired products 3ja and 3ka in good yields. Notably, N-
C
DOI: 10.1021/acs.orglett.8b03079
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Letter
is irradiated by blue LED light to produce the excited-state
Eosin Y*. Excited-state Eosin Y* obtains an electron from
amine 2 affording the Eosin Y•− radical anion and nitrogen
radical cation 4. Subsequently, the oxidation of Eosin Y•− by
•−
dioxygen (air) generates the ground state Eosin Y and O2
.
Then, the deprotonation of the nitrogen radical cation 4 by
•−
•
O2 gives the hydroperoxide radical species (HO2 ) and
nitrogen radical intermediate 5. Next, the addition of nitrogen
radical 5 to quinoxalin-2(1H)-one 1 affords intermediate 6,
•
which is further oxidized by O2 or HO2 to form the nitrogen
Figure 1. ESR spectra of the DMPO-radical adduct.
cation intermediate 7 through an SET process. Finally,
deprotonation of intermediate 7 regenerates the aromatic
ring and produces the desired product 3.
should be generated from the present reaction system (Figure
1, red line).
In summary, we have illustrated the first visible-light-
promoted direct C(sp2)−H/N−H CDC-amination with both
aliphatic primary and secondary amines in air. This reaction
smoothly proceeds at room temperature to construct a new
C−N bond via a radical process under metal- and strong
oxidant-free conditions. The present protocol provides a facile
and practical approach to access diverse 3-aminoquinoxalin-
2(1H)-ones in moderate to good yields, which is of great value
from both green chemistry and organic synthesis perspectives
due to its desirable features including a cheap catalyst, eco-
energy source, high atom economy, operation simplicity, scale-
up synthesis, and mild conditions. Taken together, our findings
are expected to spur more interest in developing new
photocatalytic CDC-aminations with aliphatic amines.
Moreover, when the reaction was carried out under N2, only
a trace amount of product was detected. This result indicates
that dioxygen is essential for the present transformation
(Scheme 3c). In addition, on/off visible-light irradiation
experiments were conducted to prove the effect of photo-
irradiation, and the result demonstrates that the continuous
irradiation of visible light is necessary for this amination
reaction (Figure 2).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03079.
Experimental details and compound characterization
(PDF)
Figure 2. Visible-light irradiation on/off experiment.
AUTHOR INFORMATION
Corresponding Authors
■
The synthetic applicability of this photocatalytic protocol
was further investigated on a gram scale under the optimized
reaction conditions. The model reaction could produce the
corresponding product 3aa in 78% yield (1.15g) without
obvious loss of its catalytic efficiency, suggesting this procedure
could serve as a practical and efficient method to construct 3-
aminoquinoxalin-2(1H)-ones.
*E-mail: weiweiqfnu@163.com.
*E-mail: xhzhao@nwipb.cas.cn.
ORCID
Wei Wei: 0000-0002-0015-7636
Daoshan Yang: 0000-0002-3047-5416
Xiaobo Yang: 0000-0003-0684-8419
On the basis of these results and relevant reports,4−8,21,22
a
possible mechanism is proposed in Scheme 4. Initially, Eosin Y
Notes
The authors declare no competing financial interest.
Scheme 4. Possible Reaction Pathway
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation
of Shandong Province (ZR2018MB009 and ZR2016JL012),
the International Cooperation Project of Qinghai Province
(2018-HZ-806; 2017-HZ-806), Qinghai Key Laboratory of
Tibetan Medicine Research (2017-ZJ-Y11), and the National
Natural Science Foundation of China (Nos. 21302109,
21302110, and 21402126).
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