Direct: Para -C-H heteroarylation of anilines with quinoxalinones by metal-free cross-dehydrogenative coupling under an aerobic atmosphere

Article abstract of DOI:10.1039/d1gc01899j

Herein, a green and efficient metal-free cross-dehydrogenative coupling (CDC) for the direct para-C-H heteroarylation of anilines with quinoxalinones has been described. This reaction is performed in H2O/DMSO (v/v = 2?:?1) using air as the sole oxidant. Various anilines (primary, secondary and tertiary amines) and quinoxalinones are well compatible, affording the corresponding products in moderate-to-good yields. Such a methodology provides an environmentally friendly and efficient alternative for the late-stage modification of nitrogen-containing compounds.

Full text of DOI:10.1039/d1gc01899j

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Direct para-C–H heteroarylation of anilines
with quinoxalinones by metal-free cross-
dehydrogenative coupling under an aerobic
atmosphere†
Cite this: Green Chem., 2021, 23,
6632
Jun Xu, Lin Huang, Lei He, Chenfeng Liang, Yani Ouyang, Jiabin Shen, Min Jiang and
Wanmei Li
*
Herein, a green and efficient metal-free cross-dehydrogenative coupling (CDC) for the direct para-C–H
heteroarylation of anilines with quinoxalinones has been described. This reaction is performed in H2O/
DMSO (v/v = 2 : 1) using air as the sole oxidant. Various anilines (primary, secondary and tertiary amines)
and quinoxalinones are well compatible, affording the corresponding products in moderate-to-good
yields. Such a methodology provides an environmentally friendly and efficient alternative for the late-
stage modification of nitrogen-containing compounds.
Received 29th May 2021,
Accepted 30th July 2021
DOI: 10.1039/d1gc01899j
rsc.li/greenchem
shorten procedures and is more atom- and step-economical.5
However, most of the methods still require metal catalysts,
Introduction
Anilines are significant structural moieties, which have a wide harmful oxidants and toxic solvents, causing environmental
range of applications in pharmaceuticals, natural products pollution and increasing the manufacturing expenses.6
and advanced materials.1 Therefore, the development of novel Therefore, it is more desirable to develop cross-dehydrogena-
methods for direct C–H functionalization of anilines has tive coupling (CDC) that can be conducted under green
received much attention.2 Among these transformations, con- conditions.
siderable effort has been devoted to the ortho-C–C cross-coup-
Quinoxalinones are important bioactive skeletons, which
ling of anilines.3 However, direct para-C–C cross-coupling of widely exist in natural products and pharmaceuticals (Fig. 1).7
anilines through C–H functionalization has been rarely The development of methodologies that introduce quinoxali-
reported.4 For example, Gaunt and coworkers reported a none skeletons into the organic molecules has received con-
copper-catalyzed para-C–C coupling of aniline using iodine(III)
compounds as the arylating reagent (Scheme 1a).4a Bertrand’s
group demonstrated a para-C–C coupling of N,N-dialkyl-
anilines with alkenes by gold catalysis (Scheme 1b).4c In 2017,
Frost et al. reported a directing group strategy for the para-
C–C coupling of anilines through ruthenium catalysis
(Scheme 1c).4d Despite their uses, the requirements of prefunc-
tionalized substrates, metal catalysts, auxiliary group, organic
ligands, additives and large amounts of toxic solvents are
pushing them far away from achieving green synthesis and
atom economy.
From the viewpoint of green and sustainable chemistry,
cross-dehydrogenative coupling (CDC) has become an ideal
tool for the construction of C–C bonds because this strategy
can avoid the prefunctionalization of starting materials,
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou 311121, China. E-mail: liwanmei@hznu.edu.cn
†Electronic supplementary information (ESI) available: Detailed experimental
procedures and analytical data. See DOI: 10.1039/d1gc01899j
Scheme 1 Direct para-C–C cross-coupling of anilines.
6632 | Green Chem., 2021, 23, 6632–6638
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siderable attention.8–14 Our research interest mainly focuses
on developing a green catalytic system for the modification of
nitrogen-containing molecules.15 Herein, we demonstrated a
metal-free cross-dehydrogenative coupling for direct para-C–H
heteroarylation of anilines with quinoxalinones under an
aerobic atmosphere (Scheme 1d). The utilization of H2O/
DMSO as the solvent and air as the sole oxidant makes the
methodology meet the requirements of green chemistry.
Results and discussion
The reaction conditions were first screened by evaluating the
solvent, additive, reaction temperature and time (Table 1 and
the ESI†). As shown in Table 1, the arylated product 3 was iso-
lated in 82% yield when the cross-dehydrogenative coupling of
quinoxalinone (1a) with aniline (2a) was performed in H2O/
DMSO (1.0 mL, v/v = 2 : 1) at 100 °C under an air atmosphere
for 12 h (Table 1, entry 1). The yield decreased when the
solvent was changed (Table 1, entries 2 and 3). Addition of 1.5
equivalents of Na2S2O8 into the reaction decreased the yield
slightly (Table 1, entry 4). Further investigation on reaction
temperature and time did not enhance the product yield
(Table 1, entries 5–8).
Fig. 1 Biologically active 3-arylquinoxalinones units.
Table 1 Screening of the reaction conditionsa,b
With the optimized reaction conditions in hand, the sub-
strate scope of anilines for the cross-dehydrogenative coupling
was then explored under the standard reaction conditions. As
demonstrated in Table 2, a wide range of different functional
groups at the ortho- or meta-position of N,N-bimethylanilines
were generally compatible, providing the corresponding pro-
ducts in moderate-to-good yields. N,N-Dimethylanilines
bearing electron-donating groups could be converted into the
corresponding products (4, 5 and 7) with higher yields than
those (6–8) with electron-withdrawing groups. The cross-dehy-
Entry
Variation from given conditions
Yield (%)
1
2
3
4
5
6
7
8
None
82
70
23
69
51
77
42
78
DMSO instead of H2O/DMSO
MeCN instead of H2O/DMSO
1.5 equivalents of Na2S2O8 were added
Reaction was performed at 80 °C
Reaction was performed at 120 °C
Reaction was performed for 8 h
Reaction was performed for 16 h
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), H2O/DMSO
(1.0 mL, v/v = 2 : 1), 100 °C, air, 12 h. b Isolated yields.
Table 2 Substrate scope of anilinesa,b
a Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), H2O/DMSO (1.0 mL, v/v = 2 : 1), 100 °C, air, 12 h. b Isolated yields.
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drogenative coupling of quinoxalinone (1a) with N,N-dimethyl-
naphthylamine could also give the corresponding product (9)
in 70% yield. Other tertiary amines, such as N,N-diethyl-
anilines, N,N-dipropylanilines, N,N-butylanilines, N,N-diphenyl-
anilines etc. could also undergo the reaction smoothly,
affording the corresponding products (10–18) in 70–84%
yields. It should be noted that the reactivity of substituent-free
N,N-bifunctionalized anilines was higher than that of ortho-
substituted ones probably due to the steric hindrance effect. In
addition, sensitive groups such as hydroxyl and cyano, which
could be further functionalized, were also well tolerated, pro-
ducing the corresponding products (19–22) in 70–74% yields.
Interestingly, primary and secondary amines could also react
with quinoxalinone smoothly to give the target products
(23–26) in 45–70% yields. However, it was obvious that their
Scheme 2 Gram-scale synthesis and application.
reactivity was poorer than tertiary amines probably because drawing substituents at the ortho-, meta-, or para-position of
alkyl groups can donate electrons to the nitrogen to make it the benzyl ring provided the arylated products (36–47) in
more electronegative. The greater electron density makes the 60–79% yields. The cross-dehydrogenative coupling of N,N-di-
amine easily to be oxidated to the key intermediate. In methylaniline (2a) with quinoxalinones that bear methyl,
addition, the σ–p hyperconjugation effect of alkyl groups may fluoro, chloro or bromo groups at the C5-, C6-, or C7-positions
also stabilize the intermediate. Regrettably, heterocyclic gave the target products (48–52) in 74–81% yields. Of note,
amines including 2-aminopyrimidine (2aa) and 2-aminopyri- N-free quinoxalinone (1aa) could not undergo the reaction to
dine (2ab) could not undergo the reaction to give the desired give the desirable product. To expand the substrate scope,
products. Other electron-rich arenes such as phenol (2ac) and some other heterocycles such as quinoline (1ab), isoquinoline
thiophenol (2ad) were used instead of aniline, however, no (1ac) and benzothiophene (1ad) were tested, however, such
corresponding products were obtained under standard con- substrates could not be converted into the corresponding pro-
ditions (see the ESI†).
ducts (see the ESI†).
Subsequently, the substrate scope of quinoxalinones for the
To show the efficiency and practicality of the cross-dehydro-
cross-dehydrogenative coupling was studied (Table 3). Initially, genative coupling, the gram-scale synthesis of product 3 was
the quinoxalinones with various N-substituted groups such as performed to provide the desired product (3) in 77% yield
ethyl, isoamyl, cyclopropylmethyl, keto and ester were tested (1.07 g) (Scheme 2a). Furthermore, the transformations of bio-
under standard conditions, delivering the corresponding pro- active molecules such as vanillylacetone and vinpocetine were
ducts (27–33) in 70–80% yields. It should be noted that quin- conducted to give the target products (53 and 54) in acceptable
oxalinones with sensitive groups, such as allyl and propargyl yields (Scheme 2b). The successful transformation demon-
could be transformed into arylated products (34 and 35) with strates that the present cross-dehydrogenative coupling reac-
good yields. A wide range of quinoxalinones with different tion is a green and straightforward strategy for the modifi-
N-benzyl groups bearing electron-donating or electron-with- cation of potentially bioactive molecules.
Table 3 Substrate scope of quinoxaline-2(1H)-onesa,b
a Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), H2O/DMSO (1.0 mL, v/v = 2 : 1), 100 °C, air, 12 h. b Isolated yields.
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To deeply understand the reaction mechanism, some
control experiments were then conducted. Initially, the reac-
tion was completely suppressed when 1.5 equivalents of 2,6-di-
tert-butyl-4-methylphenol (BHT) or 2,2,6,6-tetramethyl-1-piper-
idinyloxyl (TEMPO) were added respectively (Scheme 3a, entries
1 and 2). It should be noted that the adduct of BHT with inter-
mediate radical D was detected (Scheme 5). These results
demonstrate that a radical mechanism may be responsible for
this transformation. Secondly, addition of a singlet oxygen
Fig. 2 Determination of reactive species by electron spin resonance
(ESR) spectroscopy. (a) ESR spectra of carbon radicals and superoxide
radicals captured by DMPO; (b) ESR spectra of nitrogen radicals cap-
tured by DMPO.
quencher, 9,10-dimethylanthracene, only gave
a slightly
decreased yield of the product (Scheme 3a, entry 3), excluding
the energy transfer pathway. This conclusion was also con-
firmed by electron spin resonance (ESR) spectroscopy
(Fig. S3†). Thirdly, addition of benzoquinone into the trans-
formation dramatically reduced the yield (Scheme 3a, entry 4),
suggesting the existence of superoxide radical species, which investigate the regioselectivity of this reaction, 4-methyl-N,N-di-
was further confirmed by ESR experiments (Fig. 2a). Based on methylaniline (2ae) was employed to replace N,N-dimethyl-
the above experimental results, we further investigate the aniline (2a) as the substrate (Scheme 3d). Regrettably, there
effect of reaction atmosphere on the reaction (Scheme 3b). was no new product (58) generated. In this context, we believe
When the reactions were carried out under an air or O2 atmo- that the reaction cannot take place at the ortho or meta-posi-
sphere, respectively, 82% and 80% yields of product (3) were tion of anilines. The ESR experiments verified that both nitro-
obtained. However, there was no product generated under an gen radicals and carbon radicals were included in the reaction
N2 atmosphere. This result clearly shows the importance of O2 (Fig. 2). Further kinetic isotope analysis by employing inter-
for the cross-dehydrogenative coupling. In the meantime, if molecular competition and parallel reactions demonstrated
the cross-dehydrogenative coupling of quinoxalinone with that the para-Csp2–H bond cleavage process of N,N-dimethyl-
benzene was performed under standard conditions, the target anilines is not involved in the rate determining step
product (57) could not be detected, implying that the amino (Scheme 4).16
moiety plays a central role in the reaction (Scheme 3c). To
From the standpoint of resource reutilization and environ-
mental benignancy, the utilization of the reaction system
would be favorable with simple separation and reusing.
Therefore, the recyclability and reusability of the present
system was evaluated (Fig. S4†). After the completion of the
transformation, the H2O/DMSO was recycled through vacuum
distillation and was reused for the next cross-dehydrogenative
coupling. As shown in Fig. 3, comparable yields (on average
74.6%) were obtained throughout all of the reaction cycles. In
addition, the green chemistry metrics (atom economy,17
E-factor18 and eco-scale19) for the reaction were calculated (see
the ESI†). The present reaction scored a higher atom economy
(89.1%), a lower E-factor (0.6) and a higher eco-scale value
(65). These results strongly show that this transformation is an
environmentally friendly method for the late-stage modifi-
cation of nitrogen-containing compounds.
Based on the mechanistic investigations and previous
reports,9 a plausible mechanism for the cross-dehydrogenative
coupling is proposed (Scheme 5). Initially, a single electron
transfer (SET) process takes place between aniline and oxygen
to generate a nitrogen radical (A) with a superoxide radical
under heating conditions.20 Then, the tautomerism converts
the nitrogen radical (A) into a carbon radical (B), which is
further transformed into a carbon radical (C) via subsequent
deprotonation.21 After the generation of an intermediate (D)
via the radical addition of quinoxalinone (1a) with the carbon
radical (C), the target product is obtained through the succes-
sive single electron transfer (SET) and deprotonation
processes.
Scheme 3 Mechanistic studies.
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nones. This method features merits such as atom-economy,
wide substrate scope, green oxidant and solvent. Control
experiments demonstrate that a radical pathway is responsible
for the reaction.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the Natural Science Foundation of Zhejiang Province
(no. LY21B060009) for financial support.
Notes and references
Scheme 4 Kinetic isotope effect investigation.
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