Copper-Catalyzed Three-Component Cascade Reaction of Benzaldehyde with Benzylamine and Hydroxylamine or Aniline: Synthesis of 1,2,4-Oxadiazoles and Quinazolines

Article abstract of DOI:10.1002/adsc.202001535

The analogous three-component synthesis strategy for substituted 1,2,4-oxadiazole and quinazoline derivatives from readily available benzaldehyde, benzylamine and hydroxylamine or aniline has been developed. Both the cascade reaction sequences involves nucleophilic addition of C?N bond, introduction a halogen donor, nucleophilic substitution and Cu(II)-catalyzed aerobic oxidation. This synthesis methodology demonstrated good yields, broad substrate scope and oxygen as a green oxidant. Thus, this synthesis protocol provides strategies for the construction of substituted 1,2,4-oxadiazole and quinazolines from readily and simple starting materials. (Figure presented.).

Full text of DOI:10.1002/adsc.202001535

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DOI: 10.1002/adsc.202001535
Copper-Catalyzed Three-Component Cascade Reaction of
Benzaldehyde with Benzylamine and Hydroxylamine or Aniline:
Synthesis of 1,2,4-Oxadiazoles and Quinazolines
Chao Wang,+a Xiyan Rui,+a Dongjuan Si,a Rupeng Dai,a Yueyue Zhu,a
Hongmei Wen,a Wei Li,a,* and Jian Liua,*
a
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China
E-mail: liujian623@njucm.edu.cn; liwaii@126.com
+
Chao Wang and Xiyan Rui contributed equally.
Manuscript received: December 9, 2020; Revised manuscript received: March 2, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001535
Abstract: The analogous three-component synthesis strategy for substituted 1,2,4-oxadiazole and quinazoline
derivatives from readily available benzaldehyde, benzylamine and hydroxylamine or aniline has been
developed. Both the cascade reaction sequences involves nucleophilic addition of CÀ N bond, introduction a
halogen donor, nucleophilic substitution and Cu(II)-catalyzed aerobic oxidation. This synthesis methodology
demonstrated good yields, broad substrate scope and oxygen as a green oxidant. Thus, this synthesis protocol
provides strategies for the construction of substituted 1,2,4-oxadiazole and quinazolines from readily and
simple starting materials.
Keywords: 1,2,4-oxadiazole; quinazoline; three-component; aerobic oxidation
Introduction
The nitrogen heterocycles and oxygen heterocycles are
privileged scaffolds existed in numerous natural prod-
ucts and synthetic molecules which produce bioactivity
and pharmacological activity. Because of the wide
coverage of activities and unique properties, two
pharmacophores, named 1,2,4-oxadiazoles and quina-
zolines, have been attracting much attention.[1] The
substituted 1,2,4-oxadiazole derivatives exhibited anti-
inflammatory, anti-depressant and anti-cancer activ-
ities, etc (Figure 1a).[2] For example, Oxolamine was
described and introduced as a cough suppressant,
Figure 1. Example of useful 1,2,4-oxadiazole (a) and quinazo-
line (b) molecules.
recently Ataluren (PTC124) has been launched for
the therapy of Duchenne muscular dystrophy.[3] Be-
sides, quinazoline-based compounds also possess a
broad spectrum of pharmacological activities, includ-
ing anti-inflammatory, anti-microbial, anti-malarial,
Previous studies reported several methods to
anti-convulsant, antiviral and anti-cancer activities, etc synthesize 1,2,4-oxadiazole and quinazoline deriva-
(Figure 1b).[4] As well-known anticancer drugs Gefiti- tives. As for the 1,2,4-oxadiazole, the traditional
nib and Erlotinib, which contained unique quinazoline synthesis protocol contains two steps: 1) O-acylation
scaffolds, have been approved for the treatment of of an amidoxime, which can be easily prepared by the
non-small cell lung cancer (NSCLC).[5]
reaction of activated carboxylic acid derivatives such
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as acid chlorides, esters and anhydrides; 2) intra- functionalized anilines (2-carbonylaniline,[10a,b,c,d] 2-
molecular dehydration of the O-acyl amidoxime with aminobenzylamine[10e,f] or 2-aminobenzonitrile[10g,h]
)
bases (Scheme 1a).[6] Recently, the 5-amino-1,2,4- with benzaldehyde, benzylamine, benzoic acid or
oxadiazole products are obtained by the insertion of benzonitrile (Scheme 1b). Moreover, another feasible
cyano or isocyanide.[7] Additionally, some works method is the oxidative cyclization of arylamidines
focused on transforming substrates that contained with I2-mediated CÀ C bond, and the later one was
amidine/guanidinium group to 1,2,4-oxadiazole scaf- formatted from C(sp3)À H and C(sp2)À H bonds.[11]
fold by NBS/iodobenzene diacetate (IBD)-mediated Other reagents such as 2-ethynylanilines, 2-alkylami-
oxidative cyclization.[8] The latest synthesis strategy nobenzonitriles, aryl diazonium salts, N-sulfinylimines,
uses iron (III) nitrate to mediate the 1,3-dipolarization imines and amidines are identified as alternative
of alkynes and nitriles, the iron (III) nitrate plays dual substrates in the synthesis of various substituted
roles in the nitration of alkynes and the activation of quinazoline derivatives.[12] Recently, Xie reported a
nitriles.[9]
Cu/Ag-catalyzed annulation of 3-aryl-2H-azirines with
Meanwhile, the general synthesis procedure for anthranils to provide (quinazolin-2-yl)methanone
quinazoline is the condensing of different ortho- derivatives.[13] Although the strategy showed signifi-
cant advancements in terms of 1,2,4-oxadiazole and
quinazoline syntheses, most of these procedures had
drawbacks such as time-consuming, harsh reaction
conditions, special starting materials, multi-step proce-
dures, and expensive transition metal complexes,
ligands, additives, oxidants, which significantly hin-
dered their further application. Most importantly, there
is rarely a general synthesis strategy has been reported
for these two heterocyclic scaffolds under the similar
reaction conditions.
Multicomponent cascade reaction serves as one of
the most important synthetic strategies for the green
access to nitrogen heterocycles, which eliminates the
purification steps of intermediates and decreases the
discrete chemical steps, waste products and operation
costs.[14] Recently, the large amounts of oxidants such
as organohalide, PhI(OAc)2, benzoquinone and metal
salts (Ag or Cu) are utilized to construct nitrogen-
containing heterocycles through transition-metal-cata-
lyzed CÀ N bond formation and annulation.[15,16,17]
There is no doubt that these methods will suffer from
numerous limitations in organic synthesis due to their
high price, toxicity and unfriendly environmental
propoerties.[17,18] Molecular oxygen is an atom-econom-
ical, abundant, and environmental-friendly energy,[19]
nowadays some researchers report using copper-cata-
lyzed aerobic oxidation to construct oxygen, nitrogen,
and sulfur-incorporated heterocycles.[20] Meanwhile, in
2016 Arndtsen described that the selective aerobic
oxidation of amines to nitriles and imines through CuI-
or CuPF6-catalyzed in different solvents.[21] As our
investigation so far, the synthesis of 1,2,4-oxadiazole
and quinazoline from easily starting material benzyl-
amine, benzaldehyde, hydroxylamine or aniline, has
not yet been explored by using similar synthesis
strategy. Herein, we report a new strategy of analogous
three-component cascade reaction to yield 1,2,4-
oxadiazole and quinazoline scaffold, which possess [2
+2+1] annulation and [3+2+1] annulation via a
Cu(II)-catalyzed dehydrogenative cyclization (Sche-
Scheme 1. Synthetic strategies for 1,2,4-oxadiazole and quina-
zoline.
me 1c). This three-component cascade annulation can
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be developed as an access to 1,2,4-oxadiazoles and uct 4a can be obtained in 10% yield (entry 1) when
quinazolines.
toluene was used as the solvent. While other solvents
such as DMSO, THF, MeOH, isopropanol and HFIP,
didn’t change the reaction activities essentially (entries
2–8). Surprisingly, the isolated yield of target product
Result and Discussion
The benzaldehyde (1a), benzylamine (2a) and hydrox- 6a boosted up to 35% and 40%, respectively, once
ylamine (3a) are easy-access materials and all of them H2O and EtOH was used as the solvent, and the EtOH
are widely utilized as key synthons in nitrogen- is selected as the best solvent for the synthesis protocol
containing functional molecular synthesis. We initiate of 1,2,4-oxadiazole. Meanwhile, the halogen donor
our studies by evaluating the feasibility of the three- “X” is also incorporated in the reaction process. By
component cascade reaction of the benzaldehyde (1a), investigating the various halogen donor, the dibromo-
benzylamine (2a) and hydroxylamine (3a) for the hydantoin (DBH) is selected as the optimal halogen
1,2,4-oxadiazole synthesis in the presence of CuBr2- donor, and the yield of 4a was up to 65% (entries 9–
mediated aerobic oxidation (Table 1). The three- 11). The key step for cascade reaction is the Cu (II)-
component [2+2+1] cascade annulation of 1,2,4- mediated oxygen dehydrogenative coupling. Different
oxadiazole involves: nucleophilic addition of CÀ N copper salt including CuI, Cu(OAc)2 and different
bond, introduction of a halogen donor, nucleophilic ligands, for instance, pyridine, bipyridine and 1,10-
substitution and Cu(II)-catalyzed aerobic oxidation. phenanthroline (1,10-phen) are conducted to further
Therefore, the solvent plays a critical role in the three- improve the yield of the target product 4a (entries 12–
component cascade transformation. The desired prod- 15). As we expected, the yield of 4a is enhanced to
90% by using 1,10-phen as a ligand, whereas other
catalysts (CuI, Cu(OAc)2) are ineffective. Besides, the
reaction proceed difficu without oxygen, which in-
Table 1. Optimization of the synthesis of 1,2,4-oxadiazole
dicates the oxygen as an essential role in this reaction
4a.[a]
(entries 16, 17). We also explored the reaction time
and reaction temperature, and the optimal reaction time
°
was 8 hours and the reaction temperature was 80 C
(See the Supporting Information for details).
After we optimized the reaction conditions, the
Entry Catalyst Ligand
“X”
Solvent
Yield (%)[b]
scope and generality of this three-component [2+2+
1] cascade annulation was initiated observing various
substituted benzaldehyde derivatives (Scheme 2). In-
terestingly, the target product 4aa bearing o-methyl
could be obtained in a high yield (82%), and the
halogen functional groups involving fluorine and
chlorine were well tolerated to afford the correspond-
ing annulated products in moderate yields (4ac: 56%;
4ad: 61%). However, the o-NO2 precursor generated
the desired product 4ab in only poor yield of 26%. In
summary, as for the ortho-substituent, the reaction
efficiency was inhibited by the strong electron-with-
drawing substituent, on the contrary the reaction
activity was enhanced by the electron-rich groups. A
similar trend was also revealed for the meta-substituted
substrates reaction efficiencies, the electron-rich
groups (4ae: 76%) performed relatively better than the
electron-deficient groups (4af: 60%; 4ag: 67%; 4ah:
61%). Besides, the small electron-donating substituent
was beneficial to the transformation of 1,2,4-oxadia-
zole, as a result the yield of product 4ai bearing p-
methyl was promoted to 94%. Whereas the substrate
containing a tert-butyl substituent decreased in their
reaction efficiencies because of the steric hindrance
phenomena (4aj: 75%). Interestingly, other electron-
deficient groups involving phenyl, chlorine, fluorine
and cyano group were also tolerated for this trans-
formation, the yield of 4a was slightly decreased
1
2
3
4
5
6
7
8
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuI
pyridine NCS[c] toluene
pyridine NCS DMSO
pyridine NCS THF
pyridine NCS EtOH
pyridine NCS MeOH
pyridine NCS H2O
10
Trace
15
40
23
35
pyridine NCS isopropanol 17
pyridine NCS HFIP
Trace
9
pyridine NBS[d] EtOH
45
32
65
13
Trace
75
90
22
0
10
11
12
13
14
15
pyridine I2
EtOH
pyridine DBH[e] EtOH
pyridine DBH EtOH
Cu(OAc)2 pyridine DBH EtOH
CuBr2
CuBr2
bipyridine DBH EtOH
1,10-phen DBH EtOH
1,10-phen DBH EtOH
1,10-phen DBH EtOH
16[f] CuBr2
17[g] CuBr2
[a] Reaction conditions: benzaldehyde (1a, 0.5 mmol), benzyla-
mine (2a, 0.5 mmol), hydroxylamine (3 a, 0.5 mmol),
catalyst (10 mmol%), ligand (20 mmol%), Et3N (0.5 mmol),
°
“X” (0.5 mmol) and solvent (4.0 mL) were stirred at 80 C
under O2 for 8 h;
[b] Isolated yield;
[c] NCS=N-Chlorosuccinimide;
[d] NBS=N-bromosuccinimide;
[e] DBH=dibromohydantoin;
[f] The reaction was carried out under air atmosphere.
[g] The reaction was carried out under N2 atmosphere.
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Scheme 3. Substrate Scope of benzylamine.[a,b]
activity (4bg: 86%; 4bh: 83%). Interestingly, the steric
effect was also investigated while the substituents were
located at the ortho-position, especially the target
product 4aj was furnished in only 53% yield while the
2,6-dimethyl benzylamine was employed. Notably,
compared to the 3-F-benzylamine (4bf) and 4-F-
benzylamine substrate (4bi), the reaction efficiency
Scheme 2. Substrate Scope of benzaldehyde.[a,b]
(4ak: 88%; 4al: 80%; 4an: 69%; 4am: 75% vs 4a: was decreased while the substrate containing a 3,4-
90%). Furthermore, the corresponding yield of di- difluoro unit (4bk: 50%), and this may due to the fact
substituted, tri-substituted and pent-substituted sub- that the two fluorine atoms strongly reduced the
strates that were combined with various substituents electronic density of benzene ring. Similarly, other
were decreased (4ao: 78%; 4ap: 83%; 4aq: 67%; aryl-functionalized benzylamines involving pyridine
4ar: 54%; 4as: 60%; 4at: 50%), indicating that the ring were also incorporated into this transformation,
steric hindrance phenomena of plays a critical role to the yield of desired product 4bl and 4bm were 67%
influence the yield of 1,2,4-oxadiazole. Other aryl- and 74%, respectively. In conclusion, substituted
functionalized benzaldehydes were also undergoing the benzylamine derivatives exhibited the similar trend to
transformation easily, the yields of the corresponding the benzaldehyde substrates, that the small electron-
products were ranging from 51% to 82% (4au–4ax). donating group enhanced the reaction ability while the
In summary, the benzaldehyde substrates bearing small bulkier substituent was not tolerated for this trans-
electron-rich groups were favourable for the 1,2,4- formation.
oxadiazole preparation, but the bulkier substituents
were not suitable, thus the electron effect and steric material for the construction of the nitrogen-containing
hindrance both influenced the reaction efficiency. heterocycle, while the starting material hydroxylamine
The aniline was also utilized as an essential
Benzylamine 2a also contributed greatly to this 3 was replaced by the aniline 5 for the first step of
reaction, and the effects of different benzylamine C=N formation, the one-step synthesis of 1,2,4-
derivatives bearing various substituents were explored oxadiazole 4 was easily extended for the synthesis of
(Scheme 3). In general, mono-substituted benzylamine quinazoline 6 (Table 2). We initiated our studies by
derivatives, show better yield of target product with repeating the optimized reaction conditions for the
electron-donating groups such as methyl and methoxy 1,2,4-oxadiazole synthesis, and the desired quinazoline
than those with electron-withdrawing substituents such 6 could be obtained in 22% yield (entry 1). It is
as fluorine (4ba, 4bc vs 4bb; 4bd, 4be vs 4bf; 4bg, potential that the solvent may significantly affect the
4bh vs 4bi). Among these compounds, the substrates reaction efficiency, so we screened various solvent and
bearing p-Me and p-OMe exhibited the best reaction tried to enhanced reaction activity (entry 2–4). The
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Table 2. Optimization of the synthesis of quinazoline 6a.[a]
°
Entry
T ( C)
time (h)
Solvent
Yield (%)[b]
1
2
3
4
5
6
7
8
80
80
80
80
60
90
8
8
8
8
8
8
8
8
EtOH
H2O
22
10
35
56
37
61
67
58
47
63
76
83
82
0
DMSO
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
100
110
100
100
100
100
100
100
9
6
10
11
12
13
14[c]
10
12
14
16
14
[a] Reaction conditions: benzaldehyde (1a, 0.5 mmol), benzyla-
mine (2 a, 0.6 mmol), aniline (5 a, 0.5 mmol), CuBr2
(10 mmol%), 1,10-phen (20 mmol%), DBH (0.5 mmol),
°
Et3N (0.5 mmol) and solvent (4.0 mL) were stirred at T C
under O2 for time;
[b] Isolated yield.
Scheme 4. Synthesis of quinazoline derivatives.[a,b]
[c] The reaction was carried out under an air atmosphere or N2
atmosphere.
ent benzaldehyde analogues, the desired quinazoline
yield of product 6a could promote to 56% while the products 6aa–6af were obtained at yields ranging
toluene was used as the solvent. Encouraged by this from 44% to 86%. The substrate with electron-rich
result, lower product yield was observed at lower substituents reacted smoother than the substrate with
reaction temperature. On the contrary, enhancing the electron-deficient groups (6aa: 69%>6ad: 45%; 6ab:
temperature helped to improve the reaction efficiency, 69%>6ae: 51%; 6ac: 85%>6af: 60%). The sub-
and the optimal reaction temperature was found to be stituents at para-position exhibited better reaction
°
100 C which resulted in the yield of product 6a efficiency than those at ortho-position and meta-
increasing to 67% (entry 5–8). Interestingly, through position. Besides, the benzylamine analogues with the
the exploring of the cascade reaction time, a relative same substituent at different positions also exhibited
higher yield could attain to 84% when the reaction the similar trend that the substrate with electron-
time was extended to 14 h (entry 9–13). On the donating groups were more favourable for this trans-
contrary, the reaction activity was inhibited while the formation, and the substrate containing an electron-
reaction was carried out under an air or N2 environ- withdrawing substituent provided relatively lower yield
ment (entry 14). Through the inspecting of other for the desired product. Among these quinazoline
reaction conditions (Supporting Information), the derivatives 6ba–6bf, the reaction ability of meta-
optimal reaction conditions could be identified as substituted compounds was better than the correspond-
following: the catalyst was CuBr2, the ligand was 1,10- ing ortho- or para-substituted compounds regardless of
phen, the halogen-donor was DBH, the solvent was electron-withdrawing or electron-donating substituents.
°
toluene, the reaction temperature and time were 100 C However, as for the aniline derivatives, the trans-
and 14 h respectively. Most importantly, the oxygen formation could only be achieved by the compounds
environment was critical to this three-component involving electron-donating substituents such as meth-
cascade reaction.
yl (6ca: 44%; 6cb: 35%; 6cc: 30%), and it was very
The optimized reaction conditions were employed difficult for substrates containing electron-withdrawing
for the synthesis of other quinazoline derivatives 6 by groups involving fluorine or nitro to accomplish this
utilizing diverse libraries of benzaldehyde 1a, benzyl- transformation. In summary, the electron effect was
amine 2a and aniline 5a for this three-component [3+ critical to this [3+2+1] annulation, the electron-
2+1] annulation (Scheme 4). Generally, as for differ- donating substituents were well tolerated in the present
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reaction system, furnishing the corresponding products was also proceeded smoothly on a gram-scale, we
in good to moderate yields. However, while the could provide the target quinazoline 6a in 68% yield
substrate containing electron-withdrawing groups, the (1.72 g) on a 10 mmol scale. As a result, the yield for
three-component cascade reaction proceeded difficulty gram-scale was lower than obtained in the small-scale.
to afford the quinazoline product.
To provide insight into the mechanism of these
To further verify the synthetic utility of this reactions, several control experiments were designed
reaction, a gram-scale three-component [2+2+1] and performed. In the synthesis process of 1,2,4-
cascade annulation of 1,2,4-oxadiazole 4a was carried oxadiazole product 4a, regardless of the reaction route,
out under the standard reaction conditions (Scheme 5). the benzylamine or hydroxylamine mainly nucleophilic
To our delight, the desired 1,2,4-oxadiazole 4a was attack the halogen donor to yield the intermediate 7a
provided in 79% yield (1.75 g) while the reaction was which was identified as the precursor of 1,2,4-
performed on a 10 mmol scale. Similarly, this three- oxadiazole heterocycles 4a. When the reaction was
component [3+2+1] annulation of quinazoline 6a performed in the absence of CuBr2 and 1,10-phen
(Scheme 6a), the intermediate 7a was furnished in
92% yield through the condensation and substitution of
benzaldehyde 1a, benzylamine 2a and hydroxylamine
3a. The product 1,2,4-oxadiazole was generated by
eliminating two molecules of hydrogen via copper-
mediated O2 dehydrogenative coupling from the inter-
mediate 7a. Similarly, the cascade annulation to obtain
quinazoline 6a revealed the analogous reaction proc-
ess, the yield of intermediate 8a was 87% in the
absence of CuBr2 and 1,10-phen (Scheme 6b). How-
ever, the reaction ceased at the stage of nucleophilic
substitution of methylbenzylamine owing to the failure
of Cu(II)-catalyzed aerobic dehydrogenative cycliza-
tion when replacing the benzylamine by meth-
ylbenzylamine under standard reaction conditions
(Scheme 6c), and the corresponding product 9a was
Scheme 5. Further Studies of the Reaction.
obtained in 83% yield. Furthermore, the isolated
intermediate 7a and 8a were processed an elimination
reaction through Cu(II)-catalyzed aerobic dehydrogen-
ative annulation (Scheme 6d and 6e), the yield of the
corresponding 1,2,4-oxadiazole product 4a and quina-
zoline 6a were 97% and 85%, respectively. In
addition, butylated hydroxytoluene (BHT, 2.0 equiv.)
as radical scavengers was added into the reaction
system under the standard conditions. As a result, 10a
was determined by HRMS, indicating that the reaction
proceeded via a radical pathway (Scheme 6f).
According to the results of these experiments, and
refer to some related studies that have been reported,[22]
a plausible mechanism was proposed for the present
three-component [2+2+1] cascade annulation of
1,2,4-oxadiazole 4a synthesis (Scheme 7). The critical
precursor of cyclization 7a was obtained through
nucleophilic addition and nucleophilic substitution
regardless Path A or Path B. Presumably, the 1,10-
phen was identified as a ligand and coordinated with
CuBr2 to provide a five-membered copper metallacycle
A. Subsequently, the aerobic oxidation was proceeded
by depriving the hydrogen radicals from the 7a to
generate the radical intermediate B, which initially
undergo a process of oxidating of Cu(II)-complex A
through oxygen. Then proton was removed via base-
mediated intramolecular elimination to afford the
Scheme 6. Control Experiments.
electron-rich C=N intermediate C. Through the Cu-
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Experimental Section
General Procedure for the Synthesis of Oxadiazole
(4a)
Benzaldehyde
1
(0.5 mmol, 1.0 equiv.), benzylamine
2
(0.5 mmol, 1.0 equiv.), hydroxylamine 3 (0.5 mmol, 1.0 equiv.),
CuBr2 (10 mmol%), 1,10-phenanthroline (20 mmol%), DBH
(0.5 mmol, 1.0 equiv.), Et3N (0.5 mmol, 1.0 equiv.) were added
°
into the EtOH (4 mL), the mixture was stirred at 80 C under O2
for 8 h. Then the mixture was cooled to room temperature, and
the reaction mixture was diluted with water, extracted with
ethyl acetate (10 mL*3). The organic solvent was washed with
brine, dried by anhydrous Na2SO4 and concentrated to give the
crude product. The crude product was purified by flash column
chromatography on silica gel (PE/EA=100:1).
General Procedure for the Synthesis of Quinazoline
(6a)
Benzaldehyde
(0.5 mmol, 1.0 equiv.), aniline 5 (0.5 mmol, 1.0 equiv.), CuBr2
(10 mmol%), 1,10-phenanthroline (20 mmol%), DBH
1
(0.5 mmol, 1.0 equiv.), benzylamine
2
Scheme 7. Proposed Reaction Mechanism of 1,2,4-oxadiazole
Synthesis.
(0.5 mmol, 1.0 equiv.), and Et3N (0.5 mmol, 1.0 equiv.) were
°
added into the toluene (4 mL), the mixture was stirred at 100 C
under O2 for 14 h. Then the reaction mixture was cooled to
room temperature, and the mixture was diluted with water,
extracted with ethyl acetate (10 mL *3). The organic layer was
promoted electron transfer, the intermediate D was
obtained. Finally, the target 1,2,4-oxadiazole product
was yielded through the intramolecular addition and
elimination of intermediate D, the reoxidation of the
Cu(I)-complex to the Cu(II)-complex would be utilized
for the next catalytic cycle. Besides, the mechanism of
quinoline was similarly, which processed a [3+2+1]
annulation through Cu(II)-mediated aerobic oxidation.
washed with
a brine, dried by anhydrous Na2SO4 and
concentrated to give the crude product. The crude product was
purified by flash column chromatography on silica gel (PE/
EA=80:1)
Acknowledgements
We gratefully acknowledge the National Science Foundation of
China (No. 81573304, 81703342), Natural Science Foundation
of Jiangsu (No. BK20161050), Natural Science Foundation of
Nanjing University of Chinese Medicine (No. NZY81703342).
Conclusion
The 1,2,4-oxadiazole and quinazoline scaffold are two
critical nitrogen-containing heterocycles, however
there is no general synthesis strategy for these two
heterocyclic scaffolds under a similar reaction con-
dition. Herein, we first report analogous three-compo-
nent cascade synthesis strategy for substituted 1,2,4-
oxadiazole and quinazoline derivatives synthesis from
readily available benzaldehyde, benzylamine and hy-
droxylamine or aniline. Both of the reaction sequences
contain nucleophilic addition of CÀ N bond, introduce
a halogen donor, nucleophilic substitution and Cu(II)-
catalyzed aerobic oxidation. The building of 1,2,4-
oxadiazole and quinazoline possess [2+2+1] annula-
tion and [3+2+1] annulation via a Cu(II)-catalyzed
dehydrogenative cyclization respectively, which dem-
onstrated good yields, broad substrate scope and
oxygen as a green oxidant. This protocol provides
efficient approach to 1,2,4-oxadiazole and quinazoline
derivatives.
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Copper-Catalyzed Three-Component Cascade Reaction of
Benzaldehyde with Benzylamine and Hydroxylamine or
Aniline: Synthesis of 1,2,4-Oxadiazoles and Quinazolines
Adv. Synth. Catal. 2021, 363, 1–10
C. Wang, X. Rui, D. Si, R. Dai, Y. Zhu, H. Wen, W. Li*, J.
Liu*