Convergent Domino Cyclization: Oxidative [3+1+1] Annulation for One-Pot Synthesis of 2-Quinoline-4,5-diaryl-oxazoles from Methyl Azaarenes, Benzoins and NH4OAc

Article abstract of DOI:10.1002/ejoc.202001561

An oxidative [3+1+1] convergent domino cyclization is disclosed. This protocol enables to get quinoline, quinoxaline, quinazolin-4(3H)-one and benzo[d]thiazole attached 2,4,5-trisubstituted oxazoles from methyl azaarenes, benzoins, and NH₄OAc i

Full text of DOI:10.1002/ejoc.202001561

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Convergent Domino Cyclization: Oxidative [3+1+1] Annulation for
One-pot Synthesis of 2-Quinoline-4,5-diaryl-oxazoles from Methyl
Azaarenes, Benzoins and NH4OAc
Authors: Yan-Ping Zhu, Fei-Fei Liang, Kai-Xuan Liu, Cong Zhao, Zhi-
Hao Shang, Hong-Mei Kong, Ya-Qing Yin, Yuan-Yuan Sun,
and Jian-Wen Yao
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001561
Link to VoR: https://doi.org/10.1002/ejoc.202001561
01/2020

10.1002/ejoc.202001561
European Journal of Organic Chemistry
COMMUNICATION
Convergent Domino Cyclization: Oxidative [3+1+1] Annulation
for One-pot Synthesis of 2-Quinoline-4,5-diaryl-oxazoles from
Methyl Azaarenes, Benzoins and NH4OAc
Fei-Fei Liang,+a Kai-Xuan Liu,+a Cong Zhao,+a Zhi-Hao Shang,a Hong-Mei Kong,a Ya-Qing Yin,a Yan-
Ping Zhu*a, Yuan-Yuan Sun*a and Jian-Wen Yao*a
[a] F.-F Liang, K.-X. Liu, C. Zhao, Z.-H, Shang, H.-M. Kong, Y.-Q. Yin, Prof. Y.-P. Zhu, Y.-Y. Sun, Prof. J.-W. Yao
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced
Drug Delivery System and Biotech Drugs in Universities of Shandong,
Yantai University, Shandong, Yantai 264005, P. R. China.
E-mail: chemzyp@foxmail.com; 252825190@qq.com; jwy5610201@vip.sina.com
Homepage：https://www.x-mol.com/groups/Zhu_Yanping
+ These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document. CCDC 2039086 ((Please delete this text if not appropriate))
Abstract: An oxidative [3+1+1] convergent domino cyclization is
disclosed. This protocol enables to get quinoline, quinoxaline,
quinazolin-4(3H)-one and benzo[d]thiazole attached 2,4,5-
trisubstituted oxazoles from methyl azaarenes, benzoins and
NH4OAc in the presence of iodine and molecular sieves without any
metal catalyst. The reaction features wide substrate scope, good
functional group tolerance, mild reaction conditions, and easily
available substrates.
Oxazoles derivatives are prevailing five-membered heterocyclic
compounds, which have been found as key structural units in a
great number of biologically active natural products,
pharmaceuticals, agrochemicals and as functional materials.[1] In
particular, 2,4,5-trisubstituted oxazole as privileged scaffold is
widely presented in many natural products, drugs, and
Figure 2. The protocols for substituted oxazoles synthesis.
remarkably bioactive molecules, such as non-steroidal anti-
Recently, some practical annulation reactions have been
inflammatory drug ditazo, anti-diabetic agent aleglitazar,
developed for the synthesis of oxazoles from commercial
antipancreatic cancer agent PC-046 and antimycobacterial
starting materials (Figure 2). For example, oxidative cyclization
natural product texaline (Figure 1).[2]
of amines or azides with alkenes, alkynes, ethyl acetoacetate,
aldehydes and isothiocyanates were reported by the groups of
Jiang, Wang, Jiao, and Pan et.al.[4] The groups of Wu, Liu and
Guo reported a serials of elegant cascade cyclization reactions
to afford oxazoles from simple aromatic ketones, thiocyanate
salts, α-methylenyl isocyanides and (NH4)2S2O8/DMSO.[5] The
annulation reactions of nitriles with alcohols, α-hydroxyl ketones,
alkynes, electronic-rich heteroarenes, arylglyoxal monohydrates
and various C-nucleophiles was also fully demonstrated.[6] The
metal catalyzed annulation of amides with ketones or alkynes
was also an efficient method.[7] Visible-light catalyzed
approaches were achieved through the cyclization of 2H-azirines
Figure 1. Oxazole contained important molecules.
with aldehydes or alkynyl bromides, α-bromoketones with
benzylamines.[8] Copper catalyzed three-component domino
Given the important biological and pharmaceutical activities of
oxazoles, many synthetic strategies have been developed for
the synthesis of functionalized oxazole skeletons, such as metal-
catalyzed transformations, condensations, cyclization of α-
acylamino ketones precursors, oxidation of oxazolines,
transition-metal-catalyzed addition of diazo compounds to
nitriles, rearrangements and Robinson−Gabriel type reaction.[3]
cyclization of oxime, arylthiol, and trifluoroacetic anhydride was
demonstrated for the synthesis of trifluoromethyl attached
oxazoles.[9] The intramolecular cyclization of 2H-azirines,
enaminones and N-propargylamides was also efficient
approach.[10]
Although the synthesis of substituted oxazole has received
much interest, oxazole attached with quinoline, quinoxaline,
quinazolin-4(3H)-one and benzo[d]thiazole at 2-position is rarely
seen, because of the difficulty in introducing these heterocycles
at the 2-position of oxazoles. Only very limited methods were
available to get 2-position isoquinolin or 2-triazole attached
oxazoles.[11] More importantly, quinoline, quinoxaline, quinazolin-
1
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10.1002/ejoc.202001561
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Optimization studies for the preparation of 3aa[a]
4(3H)-one and benzo[d]thiazolyl substituted oxozoles are new
types of heterocyclic compounds, which had not been reported
yet.
Convergent domino cyclization is
a powerful synthetic
strategy for quick and efficient construction of important
compounds.[12] It enables two or more domino processes
sequentially assembled in one-pot, improves steps economy
and simplifies operational process. Herein, we would like to
report a convergent domino annulation for the synthesis of
I2
1a:2a
Ammonium
(2.0 equiv)
T/ oC
Yield
(%) [b]
entry
(equiv)
1
2
2.5
2.0
1.5
3.0
4.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1:2
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4Cl
120
120
120
120
120
120
120
120
110
100
130
140
120
120
120
120
120
120
120
120
43
30
quinoline,
quinoxaline,
quinazolin-4(3H)-one
and
benzo[d]thiazole attached 2,4,5-trisubstituted oxazoles from
common and readily available benzoin derivatives, methyl
azaarenes and NH4OAc under mild conditions (schemes 1).
Firstly, 2-methyl quinoline undergoes tandem iodination and
oxidation to form 2-(iodomethyl)quinoline and quinoline-2-
carbaldehyde via direct oxidative functionalization of sp3 C–H
bonds.[13] At the same time, benzoin undergoes condensation
with NH4OAc and isomerization to generate α-amino ketone and
isomer. Finally, quinoline-2-carbaldehyde and α-amino ketone
undergoes convergent annulation to give 2-quinoline-4,5-
diphenyl-oxazole.
3
32
4
38
5
29
6
16
7
(NH4)2SO4
HCO2NH4
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
32
8
36
9
30
10
11
12
13
14
15
16
17
18
19
20
34
17
14
29
Scheme 1. The protocol for 2-quinoline-4,5-diphenyl-oxazole synthesis
2:1
39
3:1
56
4:1
70
With the idea in mind, we initially optimized the reaction
conditions using benzoin (1a) and 2-methylquinoline (2a) as the
model substrates (Table 1). As shown in entry 1, the reaction
could give the product 3aa in 43% yield under the condition of
iodine (2.5 equiv), NH4OAc (2.0 equiv) at 120 oC in DMSO for 12
h. Next, the dose of iodine was optimized. Increasing or
decreasing the amount of iodine could not improve the yield
(Table 1, entry 2-5). Various ammonium salts, such as NH4Cl,
(NH4)2SO4 and HCO2NH4, were also screened in the presence of
iodine in DMSO at 120 oC. The desired product could be
obtained in only low yield (Table 1, entry 6-8). The effect of
reaction temperature on the yield was subsequently examined;
thus indicating that 120 oC was the optimal temperature (Table 1,
entries 9–12). The mole ratios of benzoin (1a) /2-methylquinoline
(2a) were screened from 1 : 2 to 6 : 1. Notably, the yield was
significantly increased with the more amount of benzoin 1a was
used (Table 1, entry 13-18). The best result was obtained when
the ratio of 1a and 2a is 5/1 (Table 1, entry 17). The further
increase in the ratio of 1a and 2a did not give a better result, and
the excess benzoin (1a) led to the lower yield of 3aa (Table 1,
entry 18). Interestingly, upon addition of molecular sieve, the
yield was significantly increased (Table 1, entry 19 and 20).
Finally, optimal conditions were identified, that is 2-
methylquinoline 2a (1.0 equiv), benzoin 1a (5.0 equiv),
ammonium acetate (2.0 equiv), and iodine (2.5 equiv) and
molecular sieves (4 Å, 200 mg) in DMSO (3 mL) at 120 oC
(Table 1, entry 20).
5:1
74
6:1
62
5:1
80 [c],[d]
87 [c],[e],[f]
5:1
[a] Reaction conditions: benzoin 1a, 2-methyl quinoline 2a (0.3 mmol), I2 and
Ammonium were heated in DMSO (3 mL). [b] Isolated yields. [c] 200 mg of 4 Å
molecular sieves was added. [d] Benzil was obtained in 81% yield. [e] 2a (0.3
mmol) and I2 in DMSO (3 mL) at 120 oC for 4 h, then added benzoin 1a,
NH4OAc and 4 Å molecular sieves and stirred at 120 oC for another 2-3 h. [f]
Benzil was obtained in 70% yield, which can be recycled by NaBH4 to benzoin
in quantitative yield.
With the optimal reaction conditions in hand, the reaction
scope was subsequently explored. We examined the steric and
electronic effects of the substituents adjacent to the methyl
quinoline 2 using benzoin (1a) as the model substrate (Scheme
2). First of all, 2-methyl quinolines attached with electron
donating groups (6-Me, 6-OMe, 6-OEt, 8-OMe, 4-Ph) were
tolerant for this reaction to afford the corresponding products
(3ab-3af). The structure of 3ac was further confirmed by X-ray
crystallographic analysis. 3-Methylbenzo[f]quinoline was also
suitable for the reaction to give the product 3ag in 63% yield. 2-
Methyl quinolines attached with halogen atoms (6-F, 6-Cl, 7-Cl,
6-Br) were also investigated, the corresponding products were
generated in moderate to good yields (3ah-3ak). It was worth
noting that the strongly electron-deficient substrates 2l and 2m
2
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10.1002/ejoc.202001561
European Journal of Organic Chemistry
COMMUNICATION
(with 6-methyl ester and 6-ethyl ester, respectively) could be
applied to this protocol, giving the corresponding products in
moderate yields (3al and 3am). These results showed that 2-
methyl quinolines bearing electron-donating groups could give
high yields than those bearing halogen atoms or electron-
deficient groups substrates. Intriguingly, 4-methyl quinoline and
substituted 4-methylquinoline were similarly found to be suitable
substrates for the transformation and giving the desired products
in good to excellent yields. For example, 4-methylquinoline
bearing electron-donating substituents on the aryl ring (e.g. 6-
Me, 6-Et, 6,7-Me2, 6-OMe, 7-OMe, 2-Ph-6-Me, 2-Ph-6-OMe)
were all successfully cyclization into the desired compounds
3ao-3au in 72%-83% yields. Molecules containing halogen atom
substituents on the aryl ring (e.g. 6-Cl, 2-Ph-6-Cl) were all
smoothly cyclization to the corresponding products 3av-3aw with
good yields. Moreover, three heteroatoms containing substrates
2-methylquinoxaline 2x, 2-methylquinazolin-4(3H)-one 2y and 2-
methylbenzothiazole 2z were also tolerant to react with benzoin,
generating the desired products 3ax-3az in moderate yields.
We next examined the scope of this reaction for benzoin
derivatives 1 (Scheme 3). We firstly studied the benzoin in which
on the phenyl ring had electron-rich substituents (e.g. 4,4’-(Me)2,
4,4’-(OMe)2), and the annulation reactions proceeded smoothly
to deliver products 3ba-3ca in 67-72% yields. Moreover, the
phenyl ring of benzoin bearing halogen atoms (e.g. 4,4’-diF, 4,4’-
diBr), the reactions could also afford the desired products (3da,
3di and 3ea) in good yields. In addition, it was worth noting that
2-hydroxy-1,2-di(thiophen-2-yl)ethan-1-one 1f was also tolerant
in this reaction with 2-methylquinoline and 4-methylquinoline to
generate expected products 3fa and 3fn in moderate yields.
However, furanyl and pyridyl contained substrates 1g and 1h
could not perform the reaction. Moreover, aliphatic 3-
hydroxybutan-2-one 1i also suitable for the reaction to give
desired product 3ia in 30% yield. When 2-hydroxyacetophenone
1j was reacted with 2-methylquinoline 2a in this reaction,
product 3ja could be affored in 32% yield. In addition, 1-(4-
chlorophenyl)-2-hydroxypropan-1-one 1k was also tolerant
under the standard conditions to generate the expected products
3ka with a moderate yield.
However,
2-methylbenzo[d]oxazole
and
2-methyl-1H-
benzo[d]imidazole were not suitable for this reaction.
Furthermore, 4-methylpyridine were successfully cyclization into
the desired compounds 3az-2 in 42% yield. However, 2-
methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and
toluene were not suitable for this reaction.
Scheme 3. Scope of substituted benzoin derivatives and methylquinolines.
Reaction conditions: 2 (0.3 mmol), I2 (0.75 mmol) in DMSO (3 mL) at 120 oC
for 4-6 h, then added benzoin derivatives 1 (1.5 mmol), NH4OAc (0.6 mmol)
and 4 Å molecular sieves (200 mg) and stirred at 120 oC for another 2-3 h.
Isolated yields provided.
To obtain more information about the reaction mechanism,
some control experiments were conducted (Scheme 4). When
the standard reaction conducted for 60 mins, product 3aa was
obtained in 25% yield and quinoline-2-carbaldehyde 2ab could
be detected by MS (APCI). The two reactions, 2-
(iodomethyl)quinoline 2aa with benzoin 1a and quinoline-2-
carbaldehyde 2ab with benzoin 1a, could work smoothly under
standard conditions to generate product 3aa in 90% and 92%
yields, respectively. When without iodine in these reactions, the
yields were decreased. Benzoin 1a could be oxidized to benzyl
4a in high yield under standard conditions. However, the
reaction of benzyl 4a with 2-methylquinoline 1a could not react
to form product 3aa. This result indicated that benzyl 4a is not
the potential intermediate in this reaction. In order to confirm the
Scheme 2. Scope of substituted methyl quinolines and derivatives. Reaction
conditions: 2 (0.3 mmol), I2 (0.75 mmol) in DMSO (3 mL) at 120 oC for 4-6 h,
then added benzoin 1a (1.5 mmol), NH4OAc (0.6 mmol) and 4 Å molecular
sieves (200 mg) and stirred at 120 oC for another 2-3 h. Isolated yields
provided.
regioselectivity
of
this
reaction,
we
chose
2-
hydroxyacetophenone 1j and benzaldehyde as model substrates
to testify the result under standard conditions. The reaction
maybe has two potential pathways to form product 6a or 7a. In
path A, 2-hydroxyacetophenone 1j reacted with NH4OAc to form
3
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10.1002/ejoc.202001561
European Journal of Organic Chemistry
COMMUNICATION
intermediate 8 or 9, which would further cyclization with
benzaldehyde to generate 6a. In path B, intermadiate 10 or 11
were firstly generated, then condensated with benzaldehyde to
afford product 7a. Through comparison with authentic samples
6a and 7a, 7a could be isolated in 43% yield in reaction (f), 6a
was not observed. Further control experimental for 1j with 2a
under standard conditions was also condected (See SI). Thses
results disclosed that path B is the potential reaction process.
In summary, we have developed an oxidative [3+1+1]
convergent domino cyclization to prepare 2,4,5-trisubstituted
oxazoles in the presence of iodine and molecular sieves. This
process provides a new approach for one-pot synthesis of
quinoline,
quinoxaline,
quinazolin-4(3H)-one
and
benzo[d]thiazole attached 2,4,5-trisubstituted oxazoles without
any metal catalyst. It features wide substrate scope, good
functional group tolerance, mild reaction conditions, and easily
available substrates. Mechanism investigation uncovered that 2-
(iodomethyl)quinoline, quinoline-2-carbaldehyde and 2-imino-
1,2-diphenylethan-1-ol or isomer are the potential intermediates.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21702091), Science and Technology
Innovation Development Plan of Yantai (2020MSGY114) and
Yantai “Double Hundred Plan”. The authors also thank Talent
Induction Program for Youth Innovation Teams in Colleges and
Universities of Shandong Province. The Graduate Innovation
Foundation of Yantai University (YDZD2035) is gratefully
acknowledged (for Z.-H. Shang). The College Students
Innovation
and
Entrepreneurship
Training
Program
(S202011066007) are gratefully acknowledged (for K.-X., Liu).
Keywords: 2-Quinoline-4,5-diaryl-oxazole • Iodine • Methyl
azaarenes • Convergent domino cyclization
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Scheme 4. Control experiments.
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Scheme 5. A plausible reaction mechanism for the preparation of 2-quinoline-
4,5-diphenyl-oxazole.
4
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10.1002/ejoc.202001561
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
A metal-free oxidative [3+1+1] convergent domino annulation has been developed for the synthesis of 2,4,5-trisubstituted oxazoles.
Compared with existing methods, this method has the advantages of wide substrate scope, mild reaction conditions, and obtaining
raw materials.
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This article is protected by copyright. All rights reserved.