Copper-Catalyzed Oxidative Multicomponent Annulation Reaction for Direct Synthesis of Quinazolinones via an Imine-Protection Strategy

Article abstract of DOI:10.1021/acs.orglett.9b01608

Via an imine-protection strategy, we herein present an unprecedented copper-catalyzed oxidative multicomponent annulation reaction for direct synthesis of quinazolinones. The construction of various products is achieved via formation of three C-N and one

Full text of DOI:10.1021/acs.orglett.9b01608

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Oxidative Multicomponent Annulation Reaction
for Direct Synthesis of Quinazolinones via an Imine-Protection
Strategy
Yantang Liang,† Zhenda Tan,† Huanfeng Jiang,† Zhibo Zhu,*,‡ and Min Zhang*,†
†Key Lab of Functional Molecular Engineering of Guangdong Province and Guangdong Engineering Research Center for Green
Fine Chemicals, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, P. R.
China
‡Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 13# Shiliugang Road, Haizhu district,
Guangzhou 510315, China
S
* Supporting Information
ABSTRACT: Via an imine-protection strategy, we herein present an
unprecedented copper-catalyzed oxidative multicomponent annulation
reaction for direct synthesis of quinazolinones. The construction of
various products is achieved via formation of three C−N and one C−
C bonds in conjunction with the benzylic functionalization. The
merits of easily available feedstocks, naturally abundant catalyst, good
functional group and substrate compatibility, and release of H2O as the byproduct make the developed chemistry a practical way
to access quinazolinones.
uinazolinones constitute an important class of N-
protocols by employing the combinations of anthranilamides
with aryl bromide (method a),5a 2-haloanilines with trimethoxy-
methanes and amines (method b),5b,c and 1-bromo-2-
isocyanatobenzenes with nitro compounds (method c),5d
respectively; (2) palladium-catalyzed three-component cou-
pling of anthranilamides with isocyanides and arylboronic acids
(method d);6 (3) Ph3P−I2-mediated cyclization of anthranilic
esters with N-substituted amides (method e);7 (4) and the Cu-
catalyzed addition of 2-halobenzamide to nitriles followed by
SNAr reaction (method f).8 More recently, our group has
demonstrated a synthesis of ring-fused quinazolinones via direct
oxidative functionalization of cyclic amines with 2-amino-
arylmethanols.9
Despite the significant utility, all of the above transformations
are based on the utilization of 1,2-difunctional benzenes, such as
anthranilamides, 2-haloanilines, anthranilic esters, 2-halo-
isocyanatobenzenes, and 2-aminoarylmethanols. The key issue
is that the preparation of these reactants generally requires
multiple prefunctionalization steps.10 As a result, the application
of these protocols toward synthetic diversity is easily restricted.
From the viewpoint of step and atom-economic concerns, the
development of shortcuts enabling direct access to quinazoli-
nones from readily available feedstocks, preferably monofunc-
tional benzenes, would be highly desirable. However, to the best
of our knowledge, it has remained an unresolved goal.
Q heterocycles. To date, numerous relevant compounds
have been found to exhibit diverse biological and therapeutic
activities, such as antitubercular, antiproliferation, antivirus,
anticancer, antihypertension, antidepressant, antifungal, and
antiulcer.1 In addition, quinazolinones have been utilized as
useful building blocks2 for various synthetic purposes and the
development of functional materials.3 Consequently, the search
for efficient methods to access quinazolinones is of high
importance in the scientific community. Generally, the goal is
realized by the oxidative condensation of 2-aminobenzamides
with aldehydes or the equivalents.4 In addition, other
representative approaches are listed in Scheme 1: (1) via the
strategy of palladium-catalyzed carbonylation followed by
cyclization, the Beller and Wu groups have developed several
Scheme 1. Existed Syntheses of Quinazolinones
As our sustained effort toward the construction of functional
N-heterocycles,11 we have recently reported an aerobic copper-
catalyzed synthesis of benzimidazoles from diarylamines and
Received: May 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01608
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Letter
alkylamines via tandem triple C−H aminations, and benzimi-
dazolones from diarylamines and dialkylamines via tandem C−
H aminations11a and alkyl deconstructive carbofunctionaliza-
tion.11b However, the utilization of the most easily available
primary anilines 1 and alkylamines 2 in both cases generated the
azo compounds 1′ via dehydrogenative dimerization of 1,12 and
imines 2′ and aldehydes 2′′ via dehydrogenation and hydrolysis
of the alkylamines 2 (Scheme 2, eq 1).13 To avoid the formation
Scheme 3. Variation of Arylamine
Scheme 2. Newly Observed Synthetic Protocol
of these undesired products, we envisaged that an imine-
protection strategy with formaldehyde might offer a solution
(Scheme 2, eq 1), as the presence of formaldehyde in the aerobic
copper-catalyzed reaction of 1 and 2 initially forms the imine
intermediates via a condensation step, and the single-electron
oxidation (SEO) of the electron-rich amines 1 and 2 is therefore
suppressed.11 Interestingly, when we performed the reaction of
aniline 1a, benzylamine 2a, and formaldehyde in toluene at 100
°C for 18 h with a CuCl2/O2 system, we observed that, instead of
smoothly and furnished the desired 3-N-benzyl-4(3H)-
quinazolinones in reasonable to good yields upon isolation
(Scheme 3, 3a−3i). Various functional groups on the aryl ring of
anilines 1 are well tolerated, and their electronic properties
significantly influenced the product formation. Especially,
anilines 1 containing electron-rich groups afforded the products
(3b−3e) in higher yields than those having an electron-
withdrawing group (3f−3g), presumably because the electron-
rich anilines enhance the nucleophilicity of the reaction
intermediates, thus favoring the cyclization process. Such a
hypothesis is further supported by the fact that anilines
containing a strong electron-withdrawing group (i.e., −CF3,
−CO2Et, and −NO2) were unable to afford the desired
products. Gratifyingly, ring-fused arylamines, such as 5-amino-
quinoline 1h and 1-naphthylamine 1i, could be transformed into
the extended π-conjugated products 3h and 3i in acceptable
yields. As expected, two regioisomers (3j, 3j′) in a combined
yield of 64% were detected when meta-substituted aniline 1k
was employed as a substrate, and compound 3j from the
cyclization occurring at the sterically less-hindered site
constitutes the major product. The reactions of two anilines
(1b, 1d, and 1j) with HCHO also underwent efficient
cyclization, affording the 3-N-aryl quinazolinones in moderate
to good yields (3k−3m). Noteworthy, a small amount of 3-N-
aryl quinazolinones were also detected when the reactions
employed anilines and alkylamines as the coupling partners; the
highly selective generation of 3-N-alkyl quinazolinones (3a−3j)
is assigned to the better reactivity of alkylamines than the
anilines.
anticipated benzimidazoles11a or benzimidazolones,11b
a
quinazolinone 3a was detected in 15% yield (Scheme 2, eq 2).
Based on this finding, we wish herein to report, for the first time,
a copper catalyzed oxidative three-component annulation
reaction for direct synthesis of quinazolinones from easily
available anilines, alkylamines, and HCHO.
To formulate a more efficient reaction system, we chose the
synthesis of product 3a from aniline 1a, benzylamine 2a, and
HCHO as a model system to evaluate different reaction
parameters (Table S1 in the SI). Initially, we tested several
HCHO equivalents by performing the reaction at 100 °C for 18
h, including paraformaldehyde, methanol, DMSO, and DMF.14
However, all of them failed to give the desired product 3a
(entries 1−4, Table S1). Then, the screening of various copper
catalysts and solvents showed that the combination of
Cu(OTf)2 and DMSO exhibited the best performance (Table
1, entries 5−10). By using Cu(OTf)2 and DMSO as the
preferred catalyst and solvent, respectively, the increase of
reaction temperature to 120 °C is sufficient to improve the yield
to 58% (entries 11 and 12). Further, the presence of acid
additives has little influence on the product yields (entry 13),
whereas the bases significantly diminished the yields (entry 14).
Interestingly, additional oxidant evaluation (entries 15−17) led
us to find that the introduction of 30 mol % of di-tert-butyl
peroxide (DTBP) could further improve the yield to 72%.
However, the use of excess DTBP under O2-free conditions
failed to generate product 3a (entry 18). Thus, the optimal
conditions are as shown in entry 15 of Table S1 (standard
conditions).
Subsequently, we turned our attention to the variation of
primary alkylamines 2. As illustrated in Scheme 4, all the
reactions underwent smooth dehydrogenative cyclization,
affording the 3-alkyl-4(3H)-quinazolinones in moderate to
good isolated yields. Similar to the results described in Scheme
3, various functional groups (−Me, −OMe, −Br, and −Cl) on
amines (2b−2h, 2n−2o) were compatible with the trans-
formation (3m−3s, 3z−3aa). Benzylamines 2 containing an
With the optimal reactions in hand, we then examined the
generality and the limitation of the synthetic protocol.
Benzylamine 2a was further employed to couple with various
anilines (1a−1i, 1k for their structures, see Scheme S1 in SI) and
HCHO. As shown in Scheme 3, all the reactions proceeded
B
DOI: 10.1021/acs.orglett.9b01608
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Letter
maximum yield in 0.5 h and then gradually converted into
quinazolinone 3m in 6 h. The results indicate that both 1d′ and
3m′ are the key reaction intermediates. A similar time−yield
profile was observed by monitoring the coupling of o-toluidine
1d, benzylamine 2a, and HCHO (see SI, Figure S1b).
Scheme 4. Variation of Alkylamines
In consideration that a small portion of N-methylated
products (1a′ and 2a′, Scheme 5) and the formamides (1a′′
Scheme 5. Control Experiments
electron-donating group afforded the corresponding products in
relatively higher yields (3m−3o) than those bearing an electron-
withdrawing group (3p−3r). However, due to the relatively
easier decomposition of the 4-bromobenzyl amine (2e) and 4-
methoxybenzylamine (2n), they generated the corresponding
products (3q and 3z) in lower yields than the products (3s and
3aa) arising from 2- and 4-chlorobenzylamines (2g and 2o).
Further, primary aliphatic amines, such as 3-methoxypropyl-
amine (2i), neopentylamine (2j), α-methylbenzylamine (2k),
phenethylamine (2l), and aminomethylcyclopropane (2m),
were effectively transformed in combination with aniline 1a and
HCHO into the 3-N-alkyl-4(3H)-quinazolinones in moderate
yields (3u−3y).
To gain mechanistic insights into the reaction, a time−yield
profile of the coupling of o-toluidine 1d and HCHO utilizing the
optimal conditions was depicted in Figure 1. The substrates
were rapidly consumed to form imine 1d′ within 15 min.
Meanwhile, dihydroquinazoline 3m′ was accumulated to a
and 2a′′, Scheme 5) were observed in the model reaction, we
therefore tested the reactions of these four compounds with the
other two coupling partners, respectively (Scheme 5, eqs 3−5).
The results showed that, except for N-methylaniline 1a′,
compounds 1a′′, 2a′, and 2a′′ failed to give product 3a. The
phenomenon is rationalized as the oxidation of 1a′ can easily
form the imine,13 a key reaction intermediate proposed in
Scheme 2. Further, the addition of excess TEMPO in the model
reaction significantly suppressed the product formation (eq 6),
implying that the reaction involves a radical process. 2-
Cyclopropylaniline 1l as a radical probe was utilized to react
with HCHO and amine 2a, which produced compound 3ab in
60% yield with retention of the cyclopropyl unit (eq 7). The
results indicate that, due to the formation of imine
intermediates, the presence of HCHO prevents the single-
electron oxidation of amines 1m and 2a. Thus, the radicals
should generate after the cyclization process. Finally, the
addition of excess H2O18 in the model reaction did not produce
even a trace of O18-labeling product (3a-O18), suggesting that
the benzylic O atom arises from the oxidants, instead of H2O (eq
8).
Based on the above findings, two plausible reaction pathways
are depicted in Scheme 6. In path a, the presence of HCHO
condenses with both amines 1 and 2 to form imines 1′ and 2′.
Then, the [4 + 2] cycloaddition15 between 1′ and 2′ followed by
isomerization would result in aminal C. Alternatively, the
addition of alkylamine 2 to imine 1′ followed by a condensation
of aminal A with HCHO would yield iminium B, and the
subsequent intramolecular Friedel−Crafts-type11c,d aminoalky-
lation at the ortho-site of the aryl ring in B also rationalizes the
formation of aminal C. Further, the single-electron oxidation-
induced dehydrogenation11a,b,16 of C under oxidative copper
catalysis generates the dihydroquinazoline D. Finally, the
Figure 1. Representative time course of the reaction.
C
DOI: 10.1021/acs.orglett.9b01608
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Letter
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product 3. Noteworthy, in consideration that the electron-rich
anilines are beneficial to the product formation (see Schemes 3
and 4), path b is believed to be a favorable pathway.
In summary, through an imine-protection strategy, we have
developed an unprecedented aerobic copper-catalyzed three-
component annulation reaction for direct synthesis of
quinazolinones. Being different from the existed approaches
utilizing bifunctional benzenes, the present protocol furnishes
the products from readily available anilines, primary amines, and
HCHO via the formation of three C−N and one C−C bonds in
conjunction with the benzylic functionalization. The significant
merits of good functional group and substrate compatibility,
release of H2O as the byproduct, and the use of the naturally
abundant catalyst makes the developed chemistry a valuable
approach in the construction of quinazolinones.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01608.
■
S
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Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: minzhang@scut.edu.cn.
*E-mail: zhuzb676@smu.edu.cn.
ORCID
Huanfeng Jiang: 0000-0002-4355-0294
Min Zhang: 0000-0002-7023-8781
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the National Key Research and Development
Program of China (2016YFA0602900), Science Foundation
for Distinguished Young Scholars of Guangdong Province
(2014A030306018), and Guangdong Province Science Foun-
dation (2017B090903003) for financial support.
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