Silver-Catalyzed Radical Cascade Cyclization toward 1,5-/1,3-Dicarbonyl Heterocycles: An Atom-/Step-Economical Strategy Leading to Chromenopyridines and Isoxazole-/Pyrazole-Containing Chroman-4-Ones

Article abstract of DOI:10.1021/acs.orglett.8b02627

A novel and convenient silver-catalyzed radical cascade cyclization toward a large variety of 1,5-/1,3-dicarbonyl heterocycles containing a chroman-4-one, indanone, or 2,3-dihydroquinolin-4(1H)-one moiety was developed, by reacting various 2-functionalized benzaldehydes, including 2-allyloxy benzaldehydes, 2-allyl benzaldehyde, and 2-N(Ts)CH₂-CH CH₂ substituted benzaldehyde, with 1,3-dicarbonyl compounds in the presence of AgNO₃/K₂S₂O₈ in one pot under mild reaction conditions. The newly obtained 1,5-/1,3-dicarbonyl-containing heterocycles were further used directly to synthesize more structurally diverse polyheterocycles, mainly including chromenopyridines as well as isoxazole- or pyrazole-containing chroman-4-ones.

Full text of DOI:10.1021/acs.orglett.8b02627

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silver-Catalyzed Radical Cascade Cyclization toward 1,5-/1,3-
Dicarbonyl Heterocycles: An Atom-/Step-Economical Strategy
Leading to Chromenopyridines and Isoxazole-/Pyrazole-Containing
Chroman-4-Ones
Hao Hu,† Xiaolan Chen,*,†,‡ Kai Sun,† Junchao Wang,† Yan Liu,† Hui Liu,† Lulu Fan,† Bing Yu,*,†
Yuanqiang Sun,† Lingbo Qu,† and Yufen Zhao†,‡
†Henan Joint International Research Laboratory of Green Construction of Functional Molecules and Their Bioanalytical
Applications. College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China
‡The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen 361005, China
S
* Supporting Information
ABSTRACT: A novel and convenient silver-catalyzed radical
cascade cyclization toward a large variety of 1,5-/1,3-
dicarbonyl heterocycles containing a chroman-4-one, inda-
none, or 2,3-dihydroquinolin-4(1H)-one moiety was devel-
oped, by reacting various 2-functionalized benzaldehydes,
including 2-allyloxy benzaldehydes, 2-allyl benzaldehyde, and
2-N(Ts)CH2−CHCH2 substituted benzaldehyde, with 1,3-
dicarbonyl compounds in the presence of AgNO3/K2S2O8 in
one pot under mild reaction conditions. The newly obtained
1,5-/1,3-dicarbonyl-containing heterocycles were further used
directly to synthesize more structurally diverse polyhetero-
cycles, mainly including chromenopyridines as well as isoxazole- or pyrazole-containing chroman-4-ones.
Chroman-4-one is a privileged structural motif found in
many natural and synthetic products that display a wide range
of biological activities such as antitumor, anti-HIV, antioxidant,
antibacterial, anticancer, antimicrobial, SIRT2 inhibitors, and
estrogenic properties.4 A number of synthetic methods have
been developed for the preparation of those scaffolds in the
past half century.5 Among them is the Stetter reaction, a
frequently used classical method for the preparation of 1,4-
dicarbonyl-containing chroman-4-ones,6 as demonstrated by
the first example developed by Ciganek in 1995 (Scheme 1a).
In the past 10 years, rapid development of radical cascade
reactions for the concise construction of diverse complexes and
usually polymolecular skeletons has been witnessed.7 The
distinguished merits of radical cascade reactions include high
atom and step economy, as well as great reduction of work and
time required to carry them out.8 In 2016, Li’s group
developed a straightforward synthesis toward phosphorylmeth-
yl-substituted chroman-4-ones via phosphoryl radical-initiated
cascade cyclization of 2-(allyloxy)arylaldehydes as shown in
Scheme 1b.9 In 2017, Wu’s group developed a synthesis
toward 1,4-dicarbonyl-containing chroman-4-ones via acyl
radical-initiated cascade cyclization reaction (Scheme 1c).10
It is especially worth emphasizing here that, by far, there is a
icarbonyl compounds are a kind of indispensable
Dbuilding block for the synthesis of many structurally
specific heterocycles. For example, 1,3-dicarbonyl compounds
are essential precursors for the synthesis of isoxazole and
pyrazole. 1,4-Dicarbonyl compounds are frequently used in
Paal−Knorr syntheses to access furans, pyrroles, and
thiophenes,1 and 1,5-dicarbonyl compounds are often used
in Paal−Knorr-like syntheses for the preparation of pyridines.2
As shown below, chromenopyridine, a pyridine-containing
polyheterocycle, is an essential structural part of diverse
biologically important polyheterocycles (Figure 1), which are
well-known for their pharmacological properties, such as
antimicrobial, estrogen receptor β-selective ligands, cytotox-
icity against some cancer cell lines, etc.3
Received: August 17, 2018
Figure 1. Significance of chromenopyridines.
© XXXX American Chemical Society
A
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Letter
experimentation, the optimized reaction conditions were thus
established as follows: 1a (0.5 mmol), 2a (2 equiv), AgNO3
(20 mol %), and K2S2O8 (3 equiv) were stirred in 3 mL of
DMSO at 40 °C for 24 h (yield 78%).
Scheme 1. Comparison with Previous Work
With the optimized conditions in hand, we further evaluated
the scope of the substrates by examining various 2-function-
alized benzaldehydes (1) and 1,3-dicarbonyl compounds (2),
and the results are illustrated in Scheme 2. As it can be seen, o-
Scheme 2. Substrate Scope for the Synthesis of 1,5-/1,3-
a
Dicarbonyl-Containing Heterocycles
a
Reaction conditions: 1 (0.5 mmol), 2 (2 equiv), AgNO3 (20 mol %),
and K2S2O8 (3 equiv) were stirred in 3 mL of DMSO at 40 °C for 24
h. Isolated yields were given. * New compound.
rare synthetic strategy being developed for the synthesis of
chroman-4-ones with 1,3- or 1,5-dicarbonyl functional groups.
Only one radical cascade cyclization strategy toward 1,5-
dicarbonyl-containing chroman-4-ones has been reported by
Zard’s group in 2013 as shown in Scheme 1d;11 unfortunately,
two reactants (A and B) of this synthesis are especially tedious
to synthesize. Herein, we present a novel and efficient silver-
catalyzed radical cascade cyclization to access a large variety of
1,5/1,3-dicarbonyl heterocycles (3) containing chroman-4-
one, indanone, or 2,3-dihydroquinolin-4(1H)-one moieties, by
reacting various 2-functionalized benzaldehydes (1) with
different 1,3-dicarbonyl compounds (2) in one pot under
mild reaction conditions (Scheme 1e). Notably, the resulting
1,5-/1,3-dicarbonyl heterocycles (3) obtained could further
react with NH4OAc, NH2OH·HCl, or PhNHNH2, to finally
yield more structurally diverse polyheterocycles including 4,
5a, and 5b, respectively, as depicted in Scheme 1e. Most of our
newly synthesized heterocycles are new compounds. To the
best of our knowledge, this is the first example of constructing
a large variety of 1,5-/1,3-dicarbonyl heterocycles as well as the
related polyheterocycles via a silver-catalyzed radical cascade
cyclization reaction by directly using 1,3-dicarbonyl com-
pounds as alkyl radical precursors.
(allyloxy)benzaldehyde (1a) reacted smoothly with different
1,3-dicarbonyl compounds under the optimized conditions,
giving the resulting 1,5-/1,3-dicarbonyl-containing chroman-4-
ones (3a−e) in good to excellent yields (71%−84%).
Pleasingly, malononitrile was also suitable for this reaction,
although with a relatively low yield of 3f. Meanwhile, various o-
(allyloxy)benzaldehyde derivatives, including those bearing an
electron-donating group (−CH3) and electron-withdrawing
substituent (−F, −Cl, −Br), reacted smoothly with acetylace-
tone (2a), affording the corresponding 1,5-/1,3-dicarbonyl-
containing chroman-4-ones (3g−o) in moderate to good
yields (48%−73%). No obvious electronic effects of sub-
stituents at the C-6 position of benzene ring were observed as
indicated in cases 3g−j. In addition, compared with
substituents at the C-6 position as in cases 3g−j, o-
(allyloxy)benzaldehyde with substituents at the C-8 and C-7
positions of the benzene ring gave relatively low yields as
indicated in cases 3k−m. Much to our delight, two other 2-
functionalized benzaldehydes, 2-allyl benzaldehyde and 2-
N(Ts)CH2−CHCH2 substituted benzaldehyde, were com-
patible for reaction with ethyl acetoacetate as well as
acetylacetone, yielding the corresponding 1,5-/1,3-dicarbonyl-
containing indanones (3p, 3q) and 2,3-dihydroquinolin-
4(1H)-ones (3r, 3s) in moderate to good yields, respectively.
Among the target products obtained, the structure of 3i was
further confirmed by X-ray crystallography (CCDC 1861520).
Afterward, we performed a scale-up reaction (gram level) with
We initiated the synthesis of 1,5/1,3-dicarbonyl-containing
chroman-4-ones by establishing optimal experimental con-
ditions using the model reaction of o-(allyloxy)benzaldehyde
(1a) with acetylacetone (2a), as summarized in Table S1. After
consulting previous reports12 and doing an intensive
B
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the desired product (3a) being obtained in 68% yield (see the
Supporting Information, SI).
More control experiments were subsequently performed to
deepen our understanding of the related mechanism (Scheme
3). When TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or
cyclization, affording radical intermediate d. Radical d
subsequently undergoes a 1,2-hydrogen atom shift, generating
more stable radical e. Finally, radical e is oxidized to
carbocation intermediate f, which transforms immediately to
final 1,5-/1,3-dicarbonyl-containing chroman-4-one 3a along
with deprotonation of f. Alternatively, the aldehyde group in 1a
is initially transformed to the corresponding acyl radical (g) via
H-abstraction by a sulfate radical anion. Then the following
intramolecular radical addition of g leads to the formation of
an unstable radical intermediate (h) which quickly reacts with
1.3-dicarbonyl alkyl radical b to give the target product 3a.
Radical h is also possibly oxidized to yield carbocation i, which
is subsequently transformed to more stable tertiary carbocation
j via a hydride migration. Byproduct 3-methyl-4H-chromen-4-
one (k) is eventually formed with loss of a proton from j.
Moreover, the ion peak [C10H8O2 + H]+ appearing at m/z
161.0601 reasonably corresponds to 3-methyl-4H-chromen-4-
one (k).
As mentioned above, dicarbonyl compounds are a kind of
indispensable building block for the synthesis of abundant
structurally specific heterocyclic skeletons. Our newly
developed synthesis toward 1,5-/1,3-dicarbonyl containing
heterocycles (3), for the first time, made it possible for us to
use those heterocycles (3) as our starting reactants directly to
synthesize more structurally complicated polyheterocycles in a
significantly more atom- and step-economical manner. As
exhibited in Scheme 5, the crude 1,5-/1,3-dicarbonyl hetero-
cycles (3) could be employed directly to react with NH4OAc,
NH2OH·HCl, and PhNHNH2, respectively, to access more
structurally diverse polyheterocycles (4a−g and 5a−b), among
Scheme 3. Control Experiments
BHT (2,6-di-tert-butyl-4-methylphenol), two widely used
radical scavengers, were added into the reaction mixture
under the optimized reaction conditions, respectively, both
cascade cyclization reactions were completely inhibited
(Scheme 3a), evidencing that the model reaction might
proceed via a radical process. The model reaction was also
performed in the presence of 1,1-diphenylethylene, another
radical scavenger, under standard reaction conditions, as
illustrated in Scheme 3b. It can be seen that a dihydrofuran
product (3a′) was detected by HRMS (Figure S1), showing
that a 1,3-dicarbonyl alkyl radical was produced from
acetylacetone and trapped by 1,1-diphenylethylene. In
addition, to determine important intermediates formed during
the reaction process, the model reaction solution was also
analyzed by HRMS. A peak at m/z 161.0601, which should
correspond to hydrogen molecular ion [C10H8O2 + H]+
(Figure S2), was observed.
Based on the experimental results and previous reports,9,13
a
a
Scheme 5. Synthesis of Polycyclic Heterocycles
plausible mechanism is proposed as shown in Scheme 4.
Scheme 4. Proposed Mechanism
a
Reaction conditions: 1 (0.5 mmol), 2 (2 equiv), AgNO3 (20 mol %),
and K2S2O8 (3 equiv) were stirred in 3 mL of DMSO at 40 °C for 24
h. The mixture was quenched with water, extracted with ethyl acetate,
washed with brine, and dried over anhydrous Na2SO4. The solvent
was evaporated to obtain crude product 3. Synthesis of 4: crude
product 3, acetic acid (2.5 mL), NH4OAc (4 mmol), 120 °C, 3 h.
Synthesis of 5a: crude product 3, EtOH (3 mL), aq HCl solution
(37%, 1 drop), NH2OH·HCl (0.75 mmol), 80 °C, 16 h. Synthesis of
5b: crude product 3, EtOH (3 mL), aq HCl solution (37%, 1 drop),
PhNHNH2 (0.75 mmol), 80 °C, 16 h. Isolated yields of two steps.
* New compound.
Initially, peroxodisulfate oxidizes Ag(I) to Ag(II), which then
reacts with acetylacetone (2a), affording a relatively stable
silver ion complex a (or a′) with deprotonation. Afterward, the
silver ion complex (a) undergoes a chain of intramolecular
electron transfer, forming dicarbonyl radical b together with
Ag(I). A cascade cyclization is thus triggered by dicarbonyl
radical b. Radical b initially regioselectively adds to the double
bond of o-(allyloxy)benzaldehyde (1a), giving radical inter-
mediate c, which then experiences an intramolecular
C
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In conclusion, we reported a novel and convenient silver-
catalyzed radical cascade cyclization to access a large variety of
1,5-/1,3-dicarbonyl heterocycles (3) containing chroman-4-
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2-allyloxy benzaldehydes, 2-allyl benzaldehyde, and 2-N(Ts)-
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in one pot under mild reaction conditions. To the best of our
knowledge, this is the first example of constructing a large
variety of 1,5-/1,3-dicarbonyl heterocycles via a silver-catalyzed
radical cascade cyclization reaction by directly using 1,3-
dicarbonyl compounds as alkyl radical precursors. More
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cascade strategy toward the 1,5-/1,3-dicarbonyl containing
heterocycles (3), for the first time, made it possible to build
structurally complicated polyheterocycles (4a−g and 5a−b) in
a significantly more atom- and step-economical manner.
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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.or-
glett.8b02627.
■
S
́
́
Experimental details and characterization data (PDF)
Accession Codes
CCDC 1861520 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chenxl@zzu.edu.cn.
*E-mail: bingyu@zzu.edu.cn.
ORCID
Xiaolan Chen: 0000-0002-3061-8456
Kai Sun: 0000-0003-2135-0838
Bing Yu: 0000-0002-2423-1212
Yufen Zhao: 0000-0002-8513-1354
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Tian, Q.-P.; Yang, S.-D. Angew. Chem., Int. Ed. 2013, 52, 3972−3976.
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Notes
The authors declare no competing financial interest.
(9) Zhao, J.; Li, P.; Li, X.; Xia, C.; Li, F. Chem. Commun. 2016, 52,
3661−3664.
ACKNOWLEDGMENTS
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(10) Yang, W. C.; Dai, P.; Luo, K.; Ji, Y. G.; Wu, L. Adv. Synth. Catal.
2017, 359, 2390−2395.
We acknowledge financial support from National Natural
Science Foundation of China (21501010), the 2017 Science
and Technology Innovation Team in Henan Province
(22120001), Major Scientific and Technological Projects in
Henan Province (No. 181100310500), and the Key Labo-
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University) (2017002).
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