Cesium-Carbonate-Mediated Benzalation of Substituted 2-Aryl-3-nitro-2 H-chromenes with Substituted 4-Benzylidene-2-phenyloxazol-5(4 H)-ones

Article abstract of DOI:10.1021/acs.orglett.9b00776

Cs₂CO₃-mediated domino benzalation reaction with a variety of 2-aryl-3-nitro-2H-chromenes and 4-benzylidene-2-phenyloxazol-5(4H)-ones has been realized. The reaction proceeds smoothly with a broad substrate scope, thus providing a va

Full text of DOI:10.1021/acs.orglett.9b00776

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cesium-Carbonate-Mediated Benzalation of Substituted 2‑Aryl-3-
nitro‑2H‑chromenes with Substituted 4‑Benzylidene-2-
phenyloxazol-5(4H)‑ones
Chenlu Dai, Naili Luo, Shan Wang, and Cunde Wang*
School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P.R. China
S
* Supporting Information
ABSTRACT: Cs2CO3-mediated domino benzalation reaction with a variety of 2-aryl-3-nitro-2H-chromenes and 4-
benzylidene-2-phenyloxazol-5(4H)-ones has been realized. The reaction proceeds smoothly with a broad substrate scope,
thus providing a variety of substituted (Z)-4-((Z)-benzylidene)chroman-3-one oximes in moderate to high yields, which were
easily transformed into biologically important 4H-chromeno[3,4-c]isoxazoles.
unctionalized chromones are privileged scaffolds found in a
derivatives.15 Subsequently, Hajra et al. reported a similar
Fwide variety of biologically active natural products and process through K2CO3-promoted Michael addition to 3-nitro-
pharmaceuticals.1−3 Among them, 2-aryl-3-nitro-2H-chromenes
2H-chromenes from enols for the synthesis of functionalized
furan-fused benzopyran derivatives.16 Additionally, Michael
addition to 3-nitro-2-phenyl-2H-chromene with 4-hydroxy
coumarin as a classical enol substrate also was studied, following
aerial oxidation to yield the coumarin−chromene hybrid
compounds.17 In 2012, Du et al. demonstrated the bis-
(thiazoline) Zn(II) complexes in combination with bis-
(oxazoline)-mediated Michael addition of 3-nitro-2-phenyl-
2H-chromene with indoles to afford indolyl(nitro)chroman
derivatives.18 Recently, there has been a potential increase in
Michael addition research of 3-nitro-2-phenyl-2H-chromene
utilizing enamines as a nucleophilic reagent to access C4-
substituted 2H-chromene derivatives.19,20 These reported
results indicated that 3-nitrochromenes are excellent building
blocks for the preparation of various more complex heterocyclic
compounds with important biological activity.21
Inspired by these results, in continuation of our interests in
constructing polysubstituted fused coumarin derivatives,22 we
thus envisioned that 4-alkylene-3-nitrochromenes would readily
take part in an intramolecular cyclization reaction or cyclo-
addition strategy for the synthesis of the polysubstituted fused
coumarin derivatives. In the present work, based on the reported
studies that show azlactones are one of the most versatile
scaffolds in organic synthesis,23 we have been seeking a direct
approach toward functionalized 4-alkylene-3-nitrochromenes
from 3-nitro-2H-chromenes with accessible azlactones. To the
best of our knowledge, no benzalation of available 2-aryl-3-nitro-
2H-chromenes with 4-benzylidene-2-phenyloxazol-5(4H)-ones
has been realized to date. Herein, we disclose Cs2CO3-promoted
have shown a number of biological properties,4 such as antiviral,
antioxidant,5 antitumor,6 antimicrobial,7 and antiproliferative8
activities. They have also been recognized as important building
blocks for the synthesis of natural products, pharmaceutical
molecules, and functional materials.3,4c For the functionalized
reactions of 2-aryl-3-nitro-2H-chromenes with a nitroolefin
moiety, the nitro group of 3-nitro-2H-chromene derivatives can
be transformed into various functional groups to produce new
derivatives.9 It is worth mentioning that Michael addition to the
nitroolefin moiety employs the formation of C−C, C−N, C−O,
or C−P bonds to synthesize chromene derivatives with
important bioactivities.10 Among these, direct alkylations of 3-
nitro-2H-chromene are the most interesting and represent
powerful tools for the introduction and construction of various
carbocyclic and heterocyclic frameworks.10d Recently, great
progress has been made in the C4-alkylations of 3-nitro-2H-
chromene. Kodess et al. utilized the direct alkylation strategy for
accessing chromanes containing the β-dicarbonyl fragment at
position C4 by the nucleophilic addition of acetylacetone and
ethyl acetoacetate at the double bond of 3-nitro-2H-
chromenes.11 Some similar strategies were disclosed to obtain
functionalized Michael adducts using activated methylene such
as malonates12 and ketones.13 In 2014, Woodward et al.
demonstrated the tetrabutylammonium triphenyldifluorosili-
cate (TBAT)-mediated Michael addition of 3-nitro-2H-
chromenes with trimethyl(trichloromethyl)silane (TMSCCl3)
to synthesis β-CCl3-substituted 3-nitro-2H-chromenes.14 More-
over, the use of a vinylogous Michael addition strategy that
allows available α,α-dicyanoolefins to participate directly in
Michael adduct formation appears to be rather efficient for the
preparation of the functionalized polyheterocyclic benzopyran
Received: March 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00776
Org. Lett. XXXX, XXX, XXX−XXX

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benzalation of 2-aryl-3-nitro-2H-chromene with 4-benzylidene-
2-phenyloxazol-5(4H)-ones for the highly stereoselective syn-
thesis of (Z)-4-((Z)-benzylidene)chroman-3-one oxime.
Initially, the reaction of 1a with 2a was conducted to screen
the reaction conditions (see the Supporting Information for
details). In the presence of 1.0 equiv of K2CO3 base, the reaction
of 1a with 2a in a 1:1.2 molar ratio occurred in tetrahydrofuran
at 60 °C, and after 12 h, although the starting materials
completely disappeared, a messy mixture was obtained.
Considering that azlactones opened the ring easily to afford
the corresponding α-benzamidocinnamic acid in basic con-
ditions, we thought the opening ring adduct should be a key
intermediate for the following nucleophilic addition to 3-nitro-
2-phenyl-2H-chromene.24
more efficient formation of 3a in a shorter reaction time (Table
1, entry 11). Reaction of 1a and 2a in DMF or toluene solvent
and in the presence of Cs2CO3 base at 65 °C also gave 3a in
lower yield (Table 1, entries 12 and 13). Ethanol as solvent failed
to produce the desired product. Under the same reaction
condition, acetonitrile solvent produced 3a in just 5% yield
because the partial hydrolysis of acetonitrile with water occurred
to inhibit the title reaction. However, dried THF as solvent gave
a slightly lower yield (Table 1, entry 16), and the dried THF
together with 4 Å molecular sieves was used in the reaction to
give 3a in just 36% yield (Table 1, entry 17). The commercial
THF contains a small amount of water help the reaction. Thus,
THF solvent promoted the reaction most efficiently.
With the optimal reaction conditions identified, we explored
the scope of this newly developed benzalation reaction in the
presence of Cs2CO3 with a variety of 2-aryl-3-nitro-2H-
chromenes and 4-benzylidene-2-phenyloxazol-5(4H)-ones.
Our results on 23 successful examples are summarized in
Table 2. For the para-substituents of Ar1, substrates 1a−f with
either electron-donating or electron-withdrawing groups could
smoothly furnish the corresponding products 3a−f (86−92%)
(Table 2, entries 1−6). With the substituent of Ar1 at the meta-
and ortho-substituents, substrates 1g and 1h were also
transformed into 3n and 3o in the yield of 83 and 82%,
respectively, which showed that the steric hindrance had hardly
any influence on the reactivity. Compounds 3t and 3u were
obtained in 80 and 85% yield, respectively, when substrate Ar1
contained heterocyclic thiophene (Table 2, entries 20 and 21),
whereas the substituent of Ar1 bearing a 1,4-dioxane unit led to
somewhat lower yields of 71 and 75%, respectively, of 3v and 3w
(Table 2, entries 22 and 23). For the R substituents of the
chroman unit (Table 2, entries 16−20), substrates 1j−n with
either electron-withdrawing or electron-donating groups could
smoothly yield 3p−t in good yields, which showed good
substrate tolerance toward the reaction. Remarkably, a
significant substituent effect could be observed, and electron-
donating groups had positive impacts on the yields.
Subsequently, the limitation of this reaction was investigated
with a variety of electronically and sterically diverse 2 subjected
to the optimal conditions. Substrates 2c−e produced 3h−j in 85,
82, and 81% yield, respectively. Substrate 2b with a strong
electron-donating group (−OMe) could afford product 3h in
slightly higher yield despite the substituent of Ar2 at the ortho-
position. It revealed that the position of substituents and the
electronic effect of Ar2 significantly influence reactivity. The
strong electron-donating group of Ar2 is propitious to the title
reaction compared with weak electron-donating and electron-
withdrawing groups. The higher yields might be rationalized by
the fact that the benzyl carboanion generated in situ could
significantly attack the β-position of nitroalkene by the electron-
rich aryl groups under basic conditions.
The stereochemistry of representative compounds 3b, 3c, and
3u was confirmed by X-ray crystallography analyses (Figure 1).
Remarkably, all benzalations and oximes were stereospecific,
which only formed the Z form at the more sterically demanding
chroman unit.
To rationalize the reaction mechanism, two control reactions
were conducted. As it is well-known that 4-benzylidene-oxazol-
5(4H)-one can be converted to 3-aryl-2-benzamidoacrylic acid
under basic conditions via hydrolysis ring opening (Scheme
1),24 1b and 3-aryl-2-benzamidoacrylic acid (2eo) were
subjected to the optimal conditions to investigate the possibility
of the reaction pathway via the intermediate of 3-aryl-2-
Thus, the mixture of 2a with K2CO3 was stirred first at 60 °C
for 3 h, and then to the resultant mixture was added 1a, which
was stirred sequentially for 12 h until full conversion of 1a was
achieved. We observed a benzalation reaction following the
formation of oxime, thus rendering 25% yield of 3a (Table 1,
Table 1. Screening of Reaction Conditions for the Synthesis
a
of 3a
b
entry
base (equiv)
solvent
temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
K2CO3 (1.0)
Cs2CO3 (1.0)
NaHCO3 (1.0)
NaOH (1.0)
DBU (1.0)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DMF
PhMe
C2H5OH
CH3CN
THF
60
60
60
60
60
60
60
60
60
50
reflux
65
65
65
65
60
60
15
12
20
15
20
20
20
6
4
9
5
4
25
57
0
37
0
DABCO (1.0)
Et3N (1.0)
0
0
Cs2CO3 (2.0)
Cs2CO3 (3.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
87
75
55
87
15
36
0
5
81
36
9
10
11
12
13
14
15
20
20
15
6
c
16
17
d
THF
6
a
Reaction conditions: 1a (1 mmol), 2a (1.2 mmol), solvent (10 mL).
b
c
d
Isolated yield. Dried THF. Dried THF and 4 Å molecular sieves.
entry 1). When the base was changed to Cs2CO3, 3a was
obtained in 57% yield after 12 h (entry 2). However, when weak
NaHCO3 was used, 3a was not observed, and a strong base such
as NaOH gave a just slightly lower 37% yield (entry 4).
Common organic bases were screened; surprisingly, the organic
bases selected could not produce 3a (Table 1, entries 5−7).
Using 2.0 equiv of Cs2CO3 as base increased the yield to 87% for
3a and needed a shorter reaction time (Table 1, entry 8),
whereas a further increase in the amount of Cs2CO3 provided
just slightly lower yield despite less reaction time (Table 1, entry
9). Subsequently, various temperatures and solvents were
explored. When the temperature was decreased to 50 °C, the
yield of 3a was obviously reduced to 55% within 9 h (Table 1,
entry 10). Increasing the temperature from 60 °C to reflux led to
B
DOI: 10.1021/acs.orglett.9b00776
Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters
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a
Table 2. Cs2CO3-Promoted Synthesis of Chroman-3-one Oximes 3a−w
b
entry
R
Ar1
Ar2
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
5
5
5
6
6
6
7
7
7
7
8
7
7
7
7
6
6.5
8
87 (3a)
91 (3b)
92 (3c)
88 (3d)
90 (3e)
86 (3f)
82 (3g)
85 (3h)
82 (3i)
81 (3j)
80 (3k)
84 (3l)
80 (3m)
83 (3n)
82 (3o)
85 (3p)
84 (3q)
82 (3r)
81 (3s)
80 (3t)
85 (3u)
71 (3v)
75 (3w)
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-BrC6H4
4-MeC6H4
2-MeOC6H4
3-MeC6H4
4-ClC6H4
3-ClC6H4
4-MeC6H4
3-ClC6H4
4-MeC6H4
3-ClC6H4
C6H5
C6H5
C6H5
C6H5
4-MeC6H4
C6H5
C6H5
C6H5
3-MeC6H4
2-MeC6H4
4-MeOC6H4
2-ClC6H4
4-MeC6H4
4-ClC6H4
thiophen-2-yl
thiophen-3-yl
3,4-(CH2O)2C6H3
3,4-(CH2O)2C6H3
6-Me
8-EtO
6-Br
6-Cl
6-Me
H
8
10
9
8
8
H
H
C6H5
4-MeC6H4
a
b
Reaction conditions: 1a−o (1 mmol), 2a−f (1.2 mmol), Cs2CO3 (2 mmol), THF (10 mL), reflux, 5−10 h. Isolated yield.
Scheme 2. One-Pot Reaction of 3-Nitrochromene 1b and
Oxazol-5(4H)-one 2e
Figure 1. X-ray crystal structure of compounds 3b, 3c, and 3u; non-
hydrogen atoms are shown at the 30% probability level.
Scheme 1. Two-Step Reactions of 3-Nitrochromene 1b and
Phenyloxazol-5(4H)-one 2e
On the basis of our results and previous reports, a plausible
mechanism was proposed (Scheme 3), Initially, 2 undergoes
hydrolysis and ring opening under basic conditions to furnish
intermediate [A], which then attacks C4 of 3-nitro-2H-
chromenes 1 as a nucleophilic reagent, delivering zwitterionic
[B], followed by oxime oxide [C] being formed via the
resonance.10f Afterward, the benzoylimino salt core of [C] is
attacked by water to yield α-hydroxyglycine [D]. Finally, [D]
undergoes sequential deprotonation and dehydration to afford
intermediate [E], which subsequently undergoes a carbon−
carbon bond cleavage to yield 3. For 3-nitrous chromene
intermediate [E], due to the higher steric hindrance of the
substituted glycine group and the stronger electronic effect, the
CAr−COH bond of intermediate [E] would be more readily
polarized, followed by consecutive deprotonation and carbon−
carbon bond cleavage to furnish 3, which can elegantly
rationalize the stereospecificity of benzalation.
benzamidoacrylic acid 2eo (Scheme 1). The desired product 3j
as the only product was furnished in higher yield; thus, the
pathway via 3-aryl-2-benzamidoacrylic acid could be affirmed.
In addition, starting materials 1b and 2e were stirred together,
and the mixture was employed for the synthesis of 3j as a one-pot
reaction (Scheme 2); surprisingly, 3j was obtained in 71% yield,
and an unexpected product, chromeno[3,4-b]pyrrole 4, was
isolated in 24% yield, which was determined unambiguously by
single-crystal X-ray crystallography (for the mechanistic ration-
alization for 4, see the Supporting Information for details).
To demonstrate the synthetic potential of the reaction, the
intramolecular oxidative coupling reaction25 of substituted (Z)-
C
DOI: 10.1021/acs.orglett.9b00776
Org. Lett. XXXX, XXX, XXX−XXX

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have the potential to be applied to construct natural products
and pharmaceuticals. Further studies on the detailed mechanism
and synthetic applications are ongoing in our laboratory.
Scheme 3. Mechanistic Rationalization for the Benzalation of
Substituted 3-Nitro-2H-chromene with 4-Benzylidene-2-
phenyloxazol-5(4H)-ones
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00776.
Detailed experimental procedures, X-ray crystallographic
data characterization of compounds 3b, 3c, 3u, 4, 5c, and
5d, characterization data of compounds, and copies of
NMR spectra (PDF)
Accession Codes
CCDC 1870366−1870367, 1879543, 1885043, 1886515, and
1888928 contain 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
4-((Z)-benzylidene)chroman-3-one oxime under the I2/KI/
NaHCO3 system was conducted (Scheme 4). The biologically
AUTHOR INFORMATION
■
Scheme 4. Synthesis of 1,4-Diphenyl-4H-chromeno[3,4-
c]isoxazole
a b
,
Corresponding Author
*E-mail: wangcd@yzu.edu.cn.
ORCID
Cunde Wang: 0000-0001-5561-979X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support of this research by the National Natural
Science Foundation of China (NNSFC 21173181) is gratefully
acknowledged by authors. A project was funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions and the Top-notch Academic Programs Project of
Jiangsu Higher Education Institutions (PPZY2015B112).
REFERENCES
■
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a
Reactions of 3 (1.0 mmol) and I2 (504 mg, 2 mmol) were carried
out in the presence of NaHCO3 (168 mg, 2 mmol) and KI (332 mg, 2
mmol) in 10 mL of THF. Isolated yields are shown.
b
important 4H-chromeno[3,4-c]isoxazoles 5a−h were obtained
in 51−62% yields. The X-ray crystallography data for 5c and 5d
have been obtained, which unequivocally confirmed their
structures.
In summary, we have developed the first example of a
divergent domino benzalation reaction with a variety of 2-aryl-3-
nitro-2H-chromenes and 4-benzylidene-2-phenyloxazol-5(4H)-
ones in the presence of Cs2CO3 to generate substituted (Z)-4-
((Z)-benzylidene)chroman-3-one oxime with moderate to
excellent yields. The advantages of the current protocol include
readily available starting materials, mild reaction conditions,
good functional tolerance, and broad substrate scope. In
addition, substituted (Z)-4-((Z)-benzylidene)chroman-3-one
oximes could easily be transformed to the biologically important
4H-chromeno[3,4-c]isoxazoles with the I2/KI/NaHCO3 sys-
tem. We believe the divergent domino benzalation reaction will
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D
DOI: 10.1021/acs.orglett.9b00776
Org. Lett. XXXX, XXX, XXX−XXX