Metal-Free, DBU-Mediated, Microwave-Assisted Synthesis of Benzo[c]xanthones by Tandem Reactions of Alkynyl-1,3-diketones

Article abstract of DOI:10.1002/adsc.202001169

A base-mediated, green, microwave-assisted efficient preparation of a diverse benzoxanthone library from variety of readily accessible γ-alkynyl 1,3-diketones is reported. The synthesis is based on tandem reactions involving intramolecular cyclization, propargyl-allenyl isomerization, and electrocyclization in one pot. Some of the benzoxanthones are also synthesized by the one-pot reaction of 1,3-diketone and alkynyl bromide under basic heating conditions. This transformation also results in the construction of one new C?C bond and one new C?O bond. (Figure presented.).

Full text of DOI:10.1002/adsc.202001169

Title: Metal Free, DBU-Mediated, Microwave-Assisted Synthesis
of Benzo[c]xanthones by Tandem Reactions of Alkynyl-1,3-
diketones
Authors: Yi-En Liang, Balaji Barve, Yao-Haur Kuo , Hsu-Wei Fang,
Ting-Shen Kuo, and Wen-Tai Li
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001169
Link to VoR: https://doi.org/10.1002/adsc.202001169

10.1002/adsc.202001169
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal-Free, DBU-Mediated, Microwave-Assisted Synthesis of
Benzo[c]xanthones by Tandem Reactions of Alkynyl-1,3-
diketones
Yi-En Liang,a, ‡ Balaji D. Barve,a, ‡ Yao-Haur Kuo,a Hsu-Wei Fang,b Ting-Shen Kuo,c
and Wen-Tai Lia,*
a
National Research Institute of Chinese Medicine, Ministry of Health and Welfare
Taipei 11221, Taiwan, R.O.C. E-mail: wtli@nricm.edu.tw
Chemical Engineering & Biotechnology Department, National Taipei University of Technology,
b
Taipei 10608, Taiwan, R.O.C.
Department of Chemistry, National Taiwan Normal University
c
Taipei 10610, Taiwan, R.O.C
‡These authors contributed equally to this work.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: A base-mediated, green, microwave-assisted
efficient preparation of a diverse benzoxanthone library from
variety of readily accessible -alkynyl 1,3-diketones is
reported. The synthesis is based on tandem reactions
involving intramolecular cyclization, propargyl-allenyl
isomerization, and electrocyclization in one pot. Some of the
benzoxanthones are also synthesized by the one-pot reaction
of 1,3-diketone and alkynyl bromide under basic heating
conditions. This transformation also results in the
construction of one new C-C bond and one new C-O bond.
Keywords: Cyclization; Isomerization; Microwave
chemistry; Synthetic methods; Tandem reactions
Figure 1. Selected biologically active benzo[c]xanthones.
Introduction
There is growing interest in the preparation of
polycyclic heteroaromatic molecules because of their
wide applicability in material and pharmaceutical
sciences. Xanthone is the core structure of secondary
metabolites in higher plants and microorganisms as
well as in other pharmaceutically active compounds.[1]
In recent decades, these secondary metabolites have
been demonstrated to have diverse biological
properties, including anti-hypertensive,[2] anti-
oxidative,[3] anti-thrombotic,[4] and anti-cancer[5]
activities. Additionally, the benzoxanthone template is
a promising building motif for the development of
several therapeutically important molecules (Fig. 1).[6-
8] Moreover, xanthones possess distinct photophysical
properties, implying their significance in the design of
fluorescent compounds and dyes.[9]
reaction of 2-benzylidene-1-tetralones (Scheme 1,
a).[11a] Liu and Cheng demonstrated a Au(I)-catalyzed
Michael
addition/6-endo-trig
cyclization/aromatization approach (Scheme 1, b).[11b]
Hu and co-workers reported palladium-catalyzed
cascade reactions of 3-iodochromones with aryl
iodides in the presence of norbornadiene (Scheme 1,
c)[11c] and a base, microwave-assisted reaction of 2-
methyl-3-(1-alkynyl)chromones
with
electron-
deficient chromone-fused dienes.[11d] Wang and He
described the Diels-Alder reactions of arynes with 2-
Over the years, notable progress has been made in
xanthone synthesis by utilizing different substrates and
methods.[10] However, there is a scarcity of research on
the preparation of benzo[c]xanthones.[11] Zheng et al.
synthesized benzo[c]xanthones via the photocatalyzed
styrylchromones
for
the
generation
of
benzo[c]xanthones.[11e] The other reported protocols
involved
multiple
procedures
and
various
benzannulation approaches for the synthesis of
1
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10.1002/adsc.202001169
Advanced Synthesis & Catalysis
Scheme 1. Reported synthesis strategies for benzoxanthones and our approach.
the desired benzo[c]xanthones.[12] Although the irradiation at 120 °C (Table 1, entry 1). This reaction
reported methods allow for efficient benzo[c]xanthone led to the formation of benzoxanthone 3a and
formation, they have certain drawbacks such as long intramolecular cyclization product I’ in 26% and 40%
reaction time with low yields;[11a,f,12d] need for yields, respectively (Scheme 2). Initially, we assumed
expensive metal catalysts[11b-c,12g] and air/moisture- the formation of substituted furan,[15] but the
sensitive reactants;[11e,12d,12g] multiple/tedious substrate generation of benzoxanthone and an interesting
preparation steps;[11b-c] limited substrate scope intermediate I’
(applicable only to 3-(furan-2-yl)-2-phenyl-4H-
chromen-4-one, only one derivative is reported);[12f,12g]
and multistep harsh synthetic routes.[12a-e] Therefore, a
safe, expedient, atom-economic, and environmentally
benign methodology for the synthesis of
benzo[c]xanthones is highly desirable.
Microwave (MW) irradiation has proven effective in
Scheme 2. Initial attempt for the generation of
enhancing the reaction rate, particularly in reactions
benzoxanthone.
that require high-temperature and high-pressure
conditions.[13] Additionally, tandem reactions have
prompted us to further investigate the present protocol.
emerged as an important tool for the preparation of
When the reaction was performed in DMSO in the
complex natural products and biologically valuable
presence of K2CO3 at elevated temperature (160 °C),
molecules, as well as for the construction of
the yield of 3a improved significantly to 74% (Table 1,
entry 2). The structure of 3a was confirmed by X-ray
carbon−carbon or carbon−heteroatom bonds.[10f,14]
Previous studies also suggest the use of the versatile -
crystal analysis.[16] With these preliminary exciting
alkynyl groups of enynones for the preparation of
results in hand, we further optimized the reaction
substituted furans via the generation of allene and
conditions using 2a as the model reaction substrate in
the presence of various bases and solvents. Weak
carbene intermediates under acidic, basic, or metal
catalyst (Pd, Cu, Rh, or Zn) conditions (Scheme 1,
inorganic bases (e.g., Cs2CO3, K3PO4, and KOAc)
d).[15] While investigating propargyl-based strategies
were found to initiate the tandem reaction (Table 1,
for heterocyclic synthesis, we envisioned a novel
entries 3–5). However, a stronger base (e.g., NaH)
produced an unidentified mixture (Table 1, entry 6).
synthetic route to benzoxanthones, wherein tandem
reactions,
intramolecular
cyclization,
and
The use of lithium bases (e.g., lithium tert-butoxide
and lithium hydroxide) provided the desired products,
albeit in moderate yields (Table 1, entries 7 and 8). We
subsequently screened a range of organic bases such as
secondary amines (Et2NH and DIPA) and tertiary
amines (Et3N, DIPEA, DABCO, DBU, and DBN) in
order to assess their ability to initiate the expected
tandem reaction (SI, Table S1). Et3N, DIPEA, and
pyridine failed to trigger the reaction, as evidenced by
the recovery of the starting material. Interestingly,
sterically hindered strong amidine bases such as DBU
and DBN triggered the expected tandem reaction and
afforded the desired product 3a in excellent yields
(Table 1, entries 11, 12). Among all the bases evaluated,
DBU (93%), DBN (91%), and KOAc (90%) gave
excellent product yields under microwave irradiation.
The reactivity of organic bases may play an important
role in this transformation. DBU being stable, strong,
and with the pKa value of 13.5 was a superior base for
electrocyclization could be conducted. As mentioned
earlierthe use of -alkynyl 1,3-diketones for furan
synthesis through intramolecular cyclization is well
known.[15] However, to the best of our knowledge, this
is the first investigation on the use of -alkynyl 1,3-
diketones to synthesize benzoxanthones.
Herein, we report novel, base-mediated, microwave-
assisted tandem reactions to construct benzoxanthone
frameworks from -alkynyl 1,3-diketones (Scheme 1,
e). This metal-free, green synthetic route provides
efficient access to a variety of benzoxanthones in
excellent yields.
Results and Discussion
We began our investigation by treating 2-butynyl 1,3-
diketone 2a with K2CO3 in DMF under microwave
2
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10.1002/adsc.202001169
Advanced Synthesis & Catalysis
the current protocol. In the absence of microwave Furthermore, -alkynyl 1,3-diketones 2j, 2k, and 2v
irradiation, benzoxanthone 3a was formed but in lower substituted with heteroaryls such as furanyl and
yield, after a prolonged reaction (Table 1, entry 13). thiophenyl rings successfully underwent the tandem
This result revealed that microwave irradiation is reactions, affording the respective benzoxanthones 3j,
crucial for the current transformation. Subsequent 3k, and 3v in good yields. Gratifyingly, other -alkynyl
optimization efforts revealed that the amount of DBU, 1,3-diketones such as 2-pentynyl 1,3-diketones (2n–2p,
reaction temperature, and type of solvent significantly 2s–2v) and 3-phenyl-2-propynyl 1,3-diketones (2w–
affected the reaction yields (Table 1, entries 14 to 20). 2ab) bearing ethyl or phenyl moieties on the terminal
For example, adding two equivalents of DBU to the alkyne gave benzoxanthones 3n–3p and 3s–3ab in
reaction afforded 3a in excellent yield (93%). Among good yields (Table 2).
the various solvents screened in this study, DMSO
Table 2. Synthesis of benzoxanthones from -alkynyl 1,3-
proved the most effective under microwave irradiation.
With the optimized reaction conditions in hand, we
next treated 2a with DBU (2.0 equiv.) and DMSO as a
solvent in a sealed microwave reactor maintained at
160 °C (150 W) for 30 min (Table 1, entry 11). Then,
we investigated the scope and generality of the current
reaction. For this one-pot tandem reaction, a variety of
-alkynyl 1,3-diketones were evaluated. Overall, a
wide range of -alkynyl 1,3-diketones (2a–2ab)
bearing an electron-donating or electron-withdrawing
substituent on the phenyl ring of the diketone group
were well tolerated under the reaction conditions. The
corresponding benzoxanthones (Table 2, 3a–3ab)
were furnished in good yields. The yields of the
benzoxanthones formed from 2f, 2i, 2p, and 2q, which
contained a methoxy group on the phenyl ring, were
diketones.[a]
Table 1. Optimization of conditions for tandem reaction. [a]
Temp
(oC)
Yield
Entry
Base
Solvent
(3a, %)[a]
1
2
K2CO3
K2CO3
Cs2CO3
K3PO4
KOAc
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1,4-Dioxane
DMF
120
160
160
160
160
160
160
160
160
160
160
160
160
160
160
160
120
140
160
160
26[b]
74[b]
85[b]
58
90[b]
mixture
54
3
4
5
6
NaH
7
LiOH
8
LiOtBu
DIPEA
DABCO
DBU
41
NR[d]
9
10
11
12
13
14
15
16
17
18
19
20
34
93[b]
91[b]
57[c]
NR[d]
65[b]
54
DBN
DBU
DBU
DBU
DBU
Xylene
DMSO
DMSO
DMSO
DMSO
DBU
59
DBU
77
DBU (1.0 equiv.)
55
[a]Reaction conditions: 2 (0.5 mmol), DBU (1.0 mmol), and
DMSO (2.0 mL) under microwave conditions at 160 °C for
30 min.
DBU (0.5 equiv.)
40
[a]Reaction conditions: 2a (0.5 mmol), base (1.0 mmol), and
1
2.0 mL of solvent. Yields were determined by the H NMR
integration method using dibromomethane as an internal
standard. [b]Isolated yield. [c]Absence of microwave
irradiation at 160 °C for 6 h. [d]No reaction.
The current protocol could be successfully applied to
-alkynyl 1,3-diketones incorporated with ortho-
substituted halogens, and the target benzoxanthones
comparatively lower than those of the benzoxanthones were obtained in acceptable yields (Scheme 3, a).
formed from 2a and 2s (without a methoxy group). Interestingly, in the above conversions, there was no
3
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10.1002/adsc.202001169
Advanced Synthesis & Catalysis
exclusive formation of substituted furans[15] and the
corresponding benzoxanthones formed, except when
treatment with 2-propynyl-1,3-diketone 2ag generated
a mixture of substituted furan and benzoxanthone in
46% and 40% yields, respectively (Scheme 3, b). The
use of 3-butynyl 1,3-diketone 2ah in the present
reaction led to an intramolecular cyclization product 3-
(3-butynyl) chromone I” (Scheme 3, c). We also
investigated the feasibility of the current study by
conducting the one-pot reaction of 1,3-diketone with
alkynyl halides to produce benzoxanthone. The
primary screening results (SI, Table S5) indicated that
in the presence of DBU as a base under microwave
irradiation, benzoxanthone 3a was formed but in low
yield (28%). Gratifyingly, when a combination of NaI
and Cs2CO3 was used under heating conditions,
benzoxanthone was formed in moderate yield (SI,
Table S5, entry 5, 61%). We employed these
conditions to prepare a few representative examples for
a one-pot strategy, as shown in Scheme 4. The
practicability of the present method was demonstrated
by performing the reaction on a one-gram scale. The
desired benzoxanthone was formed in excellent yield
(Table 2, 3a).
formation of flavone derivatives involving O-arylation
(cyclization), followed by demethoxylation, is
[18]
reported.
We believe that a similar process is
responsible for the generation of I’, which upon
subsequent reactions, affords benzoxanthone. This was
further confirmed by the observation of the methanol
signal in the NMR and GC-MS spectra of the crude
reaction mixture. Furthermore, when the reaction was
conducted in the presence of two equivalents of D2O,
deuterium atoms were incorporated at two separate
positions in benzoxanthone product 3a’, i.e., at the
phenylic (9%, d-incorporation) and benzylic positions
(27%, d-incorporation), revealing the in situ formation
of an allene intermediate.
Scheme 4. One-pot reaction involving 1,3-diketones and
propargyl bromide.[a]
Scheme 3. Scope of various substrates for DBU-promoted
tandem reactions.
[a]Reaction conditions: 1 (0.4 mmol), alkyne (0.4 mmol),
Cs2CO3 (1.2 mmol), NaI (1.2 mmol), and DMSO (2.0 mL)
under heating at 160 °C for 6 h.
Scheme 5. Synthesis of substituted furans from 2-butynyl
1,3-diketones 2a.
.
We also demonstrated the synthesis of substituted
furans from -alkynyl 1,3-diketones under microwave
irradiation. Specifically, when p-TSA or a metal
catalyst Pd(OAc)2 was added to the reaction, the furan
derivatives were obtained in satisfactory yields
(Scheme 5).[15]
Further, we attempted the treatment of o-
methoxyphenyl diketone (in the absence of a
substituted methylene alkyne) under the current
reaction conditions. To our delight, the corresponding
flavones were formed in excellent yields (Scheme 6).
Thus, the present strategy is also a suitable alternative
to traditional flavone synthesis methods.[17]
Scheme 6. Intramolecular cyclization.
We then performed various control experiments to
investigate the reaction mechanism (Scheme 7). The
addition of a radical scavenger (2,6-ditert-butyl-4-
methylphenol BHT) had no observable effect on the
outcome of the reaction, suggesting that the reaction
does not proceed via
a radical intermediate.
Additionally, we isolated 3-(2-butynyl) chromone
intermediate I’, which when treated independently
with DBU yielded the expected benzoxanthone. The
4
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10.1002/adsc.202001169
Advanced Synthesis & Catalysis
Scheme 7. Control experiments for current method.
formation of the allene. This metal-free, eco-friendly,
one-pot tandem reaction can produce a diverse range
of benzoxanthones in high yields, suggesting its
potential application in the pharmaceutical industry
and in bulk preparation. Attempts to extend this
protocol to the development of novel benzoxanthones
and the relevant natural product synthesis are
underway in our laboratory.
Experimental Section
General information
All reactions were conducted under nitrogen atmosphere
unless otherwise mentioned and in oven-dried glassware. All
reagents were used as received from commercial suppliers
unless otherwise stated. Starting materials were prepared
according to the literature reported methods unless
otherwise mentioned. The proton NMR spectra were
obtained on Varian Unity Inova 500 (500 MHz) and Varian
VNMRS600 (600 MHz) spectrometers. All NMR chemical
shifts were reported as  values in parts per million (ppm),
and coupling constants (J) were given in hertz (Hz). Melting
points were measured on a Yanaco MP-S3 micro melting
point apparatus and are uncorrected. Microwave reactions
were performed using a CEM Discover SP microwave
reactor (CEM, Matthews, NC, USA) and reaction vessel
used CEM reaction vessels.
On the basis of our findings and the previous literature
data on similar metal-free, tandem annulation reactions,
[19]
we propose a plausible mechanism for the current
protocol (Scheme 8). Initially, base-mediated
intramolecular cyclization of -alkynyl 1,3-diketone
resulting in the formation of 3-alkynyl chromone
intermediate I’.[18,20] Allene intermediate II is formed
via the propargyl-allenyl isomerization of I’.[21] At this
point, 6electrocyclization of II rapidly leads to the
generation of the six-membered annulation product
III.[22] Finally, double-bond isomerization provides the
more stable benzoxanthone 3a.
Scheme 8. Plausible reaction mechanism.
Conclusion
High-resolution mass spectra (HRMS) was carried out on
Microsaic 4000MiD mass spectrometers. Purification was
performed using preparative separations in flash column
chromatography (Merck silica gel 60, particle size of 230-
400 mesh). The compounds analyzed on the TLC plates
were visualized using a UV light, I2 vapor, or basic aqueous
potassium permanganate (KMnO4) with heating.
In summary, we have developed a novel, green, DBU-
promoted, microwave-assisted tandem reaction for the
synthesis of benzoxanthones, which involves metal-
free intramolecular cyclization, propargyl-allenyl
isomerization, and electrocyclization. We found that
the -alkynyl 1,3-diketone leads to unexpected
benzoxanthone formation under basic conditions,
instead of following the conventional route to produce
a substituted furan product. Intramolecular cyclization
plays a key role in the yield of 3-(2-butynyl) chromone.
We also successfully provided evidence for the
reaction mechanism by isolating 3-alkynyl chromone
intermediate I’ and deuterium labeling for the
1. General procedure for synthesis of compound 2.
Preparation of 2a as a representative example.
In two-neck round-bottom flask, to the solution of 1-(2-
methoxyphenyl)-3-phenylpropane-1,3-dione 1a (203 mg,
0.8 mmol), NaI (360 mg, 2.4 mmol), and Cs2CO3 (782 mg,
5
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10.1002/adsc.202001169
Advanced Synthesis & Catalysis
2.4 mmol) in THF (12 mL) under an N2 atmosphere was [5] a) H. Zhang, Y.-P. Tan, L. Zhao, L. Wang, N.-J. Fu, S.-
added 1-bromo-2-butyne (106 mg 0.8 mmol). The mixture
was heated in 70 C oil bath for 4 h and the progress of the
reaction was monitored by TLC. After completion of the
reaction, the solution was quenched by addition of saturated
aqueous NH4Cl solution. The crude mixture was extracted
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were dried over MgSO4. After removal of the solvent, the
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The microwave reaction was performed in a sealed
microwave process vial. To an oven dried, 15 mL vial
quipped with a teflon-coated magnetic stir bar, was added -
alkyne-1,3-diketone 2a (153 mg, 0.5 mmol) and 2.0 mL of
DMSO followed by the addition of DBU (0.15 mL, 1.0 [9] a) A. Katori, E. Azuma, H. Ishimura, K. Kuramochi, K.
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acetate (15 mL × 2). The combined organic layers were
washed with brine solution (15 mL), dried over MgSO4, and
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obtain 3a as a yellow solid (127 mg, 93 %).
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Acknowledgements
This project received generous support from the Ministry of
Science and Technology of Taiwan (MOST 108-2113-M-077-001-).
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Advanced Synthesis & Catalysis
FULL PAPER
Metal Free, DBU-Mediated, Microwave-Assisted
Synthesis of Benzo[c]xanthones by Tandem
Reactions of Alkynyl-1,3-diketones
Adv. Synth. Catal. Year, Volume, Page – Page
Yi-En Liang,a,‡ Balaji D. Barve,a, ‡ Yao-Haur Kuo,a
Hsu-Wei Fang,b Ting-Shen Kuo,c and Wen-Tai Li,a*
8
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