Construction of Highly Functionalized Xanthones via Rh-Catalyzed Cascade C-H Activation/ O-Annulation

Article abstract of DOI:10.1021/acs.orglett.1c00391

A facile and efficient strategy for obtaining functionalized and multihydroxylated xanthones via Rh catalysis under redox-neutral conditions is developed. Diverse salicylaldehydes bearing heterocycles, aromatics, and fused aromatics can be rapidly coupled with 1,4-benzoquinones or 1,4-hydroquinones to afford valuable xanthones via cascade C-H/O-H functionalization and annulation. This protocol provides a rapid synthetic approach to obtain biologically active materials through late-stage functionalization and prepares natural products such as subelliptenone, pruniflorone N, and ravenelin.

Full text of DOI:10.1021/acs.orglett.1c00391

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Letter
Construction of Highly Functionalized Xanthones via Rh-Catalyzed
Cascade C−H Activation/O‑Annulation
Sagar D. Nale, Debabrata Maiti,* and Yong Rok Lee*
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ABSTRACT: A facile and efficient strategy for obtaining functionalized and multihydroxylated xanthones via Rh catalysis under
redox-neutral conditions is developed. Diverse salicylaldehydes bearing heterocycles, aromatics, and fused aromatics can be rapidly
coupled with 1,4-benzoquinones or 1,4-hydroquinones to afford valuable xanthones via cascade C−H/O−H functionalization and
annulation. This protocol provides a rapid synthetic approach to obtain biologically active materials through late-stage
functionalization and prepares natural products such as subelliptenone, pruniflorone N, and ravenelin.
Scheme 1. Prior Work in the Context of the Present Study
anthones are oxygen-containing heterocycles that are
widely found in synthetic and natural products.1,2 These
X
compounds exhibit excellent biological3 and pharmacological
activities,4 and some of these are used as major drug
candidates.5,6 In particular, multihydroxylated xanthones
bearing 1,4-dihydroxyl groups have shown anticancer,
antidiabetic, antiplasmodial, antimicrobial, and anti-inflamma-
tory activities.7,8 Owing to their biological activities, a number
of synthetic procedures for preparing xanthone skeletons,
including biosynthetic approaches, have been reported.9,10
Among these, the representative strategies include Cu-
catalyzed couping of 2-nitrobenzaldehydes with phenols
(Scheme 1a),11 Rh- and Fe-catalyzed intramolecular cross-
dehydrogenative coupling of 2-aryloxybenzaldehydes (Scheme
1b),12 and base-promoted tandem reaction of alkynylchro-
mones with 1,3-dicarbonyl compound (Scheme 1c).13
However, there are no examples of the direct preparation of
biologically interesting multihydroxylated xanthones bearing
chiral moieties, polycyclic rings, and polyaromatic rings.
Recently, direct aldehyde C−H functionalization of
salicylaldehyde has been employed as a versatile tool in
organic synthesis.14−18 Neverthless, no studies have inves-
tigated the synthesis of xanthones via transition-metal-
catalyzed aldehydic C−H activation of salicylaldehydes with
readily available coupling partners. In 2018, our group
developed a novel methodology for the construction of diverse
xanthones via base-promoted benzannulation reaction of N-
tosylhydrazones with 3-formylchromones.19 This protocol
made it difficult to synthesize polyhydroxylated xantone with
chiral moieties, polycyclic rings, and polyaromatic rings. To
Received: February 1, 2021
Published: March 10, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00391
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2465−2470
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a
Table 1. Optimization of Reaction Conditions for 3a
b
entry
catalyst (5 mol %)
additive (mol %)
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
AgSbF6 (20)
Cu(OAc)2 (100)
Ag2CO3 (100)
AgOAc (100)
NaOAc (100)
CsOAc (100)
CsOAc (100)
CsOAc (100)
CsOAc (100)
CsOAc (100)
CsOAc (100)
CsOAc (100)
CsOAc (100)
CsOAc (100)
CsOAc (100)
CsOAc (100)
DCE
DCE
DCE
DCE
DCE
DCE
toluene
THF
tAmOH
DMF
DCE
DCE
DCE
DCE
DCE
DCE
24
12
12
12
12
12
12
12
12
12
16
24
24
24
24
24
0
25
27
56
70
75
35
39
22
10
11
12
13
14
20
88
0
0
trace
trace
20
c
[Ru(p-cymene)Cl2]2
[Rh2Cl2(COD)2]
[RhCl(PPh3)3]
[Cp*IrCl2]2
c
c
15
16
a
b
c
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst, and additives in solvent (3.0 mL) for 16 h. Isolated yields. 2.5 mol % of catalyst
was used.
overcome the shortcoming, the development of new strategies
is urgently required. This paper describes the first report for
the direct preparation of divergent polyhydroxylated xanthones
bearing chiral moieties, polycyclic rings, and polyaromatic rings
via Rh-catalyzed double C−H/O-H functionalization of
salicylaldehydes with 1,4-benzoquinones or 1,4-hydroquinones
(Scheme 1d).
Scheme 2. Annulation of Salicylaldehydes with
Benzoquinones
The initial reaction of salicylaldehyde (1a) and 1,4-
benzoquinone (2a) with [Cp*RhCl2]2 and AgSbF6 at 80 °C
in 1,2-dichloroethane (DCE) did not afford any products
(Table 1, entry 1). When Cu(OAc)2 was used as an additive,
3a was produced in 25% yield (entry 2). Encouraged by this
result, additives such as Ag2CO3, AgOAc, and NaOAc were
tested (entries 3−5). The use of CsOAc increased the yield of
3a up to 75% (entry 6). Interestingly, when the loading of the
catalyst was decreased to 2.5 mol % at 90 °C, the product yield
improved significantly (88%, entry 11). Changing the catalyst
from Rh (III) to Ru(II), Rh(I), and Ir(III) failed to provide 3a
in good yield (entries 13−16).
Thereafter, the scope and generality of this protocol was
investigated (Schemes 2 and 3). The reactions of 2a with
salicylaldehydes bearing electron-donating groups led to the
formation of corresponding xanthones 3b−3h in 80−96%
yields. Similarly, salicylaldehydes with electron-withdrawing
groups and halogens successfully furnished 3i−3n in 77−92%
yields. Salicylaldehydes bearing 5-phenyl, 3-allyl, and 5-allyl-3-
methoxy groups participated smoothly in the reactions (3o−
3q) to afford the corresponding xanthones in 87−88% yields.
Notably, the reactions of salicylaldehydes with heterocyclic
rings provided xanthones containing bioactive 2,2-dimethyl-
2H-chromene, flavone, and carbazole moieties in excellent
yields (4a−4c, Scheme 3). Salicylaldehydes with heteroar-
omatic rings and fused aromatic rings led to the formation of
desired xanthones (4d and 4e) and benzoxanthones (4f−4j).
To diversify the scope of this protocol, various substituted
1,4-benzoquinones were tested (Scheme 4). Symmetrically
substituted 1,4-benzoquinones were reacted with salicylalde-
hydes bearing electron-donating and electron-withdrawing
groups (5a−5e). Unsymmetrically substituted 2-methyl-1,4-
benzoquinone afforded two products 5f and 5f′ as
regioisomers in 65% and 20% yields, respectively. Similar
observations were made for 5g and 5h. Despite the different
stereoelectronic characteristics of the substituents on the
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unsymmetrical 1,4-benzoquinones, the reactions afforded the
desired products in good to excellent regioselectivity.
Remarkably, unsymmetrically substituted 1,4-benzoquinones
bearing electron-donating groups such as bulky 2-tert-butyl and
2-OMe led to products 5i−5m (80−88%) without the
formation of minor regioisomers. X-ray analysis confirmed
the structure of 5l (CCDC 2040612).
Scheme 3. Annulation with Heterocyclic and Polyaromatic
Rings
Subsequently, the late-stage functionalization of pharma-
ceutically important scaffolds using this methodology was
examined (Scheme 5a). A xanthone bearing a biologically
Scheme 5. Late-Stage Functionalizations and One-Step
Synthesis of Natural Products
Scheme 4. Substrate Scope of Substituted 1,4-
Benzoquinones
interesting estrone moiety (6) was prepared in good yield
(79%).21 Similarly, the reaction of ortho-formylated derivatives
of β-estradiol 17-acetate, β-estradiol 17-valerate, or β-estradiol
17-heptanoate with 2a provided the corresponding xanthones
7−9 bearing β-estradiol nuclei.21 Notably, this methodology
was extended to the reactions of the chiral molecules derived
from naproxen and N-benzoyl-L-tyrosine ethyl ester with 2a,
leading to the formation of biologically valuable compounds 10
(88%) and 11 (85%).21 Inspired by the production of bioactive
compounds in a single step using this method, the one-step
synthesis of natural products was investigated (Scheme 5b).
Subelliptenone (12) and pruniflorone N (13) have been
isolated from Garcinia subelliptica and Cratoxylum formosum
ssp. pruniflorum, respectively, and possess various biological
and pharmacological properties including antimalarial, anti-
bacterial, cytotoxic, and anti-inflammatory activities.7a,b Natu-
ral products 12 and 13 were obtained in preparative yields in a
single step (Scheme 5). Ravenelin (14) is a xanthone pigment
isolated from fungal species of Helminthosporium ravenelii and
H. Turcicum.7c,d The reaction of dihydroxybenzaldehyde 1ai
with 2d afforded ravenelin (14) in 66% yield and its
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regioisomer 14′ in 22% yield. Further attempts to improve the
yields by lowering the temperature (80 °C; 14 (53%) and 14′
(15%)) and decreasing the Rh catalyst amount (1 mol %; 14
(40%) and 14′ (12%)) were unsuccessful.
Scheme 7. Control Experiments and Plausible Reaction
Pathway
When salicylaldehyde was reacted with 1,4-hydroquinone
(2a′) instead of 1,4-benzoquinone (2a), xanthone formation
was not observed. However, when silver(I) oxide was added,
3a was generated in 74% yield. The versatility of this protocol
with 1,4-hydroquinone was tested (Scheme 6) with salicy-
Scheme 6. Reaction with 1,4-Hydroquinones
1,2-benzoquinone, catechol, or 1,2-naphthoquinone (instead of
1,4-benzoquinone), no annulation product was observed.
These substrates are likely to bind rhodium in a bidentate
chelating mode; therefore, olefinic coordination is improbable,
and the desired catalysis cannot proceed. When the reaction
was performed at high temperature (e.g., 130 °C), xanthone
was still obtained as the only product, and decarbonylation or
any other side product(s) was not observed.
Based on the experimental observations and literature
reports,15−18 a plausible mechanism for this protocol is
outlined in Scheme 7c. An active rhodium catalyst I is
generated in the presence of CsOAc, which undergoes C−H
metalation with 1a to form five-membered rhodacycle
intermediate II through hydroxyl-directed aldehydic C−H
bond activation. The coordination of quinone with II generates
intermediate III, which produces a seven-membered rhoda-
cycle intermediate IV via migratory insertion. Next, Rh
complex IV undergoes reductive elimination and aromatization
to afford the final product V and Rh(I) catalyst. Rh(I) is
oxidized to the active Rh(III) catalyst by air in combination
with benzoquinone and AcOH. The regenerated Rh(III)
catalyst is further used to catalyze the next catalytic cycle.20
Regiocontrol in unsymmetrically substituted 1,4-benzoqui-
nones is governed by the stereoelectronic characteristics of the
substituent, which in turn dictate the mode of migratory
insertion.
laldehyde bearing electron-donating (3b and 3c), electron-
withdrawing (3i and 3k), and other types of substituents (3q,
4e, and 4i). Interestingly, 1,4-hydroquinone was successfully
employed for the late-stage functionalization of estrone (6)
and by using substituted 1,4-hydroquinone (5a and 5l).
To gain insights into the reaction mechanism, 1a was treated
with 1, 2, and 4 equiv of CD3OD in 1,2-DCE under standard
conditions; this treatment showed the deuteration of aldehydic
C−H bond at 5, 8, and 10%, respectively (Scheme 7a). The
competitive reaction between 1a and 1a-D was carried out in
equimolar quantities. The unreacted mixture of 1a-D and 1a
showed a ratio of 1.32 based on the 1H NMR analysis (Scheme
7b).21
The combination of 2-methoxybenzaldehyde (or benzalde-
hyde) and 1,4-benzoquinone under standard conditions
remained unreacted even after 16 h, indicating the importance
of the ortho hydroxyl group. The more electron-deficient 2-
(methoxycarbonyl)-1,4-benzoquinone or 2-(methoxycarbon-
yl)-1,4-hydroquinone did not provide the annulation product
with salicylaldehyde. Similarly, 1,4-naphthoquinone, which is
significantly electron deficient compared to 1,4-benzoquinone,
did not undergo effective olefin coordination, resulting in no
annulation reaction. When salicylaldehyde was reacted with
In conclusion, one-step synthesis of diverse multihydroxy-
lated xanthone derivatives is developed via Rh(III)-catalyzed
double C−H/O−H annulation of the salicylaldehydes with
1,4-benzoquinones or 1,4-hydroquinones. This redox-neutral
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green,22 the synthetic potential of this protocol is newly
established for the late-stage functionalization of estrone and
its derivatives, naproxen and L-tyrosine ethyl ester. Moreover,
the natural products subelliptenone, pruniflorone N, and
ravenelin are synthesized in a single step, demonstrating the
versatility and practicality of this method. Sustainable C−H
activation methodologies for the direct construction of natural
products from cheap and easily available precursors are
currently under study.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00391.
General procedures, compound characterization, and
copies of NMR spectra of all products; X-ray data for 5l
(PDF)
FAIR data, including the primary NMR FID files, for
compounds 1ab−1ag, 1s, 1t, 1x, 1y, 3a−3q, 4a−4j, 5a−
5m, 6−14, and 14′ (ZIP)
Accession Codes
CCDC 2040612 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.
(5) Gomes, A. S.; Brandao, P.; Garcia Fernandes, C. S.; Pinto
Correia da Silva, M. R.; da Silva Pereira de Sousa, M. E.; de Magalhaes
Pinto, M. M. Drug-like Properties and ADME of Xanthone
Derivatives: The Antechamber of Clinical Trials. Curr. Med. Chem.
2016, 23, 3654−3686.
(6) Winter, D. K.; Sloman, D. L.; Porco, J. A. Polycyclic Xanthone
Natural Products: Structure, Biological Activity and Chemical
Synthesis. Nat. Prod. Rep. 2013, 30, 382−391.
AUTHOR INFORMATION
Corresponding Authors
■
Yong Rok Lee − School of Chemical Engineering, Yeungnam
University, Gyeongsan 38541, Republic of Korea;
orcid.org/0000-0002-4048-8341; Email: yrlee@yu.ac.kr
Debabrata Maiti − Department of Chemistry, IIT Bombay,
Mumbai 400076, India; orcid.org/0000-0001-8353-
1306; Email: dmaiti@chem.iitb.ac.in
(7) (a) Chen, J.-J.; Hung, M.-C.; Liao, H.-R.; Kuo, Y.-H.; Shu, C.-
W.; Sung, P.-J.; Lim, Y.-P.; Kuo, W.-L.; Cheng, L.-Y.; Wang, S.-L.;
Wu, J.-J. A New Xanthone and Anti-Inflammatory Constituents of
Garcinia subelliptica. Chem. Nat. Compd. 2017, 53, 649−652.
(b) Duan, Y. H.; Dai, Y.; Wang, G. H.; Zhang, X.; Chen, H. F.;
Chen, J. B.; Yao, X. S.; Zhang, X. K. Bioactive Xanthones from the
Stems of Cratoxylum Formosum ssp. J. Nat. Prod. 2010, 73, 1283−
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Chem. Soc., Perkin Trans. 1 1976, 898−904. (d) Hill, J. G.;
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(f) Fukuta, Y.; Ota, S.; Kamiya, M.; Sato, M.; Suzuki, Y. Xanthone
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Author
Sagar D. Nale − School of Chemical Engineering, Yeungnam
University, Gyeongsan 38541, Republic of Korea;
orcid.org/0000-0002-6326-3188
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00391
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a National Research Foundation
of Korea (NRF) grant funded by the Korean government
(MSIT) (2018R1A2B2004432 and 2021R1A2B5B02002436).
This work was also funded by BRNS (D.M.).
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