Synthesis of xanthones through the palladium-catalyzed carbonylation/C-H activation sequence

Article abstract of DOI:10.1016/j.tetlet.2014.09.119

A series of xanthones with the dibenzo-γ-pyrone framework were synthesized through the palladium-catalyzed carbonylation/C-H activation sequence from the ortho diazonium salts of diaryl ethers in moderate to excellent yields. After screening the reaction condition, the optimal condition was 5 mol % tetrakis (triphenylphosphine) palladium (0) as the catalyst, potassium carbonate as the base, and toluene as the solvent in the presence of catalytic amount of tetrabutyl ammonium bromide under carbon monoxide atmosphere.

Full text of DOI:10.1016/j.tetlet.2014.09.119

Accepted Manuscript
Synthesis of xanthones through the palladium-catalyzed carbonylation/C–H ac-
tivation sequence
Yingmeng Xu, Jing Zhou, Congcong Zhang, Ke Chen, Tao Zhang, Zhenting Du
PII:
S0040-4039(14)01646-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.09.119
TETL 45213
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 July 2014
22 September 2014
26 September 2014
Please cite this article as: Xu, Y., Zhou, J., Zhang, C., Chen, K., Zhang, T., Du, Z., Synthesis of xanthones through
the palladium-catalyzed carbonylation/C–H activation sequence, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.09.119
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Synthesis of xanthones through the palladium-catalyzed
carbonylation/C–H activation sequence
Leave this area blank for abstract info.
Yingmeng Xu, Jing Zhou, Congcong Zhang, Ke Chen, Tao Zhang, Zhenting Du*
R2
R2
80 oC
Pd(PPh3)4, CO
O
O
K2CO3,TBAB
+
R1
N2
R3
R1
R3
-
23 examples
30-90% yield
BF4
O
1
2

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of xanthones through the palladium-catalyzed carbonylation/C–H activation
sequence
Yingmeng Xua,§, Jing Zhoua,§, Congcong Zhanga, Ke Chena, Tao Zhanga* and Zhenting Dua,b*
a College of Science, Northwest A&F University, Yangling, Shaanxi Province, P. R. China, 712100
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, P.R. China,
20032
§The first two authors contributed equally to this work.
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of xanthones with the dibenzo-γ-pyrone framework were synthesized through the
palladium-catalyzed carbonylation/C-H activation sequence from the ortho diazonium salts of
diaryl ethers in moderate to excellent yields. After screening the reaction condition, the optimal
condition was 5 mol% tetrakis (triphenylphosphine) palladium (0) as the catalyst, potassium
carbonate as the base, toluene as the solvent in the presence of catalytic amount tetrabutyl
ammonium bromide under carbon monoxide atmosphere.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
C–H activation
Xanthone
Palladium catalyst
Carbonylation
Diazonium salt
Xanthones with the dibenzo-γ-pyrone framework are a family
of naturally occurring bioactive substances such as psorospermin
and α-mangostin. The xanthone skeleton constitutes the core of a
variety of important natural products, especially in the secondary
metabolites1. At the same time, xanthones are privileged
scaffolds in the pharmacological aspect2 such as antioxidant3,
antithrombotic4, vasorelaxant5, anti-inflammatory5, 6, antitumor7,
antimicrobial8, antiviral9 and antifungal10 activities. The earliest
efficient synthetic method towards xanthones reported by Grover
has always shown great popularity today11. Afterwards, the
syntheses of the xanthone skeleton involved multi-step
procedures, which generally require the intermediacy of a
benzophenone12 or a diaryl ether motif 11, 13companied with harsh
reaction conditions or toxic metals. Due to the diverse biological
activities of xanthones, many new efforts have been devoted to
synthesize xanthone derivatives. Recently, Larock has developed
a method using arynes as precursors to form xanthone14.
Transition metal-catalyzed C－H bond activation and oxidation
of diaryl ether with ortho aldehyde to form xanthones has been
reported by several teams15. Lei reported a novel double C－H
bond activation and carbonylation of diaryl ether16 to give
xanthones. And other miscellaneous methods toward xanthones
were also reported 17. However, these methods involved multi-
step procedures for preparation of the intermediates or lack
applicability. Therefore, it is highly desirable to find a versatile
synthetic approach that allows for the maximum amount of
flexibility to afford a range of xanthones with different ring
systems and maximum toleration of functional groups.
Scheme 1. Typical synthetic approaches to xanthones
In our pursuit of new heterocyclic structures which can serve
as potential bioactive compounds in agricultural chemicals, we
have developed a method of palladium-catalyzed intramolecular
cyclization of diazonium salts18 to synthesize different
heterocycles19. Therefore, we envisage a palladium catalyzed
carbonylation and C–H activation to synthesize xanthones from
the ortho diazonium salts of diaryl ethers (Scheme 1). Herein, we
report a palladium-catalyzed carbonylation/C－H activation to
form xanthones in good to excellent yields.
To commence our investigation, 2-phenoxybenzenediazonium
tetrafluoroborate (1a) was chosen as the starting material for the
sequential carbonylation/C － H activation reaction in the
presence of palladium catalyst as the model reaction. As a

2
Tetrahedron Letters
consequence, the desired product xanthone 2a was obtained in
used, the yields of the corresponding product increased
significantly in both acetonitrile and toluene (Table 1, entries 6-
7). The screening of bases showed that different bases
dramatically affected the reaction. The substitution of the K2CO3
by another inorganic base such as Cs2CO3 or NaCO3 was found
to be ineffective (Table 1, entries 7-9). Besides, the pressure of
CO atmosphere was crucial to the transformation. If CO balloon
was used, the desired product was obtained in less than 20%.
After screening different conditions, the optimal condition for
this conversion was as follows: The toluene as the solvent, 5
mol% Pd(PPh3)4 as the catalyst, in the presence of K2CO3 and 5%
tetrabutyl ammonium bromide as the phase transfer catalyst
(Table 1, entry 7).
26% yield when Pd(OAc)2 was used as the catalyst, in the
presence of 1 equiv. of K2CO3 (Table 1, entry 1) in acetonitrile.
With this promising result in hand, systematic screening of the
catalyst, solvent and base was carried out; the results are
summarized in Table 1. For the catalyst, PdCl2(PPh3)2 and
PdCl2(CH3CN)2 did not give better yields (Table 1, entries 1-3).
To our delight, when Pd(PPh3)4 was chosen as the catalyst, the
catalytic effect was remarkably improved. Our studies showed
that the solvent seemed to be crucial for this reaction. The yield
was 43% and 56% when this reaction was carried out in
acetonitrile and toluene, respectively (Table 1, entries 4-5).
Intriguingly, when tetrabutyl ammonium bromide (TBAB) was
Table 1. Optimization for the cyclization of 2-phenoxybenzenediazonium tetrafluoroborate in the presence of CO a
Entry
Catalyst
Pd(OAc)2
Base
K2CO3
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
CH3CN
Toluene
Toluene
Toluene
Toluene
Yields (%)b
1
2
26
15
20
43
56
58
72
8
PdCl2(PPh3)2
PdCl2(CH3CN)2
Pd(PPh3)4
K2CO3
3
K2CO3
4
K2CO3
5
Pd(PPh3)4
K2CO3
6
Pd(PPh3)4
K2CO3/ TBAB
K2CO3/ TBAB
Cs2CO3/ TBAB
Na2CO3/ TBAB
K2CO3/ TBAB
7
Pd(PPh3)4
8
Pd(PPh3)4
9
Pd(PPh3)4
30
19c
10
Pd(PPh3)4
aUnless otherwise noted, the reaction was conducted at a 0.2 Mpa pressure of CO. bIsolated yields. cCO balloon.
With this satisfactory protocol in hand, we explored the scope
of the reaction under the optimized conditions. The results are
summarized in Table 2. A wide range of structurally diverse 2-
ones with electron-withdrawing group gave low yield (Table 2,
entries 5, 6, 13). This may result from the low electron density of
phenyl ring where an electronic withdrawing group attached. As
to R2 substituent, the steric effect of R2 seemed to be detrimental
on this transformation in the case of H and Me (Table 2, entries 7,
14). Thus, all the products listed in Table 2 were easily
characterized on the basis of physical and spectral data and also
by comparison with authentic samples.
phenoxybenzenediazonium
tetrafluoroborates (Table
2),
including chloro (Table 2, entries 5, 12, 15-18), fluoro (entry 13)
and methoxy groups (entries 3, 10, 17, 19-22) were subjected to
this protocol to give the corresponding xanthones in moderate to
excellent yields. By several simple chemical operations, this
series of substrates can be provided in good overall yields18a
.
The regioselectivity in this transformation was also
investigated. A mixture of two products 2wa and 2wb was
observed with the ratio of 5:3 when R4 was the methyl group
(Scheme 2).
Notably, the electronic effect of R3 group seemed to affect the
yield significantly. The substrates with R3 as electron-donating
group gave excellent yield (Table 2, entries 2-4). However, the
Table 2. Pd(PPh3)4-Catalyzed Carbonylation Cyclization of 2-Phenoxybenzenediazonium Tetrafluoroborate

3
Entry
1
1
2
Xanthones
Yields (%)a
72
1a
2a
R1= H, R2= H, R3= H
2
3
1b
1c
1d
1e
1f
2b
2c
2d
2e
2f
R1= H, R2= H, R3= CH3
R1= H, R2= H, R3= OCH3
R1= H, R2= H, R3= t-Bu
R1= H, R2= H, R3=Cl
80
90
75
30
42
38
64
66
73
69
30
25
30
73
77
90
79
43
47
40
43
4
5
6
R1= H, R2= H, R3=CHO
R1= H, R2= CH3, R3= H
R1= CH3, R2= H, R3= H
R1= CH3, R2= H, R3= CH3
R1= CH3, R2= H, R3= OCH3
R1= CH3, R2= H, R3= t-Bu
R1= CH3, R2= H, R3= Cl
R1= CH3, R2= H, R3= F
R1= CH3, R2= CH3, R3= H
R1= Cl, R2= H, R3= H
7
1g
1h
1i
2g
2b
2i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1j
2j
1k
1l
2k
2l
1m
1n
1o
1p
1q
1r
1s
2m
2n
2e
2l
R1= Cl, R2= H, R3= CH3
R1= Cl, R2= H, R3= OCH3
R1= Cl, R2= H, R3= t-Bu
R1= OCH3, R2= H, R3= H
R1= OCH3, R2= H, R3= CH3
R1= OCH3, R2= H, R3= OCH3
R1= OCH3, R2=CH3 , R3= H
2q
2r
2c
2j
1t
1u
1v
2u
2v
aIsolated yields.

4
Tetrahedron Letters
Scheme 2. The regioselectivity of this protocol
2. Na, Y. J. Pharm. Pharmacol. 2009, 61, 707-712.
The proposed mechanism of the intramolecular cyclization is
shown in Scheme 3. The conversion started with the oxidative-
addition of Pd (0) to give intermediate I with the release of N2.
3. (a) Cheng, J.-H.; Huang, A. M.; Hour, T.-C.; Yang, S.-C.; Pu, Y.-S.; Lin,
C.-N. Eur. J. Med. Chem. 2011, 46, 1222-1231; (b) Mahabusarakam, W.;
Proudfoot, J.; Taylor, W.; Croft, K. Free Radic. Res. 2000, 33, 643-659.
4. Lin, C. N.; Hsieh, H. K.; Liou, S. J.; Ko, H. H.; Lin, H. C.; Chung, M. I.;
Ko, F. N.; Liu, H. W.; Teng, C. M. J. Pharm. Pharmacol. 1996, 48, 887-
890.
The insertion of CO gave intermediate Ⅱ and then generated the
intermediate Ⅲ in the presence of K2CO3, subsequent reductive
elimination gave the xanthone and Pd (0), which can be used in
the next catalytic cycle.
5. Nakatani, K.; Nakahata, N.; Arakawa, T.; Yasuda, H.; Ohizumi, Y.
Biochem. Pharmacol. 2002, 63, 73-79.
Scheme 3. Proposed mechanism
6. Nakatani, K.; Atsumi, M.; Arakawa, T.; Oosawa, K.; Shimura, S.;
Nakahata, N.; Ohizumi, Y. Biol. Pharm. Bull. 2002, 25, 1137-1141.
7. (a) Zou, Y.; Zhao, Q.; Hu, H.; Hu, L.; Yu, S.; Xu, M.; Wu, Q. Arch.
Pharmacal Res. 2012, 35, 2093-2104; (b) Pouli, N. M., Panagiotis Anti-
Cancer Agents in Med. Chem. 2009, 9, 77-98.
8. Saleem, M.; Nazir, M.; Ali, M. S.; Hussain, H.; Lee, Y. S.; Riaz, N.;
Jabbar, A. Nat. Prod. Rep. 2010, 27, 238-254.
9. (a) Chen, S. X.; Wan, M.; Loh, B. N. Planta Med. 1996, 62, 381-382; (b)
Shen, Y. C.; Wang, L. T.; Khalil, A. T.; Chiang, L. C.; Cheng, P. W.
Chem. Pharm. Bull. 2005, 53, 244-247.
10. (a) Rath, G.; Potterat, O.; Mavi, S.; Hostettmann, K. Phytochemistry
1996, 43, 513-520(b) Gopalakrishnan, G.; Banumathi, B.; Suresh, G. J.
Nat. Prod. 1997, 60, 519-524.
11. Grover, P. K.; Shah, G. D.; Shah, R. C. J. Chem. Soc. 1955, 3982-3985.
12. (a) Quillinan, A. J.; Scheinmann, F. J. Chem. Soc., Perkin Trans. 1 1973,
1329-1337; (b) Barbero, N.; SanMartin, R.; Domínguez, E. Tetrahedron
2009, 65, 5729-5732; (c) Hintermann, L.; Masuo, R.; Suzuki, K. Org.
Lett. 2008, 10, 4859-4862; (d) Johnson, M. M.; Naidoo, J. M.;
Fernandes, M. A.; Mmutlane, E. M.; van Otterlo, W. A. L.; de Koning,
C. B. J. Org. Chem. 2010, 75, 8701-8704; (e) Shan, G.; Han, X.; Lin, Y.;
Yu, S.; Rao, Y. Org. Biomol. Chem. 2013, 11, 2318-2322.
13. (a) Giri, R.; Goodell, J. R.; Xing, C.; Benoit, A.; Kaur, H.; Hiasa, H.;
Ferguson, D. M. Bioorg. Med. Chem. 2010, 18, 1456-1463; (b) Lan, K.;
Fen, S.; Shan, Z. Aust. J. Chem. 2007, 60, 80-82; (c) Li, J.; Jin, C.; Su,
W. Heterocycles 2011, 83, 855-866; (d) Jackson, W. T.; Boyd, R. J.;
Froelich, L. L.; Gapinski, D. M.; Mallett, B. E.; Sawyer, J. S. J. Med.
Chem. 1993, 36, 1726-1734; (e) Olah, G. A.; Mathew, T.; Farnia, M.;
Prakash, G. K. S. Synlett 1999, 1067-1068; (f) Familoni, O. B.; Ionica, I.;
Bower, J. F.; Snieckus, V. Synlett 1997, 1081-1083.
In conclusion, we have developed
a Pd (0)-catalyzed
intramolecular carbonylation/C–H activation of ortho diazonium
salts of diphenyl ethers to form xanthones. By using easily
available ortho diazonium salts of diphenyl ethers, this method is
bestowed with several unique merits, such as the stability of the
substrates, cost-effectiveness and functional group tolerance.
Thus, we believe that this novel methodology will be a practical
alternative to existing procedures for the synthesis of bioactive
xanthones. Further studies on substrate scope and mechanism are
currently underway and will be reported in due course.
14. (a) Dubrovskiy, A. V.; Larock, R. C. Tetrahedron 2013, 69, 2789-2798;
(b) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 3117-3119; (c)
Zhou, C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551-3558.
15. (a) Yang, J.; Dong, C.; Li, H.; Li, H.; Li, Y. Chin. Sci. Bull. 2012, 57,
2364-2367; (b) Wertz, S.; Leifert, D.; Studer, A. Org. Lett. 2013, 15,
928-931; (c) Wang, P.; Rao, H.; Hua, R.; Li, C.-J. Org. Lett. 2012, 14,
902-905; (d) Hu, J.; Adogla, E. A.; Ju, Y.; Fan, D.; Wang, Q. Chem.
Commun. 2012, 48, 11256; (e) Menéndez, C. A.; Nador, F.; Radivoy, G.;
Gerbino, D. C. Org. Lett. 2014, 16, 2846; (f) Rao, H.; Ma, X.; Liu, Q.; Li,
Z.; Cao, S.; Li, C.-J. Adv. Synth. Catal. 2013, 355, 2191.
16. Zhang, H.; Shi, R.; Gan, P.; Liu, C.; Ding, A.; Wang, Q.; Lei, A. Angew.
Chem., Int. Ed. 2012, 51, 5204-5207.
Acknowledgments
17. Zhao, L.; Xie, F.; Cheng, G.; Hu, Y. Angew. Chem., Int. Ed. 2009, 48,
6520-6523.
Partial financial support from the Fundamental Research
Funds for the Central Universities in NWSUAF (2452013QN008)
and the National Natural Science Foundation of China (31301712)
is greatly appreciated. One of the authors would like to thank
Opening Funds of Key Laboratory of Synthetic Chemistry of
Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences for the generous financial support
for funding this project. The authors are indebted to Prof F. W. Li
in Lanzhou Institute of Chemistry and Physics for applying the
idea.
18. (a) Roglans, A.; Pla-Quintana, A.; Moreno-Mañas, M. Chem. Rev. 2006,
106, 4622-4643; (b) Galli, C. Chem. Rev. 1988, 88, 765-792.
19. (a) Du, Z.; Zhou, J.; Si, C.; Ma, W. Synlett 2011, 3023-3025; (b) Zhou, J.;
Huang, L.-Z.; Li, Y.-Q.; Du, Z.-T. Tetrahedron Lett. 2012, 53, 7036-
7039; (c) Han, P.; Zhou, J.; Zhang, C. C.; Chen, K.; Du, Z. T.
Heterocycles 2014, 89, 2151-2160.
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References and notes
1. Peres, V.; Nagem, T. J.; de Oliveira, F. F. Phytochemistry 2000, 55, 683-
710.