Novel one-pot synthesis of xanthones via sequential fluoride ion-promoted fries-type rearrangement and nucleophilic aromatic substitution

Article abstract of DOI:10.1055/s-0033-1339881

A novel and efficient synthesis of xanthones is described. 2-(Trimethylsilyl)phenyl 2-fluorobenzoate derivatives undergo Fries-type rearrangement and intramolecular S_NAr reaction in a one-pot sequential manner under fluoride ion-promoted mild conditions. The method provides efficient access to xanthones that have significant steric congestion around the C9 carbonyl, which are not readily available by conventional methods. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339881

LETTER
▌2575
lNettoervel One-Pot Synthesis of Xanthones via Sequential Fluoride Ion-Promoted
Fries-Type Rearrangement and Nucleophilic Aromatic Substitution
One-Pot Synthesis of Xanthones
Yuuki Fujimoto,a Ryohei Itakura,b Hiroki Hoshi,a Hikaru Yanai,a Yoshio Ando,b Keisuke Suzuki,b
Takashi Matsumoto*a
a
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1, Horinouchi, Hachioji, Tokyo, 192-0392, Japan
Fax +81(42)6763257; E-mail: tmatsumo@toyaku.ac.jp
b
Department of Chemistry, Tokyo Institute of Technology, 2-12-1, Ookayama, Meguro-ku, Tokyo, 152-8551, Japan
Fax +81(3)57342788; E-mail: ksuzuki@chem.titech.ac.jp
Received: 19.07.2013; Accepted after revision: 02.09.2013
ammonium fluoride (TBAF) in the presence of 4 Å mo-
Abstract: A novel and efficient synthesis of xanthones is de-
lecular sieves, 2-(trimethylsilyl)phenyl 2-fluorobenzoate
scribed. 2-(Trimethylsilyl)phenyl 2-fluorobenzoate derivatives un-
I undergoes Fries-type rearrangement via silicate II to
generate benzophenone III, possessing phenoxide and
dergo Fries-type rearrangement and intramolecular SNAr reaction in
a one-pot sequential manner under fluoride ion-promoted mild con-
ditions. The method provides efficient access to xanthones that have fluorine moieties at the C2 and C2′ positions, which im-
significant steric congestion around the C9 carbonyl, which are not
readily available by conventional methods.
mediately cyclizes into xanthone IV through an intra-
molecular SNAr reaction.12–14
Key words: xanthone, Fries-type rearrangement, nucleophilic aro-
matic substitution, fluoride ion
O
O
R2
R2
R1
R1
(n-Bu)4NF, 4 Å MS
O
THF
SiMe3
Xanthones are secondary metabolites occurring in a vari-
ety of higher plant families, fungi, lichens, and bacteria.1
Because of their diverse biological and pharmacological
properties, such as antimicrobial,2 anti-inflammatory,3 an-
tioxidative,4 antimalarial,5 anticancer,6 and enzyme inhib-
itory activities,7 a large number of synthetic approaches to
xanthones have been reported.8 Among those classical
methods are intramolecular ether formation of 2-hydroxy-
benzophenone derivatives possessing a leaving group at
the C2′ position by nucleophilic aromatic substitution
(SNAr) and the cyclization of diaryl ether derivatives by
intramolecular acylation. The former approach is most
commonly applied, although problems often arise from
steric congestion by the substituents and functional group
incompatibility in the cyclization and/or the preparation
of the precursor benzophenones. Recently published ap-
proaches include direct formation of the xanthone frame-
work by the reaction of arynes with salicylates,9 the
palladium-catalyzed annulation of 1,2-dihaloarenes and
salicyladehydes,10 and the Diels–Alder reaction of 2-vinyl-
chromones.11 In the light of the structural diversity of
xanthone derivatives of biological interests, further inves-
tigations are needed to devise new syntheses that could be
adopted, in particular, to multiply substituted derivatives
in a regiocontrolled manner with high tolerance of func-
tional groups and substitution patterns.
O
F
IV
I
– F–
F–
O
R2
R1
O
F
R2
R1
O
SiMe3
F
F
O
III
II
Scheme 1 Fluoride ion promoted one-pot synthesis of xanthone
The key features of this new method include (1) ready
availability of the substrate esters I from the correspond-
ing carboxylic acids and phenols, (2) mild conditions pro-
moted by fluoride ion, (3) capability to produce sterically
congested benzophenone intermediates III and then the
corresponding xanthones IV, which are not readily acces-
sible by conventional methods.
We initiated our studies with the synthesis of ester 5a as a
model substrate (Scheme 2). 2-Fluoro-5-methoxybenzoic
acid (3) was converted into the acid chloride by the stan-
dard procedure and then reacted with the phenolate anion
of 2-(trimethylsilyl)phenol (2), which was obtained from
2-iodophenol through an O-silylation/retro-Brook re-
arrangement sequence,15 to afford the desired ester 5a. In
a similar manner, esters 5b–h were prepared in good to
high yield (see Table 2).
Herein, we wish to report a novel one-pot synthesis of
xanthones from phenyl benzoate derivatives promoted by
fluoride ion (Scheme 1). Upon treatment with tetrabutyl-
With a series of substrate esters, we first subjected ester
5a to a commercial THF solution of TBAF (1.5 equiv) at
25 °C, only leading to hydrolysis of ester to give, after the
SYNLETT 2013, 24, 2575–2580
Advanced online publication: 30.09.2013
DOI: 10.1055/s-0033-1339881; Art ID: ST-2013-U0675-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2576
Y. Fujimoto et al.
LETTER
a, b
HO
HO
SiMe3
I
O
F
1
2
MeO
d
O
SiMe3
O
O
F
5a
MeO
MeO
Cl
c
OH
F
3
4
Scheme 2 Preparation of ester 5a. Reagents and conditions: (a) HMDS, THF, reflux, 2 h; (b) t-BuLi, THF, –78 °C, 30 min, 99% (2 steps);
(c) SOCl2, DMF (cat.), CHCl3, reflux, 5.5 h; (d) 2, NaH, THF, 0 °C, 10 min; then 4, 0 to 25 °C, 1 h, 94%.
two-hour reaction, compounds 2 and 3 in 30–40% yields
with recovery of the starting material. To our delight,
however, the situation changed by the combined use of
TBAF with 4 Å molecular sieves (Scheme 3). A solution
of TBAF in THF was admixed with powdered and freshly
dried 4 Å molecular sieves at 25 °C, to which was added
ester 5a. The starting material was gradually consumed at
25 °C, and the reaction went to completion in one hour to
afford the desired xanthone 6a as a single product. Nota-
bly, none of the other possible compounds, such as the
proto-desilylation product 7 or benzophenone 8, were de-
tected by TLC-monitoring of the reaction course.
Table 1 Optimization of the Amount of TBAF
Entry
TBAF (equiv)
Time (h)
Yield (%)a
1
1.5
1.0
1.5
6.0
10
100
100
86b
84b
7b
2
1.0
3
0.5
4
0.25
0.10
5
24
a Isolated yield.
b The starting material was recovered in 2, 4 and 81% in entries 3, 4
and 5, respectively.
With this successful result, we next attempted to reduce
the amount of TBAF used, since the reaction could, in
principle, proceed under fluoride-ion catalysis (Table 1).
Indeed, the use of 0.5 or 0.25 equivalent of TBAF led to a
fairly clean reaction, giving xanthone 6a in reasonable
yields, although the starting material was not completely
consumed even after prolonged reaction time. The yield
of the xanthone drastically decreased with 0.1 equivalent
of TBAF.
Examples of the substrate scope are summarized in Table
2, in which each reaction was carried out with 1 equiva-
lent of TBAF.17 As shown in entry 2, ester 5b gave 1-me-
thoxyxanthone (6b) in 69% yield. It is worth noting for
comparison that 2-methoxybenzoate derivative 9 under-
went the Fries-type rearrangement to give benzophenone
10 under similar conditions, but not the subsequent intra-
molecular substitution of the methoxy group even after
prolonged reaction time (Scheme 4).18 Moreover, 2,6-di-
methoxybenzoate derivative 11 only gave the proto-
desilylation product 13, revealing that steric congestion
Further extensive screening of fluoride sources, solvents,
and drying agents eventually showed the protocol detailed
above [i.e., TBAF (0.5–1.0 equiv), 4 Å molecular sieves,
THF, r.t.] to be optimal for the reaction.16
O
O
(n-Bu)4NF (1.5 equiv)
4 Å MS
MeO
MeO
O
THF, 25 °C, 1 h
quant
SiMe3
O
F
5a
6a
O
OH
O
MeO
MeO
O
F
H
F
7
8
Scheme 3 Xanthone formation from ester 5a; compounds 7 and 8 were not observed
Synlett 2013, 24, 2575–2580
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of Xanthones
2577
by two methoxy groups hindered the C–C bond formation its sterically less demanding and strongly electron-with-
from the silicate.
drawing nature,12 it not only serves as an effective leaving
group in the SNAr process to enable the one-pot formation
These results demonstrate the advantage of employing a
fluorine as the ortho substituent of the ester moiety; due to
Table 2 One-Pot Synthesis of Xanthonesa
Entry
1
Ester 5
Yield of 5 (%)b Xanthone 6
Time (min)
Yield of 6 (%)c
O
O
O
F
MeO
MeO
O
94
60
quant
SiMe3
6a
5a
MeO
O
MeO
O
O
O
2
3
4
5
6
7
8
78
68
76
85
98
81
76
60
60
15
10
60
10
60
69d,e
68d
97
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
O
O
F
6b
5b
MeO
OMOM
MeO
O
OMOM
O
F
6c
5c
F
O
OMe
F
O
O
OMe
O
O
F
6d
5d
F
OMOM
OMOM
F
O
O
O
O
O
OMOM
OMOM
96
O
O
F
6e
5e
Br
Br
O
74
O
O
F
6f
5f
F
F
O
93
O
O
F
5g
6g
Ph
OMOM
Ph
O
OMOM
30
O
F
6h
5h
a The reactions were carried out by using 1 equiv of TBAF in the presence of 4 Å MS in THF at 25 °C.
b Yields from the corresponding phenols.
c Isolated yields of chromatographically pure materials.
d The corresponding proto-desilylation product was obtained in 10% yield.
e See the literature.17
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2575–2580

2578
Y. Fujimoto et al.
LETTER
zo[a]xanthone 6g was obtained by the reaction of naph-
thyl ester 5g in high yield (entry 7), whereas the reaction
of biphenylcarboxylate 5h gave xanthone 6h, possessing
a phenyl group at the C8, only in low yield (entry 8).
O
OH
O
(n-Bu)4NF, 4 Å MS
O
THF, 25 °C, 1 h
70%
SiMe3
O
OMe
Me
Tolerance of a halogen substituent at the C1 (or C8) posi-
tion (entries 4–7) is another notable feature of this meth-
od, since it would provide various opportunities for
further transformation, as demonstrated in Scheme 5 and
Scheme 6 (see Figure 1 for numbering). 1-Fluoroxanthone
6d readily underwent SNAr reactions with pyrrolidine and
sodium ethoxide at room temperature. Introduction of a
carbon substituent to the C1 position was effected by ex-
ploiting transition-metal catalyzed coupling of a 1-bromo-
xanthone derivative (Scheme 6). Phenyl and alkynyl
xanthones 17 and 18 were successfully obtained from 16
by Sonogashira and Suzuki–Miyaura coupling, respec-
tively.20,21 Conversion of xanthone 18 into the corre-
9
10
MeO
O
OH
O
MeO
(n-Bu)4NF, 4 Å MS
O
THF, 25 °C, 1 h
0%
SiMe3
O
OMe
11
Me
12
O
MeO
O
H
OMe
Br
O
OR
13 : 85%
Scheme 4 The reactions of 2-methoxybenzoate 9 and 2,6-di-
methoxybenzoate 11
O
6f R = MOM
16 R = H
a
of the xanthone framework but also does not encumber
the C–C bond formation process.
c
We then focused on the synthesis of 1,8-disubstituted xan-
thones, which demands the intermediacy of the severely
congested ortho-tetrasubstituted benzophenone (Table 2,
entries 3–8). The lack of an effective route to such xantho-
nes is a major drawback of current xanthone syntheses,
since most of the existing methods rely on the cyclization
of the benzophenone derivatives, and the steric congestion
makes the preparation of ortho-tetrasubstituted benzophe-
nones troublesome.19 Therefore, accessibility to 1,8-di-
substituted xanthones would become a touchstone for
evaluating the utility of the new method.
O
OH
b
O
18
d
SiMe3
O
O
OTf
O
OH
Gratifyingly, we found the reaction of 5c proceeded
smoothly to afford the desired 1-methoxy-8-(methoxyme-
thoxy)xanthone (6c) in 68% yield, albeit accompanied by
a small amount (10%) of the proto-desilylation product
(entry 3). 2,6-Difluorobenzoates 5d and 5e reacted still
more cleanly, thereby giving the corresponding xanthones
6d and 6e in excellent yields (entries 4 and 5). The reac-
tion of 2-bromo-6-fluorobenzoate (5f) exclusively gave
xanthone 6f by involving the fluorine, rather than the bro-
mine, in the ether bond formation, as expected from the
general tendency of SNAr reactions (entry 6). Ben-
e
O
O
O
17
19
20
Scheme 6 Transformations of 1-bromoxanthone 6f. Reagents and
conditions: (a) 4 M HCl (aq), THF, 25 °C, 24 h, quant; (b) 7.5 mol%
Pd(PPh3)4, HC≡CSiMe3, CuI, Et3N, DMF, 70 °C, 1 h, 58%; (c) 10
mol% Pd(PPh3)4, PhB(OH)2, Ba(OH)2·8H2O, 1,2-dimethoxyethane
(DME)/H2O (4:1), reflux, 2 h, quant; (d) Tf2O, pyridine, CH2Cl2,
25 °C, 17 h, 90%; (e) 17 mol% Pd(PPh3)4, PhB(OH)2, K3PO4, 1,4-di-
oxane, 85 °C, 70 min, 72%.
N
O
OMe
F
O
OMe
EtO
O
OMe
N
H
NaOEt
THF
25 °C, 6.5 h
97%
EtOH
25 °C, 0.5 h
O
O
O
98%
14
6d
15
Scheme 5 Transformations of 1-fluoroxanthone 6d
Synlett 2013, 24, 2575–2580
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of Xanthones
2579
(b) Sousa, M. E.; Pinto, M. M. M. Curr. Med. Chem. 2005,
12, 2447.
(9) Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583; see also
ref. 14.
sponding triflate 19 allowed the introduction of a second
phenyl moiety by the Suzuki–Miyaura coupling to give
1,8-diphenylxanthone (20) in 72% yield.
(10) Wang, S.; Xie, K.; Tan, Z.; An, X.; Zhou, X.; Guo, C.-C.;
Peng, Z. Chem. Commun. 2009, 6469.
(11) Dang, A.-T.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org.
Lett. 2008, 10, 233.
O
1
8
8a
9a
2
3
7
6
9
(12) For a review on the reactions of organofluorine compounds,
see: Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
(13) For an example of xanthone synthesis by utilizing Fries-type
rearrangement, see: Horne, S.; Rodrigo, R. J. Org. Chem.
1990, 55, 4520.
O
5
4
Figure 1 Xanthone numbering
(14) Recently, Larock and co-workers reported a xanthone
synthesis involving a similar reaction pathway in which the
aryl anion, formed by nucleophilic attack of a carboxylate
anion of o-haloarenecarboxylic acid to aryne, undergoes
Fries-type rearrangement and subsequent intramolecular
SNAr reaction. See: (a) Dubrovskiy, A. V.; Larock, R. C.
Org. Lett. 2010, 12, 3117. (b) Dubrovskiy, A. V.; Larock, R.
C. Tetrahedron 2013, 69, 2789; Advantages of the present
protocol over Larock’s approach include the lower reaction
temperature (25 versus 125 °C), the shorter reaction time,
and accessibility to sterically congested xanthone
derivatives.
In summary, a novel one-pot synthesis of xanthones has
been demonstrated.22 The reaction proceeds under mild
conditions promoted by fluoride ion, and provides an effi-
cient route to 1,8-disubstituted xanthone derivatives that
are not readily accessible by conventional methods. Fur-
ther studies including application to the synthesis of natu-
ral products with densely functionalized xanthone
structures are under way.
Acknowledgment
(15) Simchen, G.; Pletschinger, J. Angew. Chem. Int. Ed. Engl.
1976, 15, 428.
We are grateful to Mr. Haruhiko Fukaya, Tokyo University of Phar-
macy and Life Sciences, for X-ray analyses. This work was suppor-
ted by a Grant-in-Aid for Specially Promoted Research (No.
23000006) from the Japan Society for the Promotion of Science
(JSPS) (Japan).
(16) (a) The following conditions were examined: TBAT ([(n-
Bu)4N]+[SiPh3F2]–), TASF ([(Me2N)3S]+ [SiMe3F2]–),
Bn(Me)3NF, Me4NF, (n-Bu)4NF·(t-BuOH)4,16b C6F6/(n-
Bu)4NCN,16c CsF, KF, ZnF2, and LiBF4 as the fluoride ion
source; Et2O, 1,4-dioxane, DME, DMF, CH2Cl2, MeCN, and
toluene as the solvent; molecular sieves 3A and 13X as the
drying agent. The use of TBAT, TASF, Bn(Me)3NF, or
Me4NF (1.5 equiv each) in the presence of 4 Å molecular
sieves in THF gave xanthone 6a in moderate yields (30–
45%). Other combinations were still less effective. (b) Kim,
D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H. Angew. Chem.
Int. Ed. 2008, 47, 8404. (c) Sun, H.; Dimagno, S. J. Am.
Chem. Soc. 2005, 127, 2050.
(17) Since the use of a catalytic amount of TBAF in the reaction
of 5b led to unacceptable yield of 1-methoxyxanthone (6b)
[60% with 0.5 equiv of TBAF (25 °C, 2 h); 38% with 0.2
equiv of TBAF (reflux, 24 h)], we opted to use 1 equiv of
TBAF in the reactions used to obtain the congested xanthone
possessing substituent(s) at C1 and/or C8.
(18) Treatment of benzophenone 10 with Cs2CO3 in DMF (80 °C,
5 h) cleanly effected the SNAr reaction to give xanthone in
90% yield.
(19) (a) Chuzel, O.; Roesch, A.; Genet, J.-P.; Darses, S. J. Org.
Chem. 2008, 73, 7800. (b) O’Keefe, B. M.; Simmons, N.;
Martin, S. F. Org. Lett. 2008, 10, 5301. (c) Lampe, J. W.;
Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu, H. J. Org.
Chem. 1994, 59, 5147.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
(1) For recent reviews on natural xanthones, see: (a) El-Seedi,
H. R.; El-Barbary, M. A.; El-Ghorab, D. M.; Bohlin, L.;
Borg-Karlson, A. K.; Göransson, U.; Verpoorte, R. Curr.
Med. Chem. 2010, 17, 854. (b) Pinto, M. M. M.; Sousa, M.
E.; Nascimento, M. S. J. Curr. Med. Chem. 2005, 12, 2517.
(2) Franklin, G.; Conceição, L. F. R.; Kombrink, E.; Dias, A. C.
P. Phytochemistry 2009, 70, 60.
(3) Park, K. H.; Park, Y.-D.; Han, J.-M.; Im, K.-R.; Lee, B. W.;
Jeong, I. Y.; Jeong, T.-S.; Lee, W. S. Bioorg. Med. Chem.
Lett. 2006, 16, 5580.
(4) Santos, C. M. M.; Freitas, M.; Ribeiro, D.; Gomes, A.; Silva,
A. M. S.; Cavaleiro, J. A. S.; Fernandes, E. Bioorg. Med.
Chem. 2010, 18, 6776.
(5) Zelefack, F.; Guilet, D.; Fabre, N.; Bayet, C.; Chevalley, S.;
Ngouela, S.; Lenta, B. N.; Valentin, A.; Tsamo, E.; Dijoux-
Franca, M.-G. J. Nat. Prod. 2009, 72, 954.
(6) (a) Sousa, E.; Pavia, A.; Nazareth, N.; Gales, L.; Damas, A.
M.; Nascimento, M. S. J.; Pinto, M. Eur. J. Med. Chem.
2009, 44, 3830. (b) Pedro, M.; Cerqueira, F.; Sousa, M. E.;
Nascimento, M. S. J.; Pinto, M. Bioorg. Med. Chem. 2002,
10, 3725.
(7) (a) Khan, M. T. H.; Orhan, I.; Şenol, F.; Kartal, M.; Sener,
B.; Dvorská, M.; Šmejkal, K.; Šlapetovám, T. Chem. Biol.
Interact. 2009, 181, 383. (b) Ryu, Y. B.; Curtis-Long, M. J.;
Lee, J. W.; Kim, J. H.; Kim, J. Y.; Kang, K. Y.; Lee, W. S.;
Park, K. H. Bioorg. Med. Chem. 2009, 17, 2744.
(8) For recent reviews on the synthesis of xanthones, see:
(a) Masters, K.-S.; Bräse, S. Chem. Rev. 2012, 112, 3717.
(20) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467. (b) Chinchilla, R.; Nájera, C. Chem.
Soc. Rev. 2011, 40, 5084.
(21) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(22) One-Pot Synthesis of Xanthones; Typical Procedure
(Table 2, Entry 4): Powdered 4 Å molecular sieves (3.0 g)
were placed in a two-necked, round-bottom flask, and dried
by heating with a heat gun under vacuum. The flask was
cooled to r.t. and filled with argon, then THF (9 mL) and
TBAF (1.0 M in THF, 0.60 mL, 0.60 mmol) were added.
After stirring for 1.5 h at 25 °C, a solution of ester 5d (202
mg, 599 μmol) in THF (10 mL) was added and stirring was
continued for 15 min. The reaction was quenched by the
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2575–2580

2580
Y. Fujimoto et al.
LETTER
addition of pH 7 phosphate buffer (0.1 M) at 0 °C, and
molecular sieves were removed by filtration through a pad of
Celite. The filtrate was washed with brine, dried over
Na2SO4, and concentrated. The residue was purified by
column chromatography on silica gel (hexane–EtOAc, 2:1)
to give xanthone 6d (141 mg, 97%) as a white solid.
Recrystallization from hexane–EtOAc gave 6d as colorless
needles.
Synlett 2013, 24, 2575–2580
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