A convenient approach to the xanthone scaffold by an aqueous aromatic substitution of bromo- and iodoarenes

Article abstract of DOI:10.1016/j.tet.2009.05.021

Unusual displacements of bromides and iodides through nucleophilic aromatic substitution reactions give a direct access to the xanthone core. This sustainable process is based on the use of water as an environmentally friendly solvent.

Full text of DOI:10.1016/j.tet.2009.05.021

Tetrahedron 65 (2009) 5729–5732
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A convenient approach to the xanthone scaffold by an aqueous aromatic
substitution of bromo- and iodoarenes
*
*
´
Nekane Barbero, Raul SanMartin , Esther Domınguez
Kimika Organikoa II Saila, Zientzia eta Teknologia Fakultatea, Euskal Herriko Unibertsitatea, PO BOX 644, 48080 Bilbao, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Unusual displacements of bromides and iodides through nucleophilic aromatic substitution reactions
give a direct access to the xanthone core. This sustainable process is based on the use of water as an
environmentally friendly solvent.
Received 24 March 2009
Received in revised form 4 May 2009
Accepted 7 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 14 May 2009
1. Introduction
of cyclised product 1 (10%) in the absence of any copper source
(Table 1, entry 1),9 we decided to study this transformation in
The nucleophilic aromatic substitution (SNAr) reaction is a clas-
sic and well established synthetic tool to build a wide range of
target molecules, among which pharmaceuticals and diverse drugs
can be found.1 These displacements have been traditionally ac-
complished under harsh reaction conditions and normally required
sufficiently activated aromatic rings (e.g., substituted with prefer-
ably more than one nitro group).2 Besides, the reaction outcome
and its rate are strongly related to the nature of the nucleophile
strength, the solvent and the leaving-group ability, which normally
is considered to be decreasing in the series of F, NO2[Cl>Br>I.3
Thus, in general, the practical synthetic utility of bromide and iodide
displacement in SNAr processes could be considered relatively
limited.4,2e
The xanthone skeleton constitutes the core of an important
natural and biologically active family of compounds present in
higher plants and microorganisms.5 One of the most employed
strategies to access to xanthones involves a SNAr reaction from
conveniently substituted benzophenones. In this context, 2,20-
dihydroxybenzophenones, 2-alkoxy-20-hydroxybenzophenones and
2,20-dialkoxybenzophenones have been the substrates of choice.6
2-Fluoro and 2-chloro-20-hydroxybenzophenone derivatives have
also given rise to xanthones successfully.7 On the contrary,
nucleophilic substitution of 2-iodo and 2-bromo-20-hydroxy-
benzophenone derivatives has never been a general approach to
the valuable xanthone skeleton.8 As in the course of our recent
work on the preparation of xanthones through a copper-catalysed
intramolecular O-arylation reaction from both 2-bromo and 2-
iodobenzophenones we observed the formation of a little amount
detail.
Herein, we wish to report a simple and general procedure for the
construction of the xanthone core based on unusual iodide and
bromide displacements. In addition, this key transformation is
performed in water, a sustainable and very convenient solvent.10
2. Results and discussion
As mentioned above we detected the formation of a little
amount of the target xanthone 1a when the reaction was carried
out stirring the previously prepared11 2-bromobenzophenone 2a
in the presence of 3.5 equiv of TMEDA in water at 120 ꢀC (Table 1,
entry 1). Encouraged by this result the reaction was screened with
several bases, studying mainly the influence of their strength and
amount in the reaction outcome, as shown in Table 1. Water
was the only evaluated solvent due to the benefits associated to its
use, as non-flammability, easy-handling and environmental
benignity.12
Considering the typical toxicity and price of nitrogen-containing
organic bases, we opted preferably for performing the reactions by
employing alkoxides and inorganic cheap bases.
When 2-bromobenzophenone 2a reacted in the presence of
3 equiv of K2CO3 at 120 ꢀC the SNAr reaction proceeded smoothly,
affording the cyclised product in 88% yield (entry 2). A change in
the counter ion from potassium to sodium only provided a curious
decrease in the yield (from 88 to 76, entries 2 vs 3). The use of
weaker bases, such as NaOAc, KOAc or pyridine resulted in the re-
covery of the unreacted substrate (entries 4 and 5).
From all the hydroxides tested KOH proved superior to both
NaOH and LiOH$H2O, delivering target xanthone 1a in an excellent
yield of 92% (entries 9 vs 6–8). Attempts to decrease the reaction
temperature and the amount of base were successful, showing
* Corresponding authors. Tel.: þ34 946 015 435; fax: þ34 946 012 748.
E-mail address: raul.sanmartin@ehu.es (R. SanMartin).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.021

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N. Barbero et al. / Tetrahedron 65 (2009) 5729–5732
Table 1
Table 2
Selected assays for the synthesis of xanthone 1aa
Preparation of a series of xanthones 1a
R'
X
Br
O
base
O
O
Method A or
Method B
R'
water, T
R
R
O
OH
O
OH
O
1a
2
X = I, Br, Cl
1
2a
Baseb
Equiv
T (ꢀC)
Yieldc (%)
Entry
Substrate
Yield 1b (%)
Entry
1
2
TMEDA
K2CO3
Na2CO3
NaOAc
py
LiOH$H2O
NaOH
NaOH
KOH
KOH
KOH
KOH
KOH
3.5
3.0
5.0
4.0
4.0
4.0
2.0
3.0
4.0
3.0
2.0
1.0
2.0
2.0
3.0
3.0
3.0
2.0
1.0
0.5
120
120
120
120
120
120
120
100
120
100
100
100
100
100
120
100
80
10
88
76
0
Method A
Method B
93c
3
Br
O
4d
5
1
93
99
90
79
91
0
6
7
8
9
85
73
79
92
90
93
67
76
93
97
95
73
97
93
69
2a
OH
10
11
12
13e
14f
15
16
17
18
19g
20
I
2
3
4
5
6
7
KOH
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
2b
O
OH
OH
100
100
100
Cl
O
92
a
The reactions were run in distilled water (12 mL/mmol) at the specified tem-
perature and overnight.
2c
b
TMEDA: N,N,N0,N0-tetramethylethylenediamine, py: pyridine.
Yield of isolated product.
The same result was obtained using KOAc.
Dilution (2 mL/mmol) was used.
c
d
e
f
Dilution (25 mL/mmol) was used.
I
A lower yield (73%) was obtained with KOtBu.
g
2d
O
OH
that still good to excellent results could be obtained using 3, 2 and
even only 1 equiv of inexpensive KOH at 100 ꢀC in neat water
(entries 10–12). When the concentration of the reactants in the
aqueous solution was increased the yield diminished to 76% (en-
tries 13 vs 11). However, the use of a more diluted solution ap-
parently did not affect the outcome of the reaction (entry 14).
Interestingly, when the more reactive NaOtBu was used, the re-
action proceeded efficiently to render the tricyclic skeleton (en-
tries 15–20), isolating the product in an excellent yield of 93%
when only 1 equiv of the base was added (entry 19). Moreover,
a still good yield of 69% of xanthone 1a was obtained when
NaOtBu was employed in substoichiometric amounts (0.5 equiv,
entry 20). An additional experiment reducing the temperature to
80 ꢀC was run, but unfortunately the yield decreased to 73% (en-
tries 16 vs 17).
Cl
O
2e
OH
Br
O
>99
OH
2f
Taking into account all the experimental results it was decided
that the best conditions involved stirring the starting material in
the presence of either 2 equiv of KOH or only one of NatOBu in
water at 100 ꢀC (Methods A and B, respectively, hereafter). It should
be pointed out the ease of the reaction setup, absence of side
products and no requirement of an inert atmosphere.
I
49
60
F
O
OH
2g
Once having optimised the conditions for the intramolecular
SNAr in aqueous media, a series of 2-iodo, 2-bromo and 2-chloro-
benzophenones 2a–n11 were subjected to them. The results are
displayed in Table 2.
As shown in Table 2 excellent results were obtained in the
cyclisation processes, regardless the nature of the halogen present
in the aromatic moiety. In contrast with the intramolecular copper-
catalysed O-arylation reaction,9 2-chlorobenzophenone derivatives
2c, 2e and 2j proved to be valuable starting materials in this
aqueous SNAr (entries 3, 5 and 10). 2-Iodo and 2-bromobenzophenone
Cl
Br
8
9
>99
O
OH
2h
Br
O
91
>99
OH
2i

N. Barbero et al. / Tetrahedron 65 (2009) 5729–5732
5731
Table 2 (continued )
Moreover, several functionalities were easily tolerated in the
substrates. Besides, the use of water as solvent makes our
methods environmentally friendly and attractive for pharma-
ceutical purposes.
Entry
Substrate
Yield 1b (%)
Method A
Method B
95
Cl
4. Experimental section
4.1. General remarks
10
87
64
O
OH
2j
Br
All reagents and solvents were purchased and used without
further purification. 1H and 13C NMR spectra were recorded in
CDCl3 solution in a Bruker AC-300. Chemical shifts are reported in
parts per million downfield (d) from Me4Si. IR spectra were
recorded on a Perkin–Elmer 1600 FT infrared spectrophotometer
and only noteworthy absorptions are listed. Melting points were
determined in a capillary tube and are uncorrected. TLC was car-
ried out on SiO2 (silica gel 60 F254, Merck), and the spots were
located with UV light. Flash chromatography was carried out on
SiO2 (silica gel 60, Merck, 230–400 mesh ASTM). Drying of organic
extracts after work-up of reactions was performed over anhydrous
11
12
13
>99
2k
O
OH
Cl
Br
86
2l
O
OH
OMe
OMe
Br
O
>99
Na2SO4. HRMS were measured using
Spectrometer.
a Waters GCT Mass
2m
OH
4.1.1. General procedure
I
14d
d
A screw-capped tube (approximate volume: 18 mL) was charged
with 2-haloarylbenzophenone 2 (1 equiv), KOH (2 equiv, Method A)
or NaOtBu (1 equiv, Method B) and water (12 mL/mmol) at room
temperature. After closing, the tube was heated to 100 ꢀC for 15 h,
allowed to cool to room temperature and the resulting mixture was
extracted with CH2Cl2. The combined organic layers were dried
over anhydrous sodium sulfate and concentrated in vacuo to give
a solid residue, which was redissolved and filtered through a short
pad of silica gel. The filtrate was evaporated under reduced pres-
sure to provide the target xanthone as a white powder.
F
O
OH
2n
a
Method A: 2 equiv of crushed KOH, distilled H2O (12 mL/mmol) at 100 ꢀC.
Method B: 1 equiv of NatOBu, distilled H2O (12 mL/mmol) at 100 ꢀC.
b
Yield of isolated product.
c
Yield (97%) was obtained using 2 equiv of NatOBu.
d
A mixture of inseparable products was observed.
derivatives afforded regioselectively the target tricyclic skeleton in
similar and sometimes even better yields to 2-chloro analogues
(Table 2, entries 1 and 2 vs 3; 4 vs 5 and 9 vs 10). These relatively
surprising results should be outlined, considering the already
established order of leaving-group ability in the SNAr, in which
iodides and bromides are the least reactive ones.
This general procedure was applied to 2-halobenzoyl-
benzophenones 2, providing the following products.
4.1.2. 2-Methylxanthen-9-one13
Starting from 2-bromobenzophenone 2a yields of >99% (Method A)
and 93% (Method B) were obtained.
Method B was only employed when the yields obtained with
Method A were moderate. Although the former method proved
superior (entries 2–4, 7, 9–11), we chose KOH due to its lower cost
and greater availability. The presence of additional halogens in the
substrate was compatible with the reaction conditions (entries 7, 8
and 12), not observing side reactions. However, on the basis of the
results displayed in entries 7, 8 and 12, it can be suggested that m-Cl
substituents activate the reaction and the use of the p-fluorinated
substrates provokes a significant decrease in the yield is observed.
Moreover, the cyclisation reaction did not proceed from 2-iodo-
benzophenone derivative 2n (entry 14). The electron-rich 2-bromo-
benzophenone 2m rendered the target xanthone in a quantitative
yield (entry 13). In the same context of relatively sterically hindered
substrates, the reaction conditions were also successful when the
hydroxyl group containing moiety was a 1-hydroxynapthalene,
obtaining the corresponding tetracycle with excellent yields rang-
ing from 86 to 100% (entries 9–12).
Starting from the 2-iodoarylbenzophenone 2b a yield of >99%
(Method A) was obtained.
Starting from 2-chlorobenzophenone 2c yields of 90% (Method A)
and 93% (Method B) were obtained.
4.1.3. 2,3-Dimethylxanthen-9-one14
Starting from the 2-iodoarylbenzophenone 2d a yield of 79%
(Method A) was obtained.
Starting from the 2-chloroarylbenzophenone 2e a yield of 79%
(Method A) was obtained.
4.1.4. 2,3-Dimethylxanthen-9-one9
Starting from the 2-chloroarylbenzophenone 2f a yield of >99%
(Method A) was obtained.
4.1.5. 2-Fluoro-6,7-dimethylxanthen-9-one9
Starting from 2-iodobenzophenone 2g yields of 49% (Method A)
and 60% (Method B) were obtained.
3. Conclusions
4.1.6. 3-Chloro-6,7-dimethylxanthen-9-one9
Starting from the 2-bromoarylbenzophenone 2h a yield of >99%
(Method A) was obtained.
In summary, two practical and high yielding methodologies
based on SNAr processes to access to the appealing xanthone
framework from the corresponding 2-halo-20-hydroxybenzo-
phenones are reported. These alternative protocols provided
excellent results from non-conventional bromo and iodo de-
rivatives, thus relativising the role of the latter leaving groups.
4.1.7. 7H-Benzo[c]xanthen-7-one14
Starting from 2-bromobenzophenone 2i yields of 91% (Method
A) and >99% (Method B) were obtained.

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N. Barbero et al. / Tetrahedron 65 (2009) 5729–5732
K. M. J. Am. Chem. Soc. 1957, 79, 385–391; (d) Cox, B. G.; Parker, A. J. J. Am. Chem.
Starting from 2-chlorobenzophenone 2j yields of 87% (Method
A) and 95% (Method B) were obtained.
Soc. 1973, 95, 408–410; (e) Um, I.-H.; Min, S.-W.; Dust, J. M. J. Org. Chem. 2007,
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(g) Acevedo, O.; Jorgensen, W. L. Org. Lett. 2004, 6, 2881–2884.
4. Some examples where iodo and bromo derivatives are used as a counterparts
in SNAr proccesses can be found in: (a) Liu, J.; Morris, M. J. J. Am. Chem. Soc.
2007, 129, 5962–5968; (b) Org. Lett. 2009, 11, 1745–1748.
5. Xanthones have numerous pharmaceutical and medicinal applications, and
important properties such as anticancer, antithrombotic and cytotoxic ones.
See: (a) Ho, C. K.; Huang, Y. L.; Chen, C. C. Planta Med. 2002, 68, 975–979; (b)
Matsumoto, K.; Akao, Y.; Kobayashi, E.; Ohguchi, K.; Ito, T.; Tanaka, T.; Iinuma,
M.; Nozawa, Y. J. Nat. Prod. 2003, 66, 1124–1127; (c) Wang, L.-W.; Kang, J.-J.;
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Y. J. Tetrahedron Lett. 1998, 39, 9103–9106.
4.1.8. 10-Methyl-7H-benzo[c]xanthen-7-one9
Starting from 2-bromobenzophenone 2k yields of 64% (Method
A) and >99% (Method B) were obtained.
4.1.9. 10-Chloro-7H-benzo[c]xanthen-7-one9
Starting from the 2-bromoarylbenzophenone 2l a yield of 86%
(Method A) was obtained.
6. (a) Pillai, R. K. M.; Naiksatam, P.; Johnson, F.; Rajagopalan, R.; Watts, P. C.;
Cricchio, R.; Borras, S. J. Org. Chem. 1986, 51, 717–723; (b) Batova, A.; Lam, T.;
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8. (a) Only an isolated example of the synthesis of dixanthones from 4,6-di-(2-
bromobenzoyl)resorcinol has been reported thus far. See: Sharghi, H.; Tam-
addon, F.; Eshghi, H. Iran. J. Chem. Chem. Eng. 2000, 19, 32–36; (b) An spattered
example of xanthone synthesis from 2-bromo-20-hydroxybenzophenone using
potassium amide and liquid ammonia has been reported. See: Gibson, M. S.;
Vines, S. M.; Walthew, J. W. J. Chem. Soc., Perkin Trans. 1 1975, 155–160.
9. Barbero, N.; SanMartin, R.; Domı´nguez, E. Green Chem. 2009. doi:10.1039/
b900931k. The assay was carried out stirring 2-bromobenzophenone derivative
2a in the presence of 3.5 equiv of TMEDA in distilled water at 120 ꢀC overnight.
10. For some recent reviews on the utility of ‘on-water’ chemistry in organic
synthesis, see: (a) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 102, 725–748; (b)
Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2005, 44, 3275–3279; (c) For C–C bond formation in
water, see: Li, C.-J. Chem. Rev. 2005, 105, 3095–3166; (d) Li, C.-J.; Chen, L. Chem.
Soc. Rev. 2006, 35, 68–82; (e) For aldol reaction in aqueous media, see: Mly-
narski, J.; Paradowska, J. Chem. Soc. Rev. 2008, 37, 1502–1511.
4.1.10. 3,4-Dimethoxyxanthen-9-one9
Starting from the 2-bromoarylbenzophenone 2m a yield of
>99% (Method A) was obtained.
Acknowledgements
This research was supported by the University of the Basque
Country/Basque Government (Projects S-PC08UN04, UNESCO07/08
and GIU06/87/IT-349-07). N.B. thanks the Spanish Ministry of Educa-
tion and Science for a predoctoral scholarship. The authors also thank
Petronor, S.A. (Muskiz, Bizkaia) for a generous donation of hexane.
Supplementary data
Typical experimental procedures, including spectroscopic and
analytical data for all the new intermediates along with NMR
spectra of the new compounds. This material is available free of
charge via ScienceDirect. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2009.05.021.
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