An efficient copper-catalytic system for performing intramolecular O-arylation reactions in aqueous media. New synthesis of xanthones

Article abstract of DOI:10.1039/b900931k

A safe, efficient protocol for the copper-catalysed intramolecular O-arylation of 2-halobenzophenones on water to afford the valuable xanthone framework is reported. The recovery and the successful reutilization of the aqueous solution containing the copp

Full text of DOI:10.1039/b900931k

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PAPER
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An efficient copper-catalytic system for performing intramolecular
O-arylation reactions in aqueous media. New synthesis of xanthones†‡
Nekane Barbero, Raul SanMartin* and Esther Dom´ınguez*
Received 15th January 2009, Accepted 6th March 2009
First published as an Advance Article on the web 19th March 2009
DOI: 10.1039/b900931k
A safe, efficient protocol for the copper-catalysed intramolecular O-arylation of
2-halobenzophenones on water to afford the valuable xanthone framework is reported. The
recovery and the successful reutilization of the aqueous solution containing the copper catalyst are
also presented. Moreover, the scalability and the easy setup and purification tasks of this
sustainable method make it appealing for bulk industry applications.
Introduction
The xanthone skeleton constitutes the core of an impor-
tant natural and biologically active family of compounds
present in higher plants and microorganisms. These secondary
metabolites have interesting pharmaceutical properties such as
anticancer,1 antithrombotic,2 antihypertensive,2 antibacterial,3
antitumoral,4 opiaceous,5 cytotoxic,6 antiviral7 and anti-inflam-
matory activity,7 among others. Moreover, they are also effective
against pathogenic fungi8 and in the inhibition of both gastric
secretion9 and biosynthesis of prostaglandin E2.10 According
to several authors, the biological role of xanthones can be
modulated by introducing specific substituents in their structure
(Fig. 1).11,12
Typically employed methods for the synthesis of the xanthone
scaffold imply the previous formation of benzophenones or
diarylethers by means of harsh experimental conditions or
harmful reactants.15,16 In recent years, alternative routes to access
Fig. 1 Some relevant natural xanthones,13 and the antibiotic FD-594.14
this appealing family of compounds have been developed. Some
of them involve photooxidative cyclisation17 or cycloaddition18
of 2-styrylchromones. More recently, another synthesis of the
xanthone core was carried out via the Diels–Alder reaction
of chromone-3-carboxaldehydes with o-benzoquinodimethane,
followed by the in situ oxidation of the cycloadducts.19 Further-
more, Larock and co-workers20 have designed a novel strategy
to prepare xanthones starting from salicylates and commercially
available silylaryl triflates, which act as aryne precursors in
the presence of four equivalents of CsF. Under these mild
reaction conditions an annulation step takes place to afford the
target products in a one-pot synthesis. They have also prepared
xanthones by palladium-catalysed arene C–H addition to nitriles
through the formation of ketones from substituted phenols and
2-fluorobenzonitriles, followed by an intramolecular cyclisation
in the presence of K2CO3.21 Another approach to the xanthone
framework accomplished by the same group implied an aryl to
imidoyl palladium migration process involving intramolecular
C–H activation.22
Although the latter methods are elegant and efficient for the
synthesis of the xanthone core, the drawbacks of palladium
catalytic systems, such as the high cost of the metal, its relative
toxicity, its air/moisture sensitivity and the difficulties found on
its removal at purification steps, have limited their use in bulk
industry.
An emerging alternative to most palladium-catalysed cross-
coupling processes is the use of copper in this context.23,24
Indeed, the copper-catalysed Ullmann-type coupling of phenols
with aryl halides has been steadily studied.25–28 These classical
Ullmann conditions were strongly limited by the large amounts
of copper catalysts and the high reaction temperatures required
(~200 ◦C), the poor substrate scope and the low to moderate
yields reached.29 As a representative example, Watson reported
the synthesis of a pyrroloxanthone by a sequence of Ullmann
Kimika Organikoa II Saila, Zientzia eta Teknologia Fakultatea, Euskal
Herriko Unibertsitatea, PO BOX 644, 48080, Bilbao, Spain.
E-mail: raul.sanmartin@ehu.es; Fax: +34 946 012748; Tel: +34
946015435
† Dedicated to Professor Luis Castedo on the occasion of his 70th
birthday.
‡ Electronic supplementary information (ESI) available: Typical exper-
imental procedures, including spectroscopic and analytical data for all
the new intermediates along with NMR spectra of the new compounds.
See DOI: 10.1039/b900931k
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coupling/F–C acylation.29 Stoichiometric amounts of copper
(Cu bronze and CuI), anhydrous conditions and temperatures
around 200 ◦C were required for the Ullmann coupling step.
All the aforementioned factors made these strategies unap-
pealing for the industry and difficult to scale-up. Research
on the use of bidentate ligands, such as aliphatic diamines,30
1,10-phenantroline,31 ethylene glycol,32 b-keto esters33 and
PPAPM,34 and additives (8-hydroxyquinoline,35 1-naphthoic
acid,25 amino acids,36 Schiff bases,37 inter alia) has attracted
much attention, since they overcome some of these inconvenient
drawbacks. Moreover, the use of soluble copper-complexes,38
ligand free conditions,39 Cu nanoparticles40 or microwave41,42
and ultrasonic43 irradiation has also contributed positively to
the efficient development of copper-catalysed O-arylation of
substituted phenols.44 Therefore, these modifications not only
shorten the reaction time but also allow the performance of the
reactions under milder conditions.
The pursuit of inexpensive and more benign and environ-
mentally friendly methodologies for the synthesis of xanthones
still remains a challenge. In this context, and considering the
experience of our group in the preparation of heterocycles
through copper-assisted arylation processes in aqueous media,45
we envisaged an approach based on the latter strategy to access
a new family of xanthones (Scheme 1). The advantages derived
from the use of water as solvent are numerous, such as safety,
non-toxicity, low cost, easy-handling, availability and greater
chemoselectivity, compared with organic solvents.46,47
Table 1 Selected O-arylation assays for the synthesis of xanthone 1a
Entry
X
Copper salt, base, liganda,b
Yield (%)c
1
2
I
Br
I
CuI, TMEDA
CuI, TMEDA
CuI, CHDA
83
90
69
95
59
75
66
57
32
tr
3
4d
I
CuI, NMP, K2CO3
CuI, NMP, K2CO3
CuI, NDMP, K2CO3
CuI, D, L-proline, K2CO3
CuI, PMDTA
CuI, BPDA, K2CO3
CuI, dba, K3PO4
CuI, TMEDA, K2CO3
CuI, TMEDA
Cu(OTf)2, TMEDA
Cu(OAc)2·H2O, TMEDA
CuBr, TMEDA
Cu2O, TMEDA
TMEDA
5d,e
6d
Br
Br
I
I
I
7d
8
9d
10d,f,g
11
12g
13
14
15
16
17
18
19
I
Br
Cl
Br
Br
Br
Br
Br
Br
Br
79
tr
62
89
86
64
10
—
—
CuI
—
a 10 mol% of the Cu salt and 3.5 equiv. of ligand when no additional
base was used. All reactions were run in water (12 mL per mmol
of 2) at 120 ◦C. b CHDA: trans-1,2-diaminocyclohexane; NDMP:
N,N¢-dimethylpiperazine; dba: trans,trans-dibenzylidene acetone;
PMDTA: N,N,N¢,N¢,N¢-pentamethyldiethylenetriamine; NMP: N-
methylpiperazine; TMEDA: N,N,N¢,N¢-tetramethylethylenediamine;
BPDA: rac-2,2¢-biphenyldiamine. c Yield of isolated products. d 20 mol%
of ligand and 2.0 equiv. of base. e A similar yield was obtained when
Cs2CO3 was used. f Complex mixture of inseparable products. g Only
traces of the cyclised product were detected.
Scheme 1 Retrosynthetic pathway to access the xanthone framework.
process are displayed in Table 1. Interestingly, when different
copper salts were employed (Table 1, entries 2, 13–16), the yields
obtained were quite similar. The possibility of using different
copper sources, regardless of their oxidation state, to perform
the target cyclisation makes this methodology advantageous and
attractive from a synthetic point of view.
Herein, we report an active catalytic system for the
straightforward synthesis of the xanthone scaffold from
o-halobenzophenones through a copper-catalysed intramolec-
ular O-arylation reaction in water as the only solvent. Taking
into account the easy setup, recyclability and the sustainability
of this procedure, it could be transferred to industrial purposes.
Although CuI, Cu(OAc)2·H2O and CuBr delivered the xan-
thone 1a in fairly similar yields (86–90% yield), copper (I) iodide
was selected due to its air and moisture stability. Then, we evalu-
ated the combination of CuI with several commercially available
aliphatic diamines, such as TMEDA, CHDA or PMDTA. As
shown in Table 1, the more basic TMEDA provided considerably
better yields (entry 1 vs. 3 and 8). Combining catalytic amounts
of CuI along with other nitrogen containing ligands (NMP,
NDMP, D,L-proline and BPDA) and additional bases gave in
most cases poorer yields (entries 4–7 and 9). The combination
of CuI and NMP in catalytic amounts with K2CO3 as base
seemed to be a good choice, as it provided an excellent yield
in the case of 2-iodobenzophenone 2a. However, a considerably
lower yield was obtained starting from the 2-bromo analogue
2a¢ (entries 4–5).49 An attempt to use the cheap dba as ligand
for this intramolecular O-arylation reaction gave a complex
mixture of inseparable products (entry 10). Unfortunately, the
Results and discussion
Initially, in order to optimise the copper-catalysed O-arylation
reaction to furnish target xanthone 1a, 2-bromo- and 2-
iodobenzophenones 2a and 2a¢ were selected as model substrates
(Table 1). These key intermediates were easily prepared in a one-
step Friedel–Crafts acylation with graphite and methanesulfonic
acid in relatively short times (3–4 hours), following the procedure
described in the literature.48 The main reason to choose this
modern protocol was the recyclability of the employed cheap
graphite, which would make our whole synthetic sequence even
more environmentally friendly.
Accordingly, a range of assays employing a survey of copper
sources and commercially available ligands in an aqueous
solution were performed. The main results of the optimisation
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Table 2 Preparation of differently substituted xanthones 1a
2-chlorobenzophenone derivative afforded negligible results and
the product was hardly detected (entry 12).
Finally, we decided to run three blank experiments. The first
one (Table 1, entry 17) was to verify that the copper was really
necessary for the intramolecular O-arylation process, and to
discard a classical aromatic substitution (SNAr) in which the
transition metal should not play any role. We recovered the
unreacted starting material as the main product, just isolating
a small amount (10%) of target xanthone 1a, thus confirming
the requirement of a copper complex to promote an effective
O-arylation (Table 1, entry 2 vs. 17). The second assay (entry
18) proved that TMEDA (which probably acts both as base and
ligand)45 was clearly needed for the reaction, since otherwise no
product was detected. Finally, no reaction was observed when
we stirred 2-bromobenzophenone 2a¢ in neat water (entry 19).
Taking into account all the experimental results it was decided
that the best conditions involved stirring the starting material in
the presence of 10 mol% of CuI and 3.5 equiv. of TMEDA in
water at 120 ◦C. The ease of the reaction setup, the absence
of side products and the lack of requirement for an inert
atmosphere should be highlighted.
Entry
1
Substrate 2
Xanthone 1b
2
The Ullmann-type coupling process of substituted phenols
with aryl halides has traditionally been accomplished using
toxic and high-boiling organic solvents as reaction media.25–28
A comparison of our procedure with the typically employed
strategies to perform this kind of O-arylation reaction revealed
that the target xanthone 1a is obtained in much better yields
when employing our simple protocol. When we carried out the
reaction using the procedure reported by Buchwald and co-
workers25 in 1997 (which involved the use of catalytic amounts
of unstable (CuOTf)2·C6H6 and EtOAc in the presence of
Cs2CO3 and 1-naphthoic acid as additive in boiling toluene)
and the method developed by Chang et al.26 (catalytic amounts
of CuI along with nBuNBr as phase transfer catalyst and
K3PO4 in DMF at reflux) we only achieved yields of 45 and
63%, respectively. These two parallel experiments outlined the
efficiency of our “on water” strategy.
3
4
5
Encouraged by these remarkable results, we decided to
evaluate the scope and limitations of this strategy. Accordingly,
the preparation of several differently substituted 2-iodo- and
2-bromobenzophenones 2 was carried out from commercially
available 2-halobenzoic acids and substituted phenols by means
of the aforementioned Friedel–Crafts acylation.48 These precur-
sors were subjected to the above described optimal conditions to
undergo the intramolecular O-arylation reaction affording the
cyclisation products with the results shown in Table 2.
Surprisingly, both 2-iodo- and 2-bromobenzophenones 2 de-
livered the cyclisation products with excellent results, regardless
of the nature of the halogen substituent (83 vs. 90% and 84
vs. 73%, in entries 1 and 2, respectively). Only when the hy-
droxyarene moiety was 1-hydroxynaphthalene, was a remarkable
difference in the yields found (62% from 2d and 89% from 2d¢,
Table 2, entry 4). In this case, the conversion of the reaction when
2d was employed as substrate was incomplete, finding significant
amounts of the unreacted starting material. Following with the
hydroxyl group containing moiety, a relatively lower yield was
obtained when electron-enriched derivative 2c was employed
(entry 3). With regard to the o-halide containing moiety,
substrates bearing additional halogens such as fluoro or chloro
6
7
8
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Table 2 (Contd.)
a copper-catalysed intramolecular O-arylation process is pre-
sented. Considering that the appealing xanthone scaffold has
normally been prepared by using harmful reagents and solvents,
the reported protocol delivers the target tricyclic skeleton in
good to excellent yields exclusively in a safe, harmless aqueous
medium. The recyclability, scalability and the easy reaction setup
combined with the low cost of the starting materials make
this simple method transferable to pharmaceutical purposes.
Finally, it can be outlined that several commercially available
copper salts afforded the cyclisation products in fairly similar
yields, not limiting the procedure to the use of only one copper
source.
Entry
9
Substrate 2
Xanthone 1b
Experimental
Typical procedure
10
22
2-Methylxanthen-9-one (1a).
A screw-capped tube (ap-
proximate volume: 18 mL) was charged with 2-iodoaryl-
benzophenone 2a (108.1 mg, 0.32 mmol), CuI (6.1 mg,
0.032 mmol), TMEDA (0.17 mL, 1.12 mmol) and water (3.8 mL)
at room temperature. After closing, the tube was heated to
◦
120 C for 15 h, allowed to cool to room temperature and the
a 10 mol% of CuI, 3.5 equiv. of TMEDA and H2O (12 mL per mmol of
2) at 120 ◦C. b Yield of isolated products. c 10 mol% of CuI, 20 mol% of
NMP, 2 equiv. of K2CO3 and H2O (12 mL per mmol of 2a) at 120 ◦C.
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 pressure to provide the
target xanthone 1a (55.9 mg, 83%) as a white powder.
The typical procedure was followed starting from 2-
bromoarylbenzophenone 2a¢ (92.2 mg, 0.31 mmol) and CuI
(6.2 mg, 0.032 mmol) to afford xanthone 1a (60.1 mg, 90%) as
a white powder. In a scale-up experiment, the typical procedure
(a round-bottom flask closed with a stopper was employed) was
applied to 2-bromoarylbenzophenone 2a¢ (48.0 g, 0.16 mol) and
CuI (3.1 g, 0.016 mol) to provide xanthone 1a (30.61 g, 91%) as
a white powder.
groups provided slightly lower yields (Table 2, entries 5–8). The
presence of these halogens offer the possibility of carrying out a
second aromatic substitution process or metal catalysed cross-
couplings (Suzuki, Heck, etc.) to achieve a more substituted
xanthone. In general, it could be affirmed that there is no clear
trend related to the electronic nature of the substituents.
At this stage, we decided to evaluate the reutilization of
the aqueous solution we used to prepare the xanthone 1a
starting from 2-bromobenzophenone 2a¢. This green solution
presumably contained a water soluble copper-TMEDA complex
formed during the process. Remarkably, when we reused this
aqueous solution the target xanthone 1a was obtained with an
excellent yield of 97%, slightly better than the one obtained in
the first run (90%). It should be pointed out that an additional
extra amount of TMEDA had to be added to the reaction, due
to its supposed double role in the process.45 After the second
run, a clear change of colour of the aqueous solution was
observed, from green to brown. The third run with this brown
water solution delivered the cyclised product 1a in a still good
yield of 58%, but observing in this case some unreacted starting
material.
20
2,3-Dimethylxanthen-9-one (1b).
The typical proce-
dure was followed starting from 2-iodoarylbenzophenone 2b
(88.2 mg, 0.25 mmol) and CuI (4.8 mg, 0.025 mmol) to afford
xanthone 1b (47.1 mg, 84%) as a white powder.
The typical procedure was followed starting from 2-
bromoarylbenzophenone 2b¢ (84.5 mg, 0.28 mmol) and CuI
(5.3 mg, 0.028 mmol). After a short flash chromatography
(20 mol% EtOAc/hexane) xanthone 1b (42.3 mg, 73%) was
obtained as a white powder.
3,4-Dimethoxyxanthen-9-one (1c). The typical procedure
was followed starting from 2-bromoarylbenzophenone 2c
(99.9 mg, 0.30 mmol) and CuI (5.7 mg, 0.030 mmol). After a
short flash chromatography (20 mol% EtOAc/hexane) xanthone
1c (53.7 mg, 70%) was obtained as a white powder. Mp 150–
152 ◦C (from hexane); IR nmax(KBr)/cm-1 1661, 1602, 1455,
1290 and 1091; 1H NMR (300 MHz, CDCl3, SiMe4) (dH, ppm):
4.01 (3H, s, OCH3), 4.03 (3H, s, OCH3), 7.01 (1H, d, J 9.0 Hz,
H2), 7.34–7.39 (1H, m, Harom), 7.55–7.57 (1H, m, Harom), 7.68–
7.74 (1H, m, Harom), 8.09 (1H, d, J 9.0 Hz, H1) and 8.32 (1H, dd,
J 7.9 and 1.7 Hz, Harom); 13C NMR (75 MHz, CDCl3, SiMe4)
(dC, ppm): 56.4, 61.5 (OCH3), 108.6 (C2), 116.7 (C9a), 118.0 (C5),
Finally, the scale-up of our method to 1 and 48 grams starting
from the 2-bromobenzophenone 2a¢ resulted in excellent results,
obtaining xanthone 1a in 93% and 91% yields, respectively, a bit
higher ones than at small scale. This preliminary result opens
the possibility of a multigram entry to biologically relevant
xanthones.
Conclusions
In summary, a highly practical and sustainable methodology for
the synthesis of the very valuable xanthone framework through
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121.5 (C8a), 122.4, 123.9, 126.6 (Carom-H), 134.5 (C6), 136.4 (C4),
150.6 (C4a), 156.1 (C4b, C3), 157.5 (C3, C4b) and 176.5 (CO); MS
(CI) m/z 258 (M + 2, 13%), 257 (M + 1, 100) and 256 (M+, 37).
HRMS (CI) [M + 1]: calculated for C15H13O4, 257.0814; found,
257.0813.
19.1 (CH3), 20.5 (CH3), 117.9 (C4, C5), 118.0 (C5, C4), 119.5 (C8a,
C8b), 120.4 (C8b, C8a), 124.4, 126.2, 128.0 (Carom-H), 133.5, 140.3,
145.7 (Carom-C), 154.5 (C4b), 156.2 (C4a) and 176.1 (CO); MS (CI)
m/z: 259 (M + 1, 100%) and 258 (M+, 42). HRMS (CI) [M + 1]:
calculated for C15H12ClO2, 259.0526; found, 259.0526.
20
7H-Benzo[c]xanthen-7-one (1d).
The typical proce-
10-Chloro-7H-benzo[c]xanthen-7-one (1h). The typical pro-
cedure was followed starting from 2-bromoarylbenzophenone
2h (91.9 mg, 0.25 mmol) and CuI (4.8 mg, 0.025 mmol). After a
short flash chromatography (20 mol% EtOAc/hexane) xanthone
1h (53.0 mg, 74%) was obtained as a white powder. Mp 204–
205 ◦C (from hexane); IR nmax(KBr)/cm-1 1655, 1602, 1431, 1379
and 1085; 1H NMR (300 MHz, CDCl3, SiMe4) (dH, ppm): 7.38
(1H, dd, J 8.5 and 1.9 Hz, Harom), 7.64–7.63 (4H, m, Harom), 7.88–
7.91 (1H, m, Harom), 8.20 (1H, d, J 8.2 Hz, Harom), 8.29 (1H, d, J
8.5 Hz, Harom) and 8.54–8.57 (1H, m, Harom); 13C NMR (75 MHz,
CDCl3, SiMe4) (dC, ppm): 117.5 (C6a), 118.0 (C11), 120.8 (C7a),
121.2, 122.6 (Carom-H), 123.7 (C11c), 124.4, 125.2, 127.0, 127.9,
128.1, 129.7 (Carom-H), 136.5 (C4a), 140.3 (C10), 153.4 (C11b), 155.7
(C11a) and 175.9 (CO); MS (CI) m/z: 283 (M + 3, 34%), 282
(M + 2, 31), 281 (M + 1, 100), 280 (M+, 43) and 245 (10).
HRMS(CI) [M + 1]: calculated for C17H10ClO2, 281.0369; found,
281.0367.
dure was followed starting from 2-iodoarylbenzophenone 2d
(122.8 mg, 0.32 mmol) and CuI (6.2 mg, 0.033 mmol). After a
short flash chromatography (20 mol% EtOAc/hexane) xanthone
1d (46.0 mg, 62%) was obtained as a white powder.
The typical procedure was followed starting from 2-
bromoarylbenzophenone 2d¢ (93.0 mg, 0.28 mmol) and CuI
(5.4 mg, 0.028 mmol) to afford xanthone 1d (63.1 mg, 89%)
as a white powder.
2-Fluoro-7-methylxanthen-9-one (1e). The typical proce-
dure was followed starting from 2-iodoarylbenzophenone 2e
(66.5 mg, 0.18 mmol) and CuI (3.5 mg, 0.018 mmol). After a
short flash chromatography (20 mol% EtOAc/hexane) xanthone
1e (28.2 mg, 69%) was obtained as a white powder. Mp 152–
154 ◦C (from hexane); IR nmax(KBr)/cm-1 1661 and 1473; H
1
NMR (300 MHz, CDCl3, SiMe4) (dH, ppm): 2.46 (3H, s, CH3),
7.37 (1H, d, J 8.5 Hz, H5), 7.41–7.49 (2H, m, H8), 7.52–7.55 (1H,
m, Harom), 7.95 (1H, dd, J 8.3 and 2.9 Hz, H6) and 8.07–8.08 (1H,
m, Harom); 13C NMR (75 MHz, CDCl3, SiMe4) (dC, ppm): 20.8
(CH3), 111.1 (d, J 25.4 Hz, C1), 117.7 (C5), 119.9 (d, J 7.9 Hz,
C4), 120.6 (C8a), 122.6 (C9a), 122.7 (d, J 25.3 Hz, C3), 125.9 (C8),
133.9 (C7), 136.6 (C6), 152.3 (d, J 1.4 Hz, C4a), 154.3 (C4b), 158.6
(d, J 244.8 Hz, C2) and 176.6 (d, J 2.2 Hz, CO); MS (CI) m/z:
229 (M + 1, 100%), 228 (M+, 41) and 209 (12). HRMS (CI) [M +
1]: calculated for C14H10FO2, 229.0665; found, 229.0659.
2,6-Dimethylxanthen-9-one (1i). The typical procedure was
followed starting from 2-bromoarylbenzophenone 2i (98.3 mg,
0.32 mmol) and CuI (6.1 mg, 0.032 mmol) to afford xanthone
1i (57.1 mg, 79%) as a white powder. Mp 118–119 ◦C (from
hexane); IR nmax(KBr)/cm-1 1655, 1619, 1437, 1302 and 1226;
1H NMR (300 MHz, CDCl3, SiMe4) (dH, ppm): 2.45 (3H, s,
CH3), 2.48 (3H, s, CH3), 7.14–7.17 (1H, m, Harom), 7.24–7.25
(1H, m, Harom), 7.35 (1H, d, J 8.5 Hz, H4), 7.50 (1H, dd, J 8.5
and 2.2 Hz, H3), 8.09–8.10 (1H, m, Harom) and 8.20 (1H, d, J
8.1 Hz, Harom); 13C NMR (75 MHz, CDCl3, SiMe4) (dC, ppm):
20.8 (CH3), 21.9 (CH3), 117.6 (C5), 119.5 (C8a), 121.5 (C9a), 125.2,
125.9, 126.5 (Carom-H), 133.5 (C2), 135.8 (C3), 146.1 (C6), 154.3
(C4a), 156.3 (C4b) and 177.0 (CO); MS (CI) m/z: 225 (M + 1,
100%) and 224 (M+, 4%). HRMS (CI) [M + 1]: calculated for
C15H13O2, 225.0916; found, 225.0907.
2-Fluoro-6,7-dimethylxanthen-9-one (1f). The typical proce-
dure was followed starting from 2-iodoarylbenzophenone 2f
(106.9 mg, 0.29 mmol) and CuI (5.2 mg, 0.027 mmol). After a
short flash chromatography (10 mol% EtOAc/hexane) xanthone
1f (35.0 mg, 54%) was obtained as a white powder. Mp 168–
169 ◦C (from hexane); IR nmax(KBr)/cm-1 1661, 1625, 1467 and
1279; 1H NMR (300 MHz, CDCl3, SiMe4) (dH, ppm): 2.37 (3H, s,
CH3), 2.39 (3H, s, CH3), 7.25–7.26 (1H, m, Harom), 7.33–7.39
10-Methyl-7H-benzo[c]xanthen-7-one (1j). The typical pro-
cedure was followed starting from 2-bromoarylbenzophenone
2j (91.6 mg, 0.27 mmol) and CuI (5.1 mg, 0.026 mmol) to afford
xanthone 1j (67.1 mg, 96%) as a white powder. Mp 220 ◦C
(decomposition); IR nmax(KBr)/cm-1 1643, 1437, 1379 and 1085;
1H NMR (300 MHz, CDCl3, SiMe4) (dH, ppm): 2.51 (3H, s,
CH3), 7.19–7.20 (1H, m, Harom), 7.13–7.14 (1H, m, Harom), 7.61–
7.69 (3H, m, Harom), 7.86–7.89 (1H, m, Harom), 8.22–8.25 (2H, m,
Harom) and 8.56–8.59 (1H, m, Harom); 13C NMR (75 MHz, CDCl3,
SiMe4) (dC, ppm): 117.5 (C6a, C7a), 117.7 (Carom-H), 120.1 (C7a,
C6a), 121.5, 122.7, 123.7 (Carom-H), 124.0 (C11c), 125.8, 126.2,
126.7, 128.0, 129.3 (Carom-H), 136.4 (C4a), 145.7 (C9), 153.4 (C11b),
155.7 (C11a) and 176.6 (CO); MS (CI) m/z: 262 (M + 2, 19%), 261
(M + 1, 100) and 260 (M+, 40). HRMS (CI) [M + 1]: calculated
for C18H13O2, 261.0916; found, 261.0918.
(2H, m, Harom), 7.66–7.68 (1H, m, Harom) and 7.72 (1H, s, H8); 13
C
NMR (75 MHz, CDCl3, SiMe4) (dC, ppm): 19.2 (s, CH3), 20.6
(s, CH3), 111.3 (d, J 25.2 Hz, C1), 118.0 (C5), 118.8 (C8a), 119.8
(d, J 7.8 Hz, C4), 122.4 (d, J 25.3 Hz, C3), 122.7 (d, J 7.1 Hz,
C9a), 126.2 (C8), 133.3 (C7), 145.8 (C6), 152.3 (d, J 1.4 Hz, C4a),
154.6 (C4b), 158.5 (d, J 244.6 Hz, C2) and 176.3 (d, J 2.1 Hz,
CO); MS (CI) m/z: 243 (M + 1, 100%) and 242 (M+, 45), 223
(15). HRMS (CI) [M + 1]: calculated for C15H12FO2, 243.0821;
found, 243.0816.
3-Chloro-6,7-dimethylxanthen-9-one (1g). The typical pro-
cedure was followed starting from 2-iodoarylbenzophenone 2g
(99.3 mg, 0.29 mmol) and CuI (5.6 mg, 0.029 mmol). After a
short flash chromatography (20 mol% EtOAc, hexane) xanthone
1g (50.1 mg, 66%) was obtained as a white powder. Mp 173–
174 ◦C (from hexane); IR nmax(KBr)/cm-1 1655, 1596 and 1420;
1H NMR (300 MHz, CDCl3, SiMe4) (dH, ppm): 2.35 (3H, s,
CH3), 2.38 (3H, s, CH3), 7.21 (s, 1H, H5), 7.30 (dd, J 8.5, 1.8 Hz,
1H, H2), 7.44 (1H, d, J 1.8 Hz, H4), 8.00 (1H, s, H8) and 8.23 (1H,
d, J 8.5 Hz, H1); 13C NMR (75 MHz, CDCl3, SiMe4) (dC, ppm):
Acknowledgements
This research was supported by the University of the Basque
Country/Regional Government of Biscay/Basque Government
834 | Green Chem., 2009, 11, 830–836
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(Projects DIPE 06/10, UNESCO07/08and GIU06/87/IT-349–
07). NB thanks the Spanish Ministry of Education and Science
for a predoctoral scholarship. The authors also thank Petronor,
S.A. (Muskiz, Bizkaia, Spain) for a generous donation of
hexane.
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836 | Green Chem., 2009, 11, 830–836
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©