Synthesis of xanthones, thioxanthones, and acridones by the coupling of arynes and substituted benzoates

Article abstract of DOI:10.1021/jo0620718

The reaction of silylaryl triflates, CsF, and ortho-heteroatom-substituted benzoates affords a general and efficient way to prepare biologically interesting xanthones, thioxanthones, and acridones. This chemistry presumably proceeds by a tandem intermolecular nucleophilic coupling of the benzoate with an aryne and a subsequent intramolecular electrophilic cyclization.

Full text of DOI:10.1021/jo0620718

Synthesis of Xanthones, Thioxanthones, and Acridones by the
Coupling of Arynes and Substituted Benzoates
Jian Zhao and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
ReceiVed October 5, 2006
The reaction of silylaryl triflates, CsF, and ortho-heteroatom-substituted benzoates affords a general and
efficient way to prepare biologically interesting xanthones, thioxanthones, and acridones. This chemistry
presumably proceeds by a tandem intermolecular nucleophilic coupling of the benzoate with an aryne
and a subsequent intramolecular electrophilic cyclization.
Introduction
presence of strong acids or toxic metals.5 Acridones are naturally
occurring compounds exhibiting a variety of biological activities.
They are important antileishmanial, antifungal, antitumor, and
DNA-intercalating anticancer drugs.6 Acridones are usually
prepared by the acid-induced ring closure of N-phenyl anthra-
nilic acids, which are usually obtained from Ullmann condensa-
tion of anilines with ortho-halogen-substituted benzoic acids.
However, harsh reaction conditions and tedious workup pro-
cedures are generally required.7 An efficient and general
synthesis of each of these heterocycles is thus highly desirable.
Xanthones are secondary metabolites found in higher plant
families, fungi, and lichens.1 This class of compounds exhibits
interesting pharmaceutical properties; specifically, antibacterial,
anti-inflammatory, anticancer, and antiviral activities have been
observed.2 Some xanthone-containing plants, for example,
(3) (a) Mahabusarakam, W.; Nuangnaowarat, W.; Taylor, W. C. Phy-
tochemistry 2006, 67, 470. (b) Gnerre, C.; Thull, U.; Gailland, P.; Carrupt,
P. A.; Testa, B.; Fernandes, E.; Silva, F.; Pinto, M.; Pinto, M. M. M.;
Wolfender, J.-L.; Hostettmann, K.; Cruciani, G. HelV. Chim. Acta 2001,
84, 552.
(4) Poondru, S.; Zhou, S.; Rake, J.; Shackleton, G.; Corbett, T. H.;
Parchment, R.; Jasti, B. R. J. Chromatogr., B 2001, 759, 175 and references
therein.
Cratoxylum cochinchinense (Lour.) Blume, have been used as
traditional medicines to treat fever, coughing, diarrhea, itching,
ulcers, and abdominal complaints.3 Thioxanthone derivatives
also exhibit interesting anticancer activities.4 Xanthones are
usually synthesized through the intermediacy of benzophenones
or diaryl ethers under harsh reaction conditions and/or in the
(5) (a) Grover, P. K.; Shah, G. D.; Shah, R. C. J. Chem. Soc. 1955,
3982. (b) Quillinan, A. J.; Scheinmann, F. J. Chem. Soc., Perkin Trans. 1
1973, 1329. (c) Jackson, W. T.; Robert, J. B.; Froelich, L. L.; Gapinski,
D. M.; Mallett, B. E.; Sawyer, J. S. J. Med. Chem. 1993, 36, 1726. (d)
Familoni, O. B.; Ionica, I.; Bower, J. F.; Snieckus, V. Synlett 1997, 1081.
(e) Hassall, C. H.; Lewis, J. R. J. Chem. Soc. 1961, 2312.
(6) (a) Tabarrini, O.; Manfroni, G.; Fravolini, A.; Cecchetti, V.; Sabatini,
S.; De Clercq, E.; Rozenski, J.; Canard, B.; Dutartre, H.; Paeshuyse, J.;
Neyts, J. J. Med. Chem. 2006, 49, 2621 and references therein. (b)
Taraporewala, I. B.; Cessac, J. W.; Chanh, T. C.; Delgado, A. V.; Schinazi,
R. F. J. Med. Chem. 1992, 35, 2744. (c) MacNeil, S. L.; Wilson, B. J.;
Snieckus, V. Org. Lett. 2006, 8, 1133. (d) Harrison, R. J.; Reszka, A. P.;
Haider, S. M.; Romagnoli, B.; Morrell, J.; Read, M. A.; Gowan, S. M.;
Incles, C. M.; Kellandc, L. R.; Neidle, S. Bioorg. Med. Chem. Lett. 2004,
14, 5845.
(1) Cardona, M. L.; Fernandez, M. I.; Pedro, J. R.; Serrano, A.
Phytochemistry 1990, 29, 3003.
(2) (a) For a recent review on naturally occurring xanthones, see: Peres,
V.; Nagem, T. J.; Faustino de Oliveira, F. Phytochemistry 2000, 55, 683.
(b) Schwaebe, M. K.; Moran, T. J.; Whitten, J. P. Tetrahedron Lett. 2005,
46, 827. (c) Kenji, M.; Yukihiro, A.; Hong, Y.; Kenji, O.; Tetsuro, I.;
Toshiyuki, T.; Emi, K.; Munekazu, I.; Yoshinori, N. Bioorg. Med. Chem.
2004, 12, 5799. (d) Pedro, M.; Cerqueira, F.; Sousa, M. E.; Nascimento,
M. S. J.; Pinto, M. Bioorg. Med. Chem. 2002, 10, 3725.
(7) (a) Nishio, R.; Wessely, S.; Sugiura, M.; Kobayashi, S. J. Comb.
Chem. 2006, 8, 459. (b) Goodell, J. R.; Madhok, A. A.; Hiasa, H.; Ferguson,
D. M. Bioorg. Med. Chem. 2006, 14, 5467.
10.1021/jo0620718 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/15/2006
J. Org. Chem. 2007, 72, 583-588
583

Zhao and Larock
TABLE 1. Optimization Studies
SCHEME 1. Aryne Insertion Reactions
fluoride
source
temp
(°C)
time
(h)
% yield
entry
solvent
(3a:4a)a
1
2
3
4
5
6
7
8
9
4 CsF
4 CsF
4 CsF
4 CsF
4 CsF
4 CsF
4 CsF
4 CsF
4 CsF
4 CsF
4 TBAF
2 CsF
MeCN
acetone
CH2Cl2
THF
toluene
MeNO2
THF
THF
THF
DME
THF
THF
rt
rt
rt
rt
100
rt
65
90
50
65
65
65
12
4
80 (40:60)
75 (38:62)
trace
20 (5:95)
trace
24
24
48
24
24
12
24
24
3
-
82 (8:92)
80 (14:86)
30 (6:94)
70 (25:75)
60 (83:17)
65 (8:92)
Benzyne, a highly reactive intermediate, was first proposed
by Wittig in 1942,8 and the structure was confirmed by Roberts
in 1956 using 14C isotope labeling.9 Since then, many methods
have been developed to generate benzynes, for example, the
base-promoted elimination of hydrogen halide from aryl ha-
lides,10 the elimination of o-dihaloaromatics with lithium
amalgam or magnesium,11 or the recently reported decomposi-
tion of 2-magnesiated aryl sulfonates.12 In 1983, Kobayashi first
reported a novel way to generate arynes from silylaryl triflate
precursors in the presence of CsF.13 Later, nucleophiles bearing
neighboring electrophiles, such as ureas,14 trifluoroacetanilides
and sulfinamides,15 and â-keto esters16 were shown to react with
these aryne precursors to afford the C-N bond or C-C bond
insertion products (Scheme 1). These nucleophiles first undergo
intermolecular nucleophilic attack on the aryne. Subsequent
intramolecular electrophilic cyclization, followed by fragmenta-
tion, affords the final insertion product.
10
11
12
24
a All reactions were conducted on a 0.25 mmol scale in 5 mL of solvent
(sealed vial). The ratio of methyl salicylate to aryne precursor is 1 to 1.1.
The ratio of 3a to 4a, in parentheses, has been determined by GC-MS
analysis.
SCHEME 2
Recently, we communicated a novel annulation reaction
utilizing readily accessible salicylates and silylaryl triflates plus
CsF, which affords an efficient one-step synthesis of biologically
interesting xanthones and thioxanthones (eq 1).17 This chemistry
presumably proceeds by a tandem intermolecular nucleophilic
coupling of the benzoate and aryne and a subsequent intramo-
lecular electrophilic cyclization. A fragmentation step, which
is inevitable in the insertion examples, is not involved in this
annulation process because the intermediate obtained from the
cyclization is a stable six-membered ring system. Herein, we
provide a full account of this efficient synthesis of xanthones
and thioxanthones; plus, we also wish to report an extension of
this coupling-cyclization strategy for the synthesis of biologically
interesting acridones.
silyl)phenyl triflate (2a) was first conducted in the presence of
4 equiv of CsF in 5 mL of MeCN. After a 12 h reaction at
room temperature, an 80% combined yield of methyl 2-phe-
noxybenzoate (3a) and xanthone (4a) was obtained in a 40:60
ratio (Table 1, entry 1). Presumably, this reaction proceeds
through the key intermediate, B, generated by nucleophilic
coupling of the aryne and the aryloxide, A (Scheme 2). The
carbanion, B, can either undergo H abstraction to afford benzoate
(3a) or intramolecular electrophilic cyclization to generate the
xanthone (4a). The major problem here is the proton abstraction
process, which could be suppressed by adjusting the reaction
conditions, for example, using different solvents and concentra-
tions. Thus, we next conducted the coupling-cyclization reaction
in acetone, and a 75% yield of diaryl ether (3a) and xanthone
(4a) was obtained in a 38:62 ratio (entry 2), which suggests
that a less polar solvent should be examined. We then performed
the reaction in CH2Cl2. However, only a trace of the xanthone
(4a) was observed by GC-MS analysis after 24 h (entry 3).
When THF was used as the solvent at room temperature, after
24 h of reaction, a 20% yield of products 3a and 4a was
obtained, and a lot of the starting materials, 1a and 2a, was
observed by GC-MS analysis. However, the ratio of 3a to 4a
was 5:95, suggesting that proton abstraction has been almost
completely suppressed (entry 4). When this reaction was
conducted in toluene, only a trace of the product was evident
by GC-MS analysis (entry 5). MeNO2 also turned out to be
an unsuitable solvent for this reaction (entry 6). At this point,
Results and Discussion
Optimization Studies. The reaction of methyl salicylate (1a)
and the commercially available aryne precursor o-(trimethyl-
(8) For a recent review, see: (a) Sander, W. Acc. Chem. Res. 1999, 32,
669. (b) Wittig, G. Naturwissenschaften 1942, 696.
(9) Roberts, J. D.; Semenow, D. A.; Simmons, H. E., Jr.; Carlsmith,
L. A. J. Am. Chem. Soc. 1956, 78, 601.
(10) (a) Huisgen, R.; Sauer, J. Angew. Chem. 1960, 72, 91. (b) Biehl,
E. R.; Nieh, E.; Hsu, K. C. J. Org. Chem. 1969, 34, 3595. (c) Bunnett, J.
F.; Kim, J. K. J. Am. Chem. Soc. 1973, 95, 2254.
(11) (a) Wittig, G.; Pohmer, L. Chem. Ber. 1956, 89, 1334. (b) Wittig,
G. Org. Synth. 1963, 4, 964.
(12) Sapountzis, I.; Lin, W.; Fischer, M.; Knochel, P. Angew. Chem.,
Int. Ed. 2004, 43, 4364 and references therein.
(13) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
(14) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem.,
Int. Ed. 2002, 41, 3247.
(15) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2006, 128, 13112.
(16) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340.
(17) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 4273.
584 J. Org. Chem., Vol. 72, No. 2, 2007

Synthesis of Xanthones, Thioxanthones, and Acridones
TABLE 2. Synthesis of Xanthonesa
a All reactions were conducted on a 0.25 mmol scale in the presence of 4 equiv of CsF and 1.1 equiv of silylaryl triflate in 5 mL of THF at 65 °C for
24 h (sealed vial), unless otherwise stated. b The reaction was conducted in 5 mL of THF at 90 °C. c The yield has been determined by GC analysis due to
the impurities in the product.
THF seemed to be the best solvent, at least as far as the reaction
selectivity was concerned. The same reaction was then carried
out at 65 °C in THF for 24 h. A 75% yield of xanthone (4a)
was isolated by flash chromatography, and GC-MS analysis
indicated only a trace of the diaryl ether 3a was obtained (entry
7). Further investigation indicated that a reaction temperature
of 90 or 50 °C reduces the amount of xanthone product (entries
8 and 9). When DME was used as the solvent, the reaction
afforded only a 70% yield of two isomers formed in a 25:75
ratio (entry 10).
After 3 h, all of the starting materials were consumed and the
proton abstraction product (3a) predominated (entry 11). A 65%
yield of an 8:92 ratio of 3a and 4a was obtained when this
reaction was carried out in the presence of 2 equiv of CsF (entry
12). In conclusion, the optimal reaction conditions for this one-
step synthesis of xanthone utilize 4 equiv of CsF in THF solvent
at 65 °C for 24 h (entry 7).
Synthesis of Xanthones. Employing our optimal reaction
conditions, we have investigated the reaction scope and limita-
tions of this process. These results are summarized in Table 2.
We first examined the effect of a methoxy substituent on the
salicylate ring to determine which position on the salicylate ring
affords the best yield of xanthone. Thus, salicylates 1b, 1c, 1d,
The effect of the fluoride source has also been examined in
this process. When tetrabutylammonium fluoride (TBAF) was
used as the fluoride source, the reaction proceeded much faster.
J. Org. Chem, Vol. 72, No. 2, 2007 585

Zhao and Larock
SCHEME 3. Aryne Precursors
SCHEME 4. Diversification of Halogen-Substituted
Xanthonesa
a Conditions: (i) 5% Pd(PPh3)4, 1 Na2CO3, 1:4 MeOH/toluene, 80 °C,
12 h; (ii) 5% Pd(OAc)2, 2 NaHCO3, 1 TBAC, DMF, 100 °C, 24 h.
and 1e were employed, and 35-69% yields of substituted
xanthones 4b-4e were obtained (entries 2-5). Having an
electron-donating methoxy group in the 5 position of the
salicylate ring gave the highest yield (entry 4). The yields of
xanthones from the 3- and 4-methoxy starting materials were
only slightly lower, but the 6-methoxy isomer gave a much
lower yield. When methyl 5-acetylsalicylate (1f) with an
electron-withdrawing group in the 5 position was used as the
starting material, a 58% yield of xanthone 4f was isolated by
flash chromatography (entry 6). On the other hand, the reaction
of methyl 5-fluorosalicylate (1g) and aryne precursor 2a affords
an 83% yield of xanthone 4g (entry 7). The reaction of methyl
5-bromosalicylate (1h) with aryne 2a affords a 75% yield of
the product 4h (entry 8). The phenyl- and methyl-substituted
salicylates, 1i and 1j, afforded 64 and 71% yields of the
corresponding xanthone products, respectively (entries 9 and
10). When methyl 5-hydroxysalicylate (1k) is allowed to react
with 2.5 equiv of aryne precursor 2a, the O-arylated xanthone
product 4k was isolated in a 52% yield (entry 11). We have
previously reported the facile arylation of phenols by these same
aryne precursors.18 From these results with 5-substituted sali-
cylates, there is no obvious correlation between the electronic
properties of the substituent and the yield. Phenyl salicylate (1l)
has been employed in this reaction, and an 81% yield of
xanthone 4a was obtained (entry 12). Assuming that 2-hydroxy-
benzoic acid would first form the corresponding phenyl ester
1l,18 which should then afford the corresponding xanthone (4a),
we treated 2 equiv of benzyne precursor 2a and 2-hydroxyben-
zoic acid (1m) in the usual fashion. Unfortunately, none of the
desired product was observed for reasons we do not really
understand at this time (entry 13). Interestingly, the cross-
coupling of methyl 1-hydroxy-2-naphthoate (1n) with silylaryl
triflate 2a affords a 73% yield of xanthone 4l, but the reaction
using methyl 2-hydroxy-3-naphthoate (1o) only generates a 48%
yield of the product 4m (entries 14 and 15). This latter reaction
produced several side products which have not been identified.
The annulation of 1p, which contains a pyridine ring, afforded
none of the xanthone product under our optimal conditions
(entry 16). Again, we are uncertain why this latter reaction
failed.
triflate 2c was employed, a 57% yield of xanthone 4o was
isolated (entry 18). Again a higher temperature was required.
The reaction of aryne precursor 2d with methyl salicylate (1a)
afforded a 51% yield of xanthone 4p (entry 19). When aryne
precursor 2e was employed, a 59% yield of two isomeric
xanthones, 4j and 4q, was obtained in a 1:1 ratio (entry 20).
This is consistent with the intermediacy of an unsymmetrical
methyl-substituted benzyne. Aryne precursor 2f afforded a 45%
yield of a single xanthone product 4r (entry 21).
One of the major advantages of this methodology is that
halogen atoms can be tolerated, which provides access to more
structurally diverse xanthone skeletons via metal-catalyzed
cross-coupling reactions. As illustrated in Scheme 4, the
halogen-substituted xanthone product 4h can be further modified
by Heck19 and Suzuki20 reactions, affording interesting xanthone
derivatives 5a and 5b for further biological examination.
Synthesis of Thioxanthones. Biologically interesting thiox-
anthone derivatives have also been prepared by this same
methodology. All of the results are summarized in Table 3.
Methyl thiosalicylate (6a) and 1.1 equiv of benzyne precursor
2a were treated with 4 equiv of CsF in 5 mL of THF at 65 °C;
after 24 h, a 35% yield of thioxanthone (7a) was isolated. The
lower yield in this example is presumably due to oxidative
homocoupling of the thiols since thiols are known to afford
disulfides in the presence of CsF on a celite solid support in
air.21 In order to suppress this undesired homocoupling process,
the same reaction was repeated under an Ar atmosphere, and a
55% yield of thioxanthone (7a) was obtained. Further optimiza-
tion indicated that a 64% yield of product 7a could be obtained
under more dilute conditions, although a small amount of
disulfide product and S-arylation product was present (Table
3, entry 1). The reaction of this thiol with benzyne precursor
2b afforded a 45% yield of the desired thioxanthone 7b (entry
2). When 2d was employed as the aryne precursor in this
reaction, a 40% yield of the product 7c was isolated (entry 3).
The reaction of 2e afforded a 56% yield of two regioisomers,
7d and 7e, in a 1:1 ratio (entry 4). Finally, aryne precursor 2f
After investigating the effect of varying the salicylate
structure, we examined the reaction efficiency using different
aryne precursors (Scheme 3). A 62% yield of a single isomeric
methoxyxanthone 4e was obtained from the reaction of methyl
salicylate 1a with aryne precursor 2b after 24 h at 90 °C (entry
17). Note that a somewhat higher temperature was required to
get a good yield. The regioselectivity of this reaction is due to
the steric and electronic effects in the step involving nucleophilic
attack on the aryne, which has been seen in several previous
reactions involving this aryne.18 When the dimethoxysilylaryl
(19) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2005, 61,
11771. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4442. (c) Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., de Meijere, A., Eds.; Wiley-Interscience:
New York, 2002; Vol. 1, p 1223 and references therein. (d) Tsuji, J.
Palladium Reagents and Catalysts; John Wiley & Sons: Chichester,
England, 2004; p 135.
(20) Tofi, M.; Georgiou, T.; Montagnon, T.; Georgios, V. Org. Lett. 2005,
7, 3347.
(21) Shah, S. T. A.; Khan, K. M.; Fecker, M.; Voelter, W. Tetrahedron
Lett. 2003, 44, 6789 and references therein.
(18) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99.
586 J. Org. Chem., Vol. 72, No. 2, 2007

Synthesis of Xanthones, Thioxanthones, and Acridones
SCHEME 5. Plausible Mechanism for the Acridone Synthesis
TABLE 3. Synthesis of Thioxanthonesa
TABLE 4. Synthesis of Acridonesa
a All reactions were conducted on a 0.25 mmol scale in the presence of
4 equiv of CsF and 1.1 equiv of silylaryl triflate in 10 mL of THF at 65 °C
under Ar. b The reaction was conducted in 10 mL of THF at 90 °C under
Ar (sealed tube). c The ratio in parentheses has been determined by 1H NMR
spectroscopy.
was allowed to react with thiosalicylate 6a, and a 62% yield of
thioxanthone 7f was isolated by flash chromatography
(entry 5).
Synthesis of Acridones. After we had a general and efficient
synthesis of xanthones and thioxanthones in hand, we attempted
to expand this methodology to the synthesis of acridones, a well-
known class of antifungal, antitumor, and anticancer com-
pounds.6 Acridones have been prepared by the coupling of
3-halogeno-4-methoxybenzynes generated from 5-(3-halogeno-
4-methoxyphenyl)thianthrenium perchlorates and LDA in THF
at reflux with 2-aminobenzoate.22 However, this protocol
employs a fairly unusual aryne precursor, and it also suffers
from the moisture-sensitive reagents and conditions. Methyl
2-aminobenzoate (8a) was first prepared and allowed to react
with aryne precursor 2a, and a 50% yield of the acridone product
9a was obtained (Table 4, entry 1). Methyl 2-(N-methylamino)-
benzoate (8b) was then allowed to react with aryne precursor
2a. After 1 day of reaction, a 72% yield of acridone 9b was
a All reactions were conducted on a 0.25 mmol scale in the presence of
4 equiv of CsF and 1.1 equiv of the silylaryl triflate in 10 mL of THF at
65 °C. b The yield was determined by GC-MS analysis. c The reaction was
conducted in 10 mL of THF at 90 °C (sealed tube). The ratio in parentheses
1
has been determined by H NMR spectroscopy.
isolated by flash chromatography (entry 2). However, the
reaction employing methyl 2-(N-phenylamino)benzoate (8c) was
very sluggish; after 2 days of reaction, only a 7% yield of the
desired product 9c was observed by GC-MS analysis. The low
(22) Yoon, K.; Ha, S. M.; Kim, K. J. Org. Chem. 2005, 70, 5741.
J. Org. Chem, Vol. 72, No. 2, 2007 587

Zhao and Larock
yield is presumably due to the steric hindrance introduced by
the presence of the phenyl substituent (entry 3). Interestingly,
the reaction of methyl 2-(N,N-dimethylamino)benzoate (8d)
affords a 65% yield of acridone product 9b, which indicates
that even tertiary amines can be successfully employed in this
transformation (entry 4). Apparently the anticipated ammonium-
containing product undergoes demethylation under the reaction
conditions. Several halogen-substituted benzoates (8e-8g) have
also been prepared from the corresponding acids and employed
in this process (entries 5-7). Yields of 48-71% of the
corresponding acridone products (9d-9f) have been obtained.
We have not employed protecting groups on nitrogen since that
could well lead to C-N insertion products.14,15
At this point, we examined the effect of the aryne structure
on the yield of acridone. When silylaryl triflate 2b was employed
with benzoate 8b, the reaction was very sluggish, and only a
trace amount of the desired acridone product 9g was observed
by GC-MS analysis (entry 8). Aryne precursor 2d afforded
only a 27% yield of the product 9h, and this reaction had to be
run at 90 °C (entry 9). The reaction of aryne precursor 2e with
benzoate 8a afforded a 51% yield of two isomeric acridones,
9i and 9j, in a 1:1 ratio (entry 10). A 35% yield of acridone
product 9k was obtained when aryne precursor 2f was employed
(entry 11). These last two reactions also had to be run at 90 °C.
A plausible mechanism for these aminobenzoate reactions is
proposed in Scheme 5. The benzoate bearing an amino group
presumably first undergoes nucleophilic attack on the aryne
generated in situ from the silylaryl triflate. When R is a proton,
the actual nucleophile involved could be either the neutral amine
or the anionic intermediate D generated by hydrogen abstraction
from the amine by CsF. However, when the tertiary amine 8d
is employed, although no proton is available for abstraction,
this reaction still works well, suggesting that the neutral amine
itself is nucleophilic enough for this transformation. Therefore,
the reaction mechanism, which proceeds via intermediates F
and G, seems more likely, although we cannot rule out possible
anionic nucleophilic attack on the aryne, which proceeds via
intermediates D and E. Subsequent intramolecular cyclization
should afford the final acridone products.
Experimental Section
Representative Procedure for the Coupling-Cyclization of
Arynes and Salicylates. CsF (1.0 mmol), the salicylate (0.25
mmol), and the silylaryl triflate (0.28 mmol) in 5 mL of anhydrous
THF were stirred at 65 or 90 °C for 24 h. The reaction mixture
was allowed to cool to room temperature, diluted with diethyl ether
(25 mL), and washed with brine (25 mL). The aqueous layer was
re-extracted with diethyl ether (2 × 25 mL). The organic layers
were combined, dried (MgSO4), filtered, and the solvent was
removed under reduced pressure. The residue was purified by flash
chromatography on silica gel. 9H-Xanthen-9-one (4a): 1H NMR
(CDCl3) δ 7.37 (t, J ) 6.0 Hz, 2H), 7.48 (d, J ) 6.4 Hz, 2H),
7.70-7.74 (m, 2H), 8.33 (dd, J ) 6.0, 1.2 Hz, 2H); 13C NMR
(CDCl3) δ 118.2, 122.1, 124.1, 126.9, 135.0, 156.4, 177.4; IR
(CDCl3) 2914, 2874, 1654, 1456 cm-1; HRMS m/z 196.0527 (calcd
for C13H8O2, 196.0524).
Representative Procedure for the Coupling-Cyclization of
Arynes and Thiosalicylates. CsF (1.0 mmol), the thiosalicylate
(0.25 mmol), and the silylaryl triflate (0.28 mmol) were added to
10 mL of anhydrous THF, and the reaction vial was flushed with
Ar. The whole reaction solution was then stirred at 65 or 90 °C for
24 h and worked up as described previously. 9H-Thioxanthen-9-
one (7a): 1H NMR (CDCl3) δ 7.48 (td, J ) 6.7, 1.5 Hz, 2H), 7.56-
7.65 (m, 4H), 8.62 (dd, J ) 7.4, 0.8 Hz, 2H); 13C NMR (CDCl3)
δ 126.2, 126.5, 129.4, 130.1, 132.5, 137.5, 180.2; IR (CDCl3) 2971,
2919, 1684, 1459 cm-1; HRMS m/z 212.0299 (calcd for C13H8OS,
212.0296).
Representative Procedure for the Coupling-Cyclization of
Arynes and 2-Aminobenzoates. CsF (1.0 mmol), the 2-aminoben-
zoate (0.25 mmol), and the silylaryl triflate (0.28 mmol) in 10 mL
of anhydrous THF were stirred at 65 or 90 °C for 24 h. The reaction
mixture was allowed to cool to room temperature, diluted with ethyl
acetate (25 mL), and washed with brine (25 mL). The aqueous layer
was re-extracted with ethyl acetate (2 × 25 mL). The organic layers
were combined, dried (MgSO4), filtered, and the solvent was
removed under reduced pressure. The residue was purified by flash
chromatography on silica gel. 10-Methyl-10H-acridin-9-one
(9b): 1H NMR (CDCl3) δ 3.88 (s, 3H), 7.28 (t, J ) 7.2 Hz, 2H),
7.50 (d, J ) 8.7 Hz, 2H), 7.69-7.73 (m, 2H), 8.55 (dd, J ) 8.0,
1.2 Hz, 2H); 13C NMR (CDCl3) δ 33.9, 115.0, 121.5, 122.7, 128.0,
134.0, 142.8, 178.3; IR (CDCl3) 2917, 2850, 1637 cm-1; HRMS
m/z 209.0843 (calcd for C14H11NO, 209.0841).
Conclusions
A general one-pot synthesis of biologically interesting xan-
thones, thioxanthones, and acridones has been developed. This
chemistry presumably proceeds by a tandem intermolecular
nucleophilic coupling of the substituted benzoates and arynes
and subsequent intramolecular electrophilic cyclization. The
mild reaction conditions and generally high reaction efficiency
provide advantages over previously reported multistep proce-
dures. In general, this strategy tolerates both electron-donating
and electron-withdrawing functionalities on the benzoate ring,
but substituents on the aryne ring appear to lower the yields of
the desired products.
Acknowledgment. We gratefully acknowledge the financial
support of this work by the National Institutes of Health and
Kansas University Chemical Methodologies and Library De-
velopment Center of Excellence (P50 GM 069663).
Supporting Information Available: Preparation and charac-
terization of the xanthones, thioxanthones, and acridones. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO0620718
588 J. Org. Chem., Vol. 72, No. 2, 2007