CAN-mediated oxidations for the synthesis of xanthones and related products

Article abstract of DOI:10.1021/jo101873v

Reaction of (2,4,5-trimethoxyphenyl)(2-hydroxyphenyl)methanone with ceric ammonium nitrate furnished the xanthone, 2,3-dimethoxy-9H-xanthen-9-one. Under the same conditions the related (1,4-dimethoxynaphthalen-2-yl)(2-hydroxyphenyl) methanone resulted in the formation of 12a-methoxy-5H-benzo[c]xanthenes 5,7(12aH)-dione. Other examples of this novel transformation are also outlined.

Full text of DOI:10.1021/jo101873v

pubs.acs.org/joc
CAN-Mediated Oxidations for the Synthesis
of Xanthones and Related Products
Myron M. Johnson,† Jeremy M. Naidoo,†
Manuel A. Fernandes,†,§ Edwin M. Mmutlane,‡
Willem A. L. van Otterlo,† and Charles B. de Koning*,†
†Molecular Sciences Institute, School of Chemistry,
University of the Witwatersrand, PO Wits 2050, South Africa,
and ‡CSIR, Biosciences, Modderfontein, South Africa.
§For correspondence regarding crystallography.
charles.dekoning@wits.ac.za
Received September 23, 2010
FIGURE 1. Examples of naturally occurring and synthetic xanthone-
containing compounds.
Finally, compound 5, a synthetic antimalarial, represents
an example of a synthetic xanthone.5
There are a number of reported methods for the synthesis
of xanthones.6 In our laboratories we have been interested in
developing new synthetic methods for the assembly of aro-
matic compounds in general,7 and this paper outlines new
methodology for the synthesis of xanthones and related
compounds.
Commercially available 1,4-dimethoxynaphthalene 6 was
subjected to 1 molar equiv of N-bromosuccinimide (NBS) to
afford the desired known brominated compound 78 in good
yield. This compound was then treated with n-BuLi and the
benzyl ester 8 to yield the aromatic ketone 9 in good yield
(89%) as shown in Scheme 1. Selective removal of the O-
benzyl substituent then yielded the required phenol 10.
Exposure of 10 to 5 molar equiv of CAN9 in the presence
of acetonitrile, water, and chloroform, with the hope of
Reaction of (2,4,5-trimethoxyphenyl)(2-hydroxyphenyl)-
methanone with ceric ammonium nitrate furnished the
xanthone, 2,3-dimethoxy-9H-xanthen-9-one. Under the
same conditions the related (1,4-dimethoxynaphthalen-
2-yl)(2-hydroxyphenyl)methanone resulted in the forma-
tion of 12a-methoxy-5H-benzo[c]xanthenes 5,7(12aH)-
dione. Other examples of this novel transformation are
also outlined.
The xanthone nucleus is present in numerous natural
products that exhibit interesting biological activity. For
example, the antitumor compound bikaverin 1,1 (Figure 1)
mangeferin 22 isolated from the mangosteen fruit, the anti-
cancer compound psorospermin 3,3 and the anti-HIV com-
pound swertifrancheside 44 all have a xanthone nucleus.
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2447–2479. For a selection of more recent papers see: (a) Barbero, N.;
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DOI: 10.1021/jo101873v
r
Published on Web 11/18/2010
J. Org. Chem. 2010, 75, 8701–8704 8701
2010 American Chemical Society

Johnson et al.
JOCNote
SCHEME 1a
SCHEME 2a
aReagents and conditions: (i) NBS, CH2Cl2, 89%; (ii) (a) n-BuLi,
THF, -78°C, (b) 8, THF, 72%; (iii) H2, 5% Pd/C, 1 atm, 89%; (iv)
CAN, H2O/MeCN/CHCl3, rt, 21, 74%, 22, 15%.
aReagents and conditions: (i) NBS, CH2Cl2, 90%; (ii) (a) n-BuLi,
THF, -78°C, (b) 8, THF, 89%; (iii) H2, 5% Pd/C, 4.5 atms, 97%;
(iv) CAN, H2O/MeCN/CHCl3, rt, 72%.
SCHEME 3a
producing the quinone 11 or the corresponding xanthone 12,
unexpectedly met with failure. The 1H NMR spectrum of the
product that was isolated after chromatography contained
what appeared to be a methoxy as part of an acetal at δ 3.03,
as well as a quinone-like singlet at δ 7.26. An X-ray crystal
structure indicated that we had formed a xanthone-related
product, dione 13 (see figure in Supporting Information).10
A possible mechanism for the synthesis of 13 involves
CAN-mediated oxidation of 10 to afford radical cation 14.11
Nucleophilic addition of the phenol to the aromatic radical
cation of 14 will then afford radical 15, which can undergo
further oxidation with another 1 equiv of CAN to afford a
cation to which water can add to yield 16. Compound 13 is
then formed by elimination of methanol from 16. Alterna-
tively, the phenoxy radical of 10 could be formed, which on
addition to the naphthalene would result in the formation of
the same radical 15. This reaction appears to represent new
methodology for the synthesis of a xanthone-like product.
After this unexpected result we decided to try the reaction
on related substrates to gauge the versatility of this novel
reaction. Instead of using 1,4-dimethoxynaphthalene 6 as the
starting material, 1,4-dimethoxybenzene 17 was used in this
investigation.
aReagents and conditions: (i) CAN, H2O/MeCN/CHCl3, rt, 26, 91%,
28, 93%, 30, 63% and 31 17%.
In a similar manner, reaction of 1,4-dimethoxybenzene 17
with NBS afforded the halogenated product 18 (Scheme 2).
Exposure of this compound to n-BuLi and the same ester 8
furnished the required compound 19. Removal of the benzyl
substituent of 19 yielded the desired substrate 20 on which we
could attempt our novel CAN-mediated reaction. Treatment
of 20 with 5 molar equiv of CAN afforded the same type of
dione 22 obtained previously, although this time it was the
minor product (15%). The major product isolated was the
xanthone 21, which was produced in 74% yield. The identity
of this product was confirmed by X-ray crystallography (see
figure in Supporting Information).
It would appear that xanthone 21 could be formed in a
similar manner as the dione 13. CAN oxidation again results
in the formation of a radical cation 23, which cyclizes by
nucleophilic addition of the phenol to yield 24. The radical 24
then undergoes elimination of a methoxy radical, which
results in the reformation of the aromatic ring to give the
observed product, xanthone 21. Presumably in this case, the
lack of an extra aromatic ring, as compared to the naphtha-
lene example, results in the major product being the fully
aromatic xanthone 21.
(10) For the use of K3[Fe(CN)6] to prepare one related compound, see:
Franck, B.; Zeidler, U. Chem. Ber. 1973, 106, 1182–1197.
(11) Tanoue, Y.; Terada, A. Bull. Chem. Soc. Jpn. 1988, 61, 2039–2045.
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Johnson et al.
JOCNote
SCHEME 4a
2H), 7.83-7.57 (m, 3H), 7.24-7.08 (m, 3H), 3.03 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 184.0, 181.0, 157.8, 143.8, 137.0, 136.6,
133.9, 130.8, 130.6, 130.2, 127.6, 126.9, 126.5, 123.2, 121.5, 118.6,
96.5, 51.5; MS (m/z) 293.07 (Mþ, 100%), 294.09 (22); HRMS (m/z)
calcd for C18H12O4, 292.0736, found 292.0778.
2-Methoxy-9H-xanthen-9-one (21) and 4a-Methoxy-2H-
xanthene-2,9(4aH)-dione (22). CAN (1.06 g, 1.94 mmoles) in water
(5 mL) was added dropwise to a stirring mixture of (2,5 dimethoxy-
phenyl)(2-hydroxyphenyl)methanone (20) (0.100 g, 0.388 mmoles)
in MeCN (10 mL) and CHCl3 (2.5 mL). The mixture was then
stirred at rt for 24 h. The reaction mixture was filtered through
Celite and washed with EtOAc (3 ꢀ 25 mL). The organic layer was
washed consecutively with a saturated aqueous NaHCO3 solution
(25 mL), brine (25 mL), and water (25 mL). The organic layer was
then dried over MgSO4. The solvent was removed in vacuo, and
column chromatography (5% ethyl acetate/hexane) afforded the
products 21 and 22 as white needles (0.065 g, 74%) and orange
grains, respectively (0.015 g, 15%). 2-Methoxy-9H-xanthen-9-one
(21): mp 131-133 °C (EtOAc), lit.12 mp 134-135 °C; IR (solid)
ν
max (cm-1) 1647, 1614, 1488, 1462, 1430; 1H NMR (CDCl3, 300
MHz) δ 8.25 (dd, J = 8.0, 1.6, 1H), 7.65-7.55 (m, 2H), 7.42-7.31
(dd, J= 7.8, 1.4, 1H), 7.29 (s, 1H), 7.28-7.14 (m, 2H), 3.83 (s, 3H);
13C NMR (CDCl3, 75 MHz) δ 176.0, 155.0, 154.9, 149.9, 133.5,
125.6, 123.8, 122.7, 121.0, 120.2, 118.4, 116.9, 104.8, 54.9; MS (m/z)
227.10 (Mþ, 100%), 228.10 (12), 249.08 (5); HRMS (m/z) calcd for
C14H10O3, 226.0630, found 226.0620. 4a-Methoxy-9H-xanthen-
2,9(4aH)-dione (22): mp 110-112 °C (EtOAc); IR (solid) νmax
(cm-1) 1693, 1669, 1644, 1604, 1577, 1464; 1H NMR (CDCl3, 300
MHz) δ7.94 (d, J = 7.8, 1H), 7.53 (t, J = 7.8, 1H), 7.11 (t, J = 7.5,
1H), 7.03 (d, J = 10.0, 1H), 6.81 (s, 1H), 6.37 (dd, J = 10.4, 1.9,
1H), 3.25 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 185.1, 180.9,
157.0, 144.5, 140.1, 137.0, 130.7, 128.5, 127.5, 123.3, 121.6, 118.5,
95.1, 51.3; MS (m/z) 243.12 (Mþ, 100%), 244.12 (15); HRMS (m/z)
calcd for C14H10O4, 242.0479, found 242.0568.
aReagents and conditions: (i) CAN, H2O/MeCN/CHCl3, rt, 33, 21%,
34, 29%, 35, 9%.
As a result of the success of this reaction, three other
related transformations were carried out. The methodology
for the synthesis of precursor 25, 27, and 29 is described in the
Supporting Information and follows a synthetic sequence
similar to that described previously. Reaction of 25 with 5
molar equiv of CAN resulted in the formation of the
xanthone 26 in an excellent yield of 91%, and reaction of
27 with CAN gave the dione 28 in 93% yield. In addition, the
phenol precursor 29 furnished the xanthone 30 and dione 31,
in 63% and 17% yield, respectively, as depicted in Scheme 3.
One final example of this CAN-mediated transformation
was attempted on substrate 32 (Scheme 4), and to our surprise
the reaction yielded the expected products 33 and 34 as well as
an unexpected product 35. The structure of this compound (35)
was confirmed by X-ray crystallography (Scheme 4). Presum-
ably the oxygen substituent in the para position to the newly
formed five-membered ring facilitates the reaction.
X-ray Crystallography. All three data sets were collected using
ω-scans on a APEX II CCD area detector diffractometer.
Crystal data for 13: C18H12O4, Mr 292.28 g mol-1; crystal
dimensions (mm) 0.49 ꢀ 0.28 ꢀ 0.25; crystal system, monoclinic;
space group, P21/n; unit cell dimensions and volume, a =
13.0183(7) A, b = 13.0356(6) A, c = 15.9224(7) A, R = 90°,
β = 98.662(3)°, γ = 90°, V = 2671.2(2) A3, no. of formula units
in the unit cell Z = 8; calculated density rcalcd 1.454 Mg/m3;
linear absorption coefficient, m 0.103 mm-1; radiation and
wavelength, Mo KR = 0.71073 A; temperature of measurement,
173(2) K, 2 Qmax 28.00°; no of measured and independent
reflections, 19971 and 6440; Rint = 0.0773; R [I > 2.0σ(I)] =
0.0789, wR = 0.1979, GoF = 0.983, refined on F; residual
In conclusion, we have developed new methodology for the
synthesis of xanthones and related products, using CAN as an
oxidant, from readily prepared precursors. Current work in
our laboratories includes further investigations into the scope
and limitation of the CAN reaction as well as attempts to
elucidate details of the mechanism of the reaction.
electron density, 1.129 and -0.306 e A-3
.
Crystal data for 21: C14H10O3, Mr 226.22 g mol-1; crystal
dimensions (mm) 0.60 ꢀ 0.07 ꢀ 0.06; crystal system, monoclinic;
space group, P21/n; unit cell dimensions and volume, a =
4.7765(2) A, b = 14.2280(5) A, c = 15.4365(6) A, R = 90°,
β = 93.426(2)°, γ = 90°, V = 1047.19(7) A3, no. of formula
units in the unit cell Z = 4; calculated density rcalcd, 1.435 Mg/m3;
linear absorption coefficient, m 0.101 mm-1; radiation and wave-
length, Mo KR = 0.71073 A; temperature of measurement, 173(2)
K, 2 Qmax 28.00°; no of measured and independent reflections,
15813 and 2533; Rint = 0.0446; R [I > 2.0σ(I)] = 0.0466, wR =
0.1070, GoF = 1.026, refined on F; residual electron density, 0.287
Experimental Section
12a-Methoxy-5H-benzo[c]xanthene-5,7(12aH)-dione (13). CAN
(13.3 g, 24.3 mmoles) in water (25 mL) was added dropwise to a
stirring mixture of (1,4-dimethoxynaphthalene-2-yl)(2-hydroxy-
phenylmethanone (9) (1.50 g, 4.86 mmoles) in MeCN (25 mL)
and CHCl3 (5 mL). The mixture was then stirred at rt for 10 min.
The reaction mixture was filtered through Celite and washed with
EtOAc (3 ꢀ 25 mL). The organic layer was washed consecutively
with a saturated aqueous NaHCO3 solution (25 mL), brine (25
mL), and water (25 mL). The organic layer was then dried over
MgSO4. The solvent was removed in vacuo, and column chroma-
tography with (5% EtOAc/hexane) afforded the product 13 as
orange rod-like crystals (1.02 g, 72%). Mp 125-127 °C (EtOAc);
IR (solid) νmax (cm-1) 1713, 1689, 1667, 1636, 1607, 1596, 1459; 1H
NMR (CDCl3, 300 MHz) δ 8.16 (d, J = 7.8, 1H), 8.07-8.02 (m,
and -0.273 e A-3
.
Crystal data for 35: C15H11ClO5, Mr 306.69 g mol-1; crystal
dimensions (mm) 0.49 ꢀ 0.05 ꢀ 0.03; crystal system, monoclinic;
space group, P21/c; unit cell dimensions and volume, a =
5.2102(3) A, b = 30.1686(16) A, c = 8.4028(5) A, R = 90°,
β = 94.569(4)°, γ = 90°, V = 1316.59(13) A3, no. of formula
(12) Bennett, O. F.; Bouchard, M. J.; Mallot, R.; Derven, P.; Saluti, G.
J. Org. Chem. 1972, 37, 1359–1376.
J. Org. Chem. Vol. 75, No. 24, 2010 8703

Johnson et al.
JOCNote
units in the unit cell Z = 4; calculated density rcalcd, 1.547 Mg/m3;
linear absorption coefficient, m 0.310 mm-1; radiation and wave-
length, Mo KR = 0.71073 A; temperature of measurement, 173(2)
K, 2 Qmax 25.00°; no of measured and independent reflections,
12081 and 2315; Rint = 0.0479; R [I > 2.0σ(I)] = 0.0479, wR =
0.0886, GoF = 1.039, refined on F; residual electron density, 0.220
spectroscopy and MS service. J. Schneider and M. Ismail from
the MS Service, University of Dortmund and Max Planck
Institute for Molecular Physiology, Dortmund, Germany, are
thanked for performing some of the HRMS, and B. Moolman
and M. Stander from the MS service at the University of
Stellenbosch are also thanked for recording some HRMS.
and -0.243 e A-3
.
Acknowledgment. This work was supported by the National
Research Foundation (NRF, GUN 2053652 and the IRDP of
the NRF provided by the Research Niche Areas programme),
Pretoria, and the University of the Witwatersrand (Science
Faculty Research Council). R. Mampa and M. Brits (Univer-
sity of the Witwatersrand) are thanked for providing the NMR
Supporting Information Available: Experimental proce-
dures and spectral data for all new compounds, including
crystallographic data for compounds 13 (CCDC 799882),
21 (CCDC 799883), and 35 (CCDC 799884). This material
is available free of charge via the Internet at http://pubs.
acs.org.
8704 J. Org. Chem. Vol. 75, No. 24, 2010