Synthesis of polyhydroxylated xanthones via acyl radical cyclizations

Article abstract of DOI:10.1016/j.tetlet.2011.10.153

2-Formylphenoxy quinones can be converted into xanthones via an acyl radical intermediate with NBS and AIBN.

Full text of DOI:10.1016/j.tetlet.2011.10.153

Tetrahedron Letters 53 (2012) 111–114
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Tetrahedron Letters
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Synthesis of polyhydroxylated xanthones via acyl radical cyclizations
⇑
George A. Kraus , Feng Liu
Department of Chemistry, Iowa State University, Ames, IA 50011, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Formylphenoxy quinones can be converted into xanthones via an acyl radical intermediate with NBS
Received 14 September 2011
Revised 27 October 2011
Accepted 29 October 2011
Available online 13 November 2011
and AIBN.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Xanthones
Cyclization
Acyl radical
NBS
Xanthones are found in many plants, including Hypericum and
Prunella species. Many xanthones bearing hydroxyl substituents
exhibit valuable biological activity.1 Daviditin A (1) preserves
endothelial dysfunction elicited by lysophosphatidyl choline
(Fig. 1). The protective effect of daviditin A on the endothelium is
related to reduction of asymmetric dimethylarginine concentra-
tion.2 Xanthone 2 was shown to relax the corpus cavernosal
smooth muscle by 97% compared to Viagra.3 Bellidifolin (3) im-
proved insulin resistance by enhancing insulin signaling.4
O
O
O
O
O
O
O
O
O
O
6
Because of the diverse biological activities of xanthones, several
approaches have been reported.5 Of these methods, Friedel–Crafts
acylation/cyclization protocols6 are the most commonly used
methods. However, synthetic methods for highly hydroxylated
xanthones are limited. Recently, strategies employing photochem-
istry,7 benzyne addition,8 and directed metallation9 have been re-
O
OH
Br
+
O
O
O
O
5
ported. We report herein
a synthesis of polyhydroxylated
4
xanthones employing acyl radical intermediates.
Scheme 1. Strategy for xanthone synthesis.
OH
O
OH
OH
OH
O
OH
OH
O
OH
OMe
OH
OMe
HO
O
O
OMe
MeO
O
OMe
OMe
1
3
2
Figure 1. Structures of xanthones.
⇑
Corresponding author. Tel.: +1 515 294 7794; fax: +1 515 294 0105.
E-mail address: gakraus@iastate.edu (G.A. Kraus).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.153

112
G. A. Kraus, F. Liu / Tetrahedron Letters 53 (2012) 111–114
O
O
OH
1. K2CO3, DMF
RT, 4h
Br
O
O
+
O
2. 6N HCl
O
O
O
RT, 1h
O
O
4
6 (78%)
5
OH
OH
O
0.2eq AIBN
2eq NBS
OH
O
O
10eq Zn
O
O
6
CHCl3 : CCl4
= 3:1
reflux, 4h
RT, 10min
O
O
8 (67%)
7
DMF, H2O,
180 C, 77%
H2, Pd/C
15%
°
OH
O
O
O
OH
9
Scheme 2. Synthesis of xanthone 9.
We recently reported that radicals generated by decarboxyl-
was unexpected and suggests that production of xanthone 7 pre-
sumably arises from a spirocyclic intermediate such as 10 that
would result from a 5-exo-trig radical cyclization. Elimination of
the phenoxide radical followed by cyclization and oxidation pro-
vides a route to 7 (Scheme 3). Attempts to isolate intermediates in
the rearrangement by conducting the reaction using only one equiv-
alent of NBS produced starting material plus a reduced yield of 7. It is
possible that the mechanism involves a 6-endo closure followed by a
rearrangement. Benzophenone 8 could be readily cyclized to form
xanthone 9 by heating in aqueous DMF at 180 °C for 16 h.7 Xanthone
9 is produced in an overall yield of 40%. Interestingly, benzophenone
8 is a natural product isolated from Dalbergia cochinchinensis.15
This procedure was applied to other bromoquinones. The re-
sults in Table 1 show the quinone precursors that were synthe-
sized. The overall yields are in the range of 52–78%.
The xanthones in Table 2 were prepared from the corresponding
quinones by cyclization with AIBN and NBS, reduction with zinc,
and cyclization in DMF/water. The xanthone in entry 2 is a natural
product isolated from Centaurium erythraea16 that had not previ-
ously been synthesized. The overall yields for different xanthones
are 40% (entry 1), 36% (entry 2), 31% (entry 3), 29% (entry 4), and
30% (entry 5).
ation of an acid with persulfate underwent intramolecular cycliza-
tion to a quinone, resulting in a direct synthesis of Bauhinoxepin
J.10 If an acyl radical could be generated from 6,11 the cyclization
could lead to a direct synthesis of xanthones (Scheme 1). The qui-
none 6 can be synthesized by a coupling reaction of acetal 4 with
bromoquinone 5.
We first tried directly coupling salicyladehyde with bromoqui-
none 5 to generate quinone 6, but the reaction failed. After conver-
sion of salicyladehyde to acetal 4,12 the reaction of acetal 4 with
bromoquinone5 and K2CO3 in DMF followedby HCl hydrolysisaffor-
ded quinone 6 in 78% yields (Scheme 2). To the best of our knowl-
edge, there have been no reports for the synthesis of xanthones
from quinones such as 6. Initially, we irradiated quinone 6 under
conditions where an intramolecular hydrogen atom abstraction
via an excited state quinone could lead to an acyl radical. Unfortu-
nately, only starting material was recovered. We next attempted
to generate the acyl radical through hydrogen atom abstraction
using the diradical of benzophenone, a strategy we had used suc-
cessfully to generate acylhydroquinones.13 This approach also
failed.
Cheung and later Marko reported that aryl aldehydes could be
converted to acid bromides with NBS.14 Although this transforma-
tion has not been extensively studied, this reaction likely proceeds
through an acyl radical intermediate. Treatment of quinone 6 with
NBS and a catalytic amount of AIBN in CHCl3 and CCl4 produced xan-
thone 7. A number of experiments were conducted to optimize the
transformation and it was found that two equivalents of NBS and
0.2 equiv of AIBN were necessary to achieve good conversion. Unfor-
tunately, xanthone 7 was not stable to column chromatography. The
xanthone 7 was reduced by catalytic hydrogenation to generate xan-
thone 9, albeit in only 15% yield after two steps. The structure of xan-
thone 9 was confirmed by X-ray spectroscopy. Reduction of
xanthone 7 with zinc in acetic acid afforded benzophenone 8 in
67% yields after two steps, whose structure was also determined
by X-ray spectroscopy. This appears to be the first example of xan-
thone cleavage under reductive conditions. Moreover, this result
In summary, the first synthesis of xanthones by acyl radical
chemistry has been achieved. Two natural products were synthe-
sized. This novel approach will permit the direct synthesis of novel
polyhydroxylated xanthones.
O
O
O
O
O
O.
O
O
7
6
O
OMe
10
Scheme 3. Proposed mechanism for the production of 7 from 6.

G. A. Kraus, F. Liu / Tetrahedron Letters 53 (2012) 111–114
113
Table 1
Reaction of 4 with 5 to generate quinone 6
O
O
O
OH
1. K2CO3, DMF
O
O
Br
RT, 4 h
+
G1
O
G2
G1
G2
2. 6N HCl
RT, 1 h
O
O
6
4
5
Entry
1
4
5
6
Isolated yield (%)
OH
O
O
Br
O
O
78
76
O
O
O
O
O
O
O
O
O
O
O
O
O
Br
OH
2
O
O
O
O
O
O
OH
O
Br
Br
Br
O
O
Cl
3
4
5
73
58
52
O
Cl
O
O
O
O
O
O
O
OH
O
O
O
O
O
O
O
O
O
OH
O
O
Br
Br
O
O
O
Table 2
Reaction of quinone 6 to generate 8 and xanthone 9
OH
OH
OH
OH
O
O
0.2eq AIBN
DMF
H2O
O
OH
O
O
O
10eq Zn
2eq NBS
G1
G1
G2
G1
G2
G2
G1
G2
CHCl3 : CCl4
= 3 : 1
reflux, 4 h
RT, 10 min
180 °C
O
O
O
O
O
9
8
7
6
Entry
1
6
8a
Isolated yield (%)
9b
Isolated yield (%)
O
OH
OH
O
OH
O
O
O
O
67
77
O
O
O
O
O
O
O
OH
OH
O
O
OH
OH
O
O
O
OH
O
2
65
72
O
OH
O
O
O
OH
(continued on next page)

114
G. A. Kraus, F. Liu / Tetrahedron Letters 53 (2012) 111–114
Table 2 (continued)
Entry
3
6
8a
Isolated yield (%)
9b
Isolated yield (%)
O
O
OH
OH
OH
O
O
OH
O
O
O
O
O
60
68
75
70
Cl
O
Cl
Cl
OH
O
OH
OH
O
OH
O
4
5
73
77
O
OH
OH
O
O
O
O
O
O
OH
OH
OH
Br
Br
Br
O
O
O
OH
O
OH
a
Entry 1 is a natural product isolated from Dalbergia cochinchinensis.
Entry 2 is a natural product isolated from Centaurium erythraea.
b
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Acknowledgment
We thank the Department of Chemistry at Iowa State University
for the partial support of this research.
10. Kraus, G. A.; Thite, A.; Liu, F. Tetrahedron Lett. 2009, 50, 5303–5304.
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13. (a) Kraus, G. A.; Kirihara, M.; Wu, Y. ACS Symposium Series 1994, 577(Benign by
Design), 76–83.; (b) Kraus, G. A.; Liu, P. Tetrahedron Lett. 1994, 35, 7723–7726.
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