Xanthone in synthesis: a reactivity profile via directed lithiation of its dimethyl ketal

Article abstract of DOI:10.1016/j.tetlet.2009.08.050

Xanthone, as its dimethyl ketal, undergoes functionalization with a synthetically useful degree of regioselectivity using a lithiation protocol. The core structure is regenerated during the work-up. Monosubstitution at C-4 or C-1 and disubstitution at C-4

Full text of DOI:10.1016/j.tetlet.2009.08.050

Tetrahedron Letters 50 (2009) 5981–5983
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Tetrahedron Letters
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Xanthone in synthesis: a reactivity profile via directed lithiation
of its dimethyl ketal
c
a
Michal R. Odrowaz-Sypniewski a, Petros G. Tsoungas b, , George Varvounis , Paul Cordopatis
*
a Department of Pharmacy, University of Patras, 265 00 Patras, Greece
b Ministry of Development, Messogion 14-16, 115 10 Athens, Greece
c Department of Chemistry, University of Ioannina, 451 10 Ioannina, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 March 2009
Revised 16 May 2009
Accepted 14 August 2009
Available online 21 August 2009
Xanthone, as its dimethyl ketal, undergoes functionalization with a synthetically useful degree of regiose-
lectivity using a lithiation protocol. The core structure is regenerated during the work-up. Monosubstitu-
tion at C-4 or C-1 and disubstitution at C-4 and C-5 or C-1 and C-5 are observed. The substitution pattern
appears to be dependent upon the experimental conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Xanthone
Lithiation
Methylation
Dimethyl ketal
Xanthone 1 is a common structure in Nature. Many of its deriv-
atives bearing methyl, hydroxy, methoxy or phenyl groups, or
those possessing complex polycyclic frameworks, have been iso-
lated from twenty families of higher plants, fungi and lichens.1 It
is also found in many natural products or other molecules exhibit-
ing a broad spectrum of bio(pharmaco)logical activities.2 Xanthone
is usually assembled from its constituent fragments to form the
middle pyranone ring.3 Other less commonly used methods have
also been reported.4 Despite the numerous reports and continuous
interest in the synthesis of 1, including linearly or angularly fused,
carbocyclic or N,O-heterocyclic derivatives and their applications,5
its reactivity profile has not enjoyed equally deserved attention.
Looking at the structure of 1, certain features are evident: (a)
two benzene rings are fused to a pyran-4-one ring, (b) the benzene
rings are identical, thus imparting symmetry elements to the struc-
ture, (c) C-1 (or C-8) and C-4 (or C-5) are acidic sites6 and (d) either
or both rings are susceptible to electrophilic substitution, facili-
tated and directed by the pyran oxygen on the one hand, while hin-
dered by the carbonyl group, on the other hand. Manipulation
allows varying substitution patterns to be accessible. The advan-
tage of this approach is to provide simpler, shorter and more effi-
cient (in certain cases) access to derivatives of 1. During the
synthesis of xanthone frameworks the core is usually constructed
at a late stage of the reaction sequence. This, presumably, mini-
mizes potential side reactions at the carbonyl group, which is
known to be susceptible to reduction (partial or complete)7 or
nucleophilic attack, if alkyl(aryl)lithium reagents8 are used.
O
O
1
We report herein, a lithiation–methylation protocol developed in
order to demonstrate the reactivity profile of 1 through various sub-
stitutionpatterns.Lithiationwaschosenasameanstointroducefunc-
tionalities. Either the ring or carbonyl oxygen atoms can act as
potential coordination sites, thus directing, in principle, metallation
to all possible peri positions. Indeed, this approach has been applied
to 9,9-dimethylxanthene 2.7a To be able to perform lithiation directly
onto 1 would be an ideal one-step process with clear-cut advantages
of synthetic value. A set of experiments were accordingly performed
but the identity of the isolated products, their tedious isolation and
their low yields discouraged further attempts along this line. Eventu-
ally, attention was focused on suitable protection of the carbonyl
group such that, (a) it could be removed easily, ideally during the
work-up stage, and (b) it would not interfere in the lithiation.
OH
R
R
LiO NEt2
O
O
O
* Corresponding author. Tel.: +30 210 775 3050; fax: +30 210 771 3810.
E-mail address: pgt@gsrt.gr (P.G. Tsoungas).
R= Me (2); OMe, (5); Cl, (6)
3
4
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.050

5982
M. R. Odrowaz-Sypniewski et al. / Tetrahedron Letters 50 (2009) 5981–5983
When a lower excess of base was used C-4 lithiation was the
Aminoalkoxide 3 (prepared in situ) was used as an intermediate
predominating process and 4-methyl-xanthone 812 was isolated
by flash column chromatography as the major product (61%)
(Scheme 2).
but work-up showed no appreciable conversion into 1. Attempts to
functionalize xanthydrol 4 were also in vain. In the light of these
unsuccessful trials it was decided that 1 be protected as its ketal
5,9b and then subjected to lithiation conditions. Since 1 is not a
conventional ketone,10 its ketal can only be obtained indirectly
via 9,9-dichloroxanthene 69 by reaction with sodium methoxide.
While 6 is stable enough to handle, it is also extremely labile to
acidic hydrolysis to regenerate the xanthone core structure. By
using 5, the acidity at C-1 (or C-8) is removed, but at the same time,
a coordination centre is introduced at the same position despite
the tetrahedral arrangement at C-9. In preliminary experiments
lithiation conditions similar to those used for the lithiation of
9,9-dimethylxanthene 27b were applied (Scheme 1). After quench-
ing with excess methyl iodide 1,5-dimethylxanthone 7 was ob-
tained accompanied by large quantities of tars. As the yield of
the isolated product 7 was not satisfactory, a set of experiments
was performed in the hope of improving the yield and to better
control the lithiation leading to monosubstitution. The parameters
varied were temperature, base (n-BuLi, sec-BuLi, t-BuLi), molar ra-
tio of base to 5 and reaction time. In our hands, very low temper-
atures (ꢀ78 °C), and long reaction times as often applied in
lithiations did not favour functionalization of 5. However, at higher
temperatures, deprotonation appeared to be quite fast. Around
ꢀ10 °C, after relatively short reaction times (45 min) and using a
sixfold excess of t-BuLi in tetrahydropyran (THP) and quenching
with an excess of methyl iodide, 1,5-dimethyl-9H-xanthen-9-one
7 was isolated in 31% yield, (Scheme 1, Table 1, entry 1).
A mixture containing 1,5-dimethylxanthone 7 and 1-methylx-
anthone 913 was formed along with 8 but only small quantities
of each, enough for spectroscopic analysis, were obtained (Scheme
2, Table 1, entry 2).
The results indicate that: (a) the primary substitution site is C-4
(C-5) and the secondary site is C-1, (C-8), (b) double deprotonation
occurs sequentially and the product ratio depends mainly on base
stoichiometry. Attack of the base at C-1 (C-8) is, we believe, driven
by coordination of lithium with the methoxy groups. To test this
hypothesis and suppress the process, a Lewis acid such as MgBr2
was used as an additive during lithiation. This approach did not
improve the regioselectivity. However, another modification of
the reaction conditions partially solved our problems. Use of the
super base LICKOR (t-BuLi/t-BuOK) has a strong effect on the regi-
oselectivity of the substitution pattern. Accordingly, primary sub-
stitution is directed at C-4 and secondary substitution occurs this
time at C-5. No substitution at C-1 (C-8) was observed. Thus when
three equivalents of LICKOR was used, the yield of 4,5-dimethylx-
anthone 10 exceeded 80%, (Scheme 3, Table 1, entry 3).
The use of a lower excess of LiCKOR (e.g., 1.5 equiv) led to a mix-
ture of 8, 10 and unreacted 1. Following the established protocol,
other functional groups were introduced with yields ranging from
moderate to excellent (Table 1, entries 4–11).
Although the aforementioned substitution pattern is generally
followed, the regioselectivity of reactions following procedure B
was seriously affected, for example, the halogenation. This may
tentatively be attributed to halogen-lithium exchange,15 rather
than sequential lithiation. Inconsistency in reactivity patterns has
been reported in the literature for a number of lithiation reac-
tions.16 The observed results, in our hands, with the probable
exception of halogenation, may well be the outcome of carbanion
generation in sequence. The pyran oxygen, through its acidifying
effect, facilitates carbanion generation predominantly at C-4 and/
or C-5 while the coordinating effect of its lone pair directs the lith-
iation at those positions. Weaker coordinating interactions, appar-
O
Me
MeO OMe
i, ii, iii
O
O
Me
31%
5
7
Scheme 1. Lithiation according to procedure A.11 Reagents and conditions: (i) t-
BuLi (6 equiv)/THP, ꢀ10 °C, 45 min; (ii) CH3I and (iii) H+/H2O.
Table 1
Functionalization of xanthone (1) via lithiation of its dimethyl ketal (5) and subsequent electrophilic quench
Entry
Electrophile
Lithiation procedure11
Product
R2
Yielda (%)
O
O
R1
R1
R3
8
1
2
3
7
6
5
4
R2
R3
1
2
3
4
5
CH3I
CH3I
CH3I
DMF
A
B
C
B
B
CH3
H
H
H
CONEt2
H
CONEt2
I
I
H
I
H
SiMe3
H
H
H
CH3
CH3
H
CH3
H
H
H
CONEt2
I
H
H
I
I
7
8
31
61b
85
50c
27
38
15
28
29
34
8
CH3
10
11
12
13
14
15
16
17
18
19
10
20
21
CHO14
Et2NCOCl
H
CONEt2
H
H
H
I
H
I
H
6
7
I2
I2
A
B
8
9
10
11
I2
C
A
C
C
67
41
69
89
Me3SiCl
Me3SiCl
D2O
SiMe3
SiMe3
D
SiMe3
D
a
b
c
Yield refers to isolated product. Flash chromatography was used for product separation.
Products of C1-monosubstitution and C1, C5-disubstitution isolated but not quantitatively (just enough material to record the NMR spectrum).
Products of C1-monosubstitution and C1, C5-disubstitution observed in the 1H NMR spectrum of the crude reaction mixture, but not isolated.

M. R. Odrowaz-Sypniewski et al. / Tetrahedron Letters 50 (2009) 5981–5983
5983
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O
O
Me
MeO OMe
i, ii, iii
+
+
7
O
O
O
Me
61%
8
9
5
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Scheme 2. Lithiation according to procedure B.11Reagents and conditions: (i) t-BuLi
(1.5 equiv)/THP, ꢀ13 °C, 30 min; (ii) CH3I and (iii) H+/H2O.
O
MeO OMe
i, ii, iii
O
O
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Me
Me
85%
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5
Scheme 3. Lithiation according to procedure C.11Reagents and conditions: (i) t-BuLi
(3 equiv), t-BuOK (3 equiv)/THP, ꢀ13 °C, 30 min; (ii) CH3I and (iii) H+/H2O.
ently emanating from the ketal oxygen lone electron pairs may ac-
count for C-1 (C-8) substitution. Deuteration, however (Table 1, en-
try 11) suggests that the reaction may have well proceeded via a
4,5-dilithio species. During the lithiation there is competition
among the lithiated species, the base and the electrophile. Whether
a prelithiation complex17 is involved, whose stability is compared
against that of the transition state structure, in concert with the
electrophile, or there is a stabilizing lithium-substituent interac-
tion18 at the rate-limiting transition structure, is in question.
In conclusion, the reactivity profile of 1 has been investigated
via directed lithiation of its ketal 5. The protocol developed allows
mono or disubstitution, directly and with synthetically useful reg-
ioselectivity, the latter being dependent upon the nature of the
electrophile. Disubstitution offers the advantage of incorporating
identical functionalities in one-step. The synthetic utility of the
protocol rests upon two elements of tactical significance: (a) the
use of xanthone, masked as its dimethyl ketal, rapidly regenerating
the core structure upon work-up, and (b) manipulation of the reac-
tion conditions leading to regioselectivity. The substitution pat-
terns so obtained provide access to various transformations such
as annelation onto or cleavage of the xanthone structure, ulti-
mately leading to diverse heterocycles.19 In this respect, the proto-
col is a valuable addition to the existing armory of indirect
approaches to xanthone derivatives. Further work along this line
is in progress and will be reported in due course.
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A
and B: 9,9-
Dimethoxyxanthene (5) (500 mg, 2 mmol) was dissolved in dry
tetrahydropyran (2 mL) (method A); (4 mL) (method B). After cooling to
ꢀ10 °C (method A); ꢀ40 °C (method B), t-BuLi solution (7.0 mL, of 1.7 mol/L,
12 mmol) (method A); (1.76 mL, of 1.7 mol/L, 3 mmol) (method B) in hexanes
was added over a period of 2 min, while the temperature was maintained
between ꢀ10 and 0 °C (method A); ꢀ40 and ꢀ30 °C (method B). Stirring was
continued at 0 to 10 °C over 45 min (method A); at ꢀ40 to ꢀ30 °C over 30 min
(method B). Next, the reaction mixture was quenched with the appropriate
electrophile while the temperature was maintained as given above, then
poured into water (50 mL), acidified to pH 3 with aqueous HCl and extracted
with ethyl acetate (3 ꢁ 15 mL). The products were isolated by flash column
chromatography on silica.General lithiation procedure according to method C:
9,9-Dimethoxyxanthene (5) (500 mg, 2 mmol) and t-BuOK (6 mmol) were
dissolved in dry tetrahydropyran (6 mL). After cooling to ꢀ40 °C, t-BuLi
solution (3.5 mL, of 1.7 mol/L, 6 mmol) in hexanes was added over a period
of 2 min, and the temperature was maintained between ꢀ40 and ꢀ30 °C. The
rest of the procedure was identical with procedure B.
Acknowledgements
Financial support from the General Secretariat of Research and
Technology through the Programme ENTER and elemental analyses
from Dr. L. Leontiadis’s Laboratory, ‘Demokritos’ Research Centre
are gratefully acknowledged.
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Supplementary data
Supplementary data (experimental procedures and full charac-
terization of all new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.08.050.
17. Whisler, M. N.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004,
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References and notes
1. For recent reviews, see: (a) Vieira, L. M. M.; Kijjoa, A. Curr. Med. Chem. 2005, 12,
2413.andreferencescitedtherein;(b)Sousa,M.E.;Pinto, M.M.M.Curr. Med.Chem.
2005, 12, 2447. and references cited therein; (c) Silva, A. M. S.;Pinto, D. C. G. A. Curr.