Improved methodologies for synthesis of prenylated xanthones by microwave irradiation and combination of heterogeneous catalysis (K10 clay) with microwave irradiation

Article abstract of DOI:10.1016/j.tet.2009.03.019

Eleven prenylated xanthone derivatives (4-9, 11-15) have been synthesized for the first time by the microwave irradiation method. Prenylation of the xanthone building blocks 1 and 2 with prenyl bromide in alkaline medium, using microwave irradiation, gave the oxyprenylated xanthones 4 and 6, as major products in high yields, as well as diprenylated by-products (5, 7, 8, and 9) in very low yields. Microwave irradiation of oxyprenylated xanthones 4 and 6 furnished three new Claisen rearranged products (11, 14, and 15), as well as the previously described dihydrofuranoxanthones (12, 13). Furthermore, three new (19, 20, 21) and three previously described (16, 17, 18) dihydropyranoxanthones have also been prepared by a one-pot synthesis from xanthones 1, 2, and 3, using Montmorillonite K10 clay as a heterogeneous catalyst and a combination of Montmorillonite K10 clay with microwave irradiation in various conditions. The presence of solvent and the type of the clay (commercial or dry) were found to have a strong influence on the product yields. This is the first report of using these methodologies for the synthesis of dihydropyranoxanthone derivatives. The structures of the prenylated xanthones obtained were established by IR, UV, HRMS, and NMR (¹H, ¹³C, HSQC, and HMBC) techniques.

Full text of DOI:10.1016/j.tet.2009.03.019

Tetrahedron 65 (2009) 3848–3857
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Improved methodologies for synthesis of prenylated xanthones by microwave
irradiation and combination of heterogeneous catalysis (K10 clay) with
microwave irradiation
,
b
,
a,
Raquel A.P. Castanheiro a, Madalena M.M. Pinto a , Sara M.M. Cravo b, Diana C.G.A. Pinto c,
*
Artur M.S. Silva c, Anake Kijjoa d
a
´
´
ˆ
´
Centro de Quımica Medicinal da Universidade do Porto/Centro de Estudos de Quımica Organica, Fitoquımica e Farmacologia da Universidade do Porto (CEQUIMED-UP/CEQOFFUP),
´
´
Faculdade de Farmacia, Universidade do Porto, Rua Anıbal Cunha 164, 4050-047 Porto, Portugal
b
ˆ
´
´
Serviço de Qu´ımica Organica, Faculdade de Farmacia, Universidade do Porto, Rua Anıbal Cunha 164, 4050-047 Porto, Portugal
Departamento de Qu´ımica & QOPNA, Universidade de Aveiro, Campus Universitario de Santiago, 3810-193 Aveiro, Portugal
d ICBAS, Instituto de Cieˆncias Biome´dicas de Abel Salazar & CIMAR, Universidade do Porto, 4099-003 Porto, Portugal
c
´
a r t i c l e i n f o
a b s t r a c t
Article history:
Eleven prenylated xanthone derivatives (4–9, 11–15) have been synthesized for the first time by the
microwave irradiation method. Prenylation of the xanthone building blocks 1 and 2 with prenyl bromide
in alkaline medium, using microwave irradiation, gave the oxyprenylated xanthones 4 and 6, as major
products in high yields, as well as diprenylated by-products (5, 7, 8, and 9) in very low yields. Microwave
irradiation of oxyprenylated xanthones 4 and 6 furnished three new Claisen rearranged products (11, 14,
and 15), as well as the previously described dihydrofuranoxanthones (12, 13). Furthermore, three new
(19, 20, 21) and three previously described (16, 17, 18) dihydropyranoxanthones have also been prepared
by a one-pot synthesis from xanthones 1, 2, and 3, using Montmorillonite K10 clay as a heterogeneous
catalyst and a combination of Montmorillonite K10 clay with microwave irradiation in various condi-
tions. The presence of solvent and the type of the clay (commercial or dry) were found to have a strong
influence on the product yields. This is the first report of using these methodologies for the synthesis of
dihydropyranoxanthone derivatives. The structures of the prenylated xanthones obtained were estab-
lished by IR, UV, HRMS, and NMR (1H, 13C, HSQC, and HMBC) techniques.
Received 6 November 2008
Received in revised form 3 February 2009
Accepted 6 March 2009
Available online 11 March 2009
Keywords:
Dihydrofuranoxanthones
Dihydropyranoxanthones
Heterogeneous catalysis
Microwave-assisted synthesis
Montmorillonite K10 clay
Prenylated xanthones
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Consequently, these processes are considered to be not only very
demanding but also environmentally unfriendly. Taking this into
Prenylated xanthones, including furan and pyran derivatives,
have been reported to mediate several interesting biological ac-
tivities, concerning a large variety of targets with therapeutic
value.1,2 Although the oxygenation pattern of these derivatives can
play an important role in their biological activity, the presence of
the prenyl side chains seems also to be associated with the en-
hanced interaction with biological membranes and with target
proteins when compared with their non-prenylated analogs.3 For
this reason, we have synthesized a series of prenylated xanthone
derivatives to evaluate their effect on the in vitro growth of some
human cancer cell lines. The synthesis of the prenylated xanthone
derivatives is normally carried out by introduction of the prenyl
side chain to the hydroxyxanthone nucleus, in a vigorous condition.
In addition, the reactions usually involved toxic reagents.4,5
account, we have looked for an alternative to obtain prenylated
xanthones.
One of the considered methods was the microwave-assisted
organic synthesis (MAOS), which has been demonstrated not only
to dramatically accelerate many organic reactions, but also to im-
prove yields and selectivity.6,7 With this technique, many reaction
parameters such as reaction temperature and time, variations in
solvents, additives, and catalysts can be evaluated to optimize the
desired chemistry.8 As a result, pharmaceutical industry is starting
to incorporate microwave (MW) methodologies in processes of
discovery of pharmacologically active small-molecules.8 On the
other hand, much attention has been paid to clays, which can act as
solid catalysts for a wide range of organic reactions and a subgroup
of clays, Montmorillonite, is particularly useful. With this clay, the
reaction proceeds not only under mild conditions but also with
selectivity, good yields, and short reaction times. As this catalyst
can be easily separated from the reaction mixture and can be
regenerated, the purification procedures are usually simple.9,10
* Corresponding author. Tel.: þ351 222078916; fax: þ351 222003977.
E-mail address: madalena@ff.up.pt (M.M.M. Pinto).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.019

R.A.P. Castanheiro et al. / Tetrahedron 65 (2009) 3848–3857
3849
Furthermore, the coupling of MW irradiation with the use of in-
organic solid supports such as Montmorillonite K10 clay, either
with solvent or under solvent-free conditions, can also provide
a chemical process with inherent advantages such as enhanced
reaction rates, high yields, ease of manipulation, and selectivity.11
Here we report the microwave-assisted synthesis of two oxy-
prenylated xanthones (4 and 6), along with four diprenylated by-
products (5, 7–9) from the simple hydroxylated xanthones (1 and
2) and prenyl bromide, as well as the synthesis of dihydro-
furanoxanthones (11–13) and two new rearranged pre-
nylxanthones (14, 15) from the oxyprenylated xanthones 4 and 6
(Fig. 1). MW method was found to dramatically increase the yields
of the two major oxyprenylated xanthones (4, 6), while the yields of
the diprenylated by-products were not improved. Furthermore,
a one-pot synthesis of dihydropyranoxanthones (16–21) from the
hydroxylated xanthones (1–3) using the Montmorillonite K10 clay
with different conditions was also described. A combination of MW
and Montmorillonite K10 clay with solvent was found to be the
method of choice to prepare dihydropyranoxanthones since it
dramatically increased the yields of products as well as shortening
the reaction time (Fig. 1).
2. Results and discussion
2.1. Synthesis of prenylated xanthones
Oxyprenylated xanthones are not only an emerging group of
biologically interesting natural products3 but also important
building blocks for the synthesis of furano- and pyranoxanthone
derivatives.12 Consequently, we have previously described the
synthesis of oxyprenylated xanthones by prenylation of xanthones
1, 2, and 3 with prenyl bromide and K2CO3 in acetone5 (Scheme 1).
O
9
R1
1
O
OH
8
2 R2
8a
9a
4a
R1
7
6
3
O
OR2
O
OH
10a
5
4
R3
R1 R2
1 OH CH3
R1
R2
R3
H
1'
2'
4
5
6
7
8
9
CH3
2 OH
H
H
3'
3
H
1"
1'
2' 3'
CH3
H
2" 3"
H
1'
O
1
8
5
2' 3'
1"
8a
9a
4a
2
2' 3'
7
6
9
1'
1'
H
H
3'
3
O
O
10a
2" 3"
2'
4
10
1'
2' 3'
1"
2" 3"
1"
1'
H
2" 3"
2' 3'
2'
O
OH
1
O
9
OH
1
O
OH
1
O
OH
8
8
8
2 R1
4'
9a
4a
8
5
8a
1
9a
4a
4'
9a
8a
8a
9a
8a
2
3'
2
2
7
6
7
6
7
9
1'
9
9
7
6'
3
3
3
5'
6
6
4a
2'
10a O
O
4a
10a O
3
10a O
OH
4'
10a O
OH
O
4
4
5
5
4
5
4
1'
5'
3'
4'
6'
14
R1
11 CH3
13
12
15
H
O
9
R1
1
O
9
O
9
R1
1
OH
1
4'
8
8
8
4'
R2
9a
4a
8a
8a
9a
4a
8a
9a
2
2
2
7
6
5'
6'
5'
6'
7
6
7
6
3
1'
O
3
10a O
O
O
10a
4a
1"
O
1'
3 O
1'
10a
4
4
5
5
5
4
2"
3"
4'
6'
5'
R1
R1
R2
21
16 OH CH3
18 OH
20
17 OH
19
H
H
H
H
Figure 1. Structures of building blocks 1–3 and of prenylated derivatives 4–21 (the numbering used concerns the NMR assignments).

3850
R.A.P. Castanheiro et al. / Tetrahedron 65 (2009) 3848–3857
O
OH
O
O
OH
O
O
OH
Prenyl bromide,
CH3
OH
CH3
O
CH3
O
K2CO3 in acetone
+
heat
O
1
4 (48%)
5 (3%)
O
O
OH
O
O
OH
O
OH
O
O
OH
O
O
OH
Prenyl bromide,
K2CO3 in acetone
+
+
+
heat
O
O
O
OH
O
O
2
6 (25%)
7 (5%)
8 (2%)
9 (3%)
O
O
Prenyl bromide,
K2CO3 in acetone
heat
O
O
O
OH
3
10 (72%)
Scheme 1.
O
O
OH
O
OH
Using this method of prenylation, xanthone 1 gave the oxy-
prenylated xanthone 4 as a major product in 48% yield and
a diprenylated by-product 5 (3%). However, xanthone 2 gave only
25% yield of the oxyprenylated xanthone 6 and three diprenylated
by-products 7 (5%), 8 (2%), and 9 (3%). On the contrary, xanthone 3
gave 72% yield of the oxyprenylated xanthone 10.
CH3
O
CH3
O
NMP
MW
O
11 (72%)
4
In order to improve the yields of the oxyprenylated xanthones 4
and 6, we used the MW irradiation instead of conventional heating.
With this method, the yields of oxyprenylated xanthones 4 and 6
were increased, respectively, to 83% and 53%. However, the yields of
the diprenylated xanthone by-products 5, 7–9 did not change sig-
nificantly (Table 1). Furthermore, the reaction time was reduced
from 8 h in the conventional heating to only 1 h in the MW method.
The oxyprenylated xanthones 4 and 6 were then used as pre-
cursors for the synthesis of the dihydrofuranoxanthones 11 and 12,
by MW irradiation. When N-methylpyrrolidone (NMP) was used as
a solvent, xanthone 4 gave the angular dihydrofuranoxanthone 11
in 72% yield while xanthone 6 gave only 20% yield of the linear
dihydrofuranoxanthone 12 (Scheme 2).
O
OH
O
OH
NMP
MW
O
O
O
O
12 (20%)
6
Scheme 2.
However, when the reaction was performed in N,N-diethylaniline
(N,N-DEA), both linear (12) and angular (13) dihydrofurano-
xanthones were obtained, from the oxyprenylated xanthone 6, to-
gether with the two new rearranged products 14 and 15 (Scheme 3).
The dihydrofuranoxanthones 12 (17.5%) and 13 (8.8%) have been
previously prepared by heating xanthone 6 in vacuum at 200 ꢀC for
2 h.12
Recently, we have also used the oxyprenylated xanthones 4 and
6 as precursors for the synthesis of dihydropyranoxanthones. By
heating these xanthones with ZnCl2 in o-xylene at 200 ꢀC for 21 h,
xanthone 4 gave the angular dihydropyranoxanthone 16 in 22%
yield, while xanthone 6 furnished both angular and linear di-
hydropyranoxanthones 17 and 18 in low yields.5 By using the same
reaction conditions, we have obtained dihydropyranoxanthones 19
and 20 from xanthone 10, also in very low yields (Scheme 4).13
In order to improve the yields, we have designed a one-pot
synthesis of these dihydropyranoxanthones by using Montmoril-
lonite K10 clay to catalyze direct condensation of the xanthones 1, 2,
and3, with prenylbromide (Scheme 5) in differentconditions, either
at room temperature (Method A) or at 100 ꢀC under conventional
thermal heating (Method B) or with MW irradiation (Method C). As
Table 1
Comparison of results obtained in the prenylation reaction of hydroxyxanthones 1, 2
under MW and classical heating conditions
O
OH
O
O
OH
Prenyl bromide,
K2CO3, Acetone
R
R
O
Heat / MW
O
OH
R1
1 R=CH3
2 R=H
Yield (%)
Classical
MW
4 R¼CH3, R1¼H
48
3
25
5
2
3
83
5
53
1
1
2
5 R¼CH3, R1¼–CH2–CH]C(CH3)2
6 R¼H, R1¼H
7 R¼–C(CH3)2–CH]CH2, R1¼H
8 R¼–CH2–CH]C(CH3)2, R1¼H
9 R¼H, R1¼–CH2–CH]C(CH3)2

R.A.P. Castanheiro et al. / Tetrahedron 65 (2009) 3848–3857
3851
O
OH
O
OH
O
OH
O
OH
O
OH
N,N-DEA
MW
+
+
+
O
O
O
O
O
O
O
OH
O
OH
12 (7%)
13 (6%)
14 (5%)
15 (5%)
6
Scheme 3.
O
OH
OH
O
OH
CH3
CH3
ZnCl2/o-xylene
200 °C
O
O
O
O
4
16 (22%)
O
OH
O
O
OH
O
ZnCl2/o-xylene
+
+
200 °C
O
17 (4%)
O
O
O
O
O
6
O
O
18 (3%)
O
O
ZnCl2/o-xylene
200 °C
O
O
O
O
10
20 (2%)
19 (5%)
Scheme 4.
expected, xanthone 1 gave only the angular dihydropyrano-
xanthone 16, while xanthone 3 gave dihydropyranoxanthones 19
and 20. However, xanthone 2 gave, besides dihydropyranox-
anthones 17 and 18, the prenylated dihydropyranoxanthone 21.
The yields of these dihydropyranoxanthones obtained by using
Montmorillonite K10 clay in different conditions and those
obtained by a classical synthesis through oxyprenylated xanthones
intermediates are found in Table 2.
O
OH
O
OH
CH3
CH3
Montmorillonite K10 clay
O
O
O
OH
OH
OH
1
16
O
OH
O
OH
O
OH
O
OH
Montmorillonite K10 clay
Montmorillonite K10 clay
+
+
+
O
O
O
O
O
O
O
O
2
21
18
17
O
O
O
O
O
O
O
3
19
20
Scheme 5.

3852
R.A.P. Castanheiro et al. / Tetrahedron 65 (2009) 3848–3857
It can be observed from Table 2 that, the yield of the dihydro-
unreported 13C NMR of compounds 12 and 13 are also included in
Table 4.
pyranoxanthone 16 was increased, when Montmorillonite K10 clay
was used as catalyst in all three methods. When the reaction is
performed at room temperature with the commercial Montmoril-
lonite K10 clay, the yield was increased about five folds when
compared to that obtained by classical synthesis (51% vs 10.5%).
However, the disadvantage of this method is its long reaction time
(5 days). The yields of xanthones 17, 18, and 21 were found to be
slightly improved but continued to be insignificant while those of
xanthones 19 and 20 were found to decrease. When the Mont-
morillonite K10 clay was used in combination with conventional
heating at 100 ꢀC (Method B), xanthone 16 was obtained in 63%
yield with a remarkably shorter reaction time (60 min). In-
terestingly, the yields of xanthones 17, 18, and 21 were also im-
proved significantly when compared to those obtained by classical
synthesis. However, when the commercial clay was replaced by dry
clay, the yield of the linear dihydrofuranoxanthone 18 was in-
creased from 12% to 18%. MW irradiation was also used instead of
conventional heating and it can be carried out with or without
solvent. The advantage of MW irradiation over conventional heat-
ing is its shorter reaction time (20 min). However, when this
method is performed without solvent, the yield of xanthone 16 was
only 53% while the yield of the xanthones 17, 18, and 21 were less
than 2%. Surprisingly, when the solvent was used, the yields of all
xanthones were dramatically increased, being 86% for xanthone 16.
Interestingly, when dry clay was used instead of the commercial
clay, the yield of xanthone 18 was increased from 14% to 20%.
The 1H and 13C NMR spectra of the prenylated xanthones 11–15
and 19–21 (Tables 3 and 4, respectively) showed that all of them
have retained a non-substituted aromatic ring of their xanthone
precursors. Like the xanthones precursors, only the 1H NMR spectra
of the xanthones 11–15 and 21 showed a proton signal of the hy-
drogen bonded hydroxyl group at ca. 13 ppm (OH-1). The 1H and
13C NMR spectra of xanthones 11, 12, and 13 showed some common
features: the presence of a 40,40,50-trimethyldihydrofuran fused
ring, which was evidenced by the two singlets of geminal methyl
groups (dH ca. 1.3 and 1.5) on the quaternary carbon (dC ca. 43) and
a doublet of another methyl group (dH 1.4, Jw7 Hz) on the oxy-
methine carbon (dC ca. 90). The EIHRMS gave an accurate molecular
mass of 310.1215 and a molecular formula of C19H18O4 for xanthone
11. As xanthone 11 was obtained by cyclization of the oxyprenylated
xanthone 4, the proton and carbon chemical shifts of the methyl
group on C-2 (dH 2.12 s; dC 7.4) of xanthone 11 were similar to those
of the methyl group of xanthone 4. That the 40,40,50-trimethyldi-
hydrofuran fused ring was on C-3 and C-4 of the xanthone nucleus
was supported by the correlations observed between the proton
signals of the geminal methyl groups (dH 1.30 s and 1.58 s) and the
carbon signal of C-4 (dC 111.8) in the HMBC spectrum (Fig. 2). In
turn, the EIHRMS gave the molecular formula of C18H16O4 for both
xanthones 12 and 13. The 1H NMR spectra of these xanthones were
similar to that of xanthone 11 except for the singlet of the aromatic
proton at dH 6.35 s for xanthone 12 and at dH 6.33 s for xanthone 13
instead of the signal of the protons of the methyl group on C-2. The
fact that xanthone 12 was a linear dihydrofuranoxanthone was
substantiated by the correlations between the proton signals of the
geminal methyl groups (dH 1.27 s and 1.51 s) and the carbon signal
of C-2 (dC 116.8) in the HMBC spectrum. In the same way, the
structure of xanthone 13 was established as an angular
dihydrofuranoxanthone.
2.2. Structure elucidation of prenylated xanthones
The structure of the new prenylated xanthones 11, 14, 15, and
19–21 were established by IR, UV, HRMS, and NMR techniques. The
spectroscopic data of compound 1–10, 12, 13, 16–18 are in agree-
ment with those found in the literature.5,12,14,15 The previously
Table 2
Results obtained with different methods for synthesis of compounds 16–21
Method
K10 clay
Reaction time
Final temp (ꢀC)
rt
Substrate
Product
Yield (%)
With K10 clay
Conventional heatinga
A: K10 clay
Commercial
5 days
1
2
16
17
18
21
19
20
51
3
9
<2
<2
<2
10.5
1
0.5
d
3
3.6
1.4
B: K10 clay with conventional heating
Commercial
Dry
60 min
60 min
100
100
1
2
16
17
18
21
16
17
18
21
63
7
12
6
63
8
18
7
10.5
1
0.5
d
1
2
10.5
1
0.5
d
C: K10 clay with MW (without solvent)
C: K10 clay with MW (with solvent)
Commercial
20 min
110
150
1
2
16
17
18
21
19
20
53
<2
<2
<2
9
10.5
1
0.5
d
132
3
3.6
1.4
3
Commercial
20 min
20 min
105
113
1
2
16
17
18
21
19
20
17
18
21
86
10
14
4
25
9
10
20
5
10.5
1
0.5
d
115
110
3
2
3.6
1.4
1
0.5
d
Dry
a
Yield of the products relative to the precursor xanthones 1, 2, and 3.

R.A.P. Castanheiro et al. / Tetrahedron 65 (2009) 3848–3857
3853
Table 4
13C NMR chemical shifts of prenylated xanthones 11–15 and 19–21a
11b
12b
13c
14b
15b
19b
20b
21b
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
161.4
102.9
164.9
111.8
117.3
134.5
123.7
126.0
180.6
7.4
150.8
155.6
120.7
103.6
d
158.7
116.8
166.2
89.5
117.5
134.6
123.8
125.7
181.0
d
158.1
89.6
166.0
113.3
117.5
134.6
123.8
125.7
180.9
d
160.8 161.9 125.4 126.6 158.4
111.3 99.5 114.9 119.0 103.7
163.6 163.3 159.6 160.4 159.3
95.0 107.2 114.8 104.1 167.1
117.5 117.5 117.6 117.7 117.5
134.9 134.9 134.0 134.1 134.6
123.8 124.1 123.8 123.5 123.4
125.8 125.9 126.6 127.5 125.8
180.9 181.1 176.6 176.5 181.1
C-9
2-CH3
C-4a
C-10a
C-8a
C-9a
C-10
C-20
C-30
C-40
30-CH3
C-50
C-60
d
d
d
d
d
157.9
155.9
120.5
103.0
d
158.8
155.9
120.5
104.1
d
156.2 154.6 155.4 156.2 152.4
156.0 155.9 156.1 156.3 156.1
120.5 120.4 121.9 121.8 120.4
103.5 104.0 108.6 115.2 102.6
34.6
16.7
35.2
17.2
d
d
d
d
d
d
d
d
d
d
d
d
150.9 150.0
d
d
d
44.0
d
43.3
d
92.6
d
d
d
16.8
d
15.3
d
16.4
d
22.7
22.7
90.4
14.3
91.1
14.3
42.9
14.2
112.2 112.3 31.6
30.9
76.2
d
31.6
76.2
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
75.7
d
40-CH3 25.9, 21.5 25.1, 20.6 28.5, 22.3
60-CH3
C-100
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
26.7
d
27.0
d
26.9
21.6
122.4
131.2
25.8
C-200
d
d
C-300
d
d
300-CH3
d
d
a
Values in parts per million (dC).
Measured in CDCl3 at 75.47 MHz.
Measured in CDCl3 at 125.77 MHz. Assignments were confirmed by HSQC and
b
c
HMBC experiments.
On the other hand, the new prenylated xanthones 14 and 15 did
not show characteristic proton and carbon signals of the 40,40,50-
trimethyldihydrofuran fused ring in their 1H and 13C NMR spectra.
Besides the singlets of the aromatic protons at dH 6.38 s and 6.30 s,
respectively, for xanthone 14 and xanthone 15, the 1H and 13C NMR
spectra showed the presence of the 3-methylbut-3-en-2-yl side
chain as was evidenced by the signals of two vinyl protons at ca. dH
5.3 s, one allylic methyl group (dH 1.79 s; dC 22.7), one allylic
methine proton (dH 4.13 q; dC 34.6 and dH 4.24 q; dC 35.2), and
another methyl group (dH 1.43 d; dC 16.7 and dH 1.49 d; dC 17.2) on
the methine carbon. That the prenyl side chain is on C-2 for the
xanthone 14 was supported by the correlation between the
methine proton of the side chain at dH 4.13 q (J¼7.0 Hz) and
the carbon signal at dC 160.8 (C-1) as well as between the signal of
the methyl proton at dH 1.43 d (J¼7.0 Hz) and the carbon signal at
dC111.3 (C-2) in the HMBC spectrum. On the contrary, the signal of
the methine proton of the side chain at dH 4.24 q (J¼6.9 Hz) was
correlated with the carbon signal at dC 154.6 (C-4a) in xanthone 15,
confirming that the prenyl side chain is on C-4.
Finally, the existence of a 60,60-dimethyldihydropyran fused ring
in the prenylated xanthones 19–21 was based on an observation of
the two geminal methyl groups (dH ca. 1.40 s, dC ca. 27) and the two
methylene groups (dH ca. 1.9 and 2.9; dC ca. 16 and 30) as well as an
oxygen bearing quaternary carbon (dC ca. 76) in the 1H and 13C NMR
spectra. The EIHRMS gave a molecular formula C18H16O3 for both
xanthones 19 and 20. However, the 60,60-dimethyldihydropyran
fused ring on C-3 and C-4 in xanthone 19 was substantiated by the
presence of the ortho coupled aromatic protons at dH 8.11
d (J¼8.9 Hz, H-1) and 6.83 d (J¼8.9 Hz, H-2), respectively. Further-
more, the HMBC spectrum showed a correlation between the
proton signal of H-40 (dH 3.0 t, J¼6.8 Hz) and the carbon signal of C-
4a (dC 155.4). Instead, the 1H NMR spectra of xanthone 20 showed
two singlets of H-1 (dH 8.07) and H-4 (dH 6.82) and thus the 60,60-
dimethyldihydropyran fused ring must be on C-2 and C-3. This was
confirmed by a correlation between the proton signal of H-40 (dH

3854
R.A.P. Castanheiro et al. / Tetrahedron 65 (2009) 3848–3857
CH
O
9
4a
O
H3C
OH
1
O
9
4a
OH
1
OH
1
O
9
8
5
3CH3
CH3
H
8
5
8
5
8a
9a
8a
9a
9a
4a
8a
CH3
O
H
O
7
6
7
6
7
6
4'
2
3
2
3
2
3
5'
10a
10a
10a
O
4
O
O
4
4
H
4' 5'
H
4' 5'
H3C
H3C
CH3
CH3
H3C
H
12
11
13
H
CH3
2'
OH
1
OH
1
O
9
4a
O
9
OH
1
O
9
4a
O
H
H
8
5
8
8
5
H
8a
9a
H
9a
8a
8a
9a
4a
H
CH3
4'
7
6
7
6
7
6
4'
1'
H
5'
6'
2
3
2
3
2
3
3'
CH3
CH3
H 5'
H
OH
10a
10a
10a
O
4
O
O
4
4
H
5
OH
1'
H
H
1''
CH3
3'
5'
H
4'
H3C
2''
3''
2'
H3C
CH3
H
H
14
15
21
Figure 2. Main connectivities found in the HMBC of prenylated xanthones 11–15 and 21.
2.93 t, J¼6.8 Hz) and the carbon signal at dC 126.6 (C-1) in the HMBC
spectrum. The molecular formula C23H24O4 (accurate mass
364.1675), obtained from EIHRMS, for the new xanthone 21
indicated the existence of two prenyl substituents. That the 60,6-
dimethyldihydropyran fused ring was on C-2 and C-3, like in xan-
thone 20, was supported by the correlations between the proton
signal of H-40 (dH 2.75 t, J¼6.9 Hz) and the carbon signal at dC 158.4
(C-1) as well as between the proton signal at dH1.89 t (H-50) and the
carbon at dC103.7 (C-2) in the HMBC spectra. Thus, another prenyl
side chain must be on C-4. The nature of the prenyl side chain on C-
4 was established as 3-methylbut-2-enyl by the characteristic
proton and carbon chemical shifts from the 1H and 13C NMR spectra
(Tables 3 and 4, respectively). The HMBC spectrum showed that the
signal of the methylene protons at dH 3.48 (H-100) gave cross peaks
with both carbon signals at dC 152.4 (C-4a) and dC 159.3 (C-3).
chloride and high temperature heating are used. As this is the first
report on the application of the combined MW irradiation and
Montmorillonite K10 clay for the synthesis of prenylated xan-
thones, it can open a new avenue for the environmentally friendly
method to obtain other classes of bioactive compounds.
4. Experimental part
4.1. General methods
Purifications of compounds were performed by flash chroma-
tography using Merck silica gel 60 (0.040–0.063 mm) and pre-
parative thin layer chromatography (TLC) using Merck silica gel 60
(GF254) plates. Reactions were monitored by TLC. MW reactions
were performed using glassware setup for atmospheric-pressure
reactions and also 12 mL and/or 50 mL closed glass reactors (in-
ternal reaction temperature measurement with a fiber-optic probe
sensor) and were carried out using an Ethos MicroSYNTH 1600
Microwave Labstation from Milestone. Melting points were
obtained in a Ko¨fler microscope and are uncorrected. IR spectra
were measured on an ATI Mattson Genesis series FTIR (software:
WinFirst v. 2.10) spectrophotometer in KBr microplates (cmꢁ1). UV
spectra were taken in ethanol16 and were recorded on a Varian
CARY 100 spectrophotometer: lmax in nm (software: Cary Win UV v.
3.0). 1H and 13C NMR spectra were taken in CDCl3 at room tem-
perature, on Bruker Avance 300 and 500 instruments. Chemical
3. Conclusions
Microwave-assisted organic synthesis (MAOS) was successfully
applied in the synthesis of oxyprenylated xanthones (4 and 6) from
the hydroxyxanthone precursors (1 and 2) with the two folds in-
crease of yields and remarkable shorter reaction times, when
compared to the conventional heating conditions. Besides, the
yields of diprenylated by-products did not suffer a significant al-
teration. Furthermore, we have applied the MW irradiation metho-
dology to prepare dihydrofuranoxanthone derivatives from the
oxyprenylated xanthones precursors (4 and 6). When NMP was
used as a solvent, the oxyprenylated xanthone 4 furnished the
angular dihydrofuranoxanthone 11 with a very good yield (72%)
while the oxyprenylated xanthone 6 gave the linear dihydro-
furanoxanthone 12, but with slightly higher yield than the pre-
viously described in the classical method. However, when the
reaction was performed in N,N-DEA, the oxyprenylated xanthone 6
gave both linear (12) and angular (13) dihydrofuranoxanthones,
together with the previously unreported prenylated derivatives 14
and 15, all in low yield. On the other hand, a combination of a MW
irradiation with the Montmorillonite K10 clay was used in the one-
pot synthesis of dihydropyranoxanthone derivatives directly from
the hydroxyxanthone precursors without prior preparation of the
oxyprenylated xanthone intermediates. One of the advantages of
this methodology is the possibility to vary the conditions such as
the type of clay, the absence or presence of solvent and the tem-
perature. Besides being environmentally friendly, this methodology
has proved to give a much higher yield (five to eight folds) of the
angular dihydropyranoxanthone 16 from the hydroxyxanthone
precursor 1, when compared to the classical method in which zinc
shifts are expressed in
d (ppm) values relative to tetramethylsilane
(TMS) as an internal reference. 1H NMR spectra were measured at
300.13 MHz and/or 500.13 MHz and assignment abbreviations are
the following: singlet (s), doublet (d), triplet (t), quartet (q), mul-
tiplet (m), doublet of doublets (dd), and double doublet of doublets
(ddd). 13C NMR spectra were measured at 75.47 MHz and/or
125.77 MHz. 13C NMR assignments were made by 2D HSQC and
HMBC experiments (long-range C, H coupling constants were op-
timized to 7 and 1 Hz). HRMS spectra were recorded as EI (elec-
tronic impact) mode on a VG Autospec M spectrometer (m/z) at
CACTIdUniversity of Vigo. Prenyl bromide 95% and Montmoril-
lonite K10 clay were purchased from Sigma Aldrich.
4.2. General procedure for the synthesis of prenylated
xanthones 4–9 under MW irradiation
A mixture of xanthones 1 or 2 (2.00 mmol), prenyl bromide
(4.00 mmol), K2CO3 (4.20 mmol) in acetone (90 mL), in a two-
necked glassware apparatus, provided with magnetic stirring bar,
fiber-optic temperature control, and reflux condenser, was heated

R.A.P. Castanheiro et al. / Tetrahedron 65 (2009) 3848–3857
3855
for 3ꢂ20 min according to the following microwave program:
Power: 200 W; temperature: 62 ꢀC; ramp time: 5 min; hold time:
15 min; final temperature 59 ꢀC. After cooling, the solid was filtered
and the solvent removed under reduced pressure and afforded the
crude product that was purified by flash chromatography (SiO2;
hexane/EtOAc 99:1 or CH2Cl2/petroleum ether/Et2O 1:96:3). The
isolation of the components of the mixture was then carried out by
preparative TLC (SiO2; hexane/EtOAc 9:1 or CH2Cl2/petroleum
ether/Et2O 5:90:5 and hexane/EtOAc 8:2). Prenylated xanthones 4,
5 were crystallized from EtOH and prenylated xanthones 6–9 were
crystallized from CH2Cl2/petroleum ether (60–80). Compounds 4–9
were shown to possess spectroscopic and analytical data according
to those previously reported.5 Compounds (yields): 4 (83%), 5 (5%),
6 (53%), 7 (1%), 8 (1%), 9 (2%).
hexane/EtOAc 95:5) and by preparative TLC (SiO2; petroleum ether/
Et2O 95:5). Compounds 12–15 were identified by their spectro-
scopic and analytical data. Compound (yield): 12 (7%) was charac-
terized as described above.
4.4.1. 5-Hydroxy-1,1,2-trimethyl-1,2-dihydrofuro[2,3-c]xanthen-6-
one (13)
Yield 6%; yellow solid; mp 89–91 ꢀC (CH2Cl2/petroleum ether);
UV (EtOH) lmax
(3): 313, 240, 223 (5763, 11,407, 9807);
(EtOHþNaOH): 385, 274, 216 (1585, 6356, 45,659); (EtOHþAlCl3):
329, 240, 223 (5437, 8785, 11,230); IR (KBr) nmax: 3422, 2961, 2921,
2855, 1658, 1611, 1455, 1315, 1155, 1104, 832, 746 cmꢁ1 1H NMR
;
data, see Table 3; 13C NMR data, see Table 4; EIMS m/z (%): 296 (46,
ꢃ
M
þ ), 281 (100), 253 (12), 237 (8), 84 (7); EIHRMS m/z: calcd for
C18H16O4: 296.1049, found: 296.1049.
4.3. General procedure for Claisen rearrangement of
monoprenylated xanthones 4 and 6 in NMP under MW
irradiation
4.4.2. 1,3-Dihydroxy-2-(3-methylbut-3-en-2-yl)-9H-xanthen-9-
one (14)
Yield 5%; yellow solid; mp 192–195 ꢀC (acetone); UV (EtOH)
A solution of monoprenylated xanthones 4 or 6 (0.35 mmol), in
NMP (15 mL), was transferred to a two-necked glassware appara-
tus, provided with magnetic stirring bar, fiber-optic temperature
control, and reflux condenser and heated for 2ꢂ30 min according
to the following microwave program: step 1: 5 min, ramp to 202 ꢀC,
800 W maximum power; step 2: 25 min, hold at 202 ꢀC, 300 W
maximum power. After completion of the reaction, the mixture was
poured onto crushed ice, acidified (5 N HCl) and extracted succes-
sively with Et2O and CH2Cl2. The organic layers were washed with
water and dried. The crude products were purified by preparative
TLC (SiO2; hexane/EtOAc 25:1 or 95:5). Compounds 11 and 12 were
crystallized from CH2Cl2/petroleum ether (60–80) and were iden-
tified by their spectroscopic and analytical data.
lmax
(
3
): 312, 238, 217 (4756, 9985, 7985); (EtOHþNaOH): 373,
276, 215 (5526, 5437, 45,926); (EtOHþAlCl3): 323, 238, 221 (4178,
8578, 9052); IR (KBr) nmax: 3435, 2963, 2921, 1644, 1609, 1444,
1316, 1257, 1143, 1073, 749 cmꢁ1
;
1H NMR data, see Table 3; 13C
ꢃ
NMR data, see Table 4; EIMS m/z (%): 296 (17, Mþ ), 281 (100), 253
(13), 97 (15), 83 (18), 69 (29); EIHRMS m/z: calcd for C18H16O4:
296.1049, found: 296.1046.
4.4.3. 1,3-Dihydroxy-4-(3-methylbut-3-en-2-yl)-9H-xanthen-9-
one (15)
Yield 5%; yellow solid; mp 193 ꢀC (decomp.); UV (EtOH) lmax
(3):
312, 259, 236, 213 (13,234, 22,997, 30,178, 24,510); (EtOHþNaOH):
368, 285, 215 (12,582, 19,763, 94,896); (EtOHþAlCl3): 416, 332, 274,
219 (4184, 16,409, 22,315, 30,772); IR (KBr) nmax: 3401, 2960, 2922,
4.3.1. 5-Hydroxy-1,1,2,4-tetramethyl-1,2-dihydrofuro[2,3-c]-
xanthen-6-one (11)
2853, 1646, 1607, 1422, 1222, 1143, 755 cmꢁ1
;
1H NMR data, see
ꢃ
Table 3; 13C NMR data, see Table 4; EIMS m/z (%): 296 (52, Mþ ), 281
(100), 253 (34), 225 (17), 213 (21), 149 (32), 69 (22); EIHRMS m/z:
calcd for C18H16O4: 296.1049; found: 296.1051.
Yield72%;yellowsolid;mp194–196 ꢀC(CH2Cl2/petroleumether);
UV (EtOH) lmax (3): 316, 259, 237, 214 (15,367, 20,445, 31,634, 27,394);
(EtOHþNaOH): 404, 295, 281, 220 (5522, 16,463, 16,163, 37,818);
(EtOHþAlCl3): 330, 264, 236, 221 (20,248, 25,502, 36,680, 37,839); IR
(KBr) nmax: 2959, 2918, 2898, 2865,1643,1620,1594,1475,1432,1311,
1221, 1142, 1101, 762 cmꢁ1; 1H NMR data, see Table 3; 13C NMR data,
4.5. General procedure for the synthesis of
dihydropyranoxanthones 16–21 with Montmorillonite K10
clay
ꢃ
see Table 4; EIMS m/z (%): 310 (13, Mþ ), 295 (100), 280 (20), 267 (17);
EIHRMS m/z: calcd for C19H18O4: 310.1205, found: 310.1215.
A slurry of the K10 clay (20 equiv by weight) in CHCl3 (ca. 50 mL)
was treated with the xanthones 1, 2 or 3 (0.50 mmol), followed by
the addition of prenyl bromide (1 mmol). The mixture was main-
tained under stirring at room temperature for 5 days. The reaction
mixture was filtered under vacuum, washed with CH2Cl2, Me2CO,
and MeOH and the filtrate concentrated under vacuum. The re-
covered clay was reactivated by washing with MeOH. The crude
product was purified by flash chromatography (SiO2; petroleum
ether/EtOAc) and by preparative TLC (SiO2; petroleum ether/EtOAc
or CH2Cl2). The products were identified by their spectroscopic and
analytical data. Compounds (yields): 165 (51%), 175 (3%), 185 (9%).
4.3.2. 4-Hydroxy-2,3,3-trimethyl-2,3-dihydrofuro[3,2-b]xanthen-
5-one (12)
Yield 20%; yellow solid; mp 151–154 ꢀC (CH2Cl2/petroleum
ether); UV (EtOH) lmax (3): 313, 240, 222 (7933, 15,185, 12,215);
(EtOHþNaOH): 390, 276, 217 (2267, 7881, 25,607); (EtOHþAlCl3):
314, 240, 222 (9274, 17,822, 16,230); IR (KBr) nmax: 3430, 2966,
2922, 2885, 1655, 1611, 1569, 1474, 1447, 1305, 1145, 821, 749 cmꢁ1
;
1H NMR data, see Table 3; 13C NMR data, see Table 4; EIMS m/z (%):
296 (32, Mþ.), 281 (100), 266 (9), 253 (7), 88 (42); EIHRMS m/z:
calcd for C18H16O4: 296.1049, found: 296.1049.
4.5.1. 3,3-Dimethyl-2,3-dihydropyrano[2,3-c]xanthen-7(1H)-
4.4. General procedure for Claisen rearrangement of
monoprenylated xanthone 6 in N,N-DEA under MW
irradiation
one (19)
Yield <2%; white solid; mp 158–160 ꢀC (Me2CO); IR (KBr) nmax
:
2962, 2924, 2854, 1648, 1611, 1463, 1431, 1345, 1265, 1228, 1159,
1114, 1061, 748 cmꢁ1; 1H NMR data, see Table 3; 13C NMR data, see
ꢃ
A
solution of the monoprenylated xanthone
6
(100 mg;
Table 4; EIMS m/z (%): 280 (31, Mþ ), 265 (11), 225 (100); EIHRMS
0.34 mmol), in N,N-DEA (4 mL), under nitrogen atmosphere, was
irradiated for 3ꢂ15 min at 750 W and 225 ꢀC. After completion of
the reaction, the reaction mixture was diluted with water, acidified
(5 N HCl), and extracted successively with petroleum ether, Et2O,
and CH2Cl2. The organic layers were washed with water and dried.
The crude product was purified by flash chromatography (SiO2;
m/z: calcd for C18H16O3: 280.1100, found: 280.1111.
4.5.2. 2,2-Dimethyl-3,4-dihydropyrano[3,2-b]xanthen-6(2H)-
one (20)
Yield <2%; white solid; mp 135–138 ꢀC (Me2CO); IR (KBr) nmax
:
;
2964, 2921, 2852,1655, 1615, 1460, 1311, 1272, 1154, 1115, 755 cmꢁ1

3856
R.A.P. Castanheiro et al. / Tetrahedron 65 (2009) 3848–3857
1H NMR data, see Table 3; 13C NMR data, see Table 4; EIMS m/z (%):
chromatography (SiO2; petroleum ether/EtOAc) and by pre-
parative TLC (SiO2; petroleum ether/EtOAc or CH2Cl2). The pro-
ducts were identified by their spectroscopic and analytical data.
Compounds (yields): 165 (53%), 175 (<2%), 185 (<2%). Compounds
(yields): 19 (9%), 20 (3%), 21 (<2%) were characterized as de-
scribed above.
ꢃ
280 (32, Mþ ), 265 (19), 225 (100); EIHRMS m/z: calcd for C18H16O3:
280.1100, found: 280.1103.
4.5.3. 5-Hydroxy-2,2-dimethyl-12-(3-methylbut-2-enyl)-3,4-
dihydropyrano[3,2-b]xanthen-6(2H)-one (21)
Yield <2% as a yellow solid; mp 96–99 ꢀC (Me2CO); UV (EtOH)
lmax
(3): 317, 261, 237, 217 (11,403, 17,541, 23,333, 23,716);
4.9. General procedure for the synthesis of
dihydropyranoxanthones 16–21 with commercial
Montmorillonite K10 clay and MW irradiation with solvent
(EtOHþNaOH): 410, 280, 214 (3479, 13,534, 60,000); (EtOHþAlCl3):
332, 265, 222 (10,674, 14,572, 24,681); IR (KBr) nmax: 3441, 2967,
2920, 2855, 1646, 1611, 1580, 1473, 1434, 1224, 1159, 1109, 1037,
748 cmꢁ1
;
1H NMR data, see Table 3; 13C NMR data, see Table 4;
A slurry of the K10 clay (20 equiv by weight) in CHCl3 (ca. 8 mL)
was treated with the xanthones 1, 2 or 3 (0.140 mmol), followed by
the addition of prenyl bromide (1.15 mmol), in a 12 mL closed mi-
crowave reactor. The mixture under stirring was irradiated at
150 W for 20 min and final temperatures range were 105–115 ꢀC.
The reaction mixture was filtered under vacuum, washed with
CH2Cl2, Me2CO, and MeOH, and the filtrate concentrated under
vacuum. The recovered clay was reactivated by washing with
MeOH. The crude product was purified by flash chromatography
(SiO2; petroleum ether/EtOAc) and by preparative TLC (SiO2; pe-
troleum ether/EtOAc or CH2Cl2). The products were identified by
their spectroscopic and analytical data. Compounds (yields): 165
(86%), 175 (10%), 185 (14%). Compounds (yields): 19 (25%), 20 (9%),
21 (4%) were characterized as described above.
ꢃ
EIMS m/z (%): 364 (25, Mþ ), 309 (21), 293 (49), 265 (29), 253 (100);
EIHRMS m/z: calcd for C23H24O4: 364.1675, found: 364.1675.
4.6. General procedure for the synthesis of
dihydropyranoxanthones 16–18 and 21 with Montmorillonite
K10 clay and conventional heating
A slurry of the K10 clay (20 equiv by weight) in CHCl3 (ca.
20 mL) was treated with the xanthones 1 or 2 (0.40 mmol), fol-
lowed by the addition of prenyl bromide (0.80 mmol), in a sealed
tube. The mixture was maintained under stirring at 100 ꢀC in an
oil bath for 60 min. The reaction mixture was filtered under
vacuum, washed with CH2Cl2, Me2CO, and MeOH, and the filtrate
concentrated under vacuum. The recovered clay was reactivated
by washing with MeOH. The crude product was purified by col-
umn chromatography (SiO2; hexane/EtOAc) and by preparative
TLC (SiO2; hexane/EtOAc). The products were identified by their
spectroscopic and analytical data. Compounds (yields): 165 (63%),
175 (7%), 185 (12%). Compound (yield): 21 (6%) was characterized
as described above.
4.10. General procedure for the synthesis of
dihydropyranoxanthones 17, 18, and 21 with dry
Montmorillonite K10 clay and MW irradiation with solvent
Montmorillonite K10 clay (2 g) was measured into a vial and
heated in an oven at approximately 110 ꢀC for 2 h. The activated
clay was transferred to a desiccator and allowed to cool to room
temperature. To the clay was added CHCl3 (ca. 11 mL), xanthone 2
(0.43 mmol), followed by the addition of prenyl bromide
(0.86 mmol), in a 50 mL closed microwave reactor. The mixture
under stirring was irradiated at 250 W for 20 min and the final
temperature was 110 ꢀC. The reaction mixture was filtered under
vacuum, washed with CH2Cl2, Me2CO, and MeOH, and the filtrate
concentrated under vacuum. The recovered clay was reactivated by
washing with MeOH. The crude product was purified by flash
chromatography (SiO2; petroleum ether/EtOAc) and by preparative
TLC (SiO2; petroleum ether/EtOAc). The products were identified by
their spectroscopic and analytical data. Compounds (yields): 175
(10%), 185 (20%). Compound (yield): 21 (5%) was characterized as
described above.
4.7. General procedure for the synthesis of
dihydropyranoxanthones 16–18 and 21 with dry
Montmorillonite K10 clay and conventional heating
Montmorillonite K10 clay (2 g) was measured into a vial and
heated in an oven at approximately 110 ꢀC for 2 h. The activated
clay was transferred to a desiccator and allowed to cool to room
temperature. To the clay was added CHCl3 (ca. 20 mL), xanthones 1
or 2 (0.40 mmol), followed by the addition of prenyl bromide
(0.80 mmol), in a sealed tube. The mixture was maintained under
stirring at 100 ꢀC in an oil bath for 60 min. The reaction mixture was
filtered under vacuum, washed with CH2Cl2, Me2CO, and MeOH,
and the filtrate concentrated under vacuum. The recovered clay
was reactivated by washing with MeOH. The crude product was
purified by column chromatography (SiO2; hexane/EtOAc) and by
preparative TLC (SiO2; hexane/EtOAc). The products were identified
by their spectroscopic and analytical data. Compounds (yields): 165
(63%), 175 (8%), 185 (18%). Compound (yield): 21 (7%) was charac-
terized as described above.
Acknowledgements
˜
ˆ
The authors thank Fundaçao para a Ciencia e a Tecnologia (FCT),
I&D Units 226/2003 (CEQOFFUP), 4040/2007 (CEQUIMED-UP), 62/
94 (QOPNA) and FEDER, POCI for financial support; FCT for the Ph.D.
grant to R.A.P.C. (SFRH/BD/13167/2003). We also thank Gisela
Adriano for technical support.
4.8. General procedure for the synthesis of
dihydropyranoxanthones 16–21 with Montmorillonite K10
clay and MW irradiation without solvent
References and notes
Xanthones 1, 2 or 3 (0.140 mmol) were mixed and grounded
with K10 clay (20 equiv by weight) in a mortar. The mixture was
transferred to a 12 mL closed microwave reactor and prenyl bro-
mide (1.15 mmol) was added. The mixture under stirring was ir-
radiated at 150 W for 20 min and final temperatures range were
110–150 ꢀC. The reaction mixture was filtered under vacuum,
washed with CH2Cl2, Me2CO, and MeOH, and the filtrate con-
centrated under vacuum. The recovered clay was reactivated by
washing with MeOH. The crude product was purified by flash
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