An Efficient Two-Step Protocol for the Isoprenylation of Xanthone at the C2 Position Starting from 1-Fluoroxanthone Derivative

Article abstract of DOI:10.1055/s-0039-1690891

The S _NAr reaction of 1-fluoroxanthone derivatives with alkoxide of 1,1-dimethylallyl alcohol cleanly afforded the corresponding ethers, which have thus far been unavailable. The obtained ethers underwent the Claisen rearrangement at room tempe

Full text of DOI:10.1055/s-0039-1690891

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2020, 31, 1423–1429
letter
1423
en
Synlett
Y. Fujimoto et al.
Letter
An Efficient Two-Step Protocol for the Isoprenylation of Xanthone
at the C2 Position Starting from 1-Fluoroxanthone Derivative
Yuuki Fujimoto
0
0
0
0-0
0
0
1-
9
3
5
1-9
4
5
8
F
O
O
O
OH
O
Chisato Furukawa
Kanae Takahashi
Miho Mochizuki
silica gel
25 °C
–
O
O
SNAr reaction
O
Claisen
rearrangement
O
Hikaru Yanai
0
0
0
0-0
0
0
3-4
6
3
8-
5
1
1
3
95%
Takashi Matsumoto*
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0-0
0
0
3-
0
6
3
9-9
2
6
2
School of Pharmacy, Tokyo University of Pharmacy and
Life Sciences, 1432-1 Horinouchi, Tokyo 192-0392,
Japan
14 examples
3–99% yield
6
85%
71%
99%
etc.
tmatsumo@toyaku.ac.jp
Received: 04.03.2020
Accepted: 24.03.2020
Published online: 14.05.2020
DOI: 10.1055/s-0039-1690891; Art ID: st-2020-u0125-l
O
OH
OH
O
OH
HO
HO
3
-methylbut-2-en-1-yl
O
O
OH
Abstract The S Ar reaction of 1-fluoroxanthone derivatives with
(isoprenyl)
N
OH
alkoxide of 1,1-dimethylallyl alcohol cleanly afforded the corresponding
ethers, which have thus far been unavailable. The obtained ethers un-
derwent the Claisen rearrangement at room temperature by treatment
with silica gel in toluene. This two-step protocol provides expeditious
and high-yield access to xanthones possessing isoprenyl or the related
allylic side chain at the C2 position.
OH
O
O
elliptoxanthone A
cratoxyarborenone A
HO
OH
OH
OH
O
O
O
garcinone A
8
1
8
a
9a
7
6
2
3
9
Key words xanthone, isoprenylation, S Ar reaction, Claisen rear-
rangement
OH
10aO 4a
5
N
4
OH
xanthone nucleus
and its numbering
subelliptenone F
Figure 1 Examples of naturally occurring prenylxanthone
Xanthones constitute a large class of secondary metabo-
1,2
lites, mainly found in higher plant families. Although xan-
thone itself is a simple tricycle, the prenyl modification and
the oxygenation offers a large structural diversity of the de-
rivatives (Figure 1). The prenyl moieties exert significant in-
fluence on their biological activities by its lipophilic nature
and sterics depending on the position and the number on
port an efficient isoprenylation of the C2 position through
the nucleophilic aromatic substitution (S Ar) reaction of a
N
1-fluoroxanthone with alkoxide of 1,1-dimethylallyl alco-
(A) Isoprenylation at C1 (or C8) via the Grignard addition/oxy-Cope rearrangement
3
the tricyclic scaffold.
F
O
O
During the course of our studies on the synthesis of bio-
F
OH
MgX
1
base
4
logically active xanthone derivatives, we recently devel-
Grignard
addition
aromatic
oxy-Cope
rearrangement
oped an efficient two-step approach for the installation of
isoprenyl (i.e., 3-methylbut-2-en-1-yl) group to the C1 (or
C8) position of xanthones, which utilizes the uncommon
anion-accelerated aromatic oxy-Cope rearrangement start-
ing from 1-fluoroxanthone derivatives (Scheme 1, A).4b In
addition to its broad substrate scope and high product
yield, ready accessibility to a range of fluoroxanthone de-
rivatives ensures the overall effectiveness of the method, as
demonstrated by the application to the synthesis of a natu-
O
O
O
I
II
III
(B) Isoprenylation at C2 (or C7) via the S Ar reaction/Claisen rearrangement
N
O
O
OH
O
–
O
silica gel
I
2
SNAr reaction
Claisen
rearrangement
O
O
IV
V
4c
ral xanthone, elliptoxanthone A (see Figure 1).
Scheme 1 Two approaches for the isoprenylation of xanthone frame-
work by utilizing fluoroxanthone derivatives
In this communication, as an extension of the prenyl-
xanthone synthesis by exploiting fluoroxanthones, we re-
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2020. Thieme. All rights reserved. Synlett 2020, 31, 1423–1429
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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Letter
hol (2-methylbut-3-en-2-ol) followed by the Claisen rear-
rangement (Scheme 1, B).5,6 It is worth mentioning before-
hand that despite the Claisen rearrangement being a com-
mon and ordinary approach for the installation of an allylic
O
O
OH
O
toluene, 100 °C, 5 h (98%)
or
O
silica gel (100 wt%)
toluene, 25 °C, 2.5 h (97%)
O
7
moiety on xanthone core, there is no precedent for the ap-
3a
5a
plication to isoprenylation of the C2 position. This is at-
tributed to the difficulty in preparation of the reaction pre-
cursor: No method is available for the conversion of C1-hy-
droxy group of xanthone, which is strongly hydrogen-
bonded to the carbonyl group, into the corresponding 1,1-
Scheme 2 The Claisen rearrangements of 3a under the thermal and
the silica-gel accelerated conditions
more, the reaction was remarkably accelerated by the pres-
8–12
13,14
dimethylallyl ether.
ence of silica gel to proceed at 25 °C.
Our study began with examining the S Ar reaction of 1-
Table 2 shows selected results of screening of other pro-
moters and optimization of the conditions. With respect to
the reactions with silica gel, toluene was the choice of sol-
vents (Table 2, entries 1–4), and it was possible to lower the
loading into 30 wt% of the substrate 3a without significant
decrease in the product yield (Table 2, entry 5). Florisil (30
wt%) was equally as effective as silica gel (Table 2, entry 6).
However, higher loading of Florisil caused the ether bond
cleavage to give 1-hydroxyxanthone (4a), decreasing the
yield of 5a (not shown in Table 2). Formation of 4a was also
unavoidable in the reaction with molecular sieves 13X (Ta-
ble 2, entry 7), and the reaction progress was sluggish with
molecular sieves 4Å or neutral alumina (Table 2, entries 8,
N
fluoroxanthone (1a) as the model compound with 1,1-di-
methylallyl alcohol (2). As a result, the use of the alkoxide
of alcohol 2, generated by the treatment with NaH or KH,
proved effective. Thereby, the expected reaction occurred
cleanly and smoothly at 25 °C in THF or DMF (Table 1).
Table 1 Optimization of the Conditions for the S Ar Reactiona
N
F
O
O
O
OH
2
base
O
O
1a
3a
9). The use of Brønsted and Lewis acids, such as TsOH,
Entry Base (equiv)
Solvent Temp (°C) Time (h) Conversion (%)b
BF ·OEt , and EtAlCl (Table 2, entries 11–13), was less effec-
3
2
2
tive, giving 5a in modest yield along with 4a as the major
product and a small amount of 4-isoprenyl product 6a.
Substrate scope was briefly evaluated by the reactions
1
NaH (2.0)
NaH (2.0)
NaH (3.0)
KH (2.0)
DMF
THF
THF
DMF
THF
DMF
DMF
25
1.75
24
>99
86c
>99
>99
>99
6
2
25
3d
4
25
5.5
0.25
0.25
3
of 1-fluoroxanthones 1b–f (Table 3). For the S Ar reaction
N
25
step, we opted for the conditions with sodium alkoxide of
alcohol 2, despite a little less reactive than the correspond-
ing potassium alkoxide (see Table 1), by taking into account
the easiness in handling of the requisite base, NaH rather
than KH. The crude materials of the obtained ethers 3b–f
were used for the following Claisen rearrangement with sil-
ica gel (100 wt%) in toluene. This procedure, in which the
intermediate purification stage was omitted, was also ap-
plied to 1-fluoroxanthone (1a), and the result was compiled
together in Table 3 (entry 1).16
5
KH (2.0)
25
6e
7e
DBU (2.0)
reflux
reflux
Cs
2
CO
3
(3.0)
3
32c
OH
O
O
4a
a
The reactions were carried out by using 3 equiv of alcohol 2, unless other-
wise stated.
b
1
Determined by H NMR analysis of the crude material.
c
The points worth noting are the following. The S Ar re-
N
A small amount of compound 4a was obtained as byproduct.
d
e
4
5
.5 equiv of alcohol 2 were used.
.0 equiv of alcohol 2 were used.
action of 1c possessing a methoxy substituent at C4 (Table
3, entry 3) needed a higher temperature (70 °C) compared
to the other cases (25 °C), as expected from increased elec-
tron density at C1 by the mesomeric effect. The Claisen re-
arrangement of 3b into 5b (Table 3, entry 2) was sufficient-
ly promoted by a reduced amount of silica gel (50 wt%). In
contrast, the reaction of 3c (Table 3, entry 3) did not take
place at 25 °C, and a little higher temperature (40 °C) was
required to attain an acceptable rate of the reaction. These
results are consistent with the property of a methoxy sub-
stituent on aromatic ring, which increases the HOMO co-
efficient of the ortho position and decreases that of the
meta position.17 As for 1d and 1e (Table 3, entries 4 and 5),
Isolation of ether 3a was attained by quickly performing
chromatographic purification with neutral alumina, where-
as a part of 3a underwent the Claisen rearrangement on ex-
posure to silica gel even in a short time for TLC analysis.13
Ether 3a, thus obtained for the first time, proved to be quite
amenable to the Claisen rearrangement under thermal con-
ditions in comparison to the reported xanthone derivatives
possessing a (1,1-dimethylallyl)oxy moiety on the position
7
other than C1 (or C8). Thus, upon heating in toluene at 100 °C
,
the rearrangement was complete in 5 h to give 1-hydroxy-
-isoprenylxanthone (5a) in 98% yield (Scheme 2). Further-
2
the S Ar reaction occurred selectively at the fluorine-
N
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Table 2 Screening of the Promoters and Optimization of the Conditions for the Claisen Rearrangementa
OH
O
O
O
OH
O
conditionsa
O
O
O
3a
5a
6a
Entry
Promoter
Solvent
Time (h)
Yield (%)b
Unreacted 3a 5a
4a
6a
1
2
3
4
5
6
7
8
9
silica gel15 (100 wt%)
silica gel15 (100 wt%)
silica gel15 (100 wt%)
silica gel15 (100 wt%)
silica gel15 (30 wt%)
Florisil15 (30 wt%)
toluene
CH Cl
2.5
7
–
97
–
–
–
–
–
–
–
2
2
–
87
3
–
DMF
THF
24
24
10.5
7
–
–
–
3
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
–
96
94
90
41
22
39
11
27
40
–
–
–
MS 13X15 (100 wt%)
MS 4Å15 (100 wt%)
24
24
25
1
–
5
–
33
77
–
–
–
neutral alumina15 (100 wt%)
montmorillonite K1015 (100 wt%)
TsOH (10 mol%)
–
–
1
1
1
1
0
41
29
46
48
18
2
1
24
1
58
–
2c
3
BF
·OEt
(10 mol%)
CH
CH
Cl
26
12
3
2
2
2
2
2
EtAlCl
2
(10 mol%)
Cl
3.5
–
a
b
c
The reactions were carried out at 25 °C, unless otherwise stated.
Isolated yield of chromatographically pure product.
The reaction was carried out at –78 °C.
substituted position despite of potential leaving ability of
methoxide and chloride at C1 or C8. The corresponding
isoprenylxanthones 5d and 5e were obtained in high yields
via the following Claisen rearrangement. On the other hand,
in the reaction of 1f (Table 3, entry 6), both of the fluorides
concurrently served as the leaving groups, giving diisopre-
nylated xanthone 5f in 79% yield over two steps.
creases population of the reactive conformer with the C2 of
xanthone core and the terminal carbon of the alkene moi-
ety close together.
Some other intriguing examples of the application are
shown below (Schemes 4 and 5).
Scheme 4 represents the reactions with 1-vinylcycloal-
kanols and 1-methylcycloalk-2-en-1-ols. In all of the cases,
Applications of the method to primary and secondary
allylic alcohols are shown in Scheme 3.
the S Ar reaction/Claisen rearrangement sequence worked
N
nicely. Though the S Ar reactions with sodium alkoxides of
N
The S Ar reactions of alcohols 7 and 8 proceeded more
alcohols 9, 12, 13 in DMF were too slow, acceptable reaction
rates were ensured by the use of the corresponding potassi-
um alkoxides in THF. It is noteworthy that the intermediate
ether 3k was less susceptible to the Claisen rearrangement
and remained intact on exposure to silica gel, allowing iso-
lation by silica-gel chromatography. And accordingly, a
higher temperature (80 °C) was needed for the progress of
the Claisen rearrangement even in the presence of silica gel.
In contrast, ether 3m underwent in situ the Claisen rear-
rangement immediately on its formation (THF, 25 °C).
We speculate that the observed unwillingness of 3k to
N
rapidly in comparison with tertiary alcohol 2, and the ob-
tained ethers 3g and 3h allowed isolation by ordinary chro-
matographic purification with silica gel. The Claisen rear-
rangement of 3g and 3h were very slow even under reflux
in toluene (10% in 5 h for 3g, 6% in 10 h for 3h) but effec-
tively accelerated by addition of silica gel (300 wt%), going
to completion in acceptable time.
Thus, it was revealed that the tendency for the interme-
diate ethers to participate in the Claisen rearrangement was
in an order of 3a–f > 3g > 3h. We postulate this is the conse-
quence of steric congestion around the ether moieties. The
congestion makes energy level of the reactant much higher
and lengthens the C–O linkages, which are going to discon-
nect, thereby facilitating the rearrangement. Another possi-
participate in the Claisen rearrangement could be account-
ed for by the Thorpe–Ingold effect.1
8c,d
That is, compressed
internal angle of the four-membered ring should cause an
3
2
enlargement of the O–C(quaternary-sp )–C(sp ) angle
(shown by blue arcs in Figure 2), thereby enhancing strain
18a–c
ble rationale relies on the gem-dialkyl effect,
which in-
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Table 3 Substrate Scope with Respect to 1-Fluoroxanthones
F
O
O
O
O
OH
O
OH
2
silica gel
toluene
NaH, DMF
O
O
R
R
R
R
R
R
1a–f
SNAr reaction
3a–f
Claisen rearrangement
5a–f
Entry Fluoroxanthone 1
S
N
Ar reactiona
Ether 3
Claisen rearrangementb Prenylxanthone 5
Yield (%)c
Temp (°C) Time (h)
Temp (°C) Time (h)
F
F
F
O
O
O
O
O
OH
O
1
25
25
1
25
25
5
3
95
O
O
1a
1b
O
O
O
O
O
3a
3b
O
O
5a
5b
OH
OH
2d
1.5
92
91
MeO 3
O
O
O
MeO
MeO
O
O
O
3
70
1
40
0.7
4
MeO
1c
1d
1e
1f
MeO
O
3c
3d
MeO
5c
5d
5e
F
O
O
O
O
O
O
OMe
8
O
O
O
OMe
OH
O
OMe
4
5
25
25
25
2.5
1
25
25
25
6.5
8
86
91
79
O
O
F
F
Cl
F
O
O
Cl
O
OH
Cl
O
O
3e
3f
O
HO
O
O
OH
6
14
6.5
O
5f
a
Unless otherwise stated, the reactions were carried out with 3 equiv of alcohol 2 and 2 equiv of NaH.
Unless otherwise stated, the reactions were carried out by using silica gel in the same weight of the respective fluoroxanthone (100 wt%).
Yield over two steps from 1.
b
c
d
The Claisen rearrangement was carried out with silica gel in an amount of 50 wt% based on 1b.
R1
OH
O
O
O
OH
O
O
R1
R2
7
silica gel
NaH, DMF
5 °C, 20 min
toluene
reflux, 3.5 h
R2
O
2
2
O
or
O
3
3
g 98%
5g quant (E/Z = 75/25)
1a
chair-like TS
boat-like TS
OH
O
OH
O
Figure 2 Possible rationale to unwillingness of 3k to participate in the
8
silica gel
Claisen rearrangement
NaH, DMF
5 °C, 15 min
toluene
reflux, 8.5 h
O
O
h 97%
5h 75%
energy in transition state. No convincing explanation is
available to unusually higher reactivity of ether 3m at this
point.19
Scheme 3 The reactions with primary and secondary allylic alcohols
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Y. Fujimoto et al.
Letter
OH
O
O
O
O
O
O
OH
O
O
9
silica gel
OH
O
O
OH
O
KH, THF
5 °C, 40 min
toluene
25 °C, 3 h
14
silica gel
1a
2
NaH, DMF
5 °C, 2 h
toluene
25 °C, 8 h
3i
5i 78%
O
O
2
3
n 90%
5n
8
5% (E/Z = 57/43)
OH
O
OH
O
10
silica gel
Scheme 5 Installation of geranyl/neryl side chain
NaH, DMF
5 °C, 1.5 h
toluene
25 °C, 4 h
2
O
O
3j
5j 85%
product yield, and ready accessibility to a range of fluoro-
xanthone derivatives, this protocol would pave a way to ex-
tensive structure–activity relationship study of the related
xanthone derivatives.
OH
O
OH
O
11
silica gel
1a
NaH, DMF
5 °C, 2 h
toluene
80 °C, 7 h
2
O
O
3
k 97%
5k 99%
Funding Information
OH
O
O
OH
O
This work was financially supported by the Japan Society for the Pro-
motion of Science (JSPS KAKENHI Grant Number JP17K15425) and
the MEXT-Supported Program for the Private University Research
12
silica gel
KH, THF
5 °C, 15 min
toluene
25 °C, 2 h
2
O
Branding Project.
M
i
n
i
stry of
E
d
u
c
ati
o
n
,
C
u
l
ture
,
S
p
orst,
S
c
i
e
n
c
e
a
n
d
T
e
c
h
n
o
l
o
g
y
()J
a
p
a
n
S
o
c
i
ety forth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(1
7
K
1
5
4
2
5)
3l
5l 71%
OH
O
O
O
OH
O
Acknowledgment
13
KH, THF
5 °C, 18 h
The authors are grateful to Professor Satoshi Yokojima, Tokyo Univer-
sity of Pharmacy and Life Sciences, for his helpful advice on computa-
tional chemistry. Mr. Haruhiko Fukaya, Tokyo University of Pharmacy
and Life Sciences, is also acknowledged for assistance with mass spec-
trometry and combustion analyses.
2
O
3m
5m 63%
Scheme 4 The reactions with 1-vinylcycloalkanols and 1-methylcy-
cloalk-2-en-1-ols
The side chain moieties, thus installed, are such that the
terminal methyls of isoprenyl group are connected through
methylene(s) (5i–k) or the double bond of isoprenyl group
is merged into cycloalkene structure (5l,m). Installation of
these elaborate isoprenyl counterfeits would make a sub-
stantial contribution to biological study of prenylated xan-
thones.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690891.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orti
n
g Inform ati
o
n
References and Notes
(1) For reviews on natural xanthones, see: (a) Klein-Júnior, L. C.;
Finally, installation of the linear C10 isoprenoid side
chain is shown in Scheme 5. Ether 3n, obtained by the reac-
tion with linalool (14), was subjected to the Claisen rear-
rangement after chromatographic purification with neutral
alumina, because the use of the crude material was less
fruitful presumably due to the nonvolatile linalool residual.
The reaction with purified ether 3n afforded the desired
product 5n in 85% yield as a mixture of E (geranyl) and Z
Campos, A.; Niero, R.; Corrêa, R.; Heyden, Y. V.; Filho, V. C.
Chemistry & Biodiversity 2020, 17, e1900499. (b) El-Seedi, H. R.;
El-Barbary, M. A.; El-Ghorab, D. M.; Bohlin, L.; Borg-Karlson, A.
K.; Göransson, U.; Verpoorte, R. Curr. Med. Chem. 2010, 17, 854.
(c) Pinto, M. M. M.; Sousa, M. E.; Nascimento, M. S. J. Curr. Med.
Chem. 2005, 12, 2517.
(
2) For reviews on the synthesis of xanthones, see: (a) Masters, K.-
S.; Bräse, S. Chem. Rev. 2012, 112, 3717. (b) Azevedo, C. M. G.;
Afonso, C. M. M.; Pinto, M. M. M. Curr. Org. Chem. 2012, 16,
(neryl) isomers (57:43).
2818. (c) Sousa, M. E.; Pinto, M. M. M. Curr. Med. Chem. 2005, 12,
In summary, an efficient two-step protocol for the syn-
2447.
thesis of xanthone derivatives possessing isoprenyl or the
related allylic side chain at the C2 position was developed.
(3) For recent examples of biological study of prenylated xantho-
nes, see: (a) Natrsanga, P.; Jongaramruong, J.; Rassamee, K.;
Siripong, P.; Tip-Pyang, S. J. Nat. Med. 2020, 74, 467. (b) Li, P.;
Yang, Z.; Tang, B.; Zhang, Q.; Chen, Z.; Zhang, J.; Wei, J.; Sun, L.;
Yan, J. ACS Omega 2020, 5, 334. (c) Jin, S.; Shi, K.; Liu, L.; Chen, Y.;
Yang, G. Int. J. Mol. Sci. 2019, 20, 4803. For a review, see:
The S Ar reaction of 1-fluoroxanthone derivatives with the
N
alkoxide of 1,1-dimethylallyl alcohol cleanly afforded the
corresponding ethers, which underwent the Claisen rear-
rangement at room temperature by the treatment with sili-
ca gel in toluene. Because of its broad substrate scope, high
(d) Pinto, M. M. M.; Castanheiro, R. A. P. In Natural Products:
Chemistry, Biochemistry and Pharmacology, Brahmachari G;
Alpha Science: Oxford, 2009, 520.
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Letter
(
4) (a) Fujimoto, Y.; Itakura, R.; Hoshi, H.; Yanai, H.; Ando, Y.;
(11) Wang et al. pointed out the propargylation/half-reduction
sequence was not capable of 1,1-dimethylallylation of C1-
hydroxy group of xanthone derivative, see: Xu, D.; Nie, Y.; Liang,
X.; Ji, L.; Hu, S.; You, Q.; Wang, F.; Ye, H.; Wang, J. Nat. Prod.
Commun. 2013, 8, 1101.
Suzuki, K.; Matsumoto, T. Synlett 2013, 24, 2575. (b) Fujimoto,
Y.; Watabe, Y.; Yanai, H.; Taguchi, T.; Matsumoto, T. Synlett
2
2
016, 27, 848. (c) Fujimoto, Y.; Yanai, H.; Matsumoto, T. Synlett
016, 27, 2229.
(
5) For examples of the S Ar reaction of xanthone derivative, see:
(12) In fact, our attempts to apply the Tsuji–Trost allylation to 1-
hydroxyxanthone (4a) under various conditions with tert-butyl
1,1-dimethylallyl carbonate resulted in failure, as exemplified
by Scheme 6.
N
(a) Sharghi, H.; Tamaddon, F. J. Heterocycl. Chem. 2001, 38, 617.
(b) Gobbi, S.; Rampa, A.; Bisi, A.; Belluti, F.; Valenti, P.; Caputo,
A.; Zampiron, A.; Carrara, M. J. Med. Chem. 2002, 45, 4931.
c) Piazzi, L.; Belluti, F.; Bisi, A.; Gobbi, S.; Rizzo, S.; Bartolini, M.;
Andrisano, V.; Recanatini, M.; Rampa, A. Bioorg. Med. Chem.
007, 15, 575. (d) Waszkielewicz, A. M.; Słoczysńka, K.; Pękala,
(
O
2
O
O (t-Bu)
OH
O
O
O
O
E.; Żmudzki, P.; Siwek, A.; Gryboś, A.; Marona, H. Chem. Biol.
Drug Des. 2017, 89, 339. (e) Kubacka, M.; Szkaradek, N.;
Mogilski, S.; Pańczyk, K.; Siwek, A.; Gryboś, A.; Filipek, B.;
Żmudzki, P.; Marona, H.; Waszkielewicz, A. M. Bioorg. Med.
Chem. 2018, 26, 3773. See also ref. 4a.
Pd(PPh3)4
X
THF
reflux, 12 h
O
4a
(98% recovery of 4a)
3a 0%
Scheme 6
(
6) For reviews on the aromatic Claisen rearrangement, see: (a) Ito,
H.; Taguchi, T. In The Claisen Rearrangement; Hiersemann, M.;
Nubbemeyer, U., Ed.; Wiley-VCH: Weinheim, 2007, 86.
(
13) For examples of solid-acid catalysis in aromatic Claisen rear-
rangement, see: (a) Dauben, W. G.; Cogen, J. M.; Behar, V. Tetra-
hedron Lett. 1990, 31, 3241. (b) Cruz-Almanza, R.; Pérez-Flores,
F.; Breña, L. J. Heterocycl. Chem. 1995, 32, 219. (c) Sucholeiki, I.;
Pavia, M. R.; Kresge, C. T.; McCullen, S. B.; Malek, A.; Schramm,
S. Mol. Diversity 1998, 3, 161. (d) Yadav, G. D.; Lande, S. V. Synth.
Commun. 2007, 37, 941. (e) Liu, Y.; Guo, Y.; Ji, F.; Gao, D.; Song,
C.; Chang, J. J. Org. Chem. 2016, 81, 4310. (f) Shiozawa, M.; Iida,
K.; Odagi, M.; Yamanaka, M.; Nagasawa, K. J. Org. Chem. 2018,
(b) Castro, A. M. M. Chem. Rev. 2004, 104, 2939.
(
7) For examples of isoprenylation of xanthone core by the Claisen
rearrangement, see: (a) Burling, E. D.; Jefferson, A.; Scheinmann,
F. Tetrahedron 1965, 21, 2653. (b) Locksley, H. D.; Quillinan, A. J.;
Scheinmann, F. J. Chem. Soc. C 1971, 3804. (c) Quillinan, A. J.;
Scheinmann, F. J. Chem. Soc., Perkin Trans. 1 1972, 1382.
(d) Quillinan, A. J.; Scheinmann, F. J. Chem. Soc., Perkin Trans. 1
1975, 241. (e) Ohira, S.; Fukamichi, N.; Nakagawa, O.; Yamada,
M.; Nozaki, H.; Iinuma, M. Chem. Lett. 2000, 464. (f) Ito, S.;
Kitamura, T.; Arulmozhiraja, S.; Manabe, K.; Tokiwa, H.; Suzuki,
Y. Org. Lett. 2019, 21, 2777. See also ref. 9a–d, 10a,b.
83, 7276.
(
14) Silica gel-induced acceleration was also observed in the reac-
tions of 2-(1,1-dimethylallyloxy)xanthone derivatives as illus-
trated in Scheme 7, which, incidentally, led to the selective iso-
prenylation at the C1 position. General aspects of the silica gel
catalysis in the Claisen rearrangement of xanthone derivatives
will be reported in due course.
(
8) So far, the selective 1,1-dimethylallylation, but not the 3,3-
dimethylallylation, of hydroxy groups of xanthones had been
achieved by utilizing the 1,1-dimethylpropargylation/half-
9
reduction sequence or the Tsuji–Trost allylation with 1,1-
10
dimethylallyl carbonate derivatives. However, these methods
7,11,12
are not effective for the reaction of the C1-hydroxy group.
(
9) For examples of 1,1-dimethylallylation of hydroxy groups of
xanthones by utilizing the 1,1-dimethylpropargylation/half-
reduction sequence, see: (a) Fellows, I. M.; Schwaebe, M.;
Dexheimer, T. S.; Vankayalapati, H.; Gleason-Guzman, M.;
Whitten, J. P.; Hurley, L. H. Mol. Cancer Ther. 2005, 4, 1729.
O
O
O
O
conditions
HO
O
15
16
toluene, reflux, 7 h
CH2Cl2, reflux, 7 h
87%
0%
(
b) Nicolaou, K. C.; Xu, H.; Wartmann, M. Angew. Chem. Int. Ed.
005, 44, 756. (c) Tisdale, E. J.; Vong, B. G.; Li, H.; Kim, S. H.;
Chowdhury, C.; Theodorakis, E. A. Tetrahedron 2003, 59, 6873.
d) Tisdale, E. J.; Slobodov, I.; Theodrakis, E. A. Org. Biomol.
Chem. 2003, 1, 4418.
2
silica gel, CH2Cl2, 25 °C, 10 h 87%
Scheme 7
(
(
10) For examples of 1,1-dimethylallylation of hydroxy groups of
(
15) Silica gel: Kanto Chemical Co. Inc. (63–210 mesh for chromatog-
raphy), Florisil: FUJIFILM Wako Pure Chemical, Ltd. (100–200
mesh for chromatography), MS 4Å: FUJIFILM Wako Pure Chemi-
cal, Ltd, MS 13X: Kanto Chemical Co. Inc., neutral alumina: MP
Biomedicals (Alumina N, Act-I for chromatography), Montmo-
rillonite K10: Sigma-Aldrich Co. LLC.
xanthones by utilizing the Tsuji–Trost allylation, see:
(
a) Chantarasriwong, O.; Cho, W. C.; Batova, A.; Chavasiri, W.;
Moore, C.; Rheingold, A. L.; Theodorakis, E. A. Org. Biomol. Chem.
009, 7, 4886. (b) Elbel, K. M.; Guizzunti, G.; Theodoraki, M. A.;
2
Xu, J.; Batova, A.; Dakanali, M.; Theodorakis, E. A. Org. Biomol.
Chem. 2013, 11, 3341. For the Tsuji–Trost allylation, see:
(16) Typical Procedure of the S Ar Reaction/Claisen Rearrange-
N
(c) Tsuji, J.; Takahshi, H.; Morikawa, M. Tetrahedron Lett. 1965,
ment Sequence for the Synthesis of 5a
49, 4387. (d) Trost, B. M.; Vranken, D. L. V. Chem. Rev. 1996, 96,
A flame-dried two-necked round-bottomed flask was charged
with NaH (60% dispersion in mineral oil, 160 mg, 4.0 mmol) and
DMF (2.0 mL). Then, 1,1-dimethylallyl alcohol 2 (0.63 mL, 6.0
mmol) was added dropwise at 0 °C. After stirring for 30 min at
395. (e) Tsuji, J. Palladium Reagents and Catalysts, New Perspec-
tives for the 21st Century; John Wiley & Sons: Chichester, 2004.
See also: (f) Kaiho, T.; Miyamoto, M.; Nobori, T.; Katakami, T.
J. Synth. Org. Chem., Jpn. 2004, 62, 27.
25 °C, the net concentration of the alkoxide was adjusted to 1.0
M by adding DMF (1.3 mL), ready to use for the S Ar reactions.
N
This solution of the alkoxide (1.0 M, 0.94 mL, 0.94 mmol) was
©
2020. Thieme. All rights reserved. Synlett 2020, 31, 1423–1429

1
429
Synlett
Y. Fujimoto et al.
Letter
added dropwise to a solution of fluoroxanthone 1a (100 mg,
J = 8.4 Hz), 7.72 (ddd, 1 H, J = 8.4, 7.2, 1.6 Hz), 8.27 (dd, 1 H, J =
13
468 mol) in DMF (0.95 mL), and the stirring was continued for
8.0, 1.6 Hz), 12.91 (s, 1 H). C NMR (100 MHz, CDCl ):  = 17.8,
3
1
h at 25 °C. The reaction was quenched with phosphate buffer
25.8, 26.9, 106.2, 108.5, 117.8, 120.5, 121.7, 122.9, 123.8, 126.0,
133.4, 135.4, 136.8, 154.5, 156.2, 159.0, 182.5. IR (ATR): 2962,
2902, 1607, 1574, 1472, 1458, 1440, 1424, 1374, 1306, 1277,
1237, 1220, 1202, 1154, 1119, 1056, 998, 918, 876, 851, 809,
(0.1 M, pH 7), and the products were extracted with Et O (3×).
2
The combined extracts were washed with water, brine, dried
over Na SO , and concentrated in vacuo. The residue was azeo-
tropically dried with toluene and used for the next step without
further purification.
2
4
–1
790, 779, 753, 666, 636, 606, 576, 524, 481, 454, 426 cm
.
+
HRMS (ESI-TOF): m/z calcd for C18H16O Na [M + Na] : 303.0997;
3
Silica gel (100 mg), placed in a two-necked round-bottomed
flask, was dried in vacuo by heating it with a heating gun and
then suspended in toluene (1.3 mL). To this suspension was
added a solution of the above-stated crude material of ether 3a
in toluene (1.0 mL) at 0 °C, and the mixture was stirred for 5 h at
found: 303.0996. Anal. Calcd for C18H16O : C, 77.12; H, 5.75.
Found: C, 77.11; H, 5.71.
(17) See the Supporting Information for HOMOs of 3b and 3c,
obtained by theoretical calculations (HF/6-311G(d,p)//B3LYP/6-
31G (d)).
3
2
5 °C. After removal of silica gel by filtration through a sintered
(18) (a) Jung, M. E.; Gervay, J. Tetrahedron Lett. 1988, 29, 2429.
(b) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224.
(c) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735. (d) Beesley,
R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans. 1915, 107,
1080.
glass filter, the filtrate was concentrated in vacuo. The residue
was purified by column chromatography (silica gel,
hexane/EtOAc = 9:1) to give xanthone 5a (124 mg, 95%) as
yellow solids and a small amount of 1-hydroxyxanthone (4a, 2
mg).
(19) DFT calculations performed at B3LYP/6-31G(d,p) level of theory
suggested that the reaction of 3m is energetically more prefera-
Mp 124.5–127.0 °C (yellow needles from hexane/EtOAc). 1H
NMR (400 MHz, CDCl ):  = 1.75 (s, 3 H), 1.77 (s, 3 H), 3.39 (d, 2
‡
ble than the reaction of 3l in 3.8 kcal/mol (ΔΔG ). For details
3
H, J = 7.2 Hz), 5.34 (br t, 1 H, J = 7.2 Hz), 6.87 (d, 1 H, J = 8.4 Hz),
including the optimized TS structures and energies, see the
Supporting Information.
7.37 (dd, 1 H, J = 8.0, 7.2 Hz), 7.44 (d, 1 H, J = 8.4 Hz), 7.47 (d, 1 H,
©
2020. Thieme. All rights reserved. Synlett 2020, 31, 1423–1429