Synthesis of Xanthones by Palladium-Catalyzed Tandem Carbonylation/C–H Activation via 2-Iodo Diaryl Ethers

Article abstract of DOI:10.1002/jccs.201700125

The ring closure of 2-iodo diaryl ether in the presence of a palladium catalyst to xanthone under carbon monoxide atmosphere is studied. A series of xanthones could be successfully obtained through this protocol, with Pd(OAc)₂ as the catalyst, P(Cy)₃ as ligand, PivONa^.H₂O as base, and PivOH and tetrabutylamonium bromide as additives in DMSO, in moderate to good yields.

Full text of DOI:10.1002/jccs.201700125

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Synthesis of Xanthones by Palladium-Catalyzed Tandem Carbonylation/C–H Activation
via 2-Iodo Diaryl Ethers
*
Rui-Yue Ma, Ya-Fang Chen, Jun-Ru Wang and Zhen-Ting Du
College of Chemistry and Pharmacy, Northwest A&F University, Yangling 712100 Shaanxi Province, P. R. China
(Received: April 8, 2017; Accepted: May 9, 2017; DOI: 10.1002/jccs.201700125)
The ring closure of 2-iodo diaryl ether in the presence of a palladium catalyst to xanthone under
carbon monoxide atmosphere is studied. A series of xanthones could be successfully obtained
.
through this protocol, with Pd(OAc) as the catalyst, P(Cy) as ligand, PivONa H O as base, and
2
3
2
PivOH and tetrabutylamonium bromide as additives in DMSO, in moderate to good yields.
Keywords: Xanthone; Palladium-catalyzed reaction; Heterocycle synthesis.
INTRODUCTION
Xanthones, also known as 9H-xanthen-9-ones, can
be found frequently in many natural products and other
bioactive heterocyclic molecules, and exhibit a broad
spectrum of biological or pharmaceutical activities.
As shown in Scheme 1, the syntheses of xanthone can be
broadly classified into two types. The first is the “classi-
this ring closure of 2-iodio of diaryl ether in the presence
CO. Here, we present these newest results using this
method.
1
2
3
–9
RESULTS AND DISCUSSION
At the outset of the investigation, we examined
the ring-closure reaction of 2-iodo diphenyl ether using
10–14
cal method” involving an intramolecular SN
Friedel–Crafts reaction.
or
Ar
5
mol% palladium acetate as catalyst, 20 mol% triphe-
1
5–22
Since the 1980s, transition-
nylphosphine as ligand, 3 equiv of cesium carbonate as
metal-catalyzed C–H bond activation of the derivatives
of diaryl ether, as the second methodology to form
xanthones, has been developed remarkably in the syn-
base, and N,N-dimethyl formamide as solvent under
0
.2 MPa pressure of CO. To our disappointment, the
desired xanthone was obtained only in 5% yield. Even
then, encouraged by this promising result, we next
screened different catalysts and phosphine ligands
2
3–29
thesis of xanthones.
Intriguingly, Larock reported a
30–32
tandem coupling–cyclization of arynes to xanthones
as a strategy to construct a phenyl ring. Nonetheless,
apart from these worthy developments, the syntheses of
the xanthone skeleton typically involved multistep pro-
cedures generally requiring functionalized benzophe-
none or diaryl ether motif often under harsh reaction
conditions or with unpredictable yields. Recently, we
reported a palladium-catalyzed carbonylation and C–H
activation to synthesize xanthones through the ortho-
(
Table 1, entries 1–4) to select best ligand. Obviously,
among PPh , P(Cy) , dppe, and dppp, tricyclohexylpho-
sphine was found to be the best. As far as the catalysts
were concerned, PdCl , Pd(PPh ) , Pd (dba) , and
Pd(TFA) proved ineffective in this reaction. It is worth
mentioning that neopentanoic acid had a remarkable
beneficial effect in the reaction (Table 1, entries
1
that different bases affected the reaction markedly.
Thus, if K CO was used, a similar yield was obtained.
3
3
2
3 4
2
3
2
1, 14–21). We then tried to change the base and found
33
diazonium salt of diaryl ether in excellent yields.
Therefore, we envisaged that 2-iodio of diaryl ether
could be employed to prepare xanthones (Scheme 1) in
the presence of CO after a catalytic de-iodide ring-
closure sequence. To the best of our knowledge, there
has been no systematic study on the ring closure of 2-
iodio diaryl ether. Therefore, as a supplement to our pre-
vious study, we were interested in seeking a protocol of
2
3
These results revealed that that PivONaÁH O was the
2
most suitable base for the transformation. Next, we
turned our attention to varying the conditions with
PivONa H O as base (Table 1, entries 14–21). With
PivONa H O as the base and pivalic acid and tetrabu-
tylammonium bromide as additives, the highest yield of
.
2
.
2
*Corresponding author. Email: duzt@nwsuaf.edu.cn
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1

Article
Ma et al.
best yields could be obtained. Lastly, we screened the
pressure of CO and found that it did not have a signifi-
cant effect upon this transformation between 0.1 and
0
.4 MPa. Finally, we found the optimum reaction con-
ditions with DMSO as solvent, 5 mol% Pd(OAc) as
2
ꢀ
catalyst, a temperature of 90 C, 100 mol% PivO-
.
Na H O as base, and 100 mol% pivalic acid and 10 mol
2
%
TBAB as additives (Table 1, entry 19).
With the optimized conditions, we next examined
Scheme 1. Synthesis of xanthones from dibenzoke-
the scope of Pd(OAc) -catalyzed cyclization of 2-iodo
2
tone and functionalized diaryl ether.
diaryl ether for the synthesis of substituted xanthones.
The results are summarized in Table 2. A range of
structurally diverse 2-iodio diaryl ehters (Table 2),
product could be obtained. Our studies subsequently
showed that the nature of reaction solvent was very
important for this reaction. In toluene, dioxane, and
acetonitrile, a yield of more or less than 40% could be
obtained (Table 1, entries 15–17). In contrast, by using
DMSO (Table 1, entry 19) as the reaction solvent, the
1
2
including different R and R groups as well as chloro
and methoxy groups were proved amenable to the reac-
tion conditions, delivering the corresponding xanthones
1
in moderate to good yields under this protocol. R can
2
be H or CH ; as for the variations of R , electron-
3
Table 1. Optimization of conditions
a
b
Entry
Catalyst (5%)
Ligand (0.2)
PPh
Base (3.0)
Additive (2.0)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
2
2
3
Cs
Cs
2
CO
CO
3
3
None
None
None
None
None
None
None
None
None
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
Toluene
Dioxane
5
26
5
7
15
9
P(Cy)
dppe
3
2
Pd(OAc)2
Pd(OAc)
PdCl
Pd(PPh3)4
Pd (dba)
Pd(TFA)
Cs CO3
2
2
dppp
Cs
Cs
2
CO
CO
3
3
2
P(Cy)
3
2
P(Cy)3
Cs CO3
2
2
3
P(Cy)
P(Cy)
3
3
Cs
Cs
2
CO
CO
3
3
0
2
2
22
20
33
37
17
56
69
44
41
39
68
70
68
40
Pd(OAc)2
Pd(OAc)2
P(Cy)3
P(Cy)3
K CO3
2
1
1
1
1
1
1
1
1
1
1
2
0
1
2
3
4
5
6
7
8
9
0
1
NaOAc
None
None
None
.
Pd(OAc)
2
P(Cy)
3
PivONa H
2
O
Pd(OAc)2
Pd(OAc)2
P(Cy)3
P(Cy)3
t-BuOK
NaOAc
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH, TBAB(10%)
.
Pd(OAc)
2
P(Cy)
3
PivONa H
2
O
.
Pd(OAc)2
Pd(OAc)2
P(Cy)3
P(Cy)3
PivONa H O
2
.
PivONa H O
2
.
c
Pd(OAc)
2
P(Cy)
3
PivONa H
2
O
3
CH CN
.
Pd(OAc)2
Pd(OAc)2
P(Cy)3
P(Cy)3
PivONa H O
DMSO
DMSO
DMSO
DMSO
2
.
d
PivONa H O
2
.
e
Pd(OAc)
Pd(OAc)2
2
P(Cy)
P(Cy)3
3
PivONa H
2
O
PivOH, TBAB
.
f
2
a
PivONa H O
PivOH, TBAI
2
All reactions were carried out under 5 mol% catalyst loading, 20 mol% ligand loading, 3 equiv of base, 2 equiv of additive at
0 C, and at the atmosphere of 0.4 MPa CO if not noted otherwise.
Isolated yields.
At 80 C.
0 mol% of tetrabutylammonium bromide.
0 mol% of tetrabutylammonium bromide.
0 mol% of tetrabutylammonium bromide iodide.
ꢀ
9
b
c
d
e
f
ꢀ
1
5
1
2
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J. Chin. Chem. Soc. 2017

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Palladium-Catalyzed Heterocycles Synthesis
Table 2. Expansion of palladium-catalyzed reaction to form
xanthones
activation of an ortho aromatic C–H with the assistance
of PivO , leading to the intermediate IV. Reductive
−
elimination from IV finally affords the xanthone, with
the regeneration of Pd for the next catalytic cycle.
In conclusion, we have developed a Pd-catalyzed
intramolecular carbonylation/C–H activation of 2-iodo
diaryl ether for the synthesis of substituted xanthones.
Obviously, this method has several unique merits, such
as the stability of the substrates, cost effectiveness, and
acceptable yields. Thus, we believe that this methodol-
ogy will not only be a practical alternative to existing
procedures for the synthesis of bioactive xanthones but
also extend the application of palladium-catalyzed het-
erocycles formation.
Yield
(%)
Entry Reactant
Product
1
2
1
2
1
2
3
4
5
6
7
8
R =R =H, 1a
R =R =H, 2a
70
1
2
1
2
R =H, R =Me, 1b
R =H, R =OMe, 1c
R =H, R =t-Bu, 1d
R =Me, R =H, 1e
R =Me, R =OMe, 1f R =Me, R =OMe, 2f
R =Me, R =t-Bu, 1g R =Me, R =t-Bu, 2g
R =Me, R =Cl, 1h
R =H, R =Me, 2b
67
70
65
69
70
71
35
1
2
1
2
R =H, R =OMe, 2c
1
2
1
2
R =H, R =t-Bu, 2d
1
2
1
2
R =Me, R =H, 2b
1
2
1
2
1
2
1
2
1
2
1
2
R =Me, R =Cl, 1h
neutral (Table 2, entries 1–3, 5) or electron-rich
Table 2, entry 4) entities were good substrates for this
(
reaction, providing the desired xanthone in good yields.
But if the R was electron-deficient (Table 2, entry 6),
EXPERIMENTAL
2
Unless otherwise stated, all the solvents and
reagents were purchased from commercial sources and
the yield was not satisfactory. All the products obtained
in the reactions listed in Table 2 were easily character-
ized on the basis of their physical and spectral data and
also by comparison with authentic samples.
As to the cyclization mechanism, it may be
assumed that the cyclization reaction proceeds through
the initial oxidative addition leading to the intermediate
I (Scheme 2). Subsequently, chelation of CO and migra-
tion of intermediate II take place. Then Pd promotes
1
13
used directly. H-NMR and C-NMR spectra were
recorded in CDCl or DMSO-d at room temperature
3
6
on a Bruker NMR spectrometer (DRX 500) if not
noted otherwise. The chemical shifts scale is based on
internal TMS, and the coupling constants (J) are
reported in hertz (Hz). Standard flash chromatography
was employed to purify the crude reaction mixture
using 200–300 mesh silica gel (Tsingdao Ocean Com-
pany, Tsingdao, China) under a positive nitrogen
pressure.
Typical synthetic procedure: An autoclave was
charged with ortho-iodo diaryl ether (1 mmol),
Pd(OAc)2 (12 mg, 0.05 mmol), P(Cy)3 (56 mg,
.
0
.2 mmol), PivONa H O (280 mg, 2 mmol), PivOH
2
(10 mg, 0.1 mmol) and 3 mL DMSO. The atmosphere
in the autoclave was exchanged by CO five times, and
CO was charged at the pressure of 0.4 MPa. Then the
ꢀ
autoclave was heated to 90 C and maintained at this
temperature for 5 h. Then the reaction mixture was
diluted by ethyl acetate (30 mL), and the organic layer
was washed by saturated aqueous NaHCO and brine
3
and dried with anhydrous MgSO . The solvent was eva-
4
porated under vacuum and the residue was purified
through column chromatography to give different
xanthones (Table 2).
ꢀ
1
9
H-Xanthen-9-one (2a): mp 176–178 C. H NMR
(
400 MHz, CDCl ) δ = 8.36 (dd, J = 8.0, 1.7 Hz, 2H),
3
7
.74 (ddd, J = 8.7, 7.1, 1.7 Hz, 2H), 7.51 (dd, J = 8.4,
Scheme 2. Proposed mechanism of the palladium-
catalyzed reaction to form xanthones.
13
0.5 Hz, 2H), 7.48–7.34 (m, 2H). C NMR (100 MHz,
J. Chin. Chem. Soc. 2017
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3

Article
Ma et al.
CDCl3) δ = 177.2, 156.1, 134.7, 126.6, 124.2,
(d, J = 8.9 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 2.51 (s,
13
1
21.8, 117.9.
-Methyl-9H-xanthen-9-one (2b): mp 122–124 C.
H NMR (400 MHz, CDCl ) δ = 8.35 (dd, J = 8.0,
3H). C NMR (125 MHz, CDCl ) δ = 176.18, 154.52,
3
ꢀ
2
154.32, 136.45, 134.73, 134.16, 129.51, 126.09, 126.04,
122.67, 121.11, 119.72, 117.81, 20.85.
1
3
1
.5 Hz, 1H), 8.13 (dd, J = 1.4, 0.4 Hz, 1H), 7.72 (ddd,
J = 8.7, 7.1, 1.7 Hz, 1H), 7.58–7.52 (m, 1H), 7.49 (dd,
J = 8.5, 0.6 Hz, 1H), 7.42–7.36 (m, 2H), 2.48 (s, 3H).
ACKNOWLEDGMENTS
This work was supported by the National Natural
Science Foundation of China (31301712, 31270388). Z.-
D. would like to thank the Opening Funds of Key Lab-
oratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, for generous financial support.
1
3
C NMR (100 MHz, CDCl ) δ = 177.2, 156.4, 154.6,
3
1
1
36.0, 135.0, 134.0, 127.0, 125.9, 124.0, 121.8, 121.6,
18.0, 117.8, 20.9.
ꢀ
2
-Methoxy-9H-xanthen-9-one (2c): mp 131–133 C.
1
H
NMR (400 MHz, CDCl3): δ = 8.36 (dd,
J = 8.0 Hz, 1.6 Hz, 1H), 7.75–7.71 (m, 2H), 7.50 (d,
J = 8.4 Hz, 1H), 7.45 (d, J = 9.2 Hz, 1H), 7.40–7.33
1
3
(m, 2H), 3.93 (s, 3H). C NMR (100 MHz, CDCl ): δ
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