Palladium-copper catalyzed C(sp3)-C(sp2) bond C-H activation cross-coupling reaction: Selective arylation to synthesize 9-aryl-9: H -xanthene and 9,9-diaryl-xanthene derivatives

Article abstract of DOI:10.1039/c6ra17546e

A novel cooperatively catalyzed C(sp³)-C(sp²) bond C-H activation cross-coupling reaction has been developed. A series of 9-aryl-9H-xanthenes and 9,9-diaryl-xanthenes were selectively synthesized in moderate to good yields by control

Full text of DOI:10.1039/c6ra17546e

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DOI: 10.1039/C6RA17546E
Journal Name
COMMUNICATION
Palladium-Copper Catalyzed C(sp3)-C(sp2) Bond C-H Activation
Cross-Coupling Reaction: Selective Arylation to Synthesis 9-Aryl-
9H-Xanthene and 9,9-Diaryl-Xanthene Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Guodong Shen,* Lingyu Zhao, Yichen Wang, Wenfang Xia, Mingsen Yang and Tongxin Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel and efficient palladium-copper cooperatively catalyzed
C(sp3)-C(sp2) bond C-H activation cross-coupling reaction has been xanthene, a lot of methodologies for synthesizing xanthene
developed. series of 9-aryl-9H-xanthenes and 9,9-diaryl- derivatives have been investigated, especially some methods
Based on the broad spectrum of applications of the
A
xanthenes are selectively synthesized in moderate to good yields to synthesis of 9-substituted xanthenes. Using scandium
by controlling the reaction time and temperature by applying this triflate-catalyzed one-pot domino approach11 and Brønsted
palladium-copper co-catalysts.
acid (TfOH or MsOH) catalyzed oxidative coupling reactions12
are some of good examples. However, these methods are not
able to provide effective ways to selectively synthesize 9-aryl-
9H-xanthenes and 9,9-diaryl-xanthenes.
Xanthene derivatives are an important class of molecules and
heterocyclic scaffolds in biological, medicinal and food areas.1
For example (Figure 1), Erythrosine (A), known as Red No. 3, is
primarily used for food coloring, commonly used in sweets.2
Mangostin (B) has exhibited excellent biological properties
including antioxidant,3 anti-bacterial,4 anti-inflammatory5 and
anticancer activities.6 Uridine derivative (C) is antiarrhythmic
Palladium and copper catalyzed C-H activation and cross-
coupling (sp2-C and sp3-C) reactions are of paramount
importance in the synthesis of organic molecules.12 Numerous
C-H activation and cross-coupling systems,13 especially the
cooperative palladium-copper co-catalysed systems14 have
been applied in the preparation of pharmaceuticals,
agrochemicals and advanced materials on both laboratory and
industrial scales. In the past decades, palladium and copper
catalyzed C-X (X = C, N, O, S, etc.) bond formation reactions
have drawn considerable attention for their efficiency.15
However, there is rare report about the versatile and selective
synthesis of 9-aryl-9H-xanthenes and 9,9-diaryl-xanthenes
using the metal catalyzed cross-coupling reaction.16 Herein, as
a part of our effort, we report an efficient method for the
synthesis of 9-aryl-9H- and 9, 9-diaryl-xanthene derivatives via
the palladium-copper co-catalyzed C(sp3)-C(sp2) bond cross-
coupling reaction in high selectivity by controlling the reaction
time and temperature.
agent7 and also can be used to treat
a number of
supraventricular tachycardia that do not improve with vagal
maneuvers.8 Adenosine derivative (D) can be used for the
treatment of liver, cerebrovascular, cardiovascular and other
diseases.9 Furthermore, some xanthenes have been used as
dyes, fluorescent materials and laser technologies for their
useful spectroscopic properties.10
ONa
OH
O
O
O
I
I
OCH3
OH
NaO
O
O
HO
I
I
Erythrosine (A)
Mangostin (B)
MeO
NC
O
N
N
N
O
N
O
N
P
O
O
Table 1 Optimization of the Reaction Conditionsa
O
O
O
N
MeO
O
OMe
N
O
N
N
O
O
O
OMe
O
O
O
OMe
O
O
Catalyst, T
O
O
Atmosphere,t
Uridine derivate (C)
Adenosine derivate (D)
MeO
OMe
Fig. 1 Some useful xanthene derivatives.
1a
1b
OMe
1c
1d
1c
(%)b
1d
(%)b
0
Entry
Catalyst
T(oC)
t(h)
1
2
3
Cu(OTf)2
Cu(OTf)2
Pd(OAc)2
N2
N2
N2
140
150
140
15
15
15
5
6
0
4
0
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Pd(OAc)2
4
N2
N2
N2
Air
Air
130
140
130
130
120
15
15
25
21
35
85
40
5
11
/Cu(OTf)2
Pd(OAc)2
5
/Cu(OTf)2
Pd(OAc)2
6
2.5
2.5
2.5
trace
trace
0
/Cu(OTf)2
Pd(OAc)2
7
/Cu(OTf)2
Pd(OAc)2
8
/Cu(OTf)2
9
Pd(OAc)2
Cu(OTf)2
Pd(OAc)2
/Cu(OTf)2
Pd(OAc)2
/TfOH
Air
Air
130
130
2.5
2.5
13
41
0
0
10
34c
10
<1
80
45
0
0
0
Fig. 2 X-ray Crystallographic Structure of 1d
.
11
12
13
14
15
16
17
O2
Air
Air
Air
Air
Air
Air
130
130
145
130
130
130
130
2.5
2.5
24
lower temperature (120 °C) and using either Pd(OAc)2 or
Cu(OTf)2 alone decreased the reaction yield obviously (Table 1,
entries 8-10). We also conducted the reaction under oxygen
balloon and found that the xanthene can be oxidized to the
xanthone (Table 1, entry 11). We used TfOH instead of
Cu(OTf)2 and the reaction gave the low yield (Table 1, entry 12).
To our delight, when the reaction temperature was raised to
145 oC and the reaction time was extended to 24 h, 1d was
obtained in 80% yield (Table 1, entry 13). Some other
palladium and copper salts such as PdCl2, Pd(dppf)Cl2,
Pd(OAc)2
/Cu(OTf)2
PdCl2
80
5
2.5
2.5
2.5
2.5
/Cu(OTf)2
Pd(dppf)Cl2
/Cu(OTf)2
Pd(OAc)2
/Cu(OAc)2
Pd(OAc)2
/CuI
trace
0
.
Cu(OAc)2 H2O and CuI were also studied (Table 1, entries 14-
17), the catalyst system of Pd(OAc)2 and Cu(OTf)2 provided the
best result. We also carried out some control experiments for
the second arylation to synthesis of 9,9-diaryl-xanthenes, from
the result we can see the Pd/Cu co-catalysts still important for
the reaction (Table 1, entries 18-20). Obviously, the entries 7
and 13 are the best conditions.
0
0
18
19
Pd(OAc)2
Cu(OTf)2
Pd(OAc)2
/Cu(OTf)2
Air
Air
145
145
24
24
<5
<5
0
0
20
N2
145
24
24
15
With the optimized conditions in hand, the scope of
substrates was further investigated (Table 2). From the
experimental results we could conclude that the reaction
yields were mainly influenced by the electronic effect and
a
Reaction conditions: Pd catalyst (0.025 mmol), Cu catalyst
(0.05 mmol), xanthene 1a (0.5 mmol) in anisole (1.5 mL)
under N2/air/O2 atmosphere.
b Isolated yield after flash chromatography based on 1a
c 35% of xanthone was isolated based on 1a
steric hindrance of aromatics b. The aromatics b must have the
.
electron-donating groups such as -OMe, -OH, -SMe, -NH2 etc.
The reaction time for mono- and bis-arylation is mainly
determined by the TLC detection, when the starting material
was consumed completely, then the reaction was stopped,
and the best yield was got. The reactions of xanthene 1a with
anisole 1b, ethoxybenzene 2b, oxydibenzene 3b or 1, 2-
dimethoxybenzene 4b could generate mono-substituted
.
Initially, xanthene 1a and anisole 1b were selected as the
model substrates to identify and optimize the reaction
parameters including transition metal catalysts, reaction
temperature and reaction time. When the reaction was carried
o
out with Cu(OTf)2 (10 mol%) under N2 atmosphere at 140 C,
the desired 9-(4-methoxyphenyl)-9H-xanthene 1c could be
detected in 5% yield after 15 hours (Table 1, entry 1). Raising
the reaction temperature (150 °C) did not improve the yield of
the desired compounds (Table 1, entry 2). Only using Pd(OAc)2
to repeat this reaction did not generate the good yield either
(Table 1, entry 3). After extensive studies we found that the
yield of 1c could be improved significantly by using the co-
catalyst system of Pd(OAc)2 and Cu(OTf)2. A new compound 1d
was observed at the same time using this co-catalyst system
xanthenes (1c
2d 3d and 4d) selectively by controlling the reaction time and
temperature. However, when 1-methoxy-2-methylbenzene 5b
1-bromo-2-methoxybenzene 6b and methyl(phenyl)sulfane 7b
were used, the yields of 5c 6c and 7c were not high, increasing
, 2c, 3c and 4c) or di-substituted xanthenes (1d,
,
,
,
the reaction temperature and extending the reaction time
could not improve the yield obviously. Phenol 8b was used to
run the reaction at 130 oC for 2.5 h, we did not detect the
(Table 1, entries 4-5). The structure of 1d was unambiguously product 4-(9H-xanthen-9-yl)phenol 8c by TLC, but 4,4'-(9H-
xanthene-9,9-diyl)diphenol 8d was afforded at 140oC for 24 h
elucidated by X-ray crystallography (Figure 2). When we
reduced the reaction time to 2.5 hours, only compound 1c was
obtained in high selectivity (Table 1, entry 6). Further extensive
study was made to improve the reaction yield after we
reached the good selectivity. We finally found that the
reaction yield was greatly improved if the reaction was carried
out in the open air (Table 1, entry 7). However, the reaction at
continually (for crystal structure of 8d, see Supporting
Information). Aniline 9b and o-toluidine 10b could proceed the
reaction and the anticipated products 9c and 10c were
obtained. Because of the steric hindrance of 1,3,5-
trimethoxybenzene 11b, we could not obtain bis-substituted
2 | J. Name., 2012, 00, 1-3
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a
Reaction conditions: Palladium acetate (0.025 mmol),
Copper(II) trifluoromethanesulfonate (0.05 mmol), xanthenes
Table 2 Scope of the Palladium-Copper Catalyzed C(sp3)-C(sp2)
Bond Cross-Coupling Reactiona,b
O
a
(0.5 mmol) in aromatics
b as solvent (1.5 mL).
O
R4
b Isolated yield after flash chromatography based on
a.
R1
R2
or
R3
O
R1
R2
Pd(OAc)2/Cu(OTf)2
2.5-24h, 130-145oC
R4
R3
c 0.5g
b was added.
R4
R1
R2
d No product was detected by TLC.
e A seal tube was used.
R4
R3
R3
a
c
d
b
products. The substituted-xanthene derivatives bearing -COPh
and -COMe groups were able to react with anisole 1b to afford
the corresponding products in moderate yields (12c, 12d, 13c,
and 13d). Benzene 12b and toluend 13b could not proceed the
reaction. Benzonitrile 14b and nitrobenzene 15b with electron
poor functional groups were not detected the corresponding
products. Furthermore, our method can also be successfully
applied to synthesize the 9,9-diaryl-xanthenes with different
aromatic functional groups. As shown in Table 3, the reaction
2c, 75%
4 h (2.5h,
1c, 85%
2.5 h, 130oC
1d, 80%
17 h, 145oC
2d, 66%
17 h, 145oC
61%), 130oC
of 9-aryl-9H-xanthenes
c
with aromatics
b could afford the
anticipated 9,9-diaryl-xanthenes
d
in moderate yields (Table 3,
3c, 60%
6 h, 130oC
3d, 55%
24 h, 145oC
4c, 71%
5 h, 130oC
4d, 65% c
entries 1-5). The yields for the 3,4-di-(differently)-substituted
xanthenes were not high and it may due to the formation of
isomers.
17 h, 145oC
9H-Fluorene 4a also can reacted with anisole 1b under the
reaction condition, but only bis-substituted products 9,9-bis(4-
methoxyphenyl)-9H-fluorene 17d was isolated in 51% yield
(Scheme 1).
5c, 32%
10 h, 130oC
6c, 25%
18 h, 145oC
7c, 32%
24 h, 145oC
8c, /c,d
2.5 h, 130oC
Table 3 Palladium-Copper Catalyzed C(sp3)-C(sp2) Bond Cross-
Coupling Reaction of 9-Aryl-9H-Xanthenes
Anilino Substratesa
c
with Phenoxy or
8d, 76%c
9c, 35%
5h, 140oC
9d, 55%
24h, 140oC
10c, 34%
15 h, 140oC
24h, 140oC
Yield
(%)b
Entry
1
c
b
Product
O
1c
1b
62
10d, 61%
36 h, 140oC
11c, 45%c
12c, 85%
5.5 h, 130oC
12d, 75%
17 h, 145oC
3 h, 130oC
MeO
OMe
1d
2
3
4
5
1c
1c
1c
2b
3b
8b
48
55
52
14d
15d
16d
d,e
15c,
/
d,e
14c, /
2.5 h, 130oC
13c, 66%
3 h, 130oC
13d, 61%
17 h, 145oC
2.5 h (10 h),
130oC
d
/
2c
8b
40
17c,
d
/
16c,
2.5 h (10 h),
130oC
17d
1d+2d+14d
2.5 h, 130oC
6
1a
1b+2bc
53(3:2:4)
a
Reaction conditions: Palladium acetate (0.025 mmol),
Copper(II) trifluoromethanesulfonate (0.05 mmol), 9-(4-
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methoxyphenyl)-9H-xanthene 1c (0.5 mmol) in aromatics
b
Notes and references
(1.5 mL) as solvent for 17 h under air.
b Isolated yield after flash chromatography based on
c.
c 0.5 mL 1b and 0.5 mL 2b was used.
1
(a) K. D. Sajal, S. Ritesh and P. Gautam, Eur. J. Org. Chem.
2009, 4757; (b) G. Saint-Ruf, H. T. Hieu and J. P. Poupelin,
Naturwissenschaften. 1975, 62, 584; (c) N. P. Buu-Hoi, G.
Saint-Ruf, A. De and H. T. Hieu, Bull. Chim. Ther. 1972, 7, 83;
(d) R. M. Ion, Prog.Catal. 1997, 2, 55; (e) R. M. Ion, D.
OMe
Frackowiak, A. Planner and K. Wiktorowicz, Acta Biochim. Pol.
1998, 45, 833.
Pd(OAc)2/Cu(OTf)2
36h, 150oC
2
(a) A. S. Jennings, S. L. Schwartz, N. J. Balter, D. Gardner and
R. J. Witorsch, Toxicology and Applied Pharmacology. 1990,
103, 549; (b) G. H. Y. Lin and D. J. Brusick, Mutagenesis. 1986,
MeO
OMe
OMe
4a
1b
18d 51%
18c not detected
1
, 253.
Scheme 1 Reaction of 9H-fluorene 4a with anisole 1b
.
3
H. Jung, B. Su, W. Keller, R. Mehta and A. Kinghorn, J. Agric.
Food Chem. 2006, 54, 2077.
4
5
T. Hideo, Jpn. Tokkyo Koho, 1981, JP 56005480.
J. P. Poupelin, G. Saint-Ruf, O. Foussard-Blanpin, G. Narcisse,
G. Uchida-Ernouf and R. Lacroix, Eur. J. Med. Chem. 1978, 13
67.
,
6
7
8
9
D. Shankaranarayan, C. Gopalakrishnan and L. Kameswaran,
Arch Int Pharmacodyn Ther. 1979, 239, 257.
T. Hiroshi, M. Masayuki, F. Tetsuya, S. Mitsuo and H. Tsujiaki,
Nucleic Acids Research. 1989, 17, 8135.
T. Hiroshi, F. Tetsuya, S. Mitsuo, H. Tsujiaki, E. J. William and
Z. Gerald, Tetrahedron Lett. 1988, 29, 577.
(a) H. Tsujiaki, I. Masahide, M. Mitsuo and M. Katsuhiro, Eur.
Pat. Appl. 1994, EP 617046 A1 19940928; (b) O. Tsuneya, T.
Masaki, H. Tsujiaki and I. Masahide, Eur. Pat. Appl. 1994,
EP 624372 A2 19941117.
10 (a) S. M. Menchen, S. C. Benson, J. Y. L. Lam, W. Zhen, D. Sun,
B. B. Rosenblum, S. H. Khan and M. Taing, U. S. Patent. 2003,
US6583168; (b) A. Banerjee and A. K. Mukherjee, Stain
Technol. 1981, 56, 83.
Fig. 3 Plausible mechanism of the reaction.
11 (a) S. K. Das, R. Singh, and G. Panda, Eur. J. Org. Chem. 2009,
4757; (b) R. Singh, and G. Panda, Org. Biomol. Chem. 2010, 8,
1097.
In the process of our experiment, xanthone was isolated in
low yield under the optimal condition (Table 1, entry 7). To
gain some insight of the reaction mechanism we used the
xanthone to run the reaction and product 1c was not
detected.17 Therefore, we speculate that the reaction did not
proceed the intermediate of xanthone. Then a plausible
mechanism which accounts for the palladium-copper
cooperatively catalyzed C(sp3)-C(sp2) coupling reaction is
shown in Figure 3. Firstly, aromatics bearing electron-donating
functional groups and xanthenes can be reacted with the
metal catalyst Cu(OTf)2 and Pd(OAc)2 respectively.18 The
12 (a) X. F. Wu, H. Neumann and M. Beller, Chem. Rev. 2013,
113, 1; (b) A. PintEr, A. Sud, D. Sureshkumar and M.
Klussmann, Angew. Chem. Int. Ed. 2010, 49, 5004; (c) B.
Schweitzer-Chaput, A. Sud, A. PintEr, S. Dehn, P. Schulze and
M. Klussmann, Angew. Chem. Int. Ed. 2013, 52, 13228; (d) A.
PintEr and M. Klussmann, Adv. Synth. Catal. 2012, 354, 701.
(e) J. M. Curto and M. C. Kozlowski, J. Am. Chem. Soc. 2015,
131, 17; (f) X. Chen, C. E. Goodhue and J. Q. Yu, J. Am. Chem.
Soc. 2006, 128, 12634.
13 C. C. C. J. Seechurn, M. O. Kitching, T. J. Colacot and V.
Snieckus, Angew. Chem., Int. Ed. 2012, 51, 5062.
obtained intermediates
A
and
B
proceeded the cross-coupling
, which then translated to
14 (a) K. Semba and Y. Nakao, J. Am. Chem. Soc. 2014, 136, 7567;
(b) C. W. D. Gallop, M. T. Chen and O. Navarro, Org. let. 2014,
16, 3724; (c) K. Semba, K. Ariyama, H. Zheng, R. Kameyama, S.
Sakaki and Y. Nakao, Angew. Chem. Int. Ed. 2016, 55, 6275.
15 (a) G. Evano N., Blanchard and M. Toumi, Chem. Rev. 2008,
108, 3054; (b) F. Monnier and M. Taillefer, Angew. Chem. Int.
Ed. 2008, 47, 3096; (c) S. Matsumura, Y. Maeda, T. Nishimura
and S. Uemura, J. Am. Chem. Soc. 2003, 125, 8862; (d) S. H.
reaction to get the intermediate
C
the final product after the reductive elimination reaction.
In summary, we have developed a novel and efficient
palladium-copper cooperatively catalyzed C(sp3)-C(sp2) C-H
activation and cross-coupling reaction to synthesize 9-aryl-9H-
xanthene and 9,9-diaryl-xanthene derivatives which are very
important to chemical and pharmaceutical industry. The
newly-developed co-catalyst system demonstrated moderate
yield and good selectivity. We will use this protocol to expand
our further research to more aromatics with other functional
groups which might be potentially applicable in the
pharmaceutical and biochemical areas.
Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev. 2011, 40
5068.
16 (a) S. K. Das, R. Singh and G. Panda, Eur. J. Org. Chem. 2009,
,
4757; (b) R. Singh and G. Panda, Org. Biomol. Chem. 2010, 8,
1097.
17 S. R. Sheng, T. Li, J. W. Jiang, W. He and C. S. Song, Polym Int,
2010, 59, 1014.
18 S. J. Park, J. R. Price and M. H. Todd, J. Org. Chem., 2012, 77
949.
,
This work was financially supported by the National Natural
Science Foundation of China (No. 21402079) and the Shandong
Provincial Natural Science Foundation of China (ZR2015PB004).
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6RA17546E
Palladium-Copper Catalyzed C(sp3)-C(sp2) Bond C-H Activation
Cross-Coupling Reaction: Selective Arylation to Synthesis
9-Aryl-9H-Xanthene and 9,9-Diaryl-Xanthene Derivatives
Guodong Shen,* Lingyu Zhao, Yichen Wang, Wenfang Xia, Mingsen Yang, Tongxin
Zhang*
School of Chemistry and Chemical Engineering, School of Pharmacy, Liaocheng
University, Liaocheng 252000, Shandong, PR China
A novel and efficient palladium-copper cooperatively catalyzed C(sp3)-C(sp2) bond
C-H activation cross-coupling reaction has been developed. A series of
9-aryl-9H-xanthenes and 9,9-diaryl-xanthenes are selectively synthesized in moderate
to good yields by controlling the reaction time and temperature by applying this
palladium-copper co-catalysts.