Control of chemoselectivity by counteranions of cationic palladium complexes: A convenient enantioselective synthesis of dihydrocoumarins

Article abstract of DOI:10.1021/ol902538n

Chemical Equation Presented High chemoselectivity for the synthesis of two kinds of substituted coumarins controlled by the counteranions of the cationic palladium catalysts is described. The asymmetric version of the reaction for the synthesis of 3-alkylidene dihydrocoumarins is realized with high enantioselectivity

Full text of DOI:10.1021/ol902538n

ORGANIC
LETTERS
2010
Vol. 12, No. 1
108-111
Control of Chemoselectivity by
Counteranions of Cationic Palladium
Complexes: A Convenient
Enantioselective Synthesis of
Dihydrocoumarins
Xiuling Han and Xiyan Lu*
College of Chemistry, Chemical Engineering and Materials Science, Soochow
UniVersity, Suzhou 215123, China, and State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai, 200032, China
xylu@mail.sioc.ac.cn
Received November 2, 2009
ABSTRACT
High chemoselectivity for the synthesis of two kinds of substituted coumarins controlled by the counteranions of the cationic palladium
catalysts is described. The asymmetric version of the reaction for the synthesis of 3-alkylidene dihydrocoumarins is realized with high
enantioselectivity.
Transition-metal-catalyzed tandem reactions provide efficient
and powerful methods for the synthesis of carbo- and
heterocyclic molecules.1 Several examples of rhodium or
palladium complex catalyzed tandem reactions of arylboronic
acids and alkynals (or alkynones) to give hydroxy group
substituted five- or six-membered rings have been described.2
Recently, our group focused on exploiting reactions using
cationic palladium complexes to catalyze addition reactions
to carbon-heteroatom multiple bonds.2f,3 Inspired by the
results of the above reactions, 2-formylaryl but-2-ynoate and
arylboronic acids were chosen as the substrates to synthesize
coumarin derivatives. The coumarin moiety is an important
and central structural unit present in various biologically
(1) (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. Chem. ReV.
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2067. (d) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102,
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Lett. 2007, 9, 2947.
(3) (a) Liu, G.; Lu, X. J. Am. Chem. Soc. 2006, 128, 16504. (b) Zhao,
B.; Lu, X. Org. Lett. 2006, 8, 5987. (c) Dai, H.; Lu, X. Org. Lett. 2007, 9,
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Chem. 2007, 72, 9757
.
10.1021/ol902538n  2010 American Chemical Society
Published on Web 12/07/2009

active compounds and also widely used as an intermediate
in organic synthesis.4 Many works about the synthesis of
coumarins have been reported.5 Among them, only a few
examples were related to the synthesis of the optically active
coumarins.6 Herein, we report a mild and efficient way for
the synthesis of 3-substituted coumarins and optically active
3,4-dihydrocoumarins chemoselectively using cationic pal-
ladium complexes with different counteranions.
by selecting one of the two catalysts. The results were
summarized in Tables 2 and 3. The catalytic reaction worked
Table 2. Synthesis of Dihydrocoumarins 3 Catalyzed by 5a
In our initial investigation, alkynal 1a was used as a model
substrate in combination with PhB(OH)2 to examine the
effect of a variety of cationic palladium complexes as cata-
lysts. Catalysts Pd(CF3CO2)2/dppp and [(bpy)Pd+(µ-OH)]2-
(OTf-)23b,7 failed to give any products. When the cationic
palladium complexes with dppp as the ligand were used
as the catalysts, the reactions can proceed smoothly at
room temperature, affording the expected product dihy-
drocoumarin 3aa in excellent yields (Table 1, entries 1-3
entry
R
Ar
Ph (2a)
p-MeC6H4 (2b)
p-FC6H4 (2c)
p-ClC6H4 (2d)
p-iPrC6H4 (2e)
p-PhC6H4 (2f)
m-ClC6H4 (2g)
m-MeC6H4 (2h)
ꢀ-naphthyl (2i)
time (min)
3
yield (%)b
1
2
3
4
5
6
7
8
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
15
30
40
30
120
50
10
50
40
30
40
25
70
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3ba
3ca
3da
3ea
98
83
91
97
83
92
99
93
99
98
99
96
81
9
Table 1. Effect of Catalysts in the Reaction of 1a and
10
11
12
4-Me (1b) Ph (2a)
4-Cl (1c) Ph (2a)
4-Br (1d) Ph (2a)
Phenylboronic Acida
13c (1e)d
Ph (2a)
a Reaction conditions: 1 (0.15 mmol), ArB(OH)2 (2, 0.18 mmol, 1.2
equiv), and catalyst (5, 2 mol %) were stirred in dioxane (3 mL) at room
temperature. b Isolated yield. c 1 mol % of the catalyst was used. d The
substrate 1e was 1-formyl-ꢀ-naphthyl but-2′-ynoate.
yield (%)b
entry
catalyst
time (h)
3aa
4aa
well with a variety of arylboronic acids and 2-formylaryl
but-2-ynoates. In the reaction catalyzed by 5, 3-alkylidene-
dihydrocoumarins 3aa-3ea can be obtained in good yields
within 15-120 min at room temperature (Table 2). The
stereochemistry of the exocyclic double bond was assigned
1
5
5
5
6
6
6
6
6
0.33
0.25
60
0.5
40
40
60
72
98
98
96
trace
93
61
40
trace
0
0
2c
3c
4
trace
0
trace
trace
45
5
6c
7
8
75
a Reaction conditions: 1a (0.15 mmol), PhB(OH)2 (2a, 0.18 mmol, 1.2
equiv), and catalyst (2 mol %) were stirred in the solvent (3 mL, dioxane/
H2O ) 150/1) at room temperature. b Isolated yield. c The solvent was
dioxane.
Table 3. Synthesis of 4 Catalyzed by 6a
and 5). It is surprising that the counteranions of the two
cationic palladium complexes have great influence on the
reactivity and chemoselectivity. The reaction catalyzed by
[Pd(dppp)(H2O)2]2+(BF4-)2 (5)8 was completed within a
much shorter time and was not influenced by the addition
of a small amount of water as compared with that of
[Pd(dppp)(H2O)2]2+(OTf-)2 (6)9 (Table 1, compare entries
1 and 2 with 4-6). Another important difference in
chemoselectivity between these two catalysts lies in that
6 can lead to the isomerization of 3aa to coumarin 4aa at
room temperature with prolonged time (Table 1, entries
7 and 8), but 5 cannot (Table 1, entry 3).
entry
R
Ar
Ph (2a)
p-MeC6H4 (2b)
p-FC6H4 (2c)
p-PhC6H4 (2f)
m-MeC6H4 (2h)
ꢀ-naphthyl (2i)
p-MeOC6H4 (2j)
time (h)
4
yield (%)b
1
2
3
4
5
6
7
8
9c
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
72
72
69
120
64
33
4aa
4ab
4ac
4af
4ah
4ai
75
74
70
73
64
89
86
88
56
60
74
63
42
4aj
4-Me (1b) Ph (2a)
4-Cl (1c)
120
120
120
70
4ba
4ca
4da
4ea
4fa
Ph (2a)
Ph (2a)
Ph (2a)
10c 4-Br (1d)
11
12
(1e)d
Thus, 3-alkylidenedihydrocoumarins (3) or 3-substituted
coumarins (4) can be synthesized from the same substrates
6-MeO (1f) Ph (2a)
88
a Reaction conditions: 1 (0.15 mmol), ArB(OH)2 (2, 0.18 mmol, 1.2
equiv), and catalyst (2 mol %) were stirred in the solvent (3 mL, dioxane/
H2O ) 150/1) at room temperature. b Isolated yield. c The reaction
temperature was 40 °C. d The substrate 1e was 1-formyl-ꢀ-naphthyl
but-2′-ynoate.
(4) (a) O’Kennedy, R.; Thornes, R. D. Coumarins: Biology, Applications
and Mode of Action; Wiley & Sons: Chichester, UK, 1997. (b) Yu, D.;
Suzuki, M.; Xie, L.; Morris-Natschke, S. L.; Lee, K.-H. Med. Res. ReV.
2003, 23, 322.
Org. Lett., Vol. 12, No. 1, 2010
109

as (E)-configuration based on X-ray crystallography of
product 3ab. On the other hand, 3-substituted coumarins
4aa-4fa (the structure of 4aa was confirmed by X-ray
crystallography) can also be obtained in moderate to good
yields under the catalysis of 6 within a longer time (33-120
h, Table 3).
Table 4. Enantioselective Synthesis of 3 Catalyzed by 7a
Subsequently, the asymmetric version of this cyclization
reaction was studied. We first tried to test the reaction by
using chiral bisphosphines as ligands. To simplify the
experimental procedure, Pd(CH3CN)4(BF4)2 (2 mol %)/
ligand (2.2 mol %) was used to perform the asymmetric
reactions for substrates 1a and PhB(OH)2. To our delight,
in the presence of Pd(CH3CN)4(BF4)2 and (S,S)-bdpp,
dihydrocoumarin 3aa can be afforded in moderate yield
with 93% ee value despite that most of the ligands ((R)-
binap, (S)-S1 and (S)-S2 as shown in Figure 1) tried were
entry
1
2
time (min)
3
yield (%)b
ee (%)c
1d
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
1080
20
25
20
400
80
25
40
60
40
3aa
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
65
99
99
88
76
94
99
99
93
99
75
97
96
66
93 (+)
95 (+)
95 (+)
94 (+)
87 (+)
99 (+)
96 (+)
95 (+)
94 (+)
93 (-)
91 (+)
95 (+)
95 (+)
92 (+)
2a
2a
2a
2a
40
50
30
50
3ba
3ca
3da
3ea
a The reaction conditions were similar to Table 2. b Isolated yield. c The
ee values were determined by chiral HPLC. The sign of optical rotation
was indicated in parentheses (for details see Supporting Information). d The
catalyst was Pd(CH3CN)4(BF4)2 (2 mol %)/(S,S)-bdpp (2.2 mol %).
Figure 1. Chiral ligands used.
dihydrocoumarins 3 were synthesized in excellent yields with
high enantioselectivity. The results were shown in Table 4.
Then we focused our efforts on establishing optimal
conditions for the enantioselective formation of coumarin
4aa. Similarly, Pd(OTf)2·2H2O/ligand was chosen as the
catalyst to test the reactions. Unfortunately, all of the chiral
bisphosphines including (R)-binap and those listed in Figure
1 were not suitable, giving the product in very low yield
with no enantioselectivity.
ineffective. However, the time (18 h; Table 4, entry 1)
required for this catalytic asymmetric reaction was much
longer than that catalyzed by 5 (15 min, Table 2, entry
1).
It was regarded that this time difference might be due to
the two different types of catalysts (the presence or absence
of CH3CN). Thus, the catalyst [Pd(S,S-bdpp)(H2O)2]2+(BF4-)2
(7) which has the similar structure with 5 was synthesized
to perform the reaction again. It is exciting that the
cyclization reaction was completed only in 20 min to give
the product with good yield and high enantioselectivity at
room temperature (99% yield, 95% ee, Table 4, entry 2).
Under these mild conditions, a series of optically active
Next, a reaction using 1a and 2-formylphenylboronic acid
(2k) as the substrates was conducted in the presence of 2
-
mol % of [Pd(dppp)(H2O)2]2+(BF4 )2. The expected product
3ak was not obtained, but a substituted indenol 3ak′ was
produced similar to our reported work3e (Scheme 1). This
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Lett. 2006, 8, 2703. (f) Rao, H. S. P.; Sivakumar, S. J. Org. Chem. 2006,
71, 8715. (g) Gu, Y.; Zhang, J.; Duan, Z.; Deng, Y. AdV. Synth. Catal.
2005, 347, 512. (h) Li, K.; Foresee, L. N.; Tunge, J. A. J. Org. Chem.
2005, 70, 2881. (i) Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary,
A.; Khavasi, H. R. Org. Lett. 2008, 10, 2581. (j) Piao, C.-R.; Zhao, Y.-L.;
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Scheme 1. Reaction of 1a and 2k
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3509.
means that the vinylpalladium in the intermediate generated
from carbopalladation of the alkyne in 1a predominantly adds
to the formyl group of 2k to form an indenol. The structure
of 3ak′ was confirmed by X-ray crystallography.
(8) For the preparation of complex 5, see Supporting Information.
(9) Stang, P. J.; Cao, D. H.; Poulter, G. T.; Arif, A. M. Organometallics
1995, 14, 1110.
110
Org. Lett., Vol. 12, No. 1, 2010

A plausible mechanism for this tandem reaction under the
The reason for the difference in reactivity of these two
cationic complexes (5 and 6) is not clear. Several papers
reported that the difference in reactivity of the similar cationic
complexes with these two counteranions is due to their
coordinating ability to the transition metals, and BF4- is less
coordinating than TfO-.12 Thus, catalyst 5 exhibits the more
vacant site for coordinating with the substrates, making the
reaction much easier to occur.
-
catalysis of [Pd(dppp)(H2O)2]2+(BF4 )2 (5) to produce di-
hydrocoumarins 3 is shown in Scheme 2, which involves
Scheme 2. Mechanism of the Formation of Dihydrocoumarins 3
In summary, we have developed a new cationic palladium
complex catalyzed cyclization reaction for the synthesis of
substituted coumarins under very mild conditions. It is worth
noting that counteranions in the catalysts have great influence
on the reactivity and chemoselectiviy. Two kinds of cou-
marins can be obtained selectively by utilizing catalysts with
different counteranions. The asymmetric version of the
reaction using (S,S)-bdpp as the ligand to yield 3-alkylidene-
dihydrocoumarins was successful with high enantioselectiv-
ity. Further studies on the selectivity of catalysts with
different counteranions are underway.
Acknowledgment. The National Basic Research Program
of China 2006CB806105 is acknowledged. We also thank
the National Natural Science Foundation of China (20732005,
20872158) and Chinese Academy of Sciences for financial
support.
the tandem reactions of transmetalation of arylboronic
acids with the palladium catalyst, carbopalladation of
alkynoates, and the addition of vinylpalladium species to
the aldehyde. In the case of using 6 as the catalyst, 3 may
be formed first in a similar way, followed by isomerizing
to coumarins 4 catalyzed by HOTf produced in situ from
[Pd(dppp)(H2O)2]2+(OTf-)2.10 Thus, product 3aa was
stirred in the presence of a catalytic amount of HOTf or
HBF4. It was found that HOTf can lead to the isomeriza-
tion of 3aa to 4aa in 6 h,11 but HBF4 cannot.
Supporting Information Available: Experimental pro-
cedures, characterization data copies of NMR spectra of new
compounds, HPLC data of optically active products, and CIF
files of compounds 3ab, 3ak′, and 4aa. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL902538N
(10) (a) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc.
2002, 124, 11240. (b) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem.
Soc. 1999, 121, 5450.
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Org. Lett., Vol. 12, No. 1, 2010
111