Highly regio- and stereoselective synthesis of indene and benzo[b]furan derivatives via a Pd-catalyzed carboannulation of propargyl carbonates with nucleophiles

Article abstract of DOI:10.1021/jo8002776

(Chemical Equation Presented) A new and efficient synthesis of indene and benzo[b]furan derivatives has been achieved via Pd-catalyzed carboannulation of propargyl carbonates with nucleophiles in good to excellent yields with high regio- and stereoselecti

Full text of DOI:10.1021/jo8002776

Highly Regio- and Stereoselective Synthesis of
Indene and Benzo[b]furan Derivatives via a
Pd-Catalyzed Carboannulation of Propargyl
Carbonates with Nucleophiles
Hai-Peng Bi,† Li-Na Guo,† Fa-Rong Gou,† Xin-Hua Duan,†
Xue-Yuan Liu,† and Yong-Min Liang*,†,‡
State Key Laboratory of Applied Organic Chemistry,
Lanzhou UniVersity, and State Key Laboratory of Solid
Lubrication, Lanzhou Institute of Chemical Physics,
Chinese Academy of Science,
Lanzhou 730000, People’s Republic of China
liangym@lzu.edu.cn
ReceiVed February 3, 2008
FIGURE 1. Palladium-catalyzed double addition of nucleophiles to
propargylic substrates.
intramolecular nucleophilic attack is prior to the intermolecular
reaction. In 2003, Yoshida et al. accomplished the cyclization
of 4-methoxycarbonyloxy-2-butyn-1-ols, but dihydrofuran and
epoxide were formed as the side products via a prior intermo-
lecular reaction (Figure 1c).5
A new and efficient synthesis of indene and benzo[b]furan
derivatives has been achieved via Pd-catalyzed carboannu-
lation of propargyl carbonates with nucleophiles in good to
excellent yields with high regio- and stereoselectivity. A
novel sequence of nucleophilic attack is observed, and a
possible mechanism is proposed.
Very recently, we have developed methods for the synthesis
of indene derivatives by carboannulation.4,6 Encouraged by
reported results,7 we herein report a novel Pd-catalyzed cy-
clization of propargyl carbonates with phenol nucleophiles for
the synthesis of indene derivatives with high regioselectivity.
In this process, intermolecular nucleophilic attack happened prior
to intramolecular reaction (Scheme 1).
SCHEME 1
The formation of carbon-carbon and carbon-heteroatom
bonds via Pd-catalyzed reactions of propargyl compounds with
nucleophiles has attracted much interest in the past a few
decades.1 The key step in these reactions is the formation of an
allenyl- or π-propargylpalladium complex (an equilibrium
process) by facile decarboxylation, which undergoes double
nucleophilic attack to form products. Recently, Yoshida2 and
Cacchi3 et al. reported Pd-catalyzed reactions of propargyl
carbonates with nucleophiles for the synthesis of substituted 2,3-
dihydrofurans, benzofurans, and functionalized indoles (Figure
1a). Very recently, we also reported a convenient method for
the preparation of indene derivatives via a regioselective
nucleophilic attack at different sites of propargyl carbonates
catalyzed by palladium (Figure 1b).4 In these processes,
Initially, we started our investigation of the reaction by using
1.0 equiv of propargyl carbonate (1a; 0.2 mmol) and 1.2 equiv
of phenol (2a) in the presence of 5 mol % of Pd2(dba)3 and 20
mol % dppf in THF under argon at 55 °C for 3 h; the desired
(4) (a) Duan, X.-H.; Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. Org.
Lett. 2006, 8, 5777. (b) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu, X.-Y.; Liang,
Y.-M. J. Org. Chem. 2007, 72, 1538.
(5) (a) Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am. Chem. Soc. 2003,
125, 4874. (b) Yoshida, M.; Ihara, M. Angew. Chem., Int. Ed. 2001, 40, 616.
(6) (a) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. J. Org.
Chem. 2006, 71, 3325. (b) Duan, X.-H.; Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang,
Y.-M. Org. Lett. 2006, 8, 3053. (c) Bi, H.-P.; Guo, L.-N.; Duan, X.-H.; Gou,
F.-R.; Huang, S.-H.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2007, 9, 397. (d) Bi,
H.-P.; Liu, X.-Y.; Gou, F.-R.; Guo, L.-N.; Duan, X.-H.; Liang, Y.-M. Org. Lett.
2007, 9, 3527. (e) Bi, H.-P.; Liu, X.-Y.; Gou, F.-R.; Guo, L.-N.; Duan, X.-H.;
Shu, X.-Z.; Liang, Y.-M. Angew. Chem., Int. Ed. 2007, 46, 7068. (f) Guo, L.-
N.; Duan, X.-H.; Liu, X.-Y.; Hu, J.; Bi, H.-P.; Liang, Y.-M. Org. Lett. 2007, 9,
5425.
† State Key Laboratory of Applied Organic Chemistry, Lanzhou University.
‡ State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical
Physics, Chinese Academy of Science.
(1) For reviews of Pd-catalyzed reactions of propargyl carbonates see: (a)
De Meijere, A., Diederich, F. Eds. Metal-Catalyzed Cross-Coupling Reactions;
Chapter 10; Wiley-VCH: New York, 2004. (b) Tsuji, J. Acc. Chem. Res. 1969,
2, 144. (c) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140. (d) Tsuji, J.
Tetrahedron 1986, 42, 4361. (e) Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2589.
(7) The π-propargylpalladium complex is formed in a more stable manner
in the presence of a bidentate ligand than in the presence of a monodentate
ligand, see: (a) Tsutsumi, K.; Ogoshi, S.; Nishiguchi, S.; Kurosawa, H. J. Am.
Chem. Soc. 1998, 120, 1938. (b) Tsutsumi, K.; Kawase, T.; Kakiuchi, K.; Ogoshi,
S.; Okada, Y.; Kurosawa, H. Bull. Chem. Soc. Jpn. 1999, 72, 2687.
(2) (a) Yoshida, M.; Morishita, Y.; Fujita, M.; Ihara, M. Tetrahedron Lett.
2004, 45, 1861. (b) Yoshida, M.; Morishita, Y.; Fujita, M.; Ihara, M. Tetrahedron
2005, 61, 4381.
(3) Ambrogio, I.; Cacchi, S.; Fabrizi, G. Org. Lett. 2006, 8, 2083.
10.1021/jo8002776 CCC: $40.75
Published on Web 05/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4713–4716 4713

TABLE 1. Optimization of the Pd-Catalyzed Cyclization of
Propargyl Carbonate 1a with Phenol 2aa
TABLE 2. Pd-Catalyzed Carboannulation of Propargyl
Compounds 1 with Various Phenols 2a
entry
1
ArOH (2)
R2 ) H
R2 ) 4-Me
3
time (h) yield of 3 (%)b
temp time yield of
entry
catalyst
solvent
base
(°C)
(h)
3a (%)b
1
2
3
4
5
6
7
8
9
1a, R1 ) CO2Et
1a, R1 ) CO2Et
1a, R1 ) CO2Et
1a, R1 ) CO2Et
1a, R1 ) CO2Et
1a, R1 ) CO2Et
1a, R1 ) CO2Et
1a, R1 ) CO2Et
1a, R1 ) CO2Et
3a
3b
3
3
3
3
3
3
3
3
3
3
3
3
4
4
3
91 (0)
90 (0)
85 (0)
83 (0)
86 (0)
80 (0)
76 (0)
55 (10)
0 (21)
75 (<2)
89 (0)
92 (0)
84 (0)
80 (0)
91 (0)
1
2
3
4
5
6
7
8
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd2(dba)3/dppe
Pd2(dba)3/ PPh3 THF
Pd2(dba)3
Pd(PPh3)4
THF
55
55
55
55
55
55
55
55
55
25
80
80
3
3
3
3
3
3
3
2
2
75 (6)
63 (10)
35 (48)
91 (0)
79 (0)
84 (0)
6 (78)
0 (70)
0 (76)
14 (8)
31 (54)
0 (11)
R2 ) 4-NO2 3c
toluene
DMF
THF
THF
THF
R2 ) 4-Ac
R2 ) 4-Ph
3d
3e
K2CO3
NEt3
R2 ) 4-CO2Et 3f
R2 ) 4-Br
R2 ) 2-Br
R2 ) 2-t-Bu
R-naphthol
ꢀ-naphthol
3g
3h
3i
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
THF
THF
THF
THF
10 1a, R1 ) CO2Et
11 1a, R1 ) CO2Et
3j
9
3k
3a
3a
3a
3a
10
11
12
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd(PPh3)4
10
4
4
12 1b, R1 ) CO2Me R2 ) H
13 1c, R1 ) COMe
14 1d, R1 ) COPh
R2 ) H
R2 ) H
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of
solvent under argon with 1.0 equiv of 1a, 1.2 equiv of 2a, 2.0 equiv of
base, and 0.05 equiv of [Pd]. b Isolated yields, and the numbers in
parentheses are the isolated yields of 4a.
15 1e, R1 ) PO(OEt)2 R2 ) H
a All reactions were carried out under the optimal conditions reported
in the text. b Isolated yields and the numbers in parentheses are the
isolated yields of 4a.
product 3a was obtained in 75% yield, and the byproduct 4a
was isolated in 6% yield (Table 1, entry 1). Changing the solvent
from THF to toluene or DMF did not improve the yield of 3a
nor the selectivity of the product (entries 2 and 3). To our
surprise, Using K2CO3 as a base led to a cleaner reaction,
affording the desired product 3a in 91% yield with none of the
side product 4a (entry 4). NEt3 was less effective (entry 5).
Other catalyst systems, such as Pd2(dba)3/dppe, Pd2(dba)3/PPh3,
Pd2(dba)3, and Pd(PPh3)4, were tested, and it was found that
the bidentate ligand is important for the selectivity of the two
indene products (entries 6-9).7 Lower or higher temperatures
were not beneficial to the reaction (entries 10 and 11). Reaction
conditions we have reported before4b were also attempt. But
only the byproduct 4a was obtained (entry 12). The optimum
reaction conditions thus far developed employ 1.0 equiv of 1a,
1.2 equiv of phenol, 5 mol % of Pd2(dba)3, 20 mol % of dppf,
and 2.0 equiv of K2CO3 in THF at 55 °C under argon.
To extend the general applicability of this carboannulation
reaction, the reaction of propargyl carbonate 1a with various
phenols was carried out under the above optimized conditions,
and the results are summarized in Table 2. Phenols bearing an
electron-donating group or an electron-withdrawing group in
the para position afforded the corresponding 1-substituted
indenes 3 as the sole products in moderate to high yields (entries
1-7). In addition, 2-bromophenol was also applicable and only
a very small amount of 4a was isolated (entry 8). However,
when 2-tert-butylphenol was used, only the byproduct was
obtained (entry 9). Meanwhile, the use of R-naphthol and
ꢀ-naphthol gave the corresponding products 3j and 3k in 75%
and 89% yields (entries 10 and 11). For phenols bearing an
ortho subsituent and R-naphthol, a moderate yield and the
byproduct 4a were obtained, which could be due to the steric
effects. We have also investigated the substrates 1, bearing
various leaving groups on the propargyl posotion, and the
reactions of propargyl carbonate 1b, propargyl acetate 1c,
propargyl benzoate 1d, and propargyl phosphate 1e with phenol
gave 3a as the sole products in moderate to high yields (entries
12-15). Bisphenols were then employed in this reaction under
SCHEME 2
the same conditions by using 0.2 mmol of 1a and 0.7 equiv of
2. For hydroquinone 2l and bisphenol 2m, the reaction
proceeded well in both substitution positions and afforded the
corresponding disubstituted products 3l and 3m in 81% and 76%
isolated yields, respectively. In these reactions, 4a was not
isolated (Scheme 2).
Interestingly, when 5a was subjected to the Pd-catalyzed
reaction, benzo[b]furan derivative 6a was obtained in a good
yield with high regio- and stereoselectivity (Table 3, entry
1). Similarily, R-naphthol and ꢀ-naphthol also gave the
products 6b and 6c in moderate yields (entries 2 and 3). The
reactants containing different groups in different positions
also gave the desired products in moderate yields (entries
4-7). In this process, the formation of the carbon-carbon
bond has proven to be an effective method for preparing
benzo[b]furan derivatives and only cis-fused benzo[b]furan
derivatives were obtained.
To clarify the mechanism of this process, we examined the
reaction of purified 4awith phenol (2a) and no reaction was
observed (Scheme 3). This result confirmed that the formation
of 3a was not attributed to addition of phenol to diethyl
1-vinylidene-1H-indene-2,2(3H)-dicarboxylate (4a).
The mechanism shown in Scheme 4 is proposed for this
process. It consists of the following key steps: (a) palladium(0)
reacted with the carbanion of propargyl carbonate 1 through
4714 J. Org. Chem. Vol. 73, No. 12, 2008

TABLE 3. Pd-Catalyzed Carboannulation of Propargylic Compounds 5 with Various Phenols 2a
entry
5
ArOH (2)
6
time (h)
yield of 6 (%)b
1
2
3
4
5
6
7
5a, R1 ) H, R2 ) H R3 ) Me
5a, R1 ) H, R2 ) H R3 ) Me
5a, R1 ) H, R2 ) H R3 ) Me
5b, R1 ) H, R2 ) Me R3 ) Me
5c, R1 ) H, R2 ) t-Bu R3 ) Me
5d, R1 ) H, R2 ) Cl R3 ) Me
5e, R1 ) 2,4-dimethyl, R2 ) Cl, R3 ) Et
R4 ) 4-Ac
R-naphthol
ꢀ-naphthol
R4 ) 4-Ac
R4 ) 4-Ac
R4 ) 4-Ac
R4 ) 4-Ac
6a
6b
6c
6d
6e
6f
4
4
4
4
4
4
4
75
70
68
64
71
58
61
6g
a All reactions were run under the following conditions, unless otherwise indicated: 0.20 mmol of 5, 1.2 equiv of 2, and 0.05 equiv of Pd(PPh3)4 in 2
mL of THF were stirred at 55 °C under argon for the specified period of time. b Isolated yields.
SCHEME 3
tramolecular reaction. It is noteworthy that the bidentate
ligand plays an important role in determining the stable
manner of intermediates and the sequence of intramolecular
and intermolecular nucleophilic attack for the synthesis of
indene derivatives.
SCHEME 4
Experimental Section
General Procedure for the Preparation of Indene Deri-
vatives 3. To a solution of propargylic compound 1a (0.20 mmol)
in THF (2.0 mL) was added phenols (0.24 mmol) and K2CO3 (55.2
mg, 0.40 mmol). The mixture was stirred for 1 min and Pd2(dba)3
(9.2 mg, 0.01 mmol, 5 mol %) and dppf (22.2 mg, 0.04 mmol, 20
mol %) were added. The resulting mixture was then heated under
an argon atmosphere at 55 °C. When the reaction was considered
complete as determined by TLC analysis, the reaction mixture was
allowed to cool to room temperature and quenched with a saturated
aqueous solution of ammonium chloride, then the mixture was
extracted with EtOAc. The combined organic extracts were washed
with water and saturated brine. The organic layers were dried over
Na2SO4 and filtered. Solvents were evaporated under reduced
pressure. The residue was purified by chromatography on silica
gel to afford indene derivatives 3.
3a. The reaction mixture was chromatographed with 40:1
hexanes/EtOAc to afford 69.2 mg (91%) of the indicated compound
as an oil: 1H NMR (300 MHz, CDCl3) δ 7.34-7.20 (m, 6H), 7.07
(t, J ) 7.2 Hz, 1H), 6.89 (d, J ) 7.5 Hz, 2H), 4.86 (s, 1H),
4.32-4.06 (m, 6H), 3.88 (d, J ) 1.5 Hz, 1H), 3.37 (d, J ) 16.5
Hz, 1H), 1.23 (t, J ) 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
171.3, 169.3, 162.0, 153.1, 141.1, 140.3, 129.6, 129.4, 127.7, 127.0,
124.5, 124.2, 122.7, 89.9, 64.3, 61.8, 61.4, 55.3, 39.8, 14.0, 13.9;
IR (neat, cm-1) 1728, 1248, 764. Anal. Calcd for C23H24O5: C
72.61; H 6.36. Found: C 72.44; H 6.34.
General Procedure for the Preparation of Benzo[b]furan
Derivatives 6. To a solution of propargylic compound 5a (0.20
mmol) in THF (2.0 mL) was added phenols (0.24 mmol). The
mixture was stirred for 1 min and Pd(PPh3)4 (5 mol %) was added.
The resulting mixture was then heated under an argon atmosphere
at 55 °C. When the reaction was considered complete as determined
by TLC analysis, the reaction mixture was allowed to cool to room
temperature and quenched with a saturated aqueous solution of
ammonium chloride, then the mixture was extracted with EtOAc.
The combined organic extracts were washed with water and
saturated brine. The organic layers were dried over Na2SO4 and
filtered. Solvents were evaporated under reduced pressure. The
residue was purified by chromatography on silica gel to afford
indene derivatives 6.
SN2′ substitution to form a π-propargylpalladium complex 7,
which is in an equilibrium with allenylpalladium intermediate
8;2,3,8 (b) regioselective intermolecular nucleophilic attack at
the central carbon of the π-propargylpalladium complex forms
the palladium complex 9,3 which picks up an active hydrogen
from the EtOH loosened to give the π-allylpalladium intermedi-
ate 10; (b′) regioselective intramolecular nucleophilic attack of
the carbanion forms the side product 4a; and (c) regioselective
intramolecular nucleophilic attack of the carbanion forms
product 3.
In conclusion, we have developed a novel Pd-catalyzed
carboannulation of propargyl compounds with high regio-
and stereoselectivity under very mild reaction conditions. In
these processes, indene and benzo[b]furan derivatives are
synthesized through the formation of the carbon-carbon bond
and intermolecular nucleophilic attack is prior to the in-
(8) (a) Fournier-Nguefack, C.; Lhoste, P.; Sinou, D. Synlett 1996, 553. (b)
Yoshida, M.; Nemoto, H.; Ihara, M. Tetrahedron Lett. 1999, 40, 8583. (c)
Labrosse, J. R.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1999, 40, 9025. (d)
Labrosse, J. R.; Lhoste, P.; Sinou, D. Org. Lett. 2000, 2, 527. (e) Kozawa, Y.;
Mori, M. Tetrahedron Lett. 2001, 42, 4869. (f) Kozawa, Y.; Mori, M.
Tetrahedron Lett. 2002, 43, 1499.
6a. The reaction mixture was chromatographed with 40:1
hexanes/EtOAc to afford 57.6 mg (75%) of the indicated
compound as an oil: 1H NMR (300 MHz, CDCl3); 1H NMR (300
J. Org. Chem. Vol. 73, No. 12, 2008 4715

MHz, CDCl3) δ 8.16-8.13 (m, 2H), 7.99-7.96 (m, 2H),
7.64-7.61 (m, 1H), 7.55-7.50 (m, 2H), 7.32-7.21 (m, 2H),
7.14-7.11 (m, 2H), 7.01-6.93 (m, 2H), 6.12 (d, J ) 5.7 Hz,
1H), 4.75 (d, J ) 6.0 Hz, 1H), 4.52 (d, J ) 2.4 Hz, 1H), 4.29
(d, J ) 2.7 Hz, 1H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 196.7, 194.3, 160.3, 159.2, 159.0, 134.3, 133.8, 133.4, 130.4,
129.3, 128.7, 125.6, 124.9, 121.4, 120.3, 110.2, 92.9, 85.7, 49.4,
26.5; IR (neat, cm-1) 1682, 1597, 1227, 912, 744; HRMS calcd
for C25H24NO4 [M + NH4]+ 402.1700, found 402.1706.
Acknowledgment. We thank the NSFC (NSFC-20621091,
NSFC-20672049) and the “Hundred Scientist Program” from
the Chinese Academy of Sciences for financial support.
Supporting Information Available: Typical experimental
procedure and characterization for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO8002776
4716 J. Org. Chem. Vol. 73, No. 12, 2008