Palladium-catalyzed carboannulation of propargylic carbonates and nucleophiles to 2-substituted indenes

Article abstract of DOI:10.1021/jo062377e

(Chemical Equation Presented) A new and efficient synthesis of 2-substituted indenes has been achieved via palladium-catalyzed carboannulation of propargylic carbonates with nucleophiles in good to excellent yields. A variety of nucleophiles were tolerate

Full text of DOI:10.1021/jo062377e

SCHEME 1
Palladium-Catalyzed Carboannulation of
Propargylic Carbonates and Nucleophiles to
2-Substituted Indenes
Li-Na Guo,† Xin-Hua Duan,† Hai-Peng Bi,†
Xue-Yuan Liu,† and Yong-Min Liang*,†,‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou
UniVersity, Lanzhou 730000, People’s Republic of China, and
State Key Laboratory of Solid Lubrication, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, People’s Republic of China
SCHEME 2
liangym@lzu.edu.cn
substituted 2,3-dihydrofurans and benzofurans,4 and very re-
cently, Cacchi et al. reported a convenient method for the
preparation of functionalized indoles by the palladium-catalyzed
reaction of ethyl-3-(o-trifluoroacetamidophenyl)-1-propargyl
carbonate with piperazines (Scheme 1).5
ReceiVed NoVember 17, 2006
In connection with our ongoing project on the carboannulation
reaction via palladium catalysis,6 we expected that a phenol
could react as a nucleophile with 3-(2-(di(ethoxycarbonyl)-
methyl)phenyl)prop-2-ynyl methyl carbonate (1) under pal-
ladium catalysis to give the 2-substituted indene (Scheme 2).7,8
To realize this goal, the catalytic activity of palladium
catalysts was examined for the cyclization of propargylic
carbonate 1 and phenol. Pd(PPh3)4 has proved to be the best
catalyst. Other palladium catalysts such as Pd2(dba)3‚CHCl3 and
Pd(OAc)2/PPh3 were less effective. THF was an excellent
solvent.
A new and efficient synthesis of 2-substituted indenes has
been achieved via palladium-catalyzed carboannulation of
propargylic carbonates with nucleophiles in good to excellent
yields. A variety of nucleophiles were tolerated in this
reaction.
Subsequently, the reaction was examined on various sub-
strates. Typical results of the palladium-catalyzed cyclization
of propargylic carbonates and phenols are shown in Table 1.
The reaction of propargylic carbonate 1 (0.2 mmol) with 1.2
equiv of phenol in the presence of 5 mol % of Pd(PPh3)4 in
THF under argon at 80 °C for 1 h gave the desired 2-substituted
indene 3a in 96% isolated yield (Table 1, entry 1). Phenols
bearing an electron-donating group or an electron-withdrawing
group in the para, ortho, and meta positions afforded the
corresponding 2-substituted indenes in good to high yields
(entries 2-9). Phenols bearing an electron-donating group in
the para position usually led to high yields of the 2-substituted
indenes (entries 2-4). When 4-chlorophenol (2e) and 4-nitro-
phenol (2f) were employed in the reaction with substrate 1, the
Palladium-catalyzed reactions of propargylic compounds with
nucleophiles have been shown to be extremely effective for the
construction of carbon-carbon and carbon-heteroatom bonds.1
The key step in these reactions is the formation of a π-allyl- or
π-allenylpalladium complex by facile decarboxylation, which
undergoes a variety of further transformations under neutral
conditions. Since the first report by Tsuji in 1985,2 a wide variety
of reactions in this family have been developed and applied in
the preparation of various organic substances.1,3 Recently,
Yoshida et al. reported palladium-catalyzed reactions of prop-
argylic carbonates with nucleophiles for the synthesis of
† Lanzhou University.
‡ Chinese Academy of Sciences.
(1) For reviews on the palladium-catalyzed reactions of propargylic
compounds, see: (a) Tsuji, J. Acc. Chem. Res. 1969, 2, 144. (b) Tsuji, J.;
Mandai. T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2589.
(2) (a) Tsuji, J.; Watanabe, H.; Minami, I.; Shimizu, I. J. Am. Chem.
Soc. 1985, 107, 2196. (b) Minami, I.; Yuhara, M.; Watanabe, H.; Tsuji, J.
J. Organomet. Chem. 1987, 334, 225.
(3) For recent examples of similar types of palladium-catalyzed reactions
of propargylic carbonates with nucleophiles, see: (a) Geng, L.; Lu, X.
J. Chem. Soc., Perkin Trans. 1 1992, 17. (b) Fournier-Nguefack, C.; Lhoste,
P.; Sinou, D. Synlett 1996, 553. (c) Yoshida, M.; Nemoto, H.; Ihara, M.
Tetrahedron Lett. 1999, 40, 8583. (d) Labrosse, J.-R.; Lhoste, P.; Sinou,
D. Tetrahedron Lett. 1999, 40, 9025. (e) Yoshida, M.; Ihara, M. Angew.
Chem., Int. Ed. 2001, 40, 616. (f) Labrosse, J.-R.; Lhoste, P.; Sinou, D.
J. Org. Chem. 2001, 66, 6634. (g) Kozawa, Y.; Mori, M. Tetrahedron Lett.
2002, 43, 1499. (h) Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am.
Chem. Soc. 2003, 125, 4874. (i) Duan, X.-H.; Liu, X.-Y.; Guo, L.-N.; Liao,
M.-C.; Liu, W.-M.; Liang, Y.-M. J. Org. Chem. 2005, 70, 6980.
(4) (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.
(5) Ambrogio, I.; Cacchi, S.; Fabrizi, G. Org. Lett. 2006, 8, 2083.
(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.
(7) A new palladium-catalyzed cyclization reaction of propargylic
carbonates with carbon nucleophiles to 2,3-disubstituted indenes has been
reported by us; see: Duan, X.-H.; Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang,
Y.-M. Org. Lett. 2006, 8, 5777.
(8) For recent examples of palladium-catalyzed indene synthesis, see:
(a) Teply´, F.; Stara´, I. G.; Stary´, I.; Kolla´rovicˇ, A.; Sˇaman, D.; Fiedler, P.
Tetrahedron 2002, 58, 9007. (b) Zhang, D.; Yum, E. K.; Liu, Z.; Larock,
R. C. Org. Lett. 2005, 7, 4963. (c) Furuta, T.; Asakawa, T.; Iinuma, M.;
Fujii, S.; Tanaka, K.; Kan, T. Chem. Commun. 2006, 3648. (d) Tsukamoto,
H.; Ueno, T.; Kondo, Y. J. Am. Chem. Soc. 2006, 128, 1406.
10.1021/jo062377e CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/19/2007
1538
J. Org. Chem. 2007, 72, 1538-1540

SCHEME 3
TABLE 1. Palladium-Catalyzed Carboannulation of Propargylic
Carbonate 1 with Various Phenols 2a
SCHEME 4
Bisphenols were then employed in this reaction under the
same conditions by using 0.2 mmol of 2 and 2.0 equiv of 1.
For hydroquinone and bisphenol A, the reactions proceeded well
in both substitution positions and afforded the corresponding
disubstituted products 3n and 3o in 73 and 81% isolated yields,
respectively (Scheme 3).
entry
ArOH (2)
3
isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
R ) H
3a
3b
3c
3d
3e
3f
3g
3h
3i
96
93
92
90
91
76
80
84
77
80
81
45
81
R ) 4-OMe
R ) 4-Me
R ) 4-t-Bu
R ) 4-Cl
R ) 4-NO2
R ) 2-Me
Furthermore, the reaction of 4, containing a latent nucleophilic
phenolic moiety as a part of the carbonate leaving group, was
also examined (Scheme 4). When 4 was subjected to the
palladium-catalyzed reaction, the corresponding 2-substituted
indene 3a was isolated in 83% yield. In this reaction, the
substrate initially releases the phenoxide, which then acts as a
nucleophile for the cyclized π-allyl complex to produce the
product.
R ) 2-Br
R ) 3-NO2
R ) 2,4-dimethyl
R ) 2,4-dichloro
R-naphthol
â-naphthol
3j
3k
3l
3m
a All reactions were carried out on a 0.2 mmol scale in 2 mL of THF
under argon at 80 ˚C by using 1.0 equiv of 1, 1.2 equiv of 2, and 0.05
equiv of Pd(PPh3)4; all reactions were run for 1-2 h.
To further explore the scope of this cyclization reaction,
nitrogen nucleophiles were also investigated. Based on optimi-
zation efforts, the combination of 0.2 mmol of 1, 1.2 equiv of
nucleophile, 2.0 equiv of K2CO3, 5 mol % of Pd(PPh3)4, and
the use of DMF as the solvent at 80 °C gave the best results. In
this reaction, base is essential. To our delight, various secondary
amines could react with 1 to give the desired products (Table
2). Yields are usually moderate to good with secondary amines
(entries 1-6). Aryl secondary amines such as trifluoroacetophe-
nylamine also afforded the corresponding product 6g in 62%
yield (entry 7).
corresponding products 3e and 3f were isolated in 91 and 76%
yields (entries 5 and 6). Phenols containing an electron-donating
group or an electron-withdrawing group in the ortho position
have also proven successful. For example, the reaction of
2-methylphenol and 2-bromophenol produced 80 and 84% yields
of the desired products, respectively (entries 7 and 8). The
reactions of 1 and phenols with an electron-withdrawing group,
such as the NO2 group in the meta position, afforded the desired
product 3i in good yield (entry 9). The disubstituted phenols
such as 2,4-dimethylphenol and 2,4-dichlorophenol with 1 also
worked well to give products 3j and 3k in 80 and 81% yields,
respectively (entries 10 and 11). Meanwhile, the use of
R-naphthol and â-naphthol also afforded the corresponding
products 3l and 3m in 45 and 81% yields (entries 12 and 13).
For R-naphthol, a moderate yield was obtained, which could
be due to the involvement of steric effects. In addition,
propargylic carbonate with different electron-withdrawing groups
such as ethyl-2-[2-{3-(methoxycarbonyloxy)prop-1-ynyl}phenyl]-
2-(phenylsulfonyl)acetate was also employed as a substrate, but
no reaction was observed.
A plausible mechanism accounting for the formation of the
2-substituted indenes is depicted in Scheme 5. In this process,
a palladium catalyst initially promotes decarboxylation of
propargylic carbonate 1 to generate an allenylpalladium complex
7, which would be in equilibrium with π-propargylpalladium
intermediate 8.4,5 Palladium complex 8 undergoes intramolecular
nucleophilic attack of the carbanion at the central carbon of the
allenyl/propargylpalladium complex to form the carbene com-
plex 9,5 which abstracts an active hydrogen from the nucleophile
moiety to give the π-allylpalladium intermediate 10.3-5 Finally,
J. Org. Chem, Vol. 72, No. 4, 2007 1539

TABLE 2. Palladium-Catalyzed Carboannulation of Propargylic
Carbonate 1 with Various Amines 5a
(0.24 mmol), Pd(PPh3)4 (11.5 mg, 5 mol %), and THF (2.0 mL)
was placed under an argon atmosphere in a 25 mL flask. The
resulting mixture was then heated under an argon atmosphere at
80 °C. When the reaction was considered complete, as determined
by TLC analysis, the reaction mixture was allowed to cool to room
temperature. The reaction mixture was concentrated under reduced
pressure, and the residue was purified by chromatography on silica
gel to afford the corresponding 2-substituted indenes 3.
Diethyl-2-(phenoxymethyl)-1H-indene-1,1-dicarboxylate (3a).
The reaction mixture was chromatographed using 10:1 hexanes/
EtOAc to afford 70.0 mg (96%) of the indicated compound as an
oil: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J ) 7.2 Hz, 1H), 7.34-
7.22 (m, 5H), 7.02-7.01 (d, J ) 7.6 Hz, 2H), 6.97-6.94 (m, 2H),
5.10 (s, 2H), 4.26-4.21 (q, J ) 7.2 Hz, 4H), 1.27-1.23 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 167.6, 158.7, 143.3, 141.7, 140.6,
132.6, 129.4, 128.8, 126.0, 125.2, 121.4, 120.9, 114.8, 70.7, 65.4,
62.3, 13.9; IR (neat, cm-1) 3447, 2982, 1732, 1495, 1242, 1047.
Anal. Calcd for C22H22O5: C, 72.12; H, 6.05. Found: C, 72.02; H,
5.94.
General Procedure for the Preparation of 2-Substituted
Indenes 6. To a solution of 3-(2-(di(ethoxycarbonyl)methyl)-
phenyl)prop-2-ynyl methyl carbonate (1; 69.6 mg, 0.20 mmol) in
DMF (2.0 mL) were added K2CO3 (55.2 mg, 0.40 mmol), amines
(0.24 mmol), and Pd(PPh3)4 (11.5 mg, 5 mol %). The resulting
mixture was then heated under an argon atmosphere at 80 °C. When
the reaction was considered complete, as determined by TLC
analysis, the reaction mixture was cooled to room temperature,
quenched with a saturated aqueous solution of ammonium chloride,
and 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 the corresponding 2-substituted indenes 6.
a All reactions were carried out on a 0.2 mmol scale in 2 mL of DMF
under argon at 80 °C by using 1.0 equiv of 1, 1.2 equiv of 5, 2.0 equiv of
K2CO3, and 0.05 equiv of Pd(PPh3)4; all reactions were run for 4-5 h.
b Without K2CO3.
SCHEME 5
Diethyl-2-((pyrrolidin-1-yl)methyl)-1H-indene-1,1-dicarboxy-
late (6a). The reaction mixture was chromatographed using 10:1
hexanes/EtOAc to afford 42.5 mg (62%) of the indicated compound
as an oil: 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J ) 8.0 Hz, 1H),
7.32-7.24 (m, 2H), 7.21-7.17 (m, 1H), 6.88 (s, 1H), 4.23-4.15
(m, 4H), 3.59 (s, 2H), 2.63-2.60 (t, J ) 6.4 Hz, 4H), 1.81-1.78
(m, 4H), 1.30-1.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 168.1,
145.2, 144.0, 140.9, 131.7, 128.5, 125.5, 124.9, 120.9, 71.0, 61.8,
54.5, 54.4, 23.7, 13.9; IR (neat, cm-1) 3402, 2964, 1731, 1463,
1234, 1050. Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34; N,
4.08. Found: C, 69.85; H, 7.37; N, 3.98.
regioselective intermolecular nucleophilic attack of the nucleo-
phile on 10 at the less-hindered site produces 2-substituted
indene.4,5
In conclusion, we have developed an efficient and operation-
ally simple cyclization method for the synthesis of 2-substituted
indenes. This method accommodates a variety of nucleophiles
and affords the anticipated substituted indenes in good to
excellent yields.
Acknowledgment. We thank the NSF (NSF-20021001,
NSF-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.
Experimental Section
General Procedure for the Preparation of 2-Substituted
Indenes 3. A mixture of 3-(2-(di(ethoxycarbonyl)methyl)phenyl)-
prop-2-ynyl methyl carbonate (1; 69.6 mg, 0.20 mmol), phenols
JO062377E
1540 J. Org. Chem., Vol. 72, No. 4, 2007