Highly regioselective synthesis of 2,3-disubstituted indenes via a novel palladium-catalyzed cyclization reaction of propargylic carbonates with carbon nucleophiles

Article abstract of DOI:10.1021/ol062405f

(Diagram presented) Palladium-catalyzed reaction of propargylic carbonates with carbon nucleophiles offers an efficient, direct route to highly substituted indenes. The reaction conditions and the scope of the process are examined, and a possible mechanis

Full text of DOI:10.1021/ol062405f

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5777-5780
Highly Regioselective Synthesis of
2,3-Disubstituted Indenes via a Novel
Palladium-Catalyzed Cyclization
Reaction of Propargylic Carbonates with
Carbon Nucleophiles
Xin-Hua Duan,† Li-Na Guo,† Hai-Peng Bi,† 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, P. R. China
liangym@lzu.edu.cn
Received September 29, 2006
ABSTRACT
Palladium-catalyzed reaction of propargylic carbonates with carbon nucleophiles offers an efficient, direct route to highly substituted indenes.
The reaction conditions and the scope of the process are examined, and a possible mechanism is proposed.
The reaction of π-allylpalladium complexes with carbon
nucleophiles such as malonates and â-keto esters has proven
to be a powerful method for the formation of carbon-carbon
bonds.1 Among these processes, those involving palladium-
catalyzed reactions are particularly attracting the attention
of synthetic organic chemists, and many useful synthetic
reactions based on π-allylpalladium compounds have been
discovered.2 In contrast to the extensive studies conducted
on palladium-catalyzed reactions of allylic compounds,
studies on the analogous reactions of propargylic compounds
were initiated much later and are less extensive.3 Tsuji has
reported a one-pot furan annulation reaction by a palladium-
catalyzed reaction of propargylic carbonates with carbon
nucleophiles,4 and Lu reported another palladium-catalyzed
annulation reaction with bifunctional nucleophiles.5
As part of our ongoing interest in developing methods for
the preparation of indene derivatives via organometallic
catalysis,6 we herein wish to report a new palladium-
catalyzed cyclization reaction of propargylic carbonates with
a variety of carbon nucleophiles to offer an efficient, direct
route to highly substituted indenes (Scheme 1).
We first investigated the reaction of propargylic carbonate
1a with methyl acetoacetate (2a) in the presence of Pd(PPh3)4
and K2CO3 in DMF at 80 °C for 10 h. To our delight, only
diethyl 3-((Z)-1-(methoxycarbonyl)-2-hydroxyprop-1-enyl)-
† Lanzhou University.
‡ Lanzhou Institute of Chemical Physics.
(1) (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965,
6, 4387. (b) Tsuji, J. Acc. Chem. Res. 1969, 2, 144.
(2) (a) Tsuji, J. Tetrahedron 1986, 42, 4361. (b) Trost, B. M., Verhoeven,
T. R. In ComprehensiVe Organometallic Chemistry; Wilkinson, G., Stone,
F. G. A., Abel, E., Eds.; Pergamon: Oxford, 1982; Vol. 8, p 799. (c)
Godleski, S. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Semmelhack, M. F., Eds.; Pergamon: Oxford, 1991; Vol. 4, p 585. (d)
Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron: Asymmetry 1992,
3, 1089.
(4) (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.
(5) (a) Geng, L.; Lu, X. Tetrahedron Lett. 1990, 31, 111. (b) Geng, L.;
Lu, X. J. Chem. Soc., Perkin Trans. 1 1992, 17.
(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.
(3) Tsuji, J.; Mandai. T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2589.
10.1021/ol062405f CCC: $33.50
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gave the corresponding multiply substituted indenes 3ab and
3ac in moderate to good yields (Table 2, entries 2 and 3).
Scheme 1
Table 2. Palladium-Catalyzed Cyclization of Propargylic
Carbonates with Nucleophilesa
2-methyl-1H-indene-1,1-dicarboxylate (3aa) was isolated in
70% yield and no 2-substituted indene was observed (Table
1, entry 1).7 K2CO3 proved to be the best base, whereas
Table 1. Optimization of the Palladium-Catalyzed Cyclization
of Propargylic Carbonate 1a with 2aa
yield of
entry
catalyst
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2/PPh3
Pd2(dba)3‚CHCl3
base
solvent 3aa (%)b
1
2
3
4
5
6
7
8
9
K2CO3
KOAc
KOt-Bu DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
70
52
62
DMSO
THF
NMP
NMP
NMP
NMP
55
n.r.c
83
65
n.r.c
n.r.c
Pd2(dba)3‚CHCl3/dppe K2CO3
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of solvent
at 80 °C using 1.0 equiv of 1a, 1.2 equiv of 2a, 2.0 equiv of base, and 0.05
equiv of [Pd] for 10 h. b Isolated yield. c n.r. ) no reaction.
KOAc and KOt-Bu were less effective (entries 2 and 3).
Changing the solvent from DMF to DMSO did not enhance
the yield of 3aa (entry 4), and using THF as the solvent
gave no reaction at all (entry 5). Fortunately, the yield
increased to 83% when the solvent NMP was employed
instead of DMF (entry 6). Therefore, NMP was found to be
the best solvent for the cyclization reaction. Among the
palladium catalysts tested, Pd(PPh3)4 was the most effective
catalyst for this reaction. Pd(OAc)2/PPh3 was less effective
(entry 7), and no reaction was observed when the catalyst
was replaced with Pd2(dba)3‚CHCl3 (entries 8 and 9).
We next examined other â-keto esters to clarify the scope
and limitations of this reaction. Similarly, the reaction of 1a
with â-keto esters 2b and 2c in the presence of Pd(PPh3)4
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of NMP at
80 °C using 1.0 equiv of 1, 1.2 equiv of 2, 2.0 equiv of base, and 0.05
equiv of [Pd]; all reactions were run for 5-10 h. b At 100 °C. c n.r. ) no
reaction.
The cyclization of 1a with various â-diketones was also
investigated. Not only simple â-diketones, such as pentane-
2,4-dione (entry 4), but also cyclic â-diketones, such as 1,3-
cyclohexanedione and 5,5-dimethylcyclohexane-1,3-dione,
were effective nucleophiles (entries 7 and 8). When phenyl-
substituted 1,3-dicarbonyl substrates were used, the desired
(7) For some recent examples of palladium-catalyzed reactions of
propargylic carbonates with nucleophiles for the syntheses of 2-substituted
benzofurans and indoles, in which nucleophiles attack on the less hindered
carbon of the π-allylpalladium complex, see: (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. (c)
Ambrogio, I.; Cacchi, S.; Fabrizi, G. Org. Lett. 2006, 8, 2083.
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Org. Lett., Vol. 8, No. 25, 2006

products were isolated in 71% and 34% yields, respectively
(entries 5 and 6). The use of 3-methylpentane-2,4-dione was
also effective; however, it gave a complicated mixture that
is still under investigation. No reactions were observed when
dimethyl malonate and malononitrile were treated with 1a
(entries 9 and 10). Under similar conditions, ethyl acetate
propargylic carbonate with different electron-withdrawing
groups, such as ethyl 2-[2-{3-(methoxycarbonyloxy)prop-
1-ynyl}phenyl]-2-(phenylsulfonyl)acetate (1b) produced a
complex mixture of unidentified products (entry 11).
Although the NMR spectroscopic data support the forma-
tion of 2,3-disubstituted indenes 3, the structure was unam-
biguously secured by an X-ray crystal structure analysis of
compound 3ad (Figure 1).8
Propargylic tertiary carbonate 1f with 2a afforded none
of the desired 2,3-disubstituted indenes and an identified
2-substituted indene 3fa was isolated (Scheme 2). The
Scheme 2
formation of 3fa could be attributed to steric hindrance, the
more substituted and electrophilic end being now too
crowded. This is in agreement with results observed by us
in the palladium-catalyzed three-component annulation
reaction.9
A plausible mechanism is proposed in Scheme 3. It
consists of the following key steps: (a) palladium(0) attack
Scheme 3
Figure 1. Structure of 3ad.
We then turned our attention to the cyclization reaction
using secondary carbonates. As expected, substituted second-
ary carbonate 1c react with 2a led to the desired product
3ca in 65% yield (Table 3, entry 1). Substituted secondary
Table 3. Palladium-Catalyzed Cyclization of Propargylic
Carbonates with 2aa
at propargylic carbonate through SN2′ substitution to form
an allenylpalladium complex 4;7 (b) intramolecular nucleo-
philic attack of the carbanion at the central carbon of the
allenylpalladium complex to form the palladium complex
5, which picks up an active hydrogen from the nucleophile
entry
R1
time (h)
3a
isolated yield (%)
1
2
3
R1 ) Me (1c)
10
10
12
3ca
3da
3ea
65
56
32
R1 ) Ph (1d)
(8) Crystal data for 3ad have been deposited in CCDC as deposition
number 620440: C21H24O6, MW ) 372.40, T ) 294(2) K, λ ) 0.71073 Å,
monoclinic space group, P1, a ) 11.0511(10) Å, b ) 20.5371(16) Å, c )
9.0441(8) Å, R ) 90.00°, â ) 96.047(4)°, γ ) 90.00°, V ) 2041.2(3) Å3,
Z ) 4, Dc ) 1.212 mg/m3, µ ) 0.088 mm-1, F(000) ) 816, crystal size
0.55 × 0.50 × 0.40 mm3, independent reflections 4008 [R (int) ) 0.0363],
reflections collected 11295, refinement method, full-matrix least-squares
on F2, goodness-of-fit on F2 1.183, final R indices [I > 2σ(I)] R1 ) 0.0977,
wR2 ) 0.2172, R indices (all date) R1 ) 0.0603, wR2 ) 0.1856, extinction
coefficient 0.030(5), largest diff peak and hole 0.401 and -0.233 e Å-3
(9) Duan, X.-H.; Liu, X.-Y.; Guo, L.-N.; Liao, M.-C.; Liu, W.-M.; Liang,
Y.-M. J. Org. Chem. 2005, 70, 6980.
R1 ) p-ClC6H4 (1e)
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of NMP at
80 °C using 1.0 equiv of 1, 1.2 equiv of 2a, 2.0 equiv of base, and 0.05
equiv of [Pd].
carbonates 1d and 1e, having phenyl substituents, produced
56% and 32% yields of the multiply substituted indenes,
respectively (entries 2 and 3).
Org. Lett., Vol. 8, No. 25, 2006
5779

moiety to give the π-allylpalladium intermediate, 7;3,7,10 and
(c) regioselective intermolecular nucleophilic attack of the
carbon nucleophile at the more hindered allylic terminus of
75b,11 to furnish the indene after isomerization and regenerate
the Pd(0) catalyst. From our results, a dominant electronic
effect in the transition state of this reaction leads to reactions
at the more hindered side of the π-allylpalladium complex.
In conclusion, we have developed a straightforward, highly
regioselective approach to multiply substituted indenes. This
novel palladium-catalyzed cyclization reaction worked well
with a broad range of nucleophiles to afford 2,3-disubstituted
indenes in moderate to good yields. Current studies are
focused on further exploration of the substrate scope and
synthetic utility of this methodology, as well as on probing
the mechanism of this transformation.
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 experimen-
tal procedure and characterization for all products, and X-ray
data of 3ad in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL062405F
(10) (a) Fournier-Nguefack, C.; Lhoste, P.; Sinou, D. Synlett 1996, 553.
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(11) For examples of π-allylpalladium complex and subsequent C-
alkylation, see: Tsuji, J.; Kobayashi, Y.; Kataoka, H.; Takahashi, T.
Tetrahedron Lett. 1980, 21, 1475. For some examples of nucleophiles attack
the more hindered side of the π-allylmetal complexes, see: (a) Trost, B.
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Org. Lett., Vol. 8, No. 25, 2006