Highly regio- And stereoselective synthesis of indene derivatives via electrophilic cyclization

Article abstract of DOI:10.1021/ol062683e

Indene or naphthalene derivatives are readily prepared in moderate to excellent yields with high regio- and stereoselectivity under very mild reaction conditions by the reaction of acetylenic malonates and ketones with I ₂, ICI, or NIS. The res

Full text of DOI:10.1021/ol062683e

ORGANIC
LETTERS
2007
Vol. 9, No. 3
397-400
Highly Regio- and Stereoselective
Synthesis of Indene Derivatives via
Electrophilic Cyclization
Hai-Peng Bi,† Li-Na Guo,† Xin-Hua Duan,† Fa-Rong Gou,† Shu-Hao Huang,†
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 November 2, 2006
ABSTRACT
Indene or naphthalene derivatives are readily prepared in moderate to excellent yields with high regio- and stereoselectivity under very mild
reaction conditions by the reaction of acetylenic malonates and ketones with I2, ICl, or NIS. The resulting iodides can be further elaborated
using palladium-catalyzed coupling reactions.
The electrophilic cyclization of heteroatomic nucleophiles
such as oxygen, nitrogen, sulfur, and phosphor with tethered
alkynes has proven to be an effective method of preparing a
large variety of heterocyclic ring systems.1-8 Important
heterocycles such as furans,1 pyrroles,2 thiophenes,3 indoles,4
phosphaisocoumarins,5 benzo[b]furans,6 benzo[b]thiophenes,7
and others8 have been accessed using this protocol. However,
only limited reports concerning electrophilic cyclization of
carbon nucleophiles have been presented in the literature.
In 1993, Taguchi reported an electrophilic cyclization of
4-alkynylmalonate derivatives, but the use of Ti(Ot-Bu)4 was
required for the reaction to proceed.9
† Lanzhou University.
‡ Lanzhou Institute of Chemical Physics.
(1) (a) Bew, S. P.; Knight, D. W. J. Chem. Soc., Chem. Commun. 1996,
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1995, 60, 6468. (b) Ren, X.-F.; Konaklieva, M. I.; Shi, H.; Dickey, S.;
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Angew. Chem., Int. Ed. 2003, 42, 2406. (c) Yue, D.; Larock, R. C. Org.
Lett. 2004, 6, 1037. (d) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004,
45, 539.
(8) (a) Djuardi, E.; McNelis, E. Tetrahedron Lett. 1999, 40, 7193. (b)
Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron 2001, 57, 2857.
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Lett. 2002, 4, 2409. (d) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org.
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10.1021/ol062683e CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/05/2007

Our continuing interest was in the synthesis of indene
derivatives by carboannulation.10 This work prompted us to
examine possible synthesis of indene derivatives by the
electrophilic cyclization. Herein, we wish to report a suc-
cessful electrophilic cyclization of acetylenic malonates and
ketones for the synthesis of indene derivatives with high
regio- and stereoselectivity (Scheme 1). The observed
To explore the scope of this electrophilic cyclization
strategy, the reactions of 1a with different electrophiles
(I2, ICl, and NIS) have been studied under the above
optimized conditions. When using I2, ICl, and NIS as the
electrophilic reagents, only five-membered ring products
have been obtained in excellent yields (Table 2, entries 1-3).
Table 2. Electrophilic Cyclization of Acetylenic Malonates and
Ketonesa
Scheme 1
selectivity is rare in electrophilic cyclization reactions.
Our initial study began with the reaction of dimethyl
2-(2-(2-phenylethynyl)benzyl)malonate (1a, 0.30 mmol), 2.0
equiv of t-BuOK, and 2.0 equiv of I2 in THF at room
temperature under argon for 20 min. The desired product
(E)-dimethyl 1-(iodo(phenyl)methylene)-1H-indene-2,2(3H)-
dicarboxylate (2a) was isolated in 93% yield with high regio-
and stereoselectivity (Table 1, entry 1). NaOEt and K2CO3
Table 1. Optimization of the Electrophilic Cyclization of
Dimethyl 2-(2-(2-Phenylethynyl)benzyl)malonatea
time
(min)
isolated
yield (%)
ratio
2a/3ab
entry
base
solvent
1
2
3
4
5
6
t-BuOK
NaOEt
K2CO3
t-BuOK
t-BuOK
t-BuOK
THF
THF
THF
CH2Cl2
MeOH
CH3CN
20
30
60
45
40
45
93
90
nrc
45
40
53
>99:1
>99:1
>99:1
>99:1
>99:1
a All reactions were run under the following conditions, unless otherwise
indicated: 0.30 mmol of 1a, 2.0 equiv of I2, and 2.0 equiv of base in 3 mL
of solvent were stirred at room temperature under argon for the specified
period of time. b The ratio was determined by 1H NMR analysis of the
product. c nr ) no reaction.
a All reactions were run under the following conditions, unless otherwise
indicated: 0.30 mmol of 1, 2.0 equiv of I2, and 2.0 equiv of t-BuOK in 3
mL of THF were stirred at room temperature under argon for the specified
period of time. b The ratio was determined by 1H NMR analysis of the
product. c The reaction was carried out using 2.0 equiv of ICl. d The reaction
was carried out using 2.0 equiv of NIS.
were also investigated as bases. NaOEt provided a slightly
lower yield and longer reaction time than t-BuOK (entry 2);
K2CO3 proved to be ineffective (entry 3). Other solvents such
as CH2Cl2, MeOH, and CH3CN were less effective (entries
4-6). The optimum reaction conditions thus far developed
employ 1.0 equiv of 1a, 2.0 equiv of t-BuOK, and 2.0 equiv
of electrophile in THF at room temperature under argon.
Similarly, diethyl 2-(2-(2-phenylethynyl)benzyl)malonate
(1b) gave the corresponding indene 2b in good yield (entry
4). The reactions of diethyl malonate alkynes containing
different R groups at the end of the triple bond have also
been investigated. Diethyl 2-(2-(hept-1-ynyl)benzyl)malonate
(1c) was employed in the reaction, and only the correspond-
ing five-membered ring product was isolated in high yield
(entry 5). Under similar conditions, diethyl 2-(2-(3-(tetrahy-
dro-2H-pyran-2-yloxy)prop-1- ynyl)benzyl)malonate (1d)
produced a complex mixture of unidentified products (entry
(10) (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.
398
Org. Lett., Vol. 9, No. 3, 2007

6). However, diethyl 2-(2-(2-(4-chlorophenyl)ethynyl)ben-
zyl)malonate (1e) afforded exclusively the six-membered ring
product 3e (entry 7). We believe that the resonance and
electronic effect force the carbon of the malonate group
closer to C-1 or C-2 of the acetylenic malonates, resulting
in five- or six-membered ring formation (Figure 1).6c
Figure 2. Structure of 2a.
Table 3. Electrophilic Cyclization of Acetylenic Malonatesa
Figure 1. Methylene, chloric and enolization effect on the triple
bond.
Meanwhile, acetylenes with different electron-withdrawing
groups, such as methyl 2-(2-(2-phenylethynyl)benzyl)-3-
oxobutanoate (1f), have also been used as substrate and
afforded a mixture of five- and six-membered ring products.
The five-membered ring product predominated (entry 8).
Surprisingly, 3-(2-(2-phenylethynyl)benzyl)pentane-2,4-dione
(1g) provided the six-membered ring product dimethyl
4-iodo-3-phenylnaphthalene-2,2(1H)-dicarboxylate (3g) as
the sole product (entry 9). We think that six-membered ring
formation is due to the enolization and resonance effect
(Figure 1).
The molecular structure of the representative product 2a
was determined by X-ray crystallography (Figure 2).11
Interestingly, the reaction of substituted acetylene 1h,
which has an oxygen function at the terminal position,
proceeded smoothly to give tricyclic lactone 2h as the sole
product in a short time (Table 3, entry 1). Lactonization in
the reaction of 1h must have occurred after electrophilic
cyclization because in the absence of I2 the lactone was not
formed when 1h was treated with t-BuOK. The reactions of
1h with various electrophiles (ICl and NIS) have also been
studied. Good yields of the expected product 2h have been
obtained, respectively (entries 2 and 3). Closely, substituted
a All reactions were carried out under the optimal conditions reported in
the text. b The reaction was carried out using 2.0 equiv of ICl. c The reaction
was carried out using 2.0 equiv of NIS
secondary alcohol 1i led to desired product 2i in 56% yield
(entry 4). Substituted secondary alcohols 1j and 1k, having
phenyl or p-tolyl substituents, produced 55% and 59%
yields of the tricyclic lactones, respectively (entries 5 and
6). Similarly, diethyl 2-(2-(3-(furan-2-yl)-3-hydroxyprop-
1-ynyl)benzyl)malonate (1l) led to desired product 2l in
61% yield (entry 7). Fortunately, propargylic tertiary alcohol
1m also gave the corresponding tricyclic product 2m
(entry 8).
We propose the following mechanism for this electrophilic
cyclization (Scheme 2). First, the carbon-carbon triple bond
of acetylenic malonates and ketones coordinates to the iodine
cation generated from I2 to generate an iodonium intermedi-
(11) X-ray data for compound 2a: C20H17IO4, MW ) 448.24, T ) 298-
(2) K, λ ) 0.71073 Å, monoclinic space group, P-1, a ) 7.615(16) Å, b )
9.91(2) Å, c ) 12.33(2) Å, R ) 98.11(2)°, â ) 96.80(2)°, γ ) 96.61(3)°,
V ) 906(3) Å3, Z ) 2, Dc ) 1.642 mg/m3, µ ) 1.787 mm-1, F(000) )
444, crystal size 0.50 × 0.45 × 0.38 mm3, independent reflections 3045 [R
(int) ) 0.0485], reflections collected 4244, refinement method, full-matrix
least-squares on F2, goodness-of-fit on F2 1.008, final R indices [I > 2σ-
(I)] R1 ) 0.0789, wR2 ) 0.1902, R indices (all date) R1 ) 0.0992, wR2 )
0.2136, largest diff. peak and hole 1.840 and -2.845 e Å-3
Org. Lett., Vol. 9, No. 3, 2007
399

Scheme 2
Scheme 3
philic cyclization under very mild reaction conditions has
been developed. The resulting iodine-containing products are
readily elaborated to more complex products by using known
organopalladium chemistry. Further studies into the scope
and limitations of the carboannulation reaction are underway.
ate. This is followed by attack of the carbanion on the
activated triple bond to afford the cyclized products.
A standard feature of this process is the fact that the indene
derivatives produced by iodocyclization can be further
elaborated by using various palladium-catalyzed processes.
For example, the Sonagashira coupling12 of tricyclic lactone
2h afforded the corresponding product 4h in 82% yield
(Scheme 3).
Acknowledgment. We thank the NSF (NSF-20021001,
NSF-20672049) and the “Hundred Scientist Program” from
the Chinese Academy of Sciences for financial support.
In conclusion, an efficient, highly regio- and stereoselec-
tive synthesis of indene derivatives from acetylenic ketones
and malonates by carbon nucleophiles through electro-
Supporting Information Available: Typical experimen-
tal procedure and characterization for all products, and X-ray
data of 2a in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) For reviews, see: (a) Campbell, I. B. The Sonogashira Cu-Pd-
Catalyzed Alkyne Coupling Reaction. Organocopper Reagents; Taylor, R.
J. K., Ed.; IRL Press: Oxford, U.K., 1994; pp 217-235. (b) Sonogashira,
K.; Takahashi, S. Yuki Gosei Kagaku Kyokaishi 1993, 51, 1053. (c)
Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon: Oxford, 1991; Vol. 3, pp 521-549.
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