Synthesis of indene derivatives via electrophilic cyclization

Article abstract of DOI:10.1021/ol8024956

3-Iodo-1H-indene derivatives are synthesized by iodonium-promoted 5-endo-dig carbocyclization of 2-substituted ethynylmalonates. Various 2-substituted ethynylmalonates bearing aryl-, alkyl-and ether-protected propargyl alcohols were successfully converted

Full text of DOI:10.1021/ol8024956

ORGANIC
LETTERS
2009
Vol. 11, No. 1
229-231
Synthesis of Indene Derivatives via
Electrophilic Cyclization
Zulfiqar Ali Khan and Thomas Wirth*
School of Chemistry, Cardiff UniVersity, Park Place, Cardiff CF10 3AT, U.K.
wirth@cf.ac.uk
Received October 28, 2008
ABSTRACT
3-Iodo-1H-indene derivatives are synthesized by iodonium-promoted 5-endo-dig carbocyclization of 2-substituted ethynylmalonates. Various
2-substituted ethynylmalonates bearing aryl-, alkyl- and ether-protected propargyl alcohols were successfully converted to cyclized products.
Their use in subsequent reactions as substrate and catalyst was investigated.
The indene moiety is present in a large number of drug
candidates possessing interesting biological activities.1 They
are also used as ligands in metallocene complexes, especially
group IV metallocene complexes used in the area of catalytic
olefin polymerization.2 Therefore, a number of synthetic
approaches toward the construction of indene ring systems
have been developed such as the reduction or dehydration
of indanone,3 the cyclization of substituted 1,3-butadienes
in the presence of Lewis acids,4 or the ring expansion of
suitably substituted cyclopropenes.5 A variety of transition
metal complexes, e.g., Pd,6 Ni,7 and Co,8 have been used to
synthesize indenes via carboannulations of alkynes, but there
are only limited reports for the synthesis of haloindenes, such
as the bromination of indane or indene derivatives9 and
hydrogen iodide mediated cyclizations of o-alkynylstyrenes.10
Roussel et al. reported the synthesis of 3-chloroindenes by
trifluoromethanesulfonicacidcatalyzedbenzoylationof2-meth-
yl-2-butene.11 Sauers et al. reported the synthesis of fluor-
oindenes by rearrangement of diazirines via photolysis.12
Recently, the synthesis of 3-iodo-1H-indene derivatives via
Lewis acid catalyzed Friedel-Crafts cyclizations of iodinated
allylic alcohols was published.13 Also stereoselective cy-
clizations have been developed using iodine electrophiles.14
Several of these classical methods have some drawbacks in
the preparation of indenes such as long reaction sequences,
use of expensive transition metals, strong acidic conditions,
and less tolerance for sensitive organic functionalities.
However, haloindenes are important derivatives that provide
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1999, 121, 3545. (b) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y.
Tetrahedron Lett. 1999, 40, 4089. (c) Zhang, D.; Liu, Z.; Yum, E. K.;
Larock, R. C. J. Org. Chem. 2007, 72, 251. (d) Zhang, D.; Yum, E. K.;
Liu, Z.; Larock, R. C. Org. Lett. 2005, 7, 4963. (e) Bi, H.-P.; Liu, X.-Y.;
Gou, F.-R.; Guo, L.-N.; Duan, X.-H.; Liang, Y.-M. Org. Lett. 2007, 9, 3527.
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354.
10.1021/ol8024956 CCC: $40.75
Published on Web 12/02/2008
2009 American Chemical Society

opportunity for further subsequent reactions by C-C, C-N,
or C-S bond-forming reactions.
compound 4a was confirmed by NMR spectroscopy and,
additionally, through X-ray analysis.20 Treatment of com-
pound 3a with iodine in the presence of pyridine led to
complete recovery of starting material (entry 2). The
combination of NaOtBu and iodine is known to generate tert-
butyl hypoiodite.21 Initial addition of sodium tert-butoxide
followed by iodine and heating to reflux resulted in 74%
yield of cyclized product 4a after purification (Table 1, entry
3). Even after several hours of stirring at room temperature
(Table 1, entry 4) under otherwise similar reaction conditions,
we obtained the product 4a in 69% yield. All reaction
conditions except entry 2 are almost equally effective for
these carbocyclizations, resulting in clean conversion toward
the cyclized product.
Herein, we report the synthesis of 3-iodo-1H-indenes
through an iodocarbocyclization of 2-substituted ethynyl-
malonates. Liang et al. reported the synthesis of indene
derivatives by an exo-iodocarbocyclization of 2-substituted
ethynylbenzyl malonates,15 and Barluenga et al. synthesized
iodocyclopentenes from ꢀ-ketoester derivatives.16 Taguchi
et al. also have investigated iodocyclizations of malonate
derivatives.17 To the best of our knowledge, this is the first
report for the synthesis of 3-iodo-1H-indenes by an iodo-
nium-promoted 5-endo-dig carbocyclization of 2-substituted
ethynylmalonates. Various heterocyclic compounds can also
be accessible using 5-endo-dig cyclizations of suitable
substrates.18
To investigate the scope of the reaction a variety of
differently substituted alkynyl moieties with aliphatic and
aromatic substituents were successfully converted to the
cyclized products in good yields as shown in Table 2.
Scheme 1. Synthesis of Alkynyl Malonates 3
Table 2. Formation of 3-Iodo-1H-indene Derivatives 4
The synthesis of alkynyl malonates proceeded smoothly
starting either from ethyl (2-iodophenyl)acetate 1a (R ) H)
or from (2-iodophenyl) propanedioic acid diethyl ester 1b
(R ) CO2Et).19 Sonogashira coupling led to alkynes 2 and
3f in good yields (42-76%), which were then treated
(2a-2e) with sodium hydride and diethylcarbonate to obtain
the starting materials 3 for the carbocyclization reactions.
To find optimal reaction conditions for the iodine-mediated
carbocyclizations, several reagent combinations and reaction
conditions were screened. Compound 3a (R ) Ph) was
treated with NaH before iodine was added, and the reaction
mixture was refluxed for 2 h (Table 1). Product 4a was
a 1.2 equiv of base and 1.2 equiv of iodine were used.
Electron-donating substituents such as a methoxy moiety
in the meta-position (Table 2, entry 3) or propargylic ethers
are tolerated under these conditions (Table 2, entries 4 and
5). The yields for the cyclization of substrates 3 having
Table 1. Screening of Reaction Conditions for the Cyclization
of 3a
(15) 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.
(16) Barluenga, J.; Palomas, D.; Rubio, E.; Gonza´lez, J. M. Org. Lett.
2007, 9, 2823.
(17) (a) Kitagawa, O.; Inoue, T.; Hirano, K.; Taguchi, T. J. Org. Chem.
1993, 58, 3106. (b) Kitagawa, O.; Taguchi, T. Synlett 1999, 1191.
(18) (a) Knight, D. W. Prog. Heterocycl. Chem. 2002, 14, 19. (b) Zhang,
L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 125, 6962. (c) Foot, O. F.;
Knight, D. W.; Low, A. C. L.; Li, Y. Tetrahedron Lett. 2007, 48, 647.
(19) Larock, R. C.; Fried, C. A. J. Am. Chem. Soc. 1990, 112, 5882.
(20) CCDC 705766 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via www.ccdc-
.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033; e-mail: deposit@
ccdc.cam.ac.uk).
entry
base
NaH
Pyridine
NaOtBu
NaOtBu
time [h]
temp [°C]
yield 4a [%]
1
2
3
4
2
2
2
65
65
65
20
77a
0
74
69
80
a 1.2 equiv of base and 1.2 equiv of iodine were used.
(21) (a) Montoro, R.; Wirth, T. Org. Lett. 2003, 5, 4729. (b) Montoro,
R.; Wirth, T. Synthesis 2005, 1473. (c) Minakata, S.; Morino, Y.; Ide, T.;
Oderaotoshi, Y.; Komatsu, M. Chem. Commun. 2007, 3279.
purified by column chromatography and obtained in 77%
yield as a crystalline solid (entry 1). The structure of
230
Org. Lett., Vol. 11, No. 1, 2009

simple aromatic or aliphatic substituents (Table 2, entries 1,
2, and 6) are good as well.
Scheme 3
.
Use of 4a as Catalyst in the R-Oxytosylation of
Literature evidence22 and the course of the reaction
revealed that an addition of iodine to the deprotonated
malonate 5 may result in the initial formation of an
R-iodomalonate 6.23 This quite unstable compound has also
been identified, but only as a mixture together with the
starting material 3a. In the presence of iodide (NaI) or by
reaction with elemental iodine the formation of the cyclized
product 4a via 7 is observed.
Propiophenone
bearing an oxygen close to the iodine. Attachment of a chiral
moiety to the oxygen can provide fast access to enantio-
merically pure catalysts for asymmetric synthesis.
To also exploit other reactions, compound 4a was sub-
jected to Heck reaction conditions resulting in the formation
of two compounds 10 and 11, which could not be separated
through column chromatography (Scheme 4). The reaction
Scheme 2. Mechanistic Considerations
Scheme 4. Heck Reaction Using 4a as Substrate
mixture was analyzed by GC-MS, and a ratio of 1:1 (10:11)
was established.
In conclusion, this methodolgy offers a fast way for the
facile synthesis of 3-iodo-1H-indene derivatives from easily
accessible starting materials that can further be elaborated
by other chemistries such as palladium and hypervalent
iodine chemistry.
Others and we have already shown that iodine derivatives
can be used as catalysts for the in situ generation of
hypervalent iodine compounds.24 R-Oxytosylations of pro-
piophenone 8 can be performed by using catalytic amounts
of 4a leading to the product 9 in 53% yield (Scheme 3).
Compounds of type 4d and 4e have the additional benefit of
Acknowledgment. We thank the Higher Education Com-
mission (HEC) Pakistan for a fellowship (Z.A.K.), Cardiff
University for support, and the National Mass Spectrometry
Service Centre, Swansea for mass spectrometric data.
(22) Beckwith, A. L. J.; Tozer, M. J. Tetrahedron Lett. 1992, 33, 4975.
(23) Curran, D. P.; Chen, M.-H.; Spletzer, E.; Seong, C. M.; Chang,
C.-T. J. Am. Chem. Soc. 1989, 111, 8872.
Supporting Information Available: Experimental pro-
cedures for the synthesis of 1a,1b, 2a-2e, 3a-3f, 4a-4f,
9, 10, and 11 and spectral data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(24) (a) Richardson, R. D.; Wirth, T. Angew. Chem., Int. Ed. 2006, 45,
4402. (b) Richardson, R. D.; Page, T. K.; Altermann, S. M.; Paradine, S. M.;
French, A. N.; Wirth, T. Synlett 2007, 538. (c) Ochiai, M.; Miyamoto, K.
Eur. J. Org. Chem. 2008, 4229. (d) Altermann, S. M.; Richardson, R. D.;
Page, T. K.; Schmidt, R. K.; Holland, E.; Mohammed, U.; Paradine, S. M.;
French, A. N.; Richter, C.; Bahar, A. M.; Witulski, B.; Wirth, T. Eur. J.
Org. Chem. 2008, 5315.
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