Halocyclization of o-(alkynyl)styrenes. Synthesis of 3-halo-1H-indenes

Article abstract of DOI:10.1039/c0cc02590a

o-(Alkynyl)styrenes undergo halocarbocyclization processes via a 5-endo-dig ring closure. By this strategy an efficient synthesis of 3-halo-1H-indene derivatives has been developed.

Full text of DOI:10.1039/c0cc02590a

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Halocyclization of o-(alkynyl)styrenes. Synthesis of 3-halo-1H-indenesw
Roberto Sanz,*a Alberto Martınez,a Patricia Garcı a,a
a-Garcı
´ ´ ´
´ ´
´ ´
Manuel A. Fernandez-Rodrıguez, Muhammad A. Rashid and Felix Rodrıguez
a
a
b
Received 15th July 2010, Accepted 18th August 2010
DOI: 10.1039/c0cc02590a
o-(Alkynyl)styrenes undergo halocarbocyclization processes via
a 5-endo-dig ring closure. By this strategy an efficient synthesis
of 3-halo-1H-indene derivatives has been developed.
that a direct halocyclization has occurred, probably through
the formation of a stabilized carbocation 2 that undergoes
proton elimination to afford the functionalized indene moiety
(Scheme 1). It should be noted that in contrast to those
examples recently reported by Kirsch and co-workers that
proceed through a 6-endo cyclization process,5 our reaction
implies an unprecedented 5-endo halocyclization reaction of an
enyne derivative.8 The stability of the tertiary carbocation
intermediate 2 could be the key for the success of the proposed
5-endo cyclization.
The electrophilic cyclization of heteroatomic nucleophiles with
alkynes, mainly with iodine-containing electrophiles, is a
useful method for the synthesis of functionalized heterocyclic
compounds.1 However, the analogous carbocyclization reac-
tions, i.e. the internal nucleophile is a carbon-based moiety,
have been much less developed. Few examples have been
reported involving the use of arenes2 and malonates3 as
nucleophilic partners. Remarkably, the use of olefins4 for
triggering this type of cyclization reactions has remained
unknown until very recently, when Kirsch and co-workers
have established that 1,5-enynes can undergo an iodonium-
induced carbocyclization via 6-endo-dig processes.5 On the
other hand, we have recently described the (enantioselective)
synthesis of 1H-indene derivatives by an unprecedented
gold(I)-catalyzed 5-endo-dig cyclization of ortho-(alkynyl)-
styrenes 1.6 In this context, and considering that the presence
of an halogen atom at the C-3 position of the final indene
derivative could be of interest for further functionalization, we
wondered about the feasibility of synthesizing 3-halo-1H-
indenes7 from the same o-(alkynyl)styrenes 1 as proposed in
Scheme 1.
As shown in Table 1, a variety of o-(alkynyl)styrenes 1 are
useful substrates for this iodocyclization. Reactions were
performed at reflux in few hours under an air atmosphere.9
Different substituents at the alkyne (R1), including functionalized-
aromatic, heteroaromatic, (functionalized)-alkyl, and hetero-
atomic ones, are well tolerated (Table 1, entries 1–6). Regarding
the alkene, besides two methyl groups, R2 and R3 could be
part of a cyclic alkyl moiety (Table 1, entries 8 and 9) as
well as two different groups such as methyl and phenyl
(Table 1, entries 7 and 14). However, terminal alkynes
(R1 = H) proved to be unreactive under the reaction conditions,
whereas substrates lacking a substituent at the b-position of
the styrene moiety (R2 = H) gave rise to a complex mixture of
products.10 In addition, substrates bearing electron-withdrawing
as well as electron-donating groups at the benzenoid
moiety efficiently underwent the iodocyclization reaction
(Table 1, entries 10–14).
Gratifyingly, we found that 3-iodoindene 3a (R = Ph) was
selectively formed and isolated in high yield when 1a (R = Ph)
was treated with an excess of NIS in CH2Cl2 at room tempera-
ture for 24 h, in the absence of any catalyst. This result shows
The possibility of using molecular iodine as the electrophilic
reagent was also demonstrated by the isolation of iodoindenes
3b and 3l, from treatment of substrates 1b and 1l with I2 and
base instead of NIS (Table 1, entries 2 and 12). However, the
yields were slightly lower and, moreover, in some cases, such
as the reaction of 1a, some side-products were formed along
with the desired compound.
Interestingly, the same halocyclization reaction was observed
when NBS was used. In this case, 3-bromo-1H-indenes 4a and
4j were isolated in good yields (Scheme 2).
We next decided to check the possibility of introducing
further functionality on the C-1 substituent of the indene by
performing the iodocyclization in the presence of external
oxygen nucleophiles. After some optimization, we found that
although the competitive elimination reaction that affords
iodoindenes 3 could not be completely suppressed, 1-alkoxy-
substituted 3-iodo-1H-indene derivatives 5 could be isolated in
useful yields and in pure form by using a large excess of MeOH
(Table 2). In these cases, reactions are faster and could be
performed at room temperature in 1–4 h. Better selectivities to
5 and therefore yields were obtained with substrates such as 1j
and 1k bearing electron-withdrawing substituents at the
aromatic nucleus (see entries 5 and 6 vs. 1), and with 1g
Scheme 1 Our proposal for the synthesis of 3-iodoindenes.
a
´
Departamento de Quımica, Area de Quımica Organica,
´
Facultad de Ciencias, Universidad de Burgos,
´
´
Pza. Misael Ban˜uelos s/n, 09001-Burgos, Spain. E-mail: rsd@ubu.es;
Fax: +34 947258831; Tel: +34 947258036
b
´
Instituto Universitario de Quımica Organometalica ‘‘Enrique Moles’’,
Universidad de Oviedo, 33006-Oviedo, Spain
´
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and NMR spectra. See DOI:
10.1039/c0cc02590a
c
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Chem. Commun., 2010, 46, 7427–7429 7427

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Table 1 Synthesis of 3-iodo-1H-indenes 3 by iodocyclization of
o-(alkynyl)styrenes 1
Table 2 Alkoxyiodocyclization of o-(alkynyl)styrenes 1
Yielda
(%)
Entry
1
R1
R2
R3
t/h
5
Yielda
(%)
1
2
3
4
5
6
1a
1b
1f
Ph
4-MeOC6H4
SPh
Ph
Ph
Ph
H
H
H
H
F
H
H
H
Ph
H
H
2
1
1
3
2
4
5a
5b
5f
5g
5j
66(58)b
70
Entry
1
R1
R2
R3 R4
R5
t/h
3
58
1
2
3
4
5
6
7
8
1a Ph
1b 4-MeOC6H4 Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
3
1
3a 85
3b 92(71)c
1gc
1j
81d
78
1c 3-Thb
1d nBu
1e (CH2)3CN
1f SPh
1g Ph
Me
Me
Me
Me
Ph
2.5 3c 87
2
1k
Br
5k
72
3d 81
a
15 3e 71
3f 80
4.5 3g 81
3h 71
3i 88
15 3j 79
3k 84
3l 78(67)c
16 3m 82
36 3n 55d
Isolated yield after column chromatography referred to starting
1
b
material 1. Carried out with I2/K3PO4 as electrophilic source. Used
d
as a ca. 2 : 1 mixture of geometrical isomers. Obtained as a ca. 2 : 1
c
1h Ph
1i Ph
1j Ph
1k Ph
1l Ph
1m nBu
1n nBu
À(CH2)3À
2
3
mixture of diastereoisomers.
9
À(CH2)4À
10
11
12
13
14
Me
Me
Me
Me
Ph
H
H
H
H
H
Br
7
1
–OCH2O–
Br
Br
H
H
a
Isolated yield after column chromatography referred to starting
b
material 1. 3-Thienyl. Carried out with I2/K3PO4 (3 equiv.) at rt.
d
c
B80% conversion.
Scheme 3 Synthetic applications of 3-haloindenes 3 and 4.
Scheme 2 Bromonium-mediated synthesis of 3-bromo-1H-indenes 4.
represent the first examples of electrophilic cyclizations of
alkynes promoted by halonium ions where the nucleophilic
counterpart is an alkene. In particular, our results represent
the first examples of this type of halocyclization via a 5-endo-dig
ring closure mechanism. The presence of a halogen in the final
products allows further functionalization at the C-3 position
of the indene through conventional palladium-catalyzed cross-
coupling reactions. Current efforts in our lab are devoted to
the development of an enantioselective version of this reaction
and further applications of the obtained haloindenes in the
synthesis of complex molecules.
(entry 4) that possess a phenyl group at the alkene. In
addition, we have also demonstrated that I2/K3PO4 could be
used as iodonium source in the alkoxyiodocyclization reaction
of 1a (Table 2, entry 1), although with slightly lower
selectivity.
Having in mind that 2,3-diarylindenes are known to possess
biological activity,11 we decided to employ the synthesized
3-haloindenes as precursors for the introduction of an aromatic
substituent at the C-3 of the indene moiety by Pd-catalyzed
cross-coupling reactions. In this way, 2,3-diarylindene
derivatives 6 were obtained in high yield from 3a and 3b
through a Suzuki coupling12 with phenylboronic acid and
Pd(OAc)2/SPhos as catalytic system (Scheme 3). Interestingly,
when bromoindene 4a underwent a Stille coupling13 with
2-(tributylstannyl)furan, the functionalized benzofulvene14
derivative 7 was obtained, in which further isomerization of
the propenyl group at the C-1 position of the indene scaffold
has occurred (Scheme 3).
´
We gratefully thank Junta de Castilla y Leon (BU021A09
and GR-172) and Ministerio de Educacion y Ciencia (MEC)
´
and FEDER (CTQ2007-61436/BQU and CTQ2009-09949/
BQU) for financial support. A.M., P.G.-G., M.A.F.-R.
and M.A.R. also thank MEC for FPU grant, Juan de la
Cierva, Ramon y Cajal and ‘‘Young Foreign Researchers’’
´
(SB2009-0186) contracts, respectively.
In summary, we have reported the direct halocyclization of
o-(alkynyl)styrenes to give 3-halo-1H-indene derivatives in
good to high yields under mild conditions. These results
together with those recently reported by Kirsch and coworkers
Notes and references
1 F. Rodrıguez and F. J. Fananas, in Handbook of
´ ´
Cyclization Reactions, ed. S. Ma, Wiley-VCH, Weinheim,
Germany, 2010, vol. 2, p. 951. For some particular examples on
c
7428 Chem. Commun., 2010, 46, 7427–7429
This journal is The Royal Society of Chemistry 2010

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´
´
Romanelli, L. J. Alvarez-Garcı
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´
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c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7427–7429 7429