Efficient synthesis of 3-iodoindenes via Lewis-acid catalyzed Friedel-crafts cyclization of iodinated allylic alcohols

Article abstract of DOI:10.1021/jo800232p

(Chemical Equation Presented) A convenient BF₃·Et ₂O-catalyzed Friedel-Crafts cyclization of iodinated allylic alcohols is reported. The present reaction provides an efficient protocol to 3-iodo-1H-indene derivatives in good to high

Full text of DOI:10.1021/jo800232p

aryl halides,8 [3 + 2] annulation of aromatic aldimines and
acetylenes,9 and cyclization of 2-alkyl-1-ethynylbenzenes via
a 1,5-hydrogen shift of ruthenium-vinylidene intermediates,10
etc. Haloindenes are important derivatives that provide further
structural complexation by proceeding new C-C, C-N, or C-S
bond-forming reactions. There are only limited reports for the
synthesis of haloindenes, such as the bromination of indans or
indenes11 and HI-mediated cyclization of o-alkynylstyrenes,12
etc. However, most of these methods are only effective in the
formation of simple haloindenes or specific-substituted indenes,
it is still difficult to synthesize haloindenes with a wide range
of different substituents. In this paper, we would like to report
a convenient and catalytic route for 3-iodo-1H-indenes through
Friedel-Crafts cyclization of iodinated allylic alcohols.
Efficient Synthesis of 3-Iodoindenes via
Lewis-Acid Catalyzed Friedel-Crafts Cyclization
of Iodinated Allylic Alcohols
Xiaobo Zhou, Huimin Zhang, Xin Xie, and Yanzhong Li*
Institute of Medicinal Chemistry, and Shanghai Key
Laboratory of Green Chemistry and Chemical Processes,
Department of Chemistry, East China Normal UniVersity,
3663 North Zhongshan Road, Shanghai, 200062, P. R. China
yzli@chem.ecnu.edu.cn
ReceiVed January 31, 2008
SCHEME 1
A convenient BF3 ·Et2O-catalyzed Friedel-Crafts cyclization
of iodinated allylic alcohols is reported. The present reaction
provides an efficient protocol to 3-iodo-1H-indene derivatives
in good to high yields under mild conditions. Further, the
iodoindene derivatives are valuable synthetic building blocks
for elaboration of molecular complexity, such as in the
construction of multiaryl substituted indenes by Suzuki
coupling reaction.
It was known that alkynes such as diphenylacetylene undergo
selective coupling with aldehydes or ketones mediated by
zirconocene-ethylene complex to form five-membered oxazir-
conacycles.13 Iodonolysis of this metallacycle affords the desired
iodinated allylic alcohols 1.13f,g Thus, a series of alcohol 1 were
easily prepared in 35% ∼ 55% yields using this method. With
allylic alcohol 1 in hand, we were interested in exploring the
feasibility of cyclodehydration of 1 to haloindenes. We began
our investigation with 3-iodo-1,2,3-triphenylprop-2-en-1-ol 1a
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organometals to 1-indanone followed by dehydration,7 etc. In
addition to these classical methods, metal-catalyzed protocols
have also been well developed in recent years, such as
palladium-catalyzed carboannulation of internal alkynes with
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3958 J. Org. Chem. 2008, 73, 3958–3960
10.1021/jo800232p CCC: $40.75 2008 American Chemical Society
Published on Web 04/18/2008

TABLE 1. Screening of Reaction Conditions for Cyclization
Reactions
TABLE 2. Formation of 3-Iodo-1H-indene Derivatives
entry
catalyst
mol %
time (h)
yield (%)a
1
2
3
4
5
6
HCl (3N)
10
50
50
10
10
20
24
35
2
24
12
3
–
41
72
43
40
75
HCl (concd)
H2SO4 (concd)
H2SO4 (concd)
BF3 ·Et2O
BF3 ·Et2O
a Isolated yields.
derived from alkyne-aldehyde coupling reactions. The results
are shown in Table 1. First, we tried the reaction using a catalytic
amount of 3 N HCl (10 mol %) in CH2Cl2. However, no indene
products could be detected (Table 1, entry 1). Concentrated HCl
(50 mol %) gave the desired indene in only 41% yield after
35 h (Table 1, entry 2). Changing the catalyst to concentrated
H2SO4 (50 mol %) resulted in the formation of the desired
3-iodoindene 2a in 72% yield (entry 3). Decreasing the amount
of H2SO4 to 10 mol % resulted in the indene being formed in
lower yield even after 24 h (entry 4). Interestingly, when we
use a catalytic amount of BF3 ·Et2O,14 the reaction completed
within 3 h and 2a was isolated in 75% yield (entry 6). Then
BF3 ·Et2O was selected as the catalyst for this cyclization
reaction. The structure of 2a was unequivocally confirmed by
X-ray crystal analysis (Figure 1), which clearly shows that iodine
substituted at C-3 of the indene ring.
A variety of allylic alcohols bearing phenyl ring moiety were
then subjected to the modified reaction conditions to define the
reaction scope. As shown in Table 2, the substituents on
R-carbon of alcoholic group in 1 has big influence on this
cyclization reaction. The secondary allylic alcohol 1a-c bearing
an aromatic ring at C-1 cyclized very well to generate the
corresponding indenes 2a-c in 63%-90% yields (Table 2,
entries 1-3). A thienyl-substituted 1d could also be applied in
this reaction to form compound 2d in 63% yield (entry 4).
However, when a alkyl substituted 1e or primary alcohol 1f
were used, the desired products of 2e and 2f were obtained in
low yields of 31% and 15%, respectively. Reasonable yield was
obtained when 2.0 equiv and 4.0 equiv of BF3 ·Et2O were
employed, respectively (entries 5 and 6). The results indicated
that the phenyl allyl cations formed in the reactions are less
stable in these cases. Interestingly, the substrates of 1g-I
derived from Zr-mediated alkyne-ketone coupling reactions13g
cyclized smoothly to give 2g-I in 61%-88% yields, whenever
bearing phenyl or alkyl substituents (entries 7-9).
a Isolated yields. All the reactions were carried out at room
temperature. b Reaction run using 2.0 equiv BF3 ·Et2O. c Reaction run
using 4.0 equiv BF3 ·Et2O.
SCHEME 2
The mechanism of the formation of indene 2a from 1a is
shown as follows (Scheme 2): First formation of an allyl cation
3 generated in situ by cleavage of the carbon-oxygen bond. 3
is in equilibrium with cation 4, and then 4 undergoes electro-
cyclic ring closure to indenes 2a by the elimination of a proton.
The complete absence of indene 6 in the reaction mixture
implicates that (a) the cation 3 might not exist in equilibrium
with another conformer cation 5, probably due to the steric
interaction between iodo and phenyl groups; (b) cation 5 does
not undergo an intramolecular Friedel-Crafts reaction.
Multiaryl substituted indenes, especially 2,3-diaryl indenes
have been reported to exhibit high biological activities.15 The
utility of 3-iodoindenes as useful synthetic intermediates was
(15) (a) Jordan, V. C. Pharmacol. ReV. 1984, 36, 245. (b) Hong, H. C.;
Chamberlain, T. S.; Seiber, K.; Koboldt, C. M.; Isakson, P. C.; Reitz, D. B.
Bioorg. Med. Chem. Lett. 1995, 5, 2377. (c) Anstead, G. M.; Peterson, C. S.;
Pinney, K. G.; Wilson, S. R.; Katzenellenbogen, J. A. J. Med. Chem. 1990, 33,
2726.
(14) (a) For the cyclodehydration of the phenyl-substituted allylic alcohols
using excess amount of BF3 · Et2O, see (a) ref 4d. (b) Sun, X.; Izumi, K.; Hu,
C.; Lin, G. Chin. J. Chem. 2006, 24, 430.
J. Org. Chem. Vol. 73, No. 10, 2008 3959

SCHEME 3
1,2,3-triphenylprop-2-en-1-ol (1a) (1.0 mmol) in CH2Cl2 (5 mL)
was added 0.2 mmol of BF3 ·Et2O (27 µl) at room temperature.
The reaction mixture was kept at the same temperature for 3 h.
Then it was quenched with H2O and extracted with ether (3 × 15
mL). The extract was washed with Na2S2O3 and brine and dried
over MgSO4. The solvent was evaporated under vacuo and the
residue was purified by flash chromatography on silica gel to
provide 2a as a light-yellow solid (296 mg, 75%). Mp 105-106
°C. 1H NMR (CDCl3, Me4Si) δ 4.97 (s, 1H), 6.96-7.45 (m, 14H).
13C NMR (CDCl3, Me4Si) δ 59.7, 94.9, 122.9, 123.5, 126.7, 126.9,
127.5, 127.8, 128.00, 128.0, 128.6, 128.9, 135.8, 138.4, 145.3,
146.5, 153.6. HRMS calcd for C21H15I, 394.0219; found, 394.0219.
investigated by Pd-catalyzed Suzuki-coupling reactions, which
afforded triaryl-substituted indenes 7a and 7b in 68% and 65%
yields, respectively (Scheme 3).
In summary, we have developed a convenient procedure for
the preparation of 3-iodo-1H-indene derivatives in good to high
yields under mild conditions. Further, the iodo derivatives are
valuable synthetic intermediates for elaboration reaction, such
as in the construction of multiaryl substituted indenes by Suzuki
coupling reaction.
Acknowledgment. We are grateful to the National Natural Sci-
ence Foundation of China (Grant Nos. 20442007 and 20572025)
for financial support.
Supporting Information Available: Experimental details and
spectroscopic characterization of all new compounds and CIF
file giving crystallographic data of 2a. This material is available
free of charge via the Internet at http://pubs.acs.org.
Experimental Section
A Typical Procedure for the Preparation of 3-Iodo-indenes.
3-Iodo-1,2-diphenyl-1H-indene (2a). To a solution of (Z)-3-iodo-
JO800232P
3960 J. Org. Chem. Vol. 73, No. 10, 2008