A copper(II) triflate-catalyzed tandem friedel-crafts alkylation/ cyclization process towards dihydroindenes

Article abstract of DOI:10.1002/adsc.201000966

A one-pot synthesis of dihydroindenes from substituted benzenes and haloalkenes was developed. The reaction proceeded via a copper(II) triflate [Cu(OTf)₂]-catalyzed tandem Friedel-Crafts alkylation/cyclization process with high efficiency under

Full text of DOI:10.1002/adsc.201000966

COMMUNICATIONS
DOI: 10.1002/adsc.201000966
A Copper(II) Triflate-Catalyzed Tandem Friedel–Crafts
Alkylation/Cyclization Process towards Dihydroindenes
Yugen Zhang,a,* Liwei Chen,a and Ting Lua
a
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore
Fax : (+65)-6478-9081; e-mail: ygzhang@ibn.a-star.edu.sg
Received: December 26, 2010; Revised: February 6, 2011; Published online: May 3, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000966.
Abstract: A one-pot synthesis of dihydroindenes
from substituted benzenes and haloalkenes was de-
veloped. The reaction proceeded via a copper(II)
triflate [CuACHTUNGTRENNUNG(OTf)2]-catalyzed tandem Friedel–Crafts
alkylation/cyclization process with high efficiency
under relatively mild conditions.
Keywords: dihydroindenes; Friedel–Crafts alkyla-
tion; homogeneous catalysis; tandem reactions
Many natural products and synthetic bioactive com-
pounds possess the dihydroindene ring systems.[1,2] As
such, the syntheses have been well developed and
Scheme 1. Bimolecular Friedel–Crafts cyclizations.
documented. Some elegant examples include cationic one-pot CuACTHNUTRGENUG(N OTf)2-catalyzed sequential alkylation of
cyclization,[3] organometallic catalytic reactions,[4] cy- benzenes with allylic halides and the formation of di-
cloaddition/reduction[5] and other miscellaneous hydroindene skeletons through an intramolecular cy-
routes.[6] However, most of these methods suffered
from multiple step synthesis, limited substrate scope,
ACHTUNGTRENNUNG
low yields, or tedious processes. The synthesis of such tible to Friedel–Crafts alkylation, and the regioselec-
skeletons in a direct and economical matter, while tivity largely depends on the catalyst chosen. For ex-
highly desired, remains a challenge. The Friedel– ample, it is known that with protic acid catalysts, hal-
Crafts cyclization reaction is a very important meth- oalkenes generally favor the reaction at the double
odology for the synthesis of various useful carbocyclic bond,[10,11,12] while reactions at the allylic position can
compounds through carbon-carbon bond formation be realized by some ruthenium catalysts.[13]
with aromatic substrates.[7] Bimolecular Friedel–Crafts
In this report, the efficiency and the regioselectivity
annulation, in which bifunctional electrophiles react of the Friedel–Crafts alkylations between substituted
intramolecularly with the same aromatic ring, is inher- benzenes and allylic halides with Cu(OTf)2 as catalyst
AHCTUNGTRENNUNG
ently more challenging, as competitive intermolecular were examined. Experimentally, 1 mmol of 1,2,4,5-tet-
reactions lead to non-ring products.[8] It is well known ramethylbenzene 1, 1.1 mmol of cinnamyl chloride 4
that a bifunctional substrate capable of both acylation and 2 mol% catalyst were added in 5 mL of CH2Cl2
and alkylation with aromatic compounds is appealing (Scheme 2). The mixture was stirred at 608C for 16 h.
for the formation of important cyclic aromatic ke- Instead of observing the Friedel–Crafts alkylation
tones.[5,8,9] Excess amounts of Lewis acids, Brønsted products, 2,3,4,5-tetramethyl-9-phenylindane 7 was
acids and/or strong protic acids were typically applied isolated in 78% yield. A higher yield of 7 could be
to promote these reactions, as shown in Scheme 1. achieved when an excess amount of cinnamyl chloride
The cyclic aromatic ketones could then be further re- was used (Table 1, entry 1). The structure of 7 was
duced to form dihydroindenes.[5] Herein, we report a confirmed by an X-ray single crystal diffraction study
Adv. Synth. Catal. 2011, 353, 1055 – 1060
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1055

Yugen Zhang et al.
COMMUNICATIONS
Scheme 2. (a) Proposed reaction pathway; (b) transformation conditions between 1, 2 and 7.
(Figure 1).[14] This remarkable reaction proceeds via
several challenging steps in one-pot with a single cata-
lyst.
In the first step, Friedel–Crafts alkylation of 1 hap-
pened at the allylic position to form the intermediate
2, catalyzed by CuACTHNUTRGNEUNG
(OTf)2,[15] [Scheme 2, (a)]. Al-
though there was no trace of intermediate 2 in the
final reaction mixture, the formation of 2 was con-
firmed by analysis of a reaction mixture that was
quenched at an early stage. Another possible product
5 was not observed either in the final reaction mixture
or the quenched reaction mixture. Friedel–Crafts al-
kylations are usually reversible processes, which re-
quire a large excess amount of acids, and for the anal-
ogous allylation reactions, a mixture of regiomers is
normally obtained. In our case, the catalytic amount
of CuACHTUNGTRENNUNG(OTf)2 can efficiently promote the process in a
highly regioselective manner to obtain the intermedi-
ate 2. Following the first allylation step, intermediate
2 underwent double methyl migration under acidic
Figure 1. Molecular structure of 7. Hydrogen atoms have
conditions to form intermediate 3. The Lewis acid- been omitted for clarity.
1056
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1055 – 1060

A Copper(II) Triflate-Catalyzed Tandem Friedel–Crafts Alkylation/Cyclization Process
Table 1. Optimization of the eaction conditions.[a]
[a]
Reaction conditions: durene (0.5 mmol), cinnamyl chloride (0.55 mmol), catalyst
(5.0 mol%), CH2Cl2 (2 mL), 608C, 16 h.
Excess amounts of additives (1 mmol) were used.
An unidentified product was observed.
[b]
[c]
promoted methyl migration reaction itself is well roles in the methyl migration and the intramolecular
known as a reversible process and the efficiency of alkylation steps, vide infra.
this migration is low.[16] Although we were unable to
Other protic acids or Lewis acids did not promote
isolate intermediate 3, it was clearly observed from the reaction to from product 7 (Table 1, entries 3 and
the final product that this methyl migration process 4). When cinnamyl alcohol 6 was used instead of cin-
was very efficient in this system. In the final step, in- namyl chloride 4, only 2 was isolated in low yield
termediate 3 underwent an acid-induced intramolecu- (Table 1, entry 13). However, when cinnamyl acetate
lar alkylation to form cyclized product 7.[8,17] The pref- 8 was used as the reactant, both 2 and 7 were pro-
erence to form the stable final product 7 may be the duced in a 1:2 ratio (Table 1, entry 15). This is be-
major factor in determining the equilibria of the pre- cause no strong acids were generated in both systems
vious two steps, in which the forward reaction was fa- with cinnamyl alcohol and cinnamyl acetate. Similarly,
vored, forming the desired intermediates.
In summary, Cu(OTf)2 catalyzed the first allylation
when an excess amount of a base, such as triethyl-
ACHTUNGTRENaNUNG mine or sodium carbonate, was added to the durene/
U
step of the reaction and the hydrogen chloride that cinnamyl chloride reaction system, only 2 was ob-
was generated from the first step played important served in low yield (Table 1, entries 5 and 6). Further
investigations indicated that 2 can be converted to 7
Adv. Synth. Catal. 2011, 353, 1055 – 1060
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1057

Yugen Zhang et al.
COMMUNICATIONS
Table 2. CuACTHNUTRGNEUNG
(OTf)2-catalyzed cycloaddition of arene with haloalkenes.[a]
[a]
Reaction conditions: arene (1 mmol), haloalkene (1.1 mmol), catalyst (5.0 mol%),
CH2Cl2 or C2H2Cl4 (4 mL).
GC yield and isolated yield in parentheses.
[b]
[c]
2 mmol of cinnamyl chloride were used.
under standard reaction conditions with stoichiomet- could not be converted to 7 in the presence of just
ric amounts of acid additives, such as trifluoroacetic CuACHTUNGTRENNUNG
acid, HCl or acid generated in situ from the reaction
between 1 and cinnamyl chloride [Table 1, entry 14, chloromethane gave good results (Table 1, entries 1,
Scheme 2(b)]. If no acid additives were present, 2 9–12). It was also interesting to note that without any
1058
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1055 – 1060

A Copper(II) Triflate-Catalyzed Tandem Friedel–Crafts Alkylation/Cyclization Process
spectra were recorded on a Bruker AV-400 instrument
(400 MHz).
arenes present in the reaction mixture, cinnamyl chlo-
ride alone, in the presence of Cu(OTf)2 catalyst in
AHCTUNGTRENNUNG
CH2Cl2, generated the cyclicized product (1,2-diphen-
yl-3-chloromethylcyclopentene). The isolated product
was believed to be derived from the intermolecular
reaction between two cinnamyl chloride molecules
(see Supporting Information). No such cyclic dimer
Typical Synthetic Procedure (Table 2, entry 1)
1 mmol of 1 (134 mg), 1.1 mmol of cinnamyl chloride 4
(151 mg) and 0.05 mmol of Cu
ACHTUNGRTEN(NUGN OTf)2 ( 18 mg) were added
into a reaction vial with 5 mL CH2Cl2 in a glove box. The re-
was observed when arenes were present in the reac- action vial was capped and taken out, heated to 608C and
kept stirring for 16 h. Then, the reaction mixture was cooled
to room temperature and diluted with CH2Cl2 (10 mL) and
water (15 mL). The aqueous layer was extracted with
CH2Cl2 (10 mLꢁ2). The combined organic layer was dried
(MgSO4), and concentrated. The pure product was obtained
through flash silica gel column chromatography of the resi-
due using hexane as the eluent.
tion mixture.
This reaction protocol was then extended to other
substrates. As expected, most of substituted benzenes
were active in this reaction to give the corresponding
dihydroindenes in moderate to good yields, Table 2.
As shown in entries 1–6, bis-, tris- and tetrakis-
methyl-substituted benzenes reacted with cinnamyl
chloride to form the desired products in good yield.
There were no methyl migration steps involved in the
reaction of substrates 9, 11, 13 and 15. From the
mechanism discussion of substrate 1 we know that the
methyl migration step is much slower than final cycli-
zation step. Here reactions of arenes 9, 11, 13 and 15
would prefer go through a direct cyclization. Almost
no reaction was observed between 1,3,5-trimethylben-
zene and cinnamyl chloride under similar conditions.
The same reaction was also found to be efficient for
substituted phenols, (entries 7 and 8). A very good
yield of 20 was obtained when the reaction was car-
ried out with substrate 19, indicating that the methyl
migration step must have occurred. Reactions be-
tween 3,3-dimethylallyl bromide and arenes were also
examined, and similar cycloaddition products 21–26
were obtained (Table 2, entries 9–14).
Acknowledgements
This work was supported by the Institute of Bioengineering
and Nanotechnology (Biomedical Research Council, Agency
for Science, Technology and Research, Singapore).
References
[1] a) D. B. Saxena, Phytochemistry 1986, 25, 553; b) W. M.
Welch, A. R. Kraska, R. Sarges, B. K. Kow, J. Med.
Chem. 1984, 27, 1508; c) W.-H. Lin, J.-M. Fang, Y.-S.
Cheng, Phytochemistry 1995, 40, 871; d) K. Kawazoe,
M. Yamamoto, Y. Takaishi, G. Honda, T. Fujita, E.
Sezik, E. Yesilada, Phytochemistry 1999, 50, 493; e) H.
Ohtsu, M. Iwamoto, H. Ohishi, S. Matsunaga, R.
Tanaka, Tetrahedron Lett. 1999, 40, 6419.
In conclusion, a one-pot CuACHTNUGTRENUNG(OTf)2-catalyzed syn-
thesis of dihydroindenes from substituted benzenes
and cinnamyl chloride has been developed. The final
acid-catalyzed cyclization not only achieved the struc-
turally important dihydroindene skeleton, it was also
the key contribution in promoting the preceding aro-
matic alkylation step and methyl migration step in a
smooth manner under the relatively mild condition,
both of which were considered to be very challenging
by themselves. This efficient method can be applied
to the synthesis of a variety of indane skeletons or
benzo-fused carbocycles.
[2] H. Gao, J. A. Katzenellenbogen, R. Garg, C. Hansch,
Chem. Rev. 1999, 99, 723.
[3] a) S. R. Angle, D. O. Arnaiz, J. Org. Chem. 1992, 57,
5937; b) J. Ipaktschi, G. Lauterbauch, Angew. Chem.
1986, 98, 346; Angew. Chem. Int. Ed. Engl. 1986, 25,
354.
[4] a) R. Deng, L. Sun, Z. Li, Org. Lett. 2007, 9, 5207;
b) D. L. J. Clive, R. Sunasee, Org. Lett. 2007, 9, 2677;
c) K. Yoshida, H. Takahashi, T. Imamoto, Chem. Eur. J.
2008, 14, 8246; d) W. F. Bailey, S. C. Longstaff, J. Org.
Chem. 1998, 63, 432.
[5] R. B. Woodward, T. R. Hoye, J. Am. Chem. Soc. 1977,
99, 8007.
[6] A. S. Kende, K. Koch, A. C. Smith, J. Am. Chem. Soc.
1988, 110, 2210.
[7] a) G. A. Olah, Friedel–Crafts Chemistry, Wiley-Inter-
science, New York, 1973; b) H. Heaney, in: Compre-
hensive Organic Synthesis, Vol. 2, (Eds.: B. M. Trost, I.
Fleming), Pergamon, Oxford, 1991, p 733.
[8] a) S. R. Angle, M. S. Louie, J. Org. Chem. 1991, 56,
2853; b) R. K. Thalji, K. A. Ahrendt, R. G. Bergman,
J. A. Ellman, J. Org. Chem. 2005, 70, 6775; c) G. K. S.
Prakash, P. Yan, B. Torok, G. A. Olah, Catal. Lett.
2003, 87, 109; d) T. Lomberget, E. Bentz, D. Bouyssi,
G. Balme, Org. Lett. 2003, 5, 2055.
Experimental Section
All solvents and chemicals were used as received from com-
mercial suppliers, unless otherwise noted. Dry solvents and
a glove box (Argon Innovative Technologies, Inc.) were
used for the set-up of reactions. Gas chromatography-mass
spectrometry (GC-MS) analyses were performed on a Shi-
madzu GCMS QP2010 system, while gas chromatography
(GC) analyses were conducted on an Agilent GC6890N
system. 1H and 13C nuclear magnetic resonance (NMR)
Adv. Synth. Catal. 2011, 353, 1055 – 1060
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1059

Yugen Zhang et al.
COMMUNICATIONS
[9] R. T. Hart, R. F. Tebbe, J. Am. Chem. Soc. 1950, 72,
3286.
[10] G. A. Olah, Friedel–Crafts and related reactions, Wiley,
New York, 1963/1964, Vols. I–IV.
[11] R. Koncos, B. S. Friedman, in: Friedel–Crafts and relat-
ed reactions, (Ed.: G. A. Olah), Wiley, New York, 1964,
Vol. II.
[12] M. P. D. Mahindaratne, K. Wimalasena, J. Org. Chem.
1998, 63, 2858.
[14] CCDC 783633 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[15] R. Skouta, C.-J. Li, Can. J. Chem. 2008, 86, 616.
[16] A. D. Andreou, R. V. Bulbulian, P. H. Gore, Tetrahe-
dron 1980, 36, 2101.
[17] S. L. Friess, R. Pinson Jr, J. Am. Chem. Soc. 1951, 73,
3512.
[13] G. Onodera, H. Imajima, M. Yamanashi, Y. Nishibaya-
shi, M. Hidai, S. Uemura, Organometallics 2004, 23,
5841.
1060
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1055 – 1060