Solvent-dependent behavior of arylvinylketones in HUSY-zeolite: a green alternative to liquid superacid medium

Article abstract of DOI:10.1016/j.tetlet.2007.06.056

Depending on the reaction conditions, arylvinylketones can be directly and efficiently converted using zeolites to indanones by cyclization or to dihydrochalcones through regioselective aryl addition or chemoselective hydride transfer.

Full text of DOI:10.1016/j.tetlet.2007.06.056

Tetrahedron Letters 48 (2007) 5911–5914
Solvent-dependent behavior of arylvinylketones in HUSY-zeolite:
a green alternative to liquid superacid medium
a,b
a
a
Abdelkarim Sani Souna Sido, Stefan Chassaing, Mayilvasagam Kumarraja,
b,
a
*
Patrick Pale and Jean Sommer
a
Laboratoire de Physicochimie des Hydrocarbures, Institut de Chimie associ e´ au CNRS (UMR 7177), Universit e´ L. Pasteur,
6
7000 Strasbourg, France
Laboratoire de Synth e` se et R e´ activit e´ Organique, Institut de Chimie associ e´ au CNRS (UMR 7177), Universit e´ L. Pasteur,
7000 Strasbourg, France
b
6
Received 21 March 2007; revised 31 May 2007; accepted 6 June 2007
Available online 16 June 2007
Abstract—Depending on the reaction conditions, arylvinylketones can be directly and efficiently converted using zeolites to inda-
nones by cyclization or to dihydrochalcones through regioselective aryl addition or chemoselective hydride transfer.
ꢀ
2007 Elsevier Ltd. All rights reserved.
8
Arylvinylketones represent valuable precursors in
organic synthesis, offering a diversity point toward a
number of pharmaceutically interesting compounds.
solvation via the formation of mono- and dicationic
intermediate species such as I1–4 (Scheme 2). The exact
nature of the key dicationic species is still under debate,
some authors suggesting with some computational
1
,2
Inter alia, arylvinylketones 1 can be converted in liquid
Br o¨ nsted-type superacids to different useful products.3–5
support the involvement of 1,2-dications I3
3,4,9,10
resulting from O,O-diprotonation while others suggest
7
In order to perform these acid-mediated transforma-
tions in a more eco-friendly way, we envisaged to
replace liquid superacid media by solid acids. For the
last thirty years, zeolites have indeed raised enormous
interest as catalyst in hydrocarbon chemistry with a
1,4-dicationic intermediates I4 resulting from O,C-
diprotonation.
O
6
clear environmental benefit. As a result, we recently
R1
reported that intramolecular cyclization of arylvinyl-
ketones 1 into indanones 2 can be performed using solid
acids such as zeolites, sulfated zirconia or heteropoly-
R2
2
non-nucleophilic
aromatic solvent
7
acid. We now report here that the reactivity of aryl-
vinylketones 1 can be modulated and controlled by the
reaction conditions on zeolites. Indeed, either cycliza-
tion to indanones 2, or regioselective aryl addition or
chemoselective hydride transfer to, respectively, dihydro-
chalcones 3 or 4 has been achieved (Scheme 1).
O
R1
R2
1
branched
alkane
nucleophilic
aromatic
solvent S-H
The proposed mechanistic pathways for superacid-
induced transformations rely on superelectrophilic
solvent S-H
O
O
R1
R1
S
R2
H
R2
Keywords: Zeolites; Arylvinylketones; Cyclization; Arylation; Reduc-
tion; Superelectrophile; Dication.
3
4
*
Corresponding author. Tel./fax: +33 390 241 517; e-mail addresses:
ppale@chimie.u-strasbg.fr; sommer@chimie.u-strasbg.fr
Scheme 1. Zeolite-promoted transformations of arylvinylketones.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.056

5912
A. Sani Souna Sido et al. / Tetrahedron Letters 48 (2007) 5911–5914
Table 1. Reaction conditions optimization studies: cyclization
O
R1
O
O
HUSY (eq.)
R2
1
o
-PhCl / 15 h
Ph
2
sealed tube
superelectrophilic activation
1a
2a Ph
a
b
c
H
O
H
H
Entry HUSY
Conditions
Conversion Yield
O
(
equiv)
(%)
(%)
R1
R1
R2
d
d
d
d
e
d
1
2
3
4
5
1
2
5
10
5
o-PhCl
o-PhCl
o-PhCl
o-PhCl
o-PhCl
2
2
2
2
2
, 15 h, 130 ꢁC
, 15 h, 130 ꢁC
, 15 h, 130 ꢁC 100
, 15 h, 130 ꢁC 100
—
<5
—
d
<5
R2
I1
I2
66
68
32
, 15 h, 110 ꢁC
43
H
H
O
O
a
b
c
14,15
Based on the theoretical number of acidic sites of HUSY.
The reaction was conducted in sealed tubes.
Isolated yields of pure product after complete conversion unless
otherwise stated.
Determined by H NMR analysis of the crude mixture.
Based on recovery of starting material after column chromatography.
R1
R1
R2
R2
I3
I4
d
e
1
intramolecular
cyclization
nucleophile NuR
O
O
the promising potential of HUSY-zeolite compared to
the classical liquid medium. Temperature also plays a
critical role on the reaction conversion as demonstrated
by a dramatic loss of efficiency upon a slight decrease of
the temperature (entry 5 vs 3).
R1
R1
Nu
-4
R2
R2
2
3
indanone
dihydrochalcone
Nu = Aryl or H )
(
With these reaction conditions in hand (5 molar excess
of acid sites at 130 ꢁC), we then studied the behavior
of three model phenylvinylketones 1a–c in aromatic sol-
vents having distinct nucleophilic properties (Table 2).
In benzene, a mixture of cyclization product 2 and addi-
tion product 3 was always observed. However, their
relative amount varied upon the precursor nature. Start-
ing from 1b, indanone 2b was the major product, while
from chalcone 1a, addition product 3a was the major
one (entry 7 vs 3). With 1c, this addition product could
merely be detected (entry 10 vs entries 3, 7). Interest-
ingly, the structures of addition products 3a,b showed
that they correspond to a regioselective 1,4-nucleophilic
addition of the aromatic solvent.
Scheme 2. Superelectrophilic activation of arylvinylketones.
It is nevertheless worth noting that a few O-C-diproto-
nated 1,4-dications I4 have already been detected in
liquid superacids by NMR spectroscopy.11
Despite the controversy about acidity measurement of
1
2
solid acids, the acidity in zeolite environment is esti-
1
3
mated at H -7–9, and therefore, such transient species
0
should not be considered as real dications but rather as
protosolvated intermediates, the relatively weaker acid-
ity being compensated by confinement effects.
On these bases and on the analogy between superacids
and zeolites, we reasoned that ions such as I4 should
be trapped with various donors, even inside zeolites.
We thus explored these possibilities and showed here
that this is indeed the case.
In the less nucleophilic ortho-dichlorobenzene, only
cyclization products 2a,b were observed (entries 1 and
5). In chlorobenzene, as expected, an intermediate
behavior was observed. Only the cyclization products
2b,c were observed with 1b,c (entries 6 and 9), while a
mixture of 2a and 3a was produced starting from 1a,
the indanone being the major one (entry 2).
The HUSY-induced cyclization of chalcone 1a into 3-
phenylindanone 2a was initially used to find the more
appropriate conditions. The right balance between tem-
perature and the number of acidic sites was investigated
in a poor nucleophilic solvent, that is, ortho-dichloro-
benzene (Table 1). Below or at 130 ꢁC, the use of quan-
In a more nucleophilic solvent such as toluene, the addi-
tion was the major process starting from 1a,b, the inda-
none being scarcely detected (entries 4 and 8). However,
with 1c, the cyclization remained the almost exclusive
route (entry 11).
1
4
tity corresponding to stoichiometric acidic sites or
twice this amount did not promote any transformation
(
entries 1 and 2). However, 5 molar excess of acidic sites
These results showed that for 1a,b, the product distribu-
tion appeared to be directly dependent on the nucleo-
philic character of the solvent, the more nucleophilic
the solvent is, the more adduct would be produced
(entries 1–4, 5–8). In contrast, such solvent adducts were
scarce in reactions with 1c and the cyclization products
were isolated in highest yields (up to 85%).
clearly appeared as the minimum required to complete
the reaction (entry 3 vs entreis 1, 2). Increasing further
the ratio acidic sites to substrate showed only a slight
effect on the efficiency of the process (entry 4 vs 3). It
is worthy to note that chalcone 1a has been reported
3
to be inert in triflic acid even at 80 ꢁC, highlighting

A. Sani Souna Sido et al. / Tetrahedron Letters 48 (2007) 5911–5914
Table 2. Reaction conditions optimization studies: cyclization versus arylation
5913
O
O
O
R1
HUSY (5 eq.)
R1
R2
R1
solvent S-H / 15 h
R2
sealed tube
S
R2
1
2
3
a
a
Entry
Substrate
Solvent S–H
o-PhCl
PhCl
PhH
Yield (%) 2a–c
Yield (%) 3a–c
b
1
2
3
4
2
66
46
23
5
—
O
c
29
1
a
47
c
PhCH
3
42
Ph
b
5
6
7
8
O
O
o-PhCl
PhCl
PhH
2
47
55
40
—
b
—
1
b
22
b
c
PhCH
3
<5
35
9
0
1
PhCl
PhH
85
84
77
<5
<5
<5
Ph
1
c
1
1
PhCH
3
a
b
c
Isolated yields of pure product after complete conversion unless otherwise stated.
Not detected even by H NMR analysis of the crude mixture.
Mixture of ortho- and para-substituted isomers.
1
The difference in the reactivity of 1a,b versus 1c is clearly
in favor of a carbocationic pathway. A more stabilized
carbocation would have a longer half-life and thus be
more prone to intermolecular reactions, this is indeed
observed with the arylation described above. The fact
that a single adduct regioisomer (the 1,4-adduct) was
observed revealed that the cationic center is mainly
localized at position 4 (enone numbering, species I2 or
I4 in Scheme 2). Moreover, the size of the nucleophile
does not seem to be important, but rather its nucleophi-
licity, toluene reacting faster than benzene, itself faster
than chlorobenzene, even faster than dichlorobenzene.
With such evidences for a 4-carbocationic species being
created within the zeolite, we then tried to trap it with
hydrogen donors in order to get a formal regioselective
reduction of the enone system.
Alkanes being prone to hydrogen transfer in superac-
5
ids, we submitted our model arylvinylketones to HUSY
in various alkanes (Table 3). In heptane, the reaction
was not really efficient yielding around 40% of the prod-
ucts. The major process was cyclization (entries 1 and 5).
Interestingly enough, a small amount of the expected
reduction product 4a could be isolated from the reaction
Table 3. Optimization studies of the reaction conditions: cyclization versus hydride transfer
O
O
O
R1
HUSY (5 eq.)
R1
R2
R1
solvent S-H / 15 h
R2
sealed tube
H
R2
1
2
4
a
a
Entry
Substrate
Solvent S–H
Yield (%) 2a–c
Yield (%) 4a–c
1
2
3
4
O
Heptane
Cyclohexane
Methylcyclopentane
2,3-Dimethylpentane
39
47
8
4
29
69
1
a
b
c
Ph
Ph
—
21
O
O
b
5
6
7
Heptane
Cyclohexane
Methylcyclopentane
42
38
—
1b
1c
5
60
b
<5
8
Methylcyclopentane
66
14
a
b
c
Isolated yields of pure product after complete conversion unless otherwise stated.
Not detected even by H NMR analysis of the crude mixture.
Mixture of unidentified products.
1

5914
A. Sani Souna Sido et al. / Tetrahedron Letters 48 (2007) 5911–5914
of 1a. In cyclohexane, this product was now formed in
almost 30% in the reaction of 1a, but still in low amount
with 1b (entries 2 and 6).
Bioorg. Med. Chem. 2005, 13, 6588; Dai, J.; Krohn, K.;
Fl o¨ rke, U.; Draeger, S.; Schulz, B.; Kiss-Szikszai, A.;
Antus, S.; Kurtan, T.; van Ree, T. Eur. J. Org. Chem.
2
006, 35, 3498; Das, U.; Gul, H. I.; Alcorn, J.; Shrivastav,
A.; George, T.; Sharma, R. K.; Nienaber, K. H.; De
Clercq, E.; Balzarini, J.; Kawase, M.; Kan, N.; Tanaka,
T.; Tani, S.; Werbovetz, K. A.; Yakovich, A. J.; Mana-
vathu, E. K.; Stables, J. P.; Dimmock, J. R. Eur. J. Med.
Chem. 2006, 41, 577; Giner, J.-L.; Kehbein, K. A.; Cook,
J. A.; Smith, M. C.; Vlahos, C. J.; Badwey, J. A. Bioorg.
Med. Chem. Lett. 2006, 16, 2518.
Since branched alkanes should be better hydrogen
donors, we investigated the effect of methylcyclopentane
and 2,3-dimethylpentane. The latter led to a complex
mixture of products where the expected product 4a
was the sole compound isolated, although in low yield
(
entry 4). Fortunately, methylcyclopentane proved to
be the best compromise between reactivity and selectiv-
ity. In this solvent, the reduction was now the major
process with 1a,b (entries 3 and 7), indanone 2b being
barely detectable starting from 1b (entry 7). Not so sur-
prisingly, cyclization was still the major process with the
very reactive 1c (entry 8).
2. For recent examples of pharmaceutically active dihydro-
chalcone derivatives, see Rezk, B. M.; Haenen, G. R. M.
M.; Van Der Vijgh, W. J. F.; Bast, A. Biochem. Biophys.
Res. Commun. 2002, 295, 9; Williams, C. A.; Grayer, R. J.
Nat. Prod. Rep. 2004, 21, 539; Nakatani, N.; Ichimaru,
M.; Moriyasu, M.; Kato, A. Biol. Pharm. Bull. 2005, 28,
8
3.
3
. For liquid superacid-induced intramolecular cyclization of
arylvinylketones, see Suzuki, T.; Ohwada, T.; Shudo, K. J.
Am. Chem. Soc. 1997, 119, 6774.
Therefore, these results showed that regioselective reduc-
tion of enones is also possible in HUSY. They also
revealed that the more branched the alkane is, the
more reduction product would be formed (entry 3 vs
entries 1, 2).
4. For liquid superacid-induced arylation of arylvinyl-
ketones, see Ohwada, T.; Yamagata, N.; Shudo, K. J.
Am. Chem. Soc. 1991, 113, 1364.
5
. For liquid superacid-induced reduction of C,C-double
bond of arylvinylketones, see Coustard, J. M.; Douteau,
M. H.; Jacquesy, J. C.; Jacquesy, R. Tetrahedron Lett.
In summary, we have further expanded the scope of syn-
thetic applications of H-zeolites, demonstrating that
either cyclization or regioselective aryl addition or regio-
selective reduction of arylvinylketones can be achieved
in good yield by zeolite catalysis under the appropriate
conditions.
1
975, 25, 2029.
6
7
. Corma, A. Chem. Rev. 1995, 95, 559–614.
. Koltunov, K. Y.; Walspurger, S.; Sommer, J. Tetrahedron
Lett. 2005, 46, 8391–8394.
8. Olah, G. A.; Klumpp, D. A. Acc. Chem. Res. 2004, 37,
11.
2
It is worthy mentioning the ease to perform such reac-
tions and to recover the products. Moreover, the zeolite
catalyst can be reused three times without significant
decrease in yields.
9. Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767.
0. Nenajdenko, V. G.; Shevchenko, N. E.; Balenkova, E. S.;
Alabugin, I. V. Chem. Rev. 2003, 103, 229–282.
1. Koltunov, K. Y.; Repinskaya, I. B.; Borodkin, G. I. Russ.
J. Org. Chem. 1994, 30, 97; Vasilyev, A.; Walspurger, S.;
Haouas, M.; Pale, P.; Sommer, J.; Rudenko, A. P. Org.
Bio. Chem. 2004, 2, 3483–3489; Vasilyev, A.; Walspurger,
S.; Sommer, J.; Pale, P. Tetrahedron 2005, 61, 3559–
1
1
Therefore, zeolites appear as green alternatives to con-
ventional Br o¨ nsted acids and superacids.
3
564.
Further works are now in progress to further explore the
scope of these reactions and to apply them in organic
synthesis.
12. Farneth, W. E.; Gorte, R. J. Chem. Rev. 1995, 95, 615–
635; Gorte, R. J. Catal. Lett. 1999, 62, 1–13.
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Umansky, B. S.; Engelhardt, J.; Hall, K. J. Catal. 1991,
1
27, 128–140.
1
1
4. For a recent method of determination of Br o¨ nsted acid
sites on zeolites, see Louis, B.; Walspurger, S.; Sommer, J.
Catal. Lett. 2004, 93, 81.
Acknowledgments
K.S.-S.-S., S.C., and M.K. thank the Loker Hydrocar-
bon Institute, USC, Los-Angeles, for financial support.
P.P. and J.S. thank the ‘CNRS’ and the French Ministry
of Research for financial support.
5. Characteristics of HUSY-zeolite: source: Zeolyst Interna-
˚
tional (CBV 500), topology: cage, pore diameter (A):
7
.4 · 7.4, Si/Al ratio: 2.8.
Typical procedure: Zeolite USY (SiO /Al O = 5.64, CBV
5
2
2
3
þ
00, Zeolyst International) in NH4 form was activated at
5
50 ꢁC for 4 h under air. The number of acid sites was
References and notes
estimated to be 4.33 mmol/g.
Synthesis of 2c (Table 2, entry 9): Activated zeolite
(2.52 g, 10.92 mmol sites), chlorobenzene (10 mL), and
compound 1c (454 mg, 2.18 mmol) were successively
loaded in 20 mL pressure tube. The resulting suspension
was magnetically stirred at 130 ꢁC overnight. After cool-
ing, the mixture was added to 50 mL of MeOH, then
stirred at 80 ꢁC for 5 h. After cooling, the catalyst was
filtered off and the organic phase was concentrated to
provide the crude product (434 mg). A chromatographic
purification (silica gel, pentane/ethyl acetate 9:1) gave pure
2c (387 mg, 85%).
1
. For recent examples of pharmaceutically active indanone
derivatives, see Ernst-Russell, M. A.; Chai, C. L. L.;
Wardlaw, J. H.; Elix, J. A. J. Nat. Prod. 2000, 63, 129;
Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew.
Chem., Int. Ed. 2004, 43, 1998; Ito, T.; Tanaka, T.;
Iinuma, M.; Nakaya, K.-i.; Tanakashi, Y.; Sawa, R.;
Murata, J.; Darnaedi, D. J. Nat. Prod. 2004, 67, 932;
Alonso, D.; Dorronsoro, I.; Rubio, L.; Munoz, P.; Garcia-
Palomero, E.; Del Monte, M.; Bidon-Chanal, A.; Orozco,
M.; Luque, F. J.; Castro, A.; Medina, M.; Martinez, A.