Copper(I) zeolites as heterogeneous and ligand-free catalysts: [3+2] cycloaddition of azomethine imines

Article abstract of DOI:10.1002/chem.200802191

Copper(I)-exchanged zeolites were used as heterogeneous ligand-free catalysts for [3+2] cycloaddition of azomethine ylides, which allows versatile, efficient, and highly regioselective synthesis of pyrazolone derivatives. These cheap and easy-to-prepare c

Full text of DOI:10.1002/chem.200802191

DOI: 10.1002/chem.200802191
Copper(I) Zeolites as Heterogeneous and Ligand-Free Catalysts:
[3+2] Cycloaddition of Azomethine Imines
Murielle Keller,[a] Abdelkarim Sani Souna Sido,[a, b] Patrick Pale,*[b] and Jean Sommer*[a]
Abstract: Copper(I)-exchanged zeolites were used as heterogeneous ligand-free
catalysts for [3+2] cycloaddition of azomethine ylides, which allows versatile, effi-
cient, and highly regioselective synthesis of pyrazolone derivatives. These cheap
and easy-to-prepare catalysts exhibit wide scope and compatibility with functional
groups. They are very simple to use, easy to remove (by simple filtration), and re-
cyclable (up to six times without loss of activity).
Keywords: click chemistry · copper ·
cycloaddition
·
heterogeneous
catalysis · zeolites
Introduction
Pyrazolone heterocycles and especially dihydropyrazolones
are widely used as dyes for various applications in the food,
textile, photography, and cosmetics industries.[1] Some of
these heterocycles exhibit useful biological properties, for
example, phenazone (Scheme 1) was one of the first synthet-
ic drugs. The corresponding saturated pyrazolidin-3-ones ex-
hibit similar properties, as exemplified by the anti-inflamma-
tory drug phenylbutazone (Scheme 1),[1] but they have also
been investigated as b-lactam mimics towards new antibiot-
ics.[2,3] In the latter context, N,N-bicyclic derivatives, espe-
cially tetrahydropyrazolo[1,2-a]pyrazolones (e.g., LY in
Scheme 1. Examples of biologically active dihydropyrazolones, pyrazoli-
din-3-ones, and N,N-bicyclic pyrazolidin-3-one derivatives
AHCTUNGTRENNUNG
Scheme 1) have been investigated since the late 1980s as an-
alogues of penicillin and cephalosporin antibiotics.[2,3] These
bicyclic heterocycles proved to have other important and
useful bioactivities, and they have been developed as herbi-
cides and pesticides,[4] antitumor agents,[5] calcitonin ago-
nists,[6] and as potent drugs for treatment of cognitive dys-
functions such as Alzheimerꢀs disease (Scheme 1).[7]
Because of this broad interest, several routes have been
developed for the synthesis of pyrazolidin-3-ones and their
N,N-bicyclic derivatives. The most common method relies
on 1,3-dipolar cycloaddition of azomethine imines, especially
for the formation of N,N-bicyclic pyrazolidinone deriva-
tives.[1] Described as early as 1968 by Dorn et al., the latter
route requires harsh conditions and usually leads to mix-
tures of regioisomers in variable yields [Scheme 2,
Eq. (a)].[8] Most 1,3-dipolar cycloadditions have been im-
proved by copper catalysis,[9] and Fu et al. recently reported
that copper(I) iodide in the presence of certain amines cata-
lyzes such [3+2] cycloadditions and dramatically enhances
their regioselectivity [Scheme 2, Eq. (b)].[10] The obvious
analogy between the conditions used by Fu et al. and the
improved cycloaddition in the Meldal–Sharpless copper(I)-
catalyzed version of the Huisgen cycloaddition of azides[11]
led us to consider applying copper(I) zeolites as catalysts in
[a] Dr. M. Keller, A. S. S. Sido, Prof. Dr. J. Sommer
Laboratoire de Physicochimie des Hydrocarbures
Institut de Chimie de Strasbourg
4 rue Blaise Pascal, 67000 Strasbourg (France)
Fax : (+33)390241487
E-mail: sommer@chimie.u-strasbg.fr
[b] A. S. S. Sido, Prof. Dr. P. Pale
Laboratoire de Synthꢁse et Rꢂactivitꢂ Organiques
Institut de Chimie de Strasbourg
4 rue Blaise Pascal, 67000 Strasbourg (France)
Fax : (+33)390241517
E-mail: ppale@chimie.u-strasbg.fr
Supporting information for this article (detailed experimental proce-
dures for 1a–j and NMR spectra of all new compounds) is available
on the WWW under http://dx.doi.org/10.1002/chem.200802191.
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FULL PAPER
Table 1. Screening conditions for the CuI-USY-catalyzed cycloaddition of
1a with ethyl propiolate.[a]
Entry
Catalyst
Solvent
T
[8C]
t
Recovered
Yield of
[h]
1a [%][b]
3a [%][b]
[c]
Scheme 2. Cycloaddition of azomethine imines.
1
2
3
4
5
6
7
8
none
CuI
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
20
20
20
40
40
20
60
60
60
60
60
20
60
60
24
20
24
24
60
24
24
72
12
24
72
24
4
98
80–95
54
42
–
96
71
61
30
–
0
[c]
traces
40
CuI-USY
CuI-USY
CuI-USY
CuI-USY
CuI-USY
CuI-USY
CuI-USY
CuI-USY
CuI-USY
CuI-USY
CuI-USY
H-USY
55
the cycloaddition of azomethine imines. As successfully
shown for the “click” Huisgen reaction,[12] we reasoned that
the zeolite framework could act as ligand toward copper(I)
that stabilizes this inherently labile species and thus avoid
the addition of stabilizing and activating ligands [Scheme 2,
Eq. (c)]. Furthermore, the inherent heterogeneous nature of
zeolites should greatly facilitate product recovery (through
simple filtration) and catalyst recycling.
In this context and in connection with our current studies
on zeolites as catalysts in organic synthesis,[12,13] we explored
the cycloaddition of azomethine imines derived from pyra-
zolidinones in the presence of copper(I) zeolites. We report
here that copper(I) zeolites indeed act as ligand-free cata-
lysts for the cycloaddition of azomethine imines and we
detail here the scope of this first zeolite-catalyzed cycloaddi-
tion of azomethine imines [Scheme 2, Eq. (c)].
60[d]
traces
20
Cl
Cl
Cl
U
26
60
9
THF
10
11
12
13
14
MeCN
MeOH
PhMe
PhMe
PhMe
27[d]
20[d]
traces
90
–
87
–
72
98
0
[a] Reaction performed on 1 mmol of 1a and 1.2 mmol of 2a in 2 mL of
solvent with 7–10 mg of CuI-zeolite (i.e., approximately 5 mol% of
CuI [15]). [b] Yields of isolated pure product. [c] THF, acetonitrile, toluene,
and methanol were also examined without success. [d] Some degradation
occurred.
lated in good yield within reasonable reaction time (Table 1,
entry 9). However, in more polar or in protic solvents, the
reaction was again very slow whatever the temperature, and
degradation occurred (Table 1, entries 10 and 11). Warm tol-
uene proved to be the best choice, allowing the adduct 3a to
be isolated in high yield after a few hours, while the reaction
performed at room temperature was again very slow
(Table 1, entry 13 versus entry 12). Control experiments
under these conditions with untreated H-USY confirmed
the dramatic role of copper(I) loaded into the zeolite, since
no transformation occurred (Table 1, entry 14).
Results and Discussion
Reaction conditions: In an initial series of experiments, we
examined the behavior of the readily accessible (Z)-1-ben-
zylidene-5,5-dimethyl-3-oxo-1-pyrazolidinium-2-ide
(1a)
with ethyl propiolate (2a) in the presence of CuI-modified
USY zeolite under various conditions (Table 1). This zeolite
was selected first, since it proved efficient for several other
reactions[12,13] and its large pores can accommodate several
molecules.
Catalyst screening: In the search for the optimal zeolite cat-
alyst, CuI-USY was compared to four other representative
zeolites. Zeolites H-Y, H-MOR, H-ZSM5, and H-b were
modified by treatment with CuCl[14] and used as catalysts in
the same reaction under the above conditions (Table 2).
As already observed for the cycloaddition of azides,[12a–c]
all modified zeolites proved to efficient catalysts for Dorn
cycloaddition, giving the expected adduct 3a in good to high
yields (69–95%; Figure 1). As expected for a reaction in
No reaction took place without catalyst whatever the sol-
vent (Table 1, entry 1). As reported,[10] CuI alone was not a
good catalyst in dichloromethane, only giving the expected
adduct 3a in very low yield (Table 1, entry 2). Under similar
conditions, CuI-USY was a better catalyst providing 3a in
modest yield but in a clean reaction (Table 1, entry 3).
Better yields were achieved in dichloromethane at reflux
(Table 1, entries 4 and 5), but on prolonged reaction some
degradation occurred (Table 1,
entry 5). Surprisingly, dichloro-
Table 2. Catalyst screening for cycloaddition of 1a with ethyl propiolate.[a]
ethane did not help and was
even deleterious, with modest
conversion (Table 1, entries 6
and 7) even after prolonged re-
action time (Table 1, entry 8).
Entry
Catalyst
Yield [%]
Topology
Pore diameter [ꢄ]
Si/Al ratio
Acidic sites [mmolgÀ1
]
1
2
3
4
5
CuI-USY
CuI-Y
95
95
69
80
89
cage-type
cage-type
channel-type
channel-type
channel-type
7.4ꢅ7.4
7.4ꢅ7.4
7.6ꢅ6.4 5.5ꢅ5.5
5.1ꢅ5.5 5.3ꢅ5.6
6.5ꢅ7.0 3.4ꢅ3.8
2.8
4.39
1.5
6.67
CuI-b
12.5–17.5
15
0.90–1.23
1.04
CuI-ZSM5
CuI-MOR
Increasing
solvent
polarity
10.3
1.48
seemed to help, since in THF
[a] Reaction conditions: 1 mmol of 1a and 1.2 mmol of 2a in 2 mL of toluene at 608C for 4 h in the presence
3a was again obtained and iso- of 7–10 mg of CuI-zeolite. [b] Yields determined by NMR spectroscopy with internal standard.
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P. Pale, J. Sommer et al.
and regenerated by heating before being reused in the next
run.[17] As shown in Figure 3, the CuI-USY catalyst could be
recycled at least up to six times without dramatic changes. It
seems, however, that every two runs a slight decrease in
yield occurred, but the catalyst was still active after the sixth
reuse, still giving the product with a reasonable 75% yield.
Figure 1. Efficiency of Cu-zeolite-catalyzed cycloaddition in dependence
on zeolite nature.
which two molecules must meet within zeolite pores, cage-
type zeolites having larger pore size were better catalysts
than the smaller channel zeolites (Figure 1). However, size
discrimination was clearly not the sole factor since Cu mor-
denite, which has the smallest pores in one of its channel
systems, proved almost as effective as Cu-Y and Cu-USY
(Figure 1).
Unexpectedly, it seemed that the catalyst efficiency of the
modified zeolites could be correlated to the Si/Al ratio
(Figure 2). The lower the Si/Al ratio, the better the catalyst.
Figure 3. CuI-USY recycling and reuse for the cycloaddition of 1a with
ethyl propiolate.
Scope and limitations: In one series of experiments, the
readily available (Z)-1-benzylidene-5,5-dimethylpyrazolidin-
3-one ylide (1a) was treated with various alkynes 2a–i bear-
ing different groups in the presence of CuI-USY as catalyst
(Table 3). As for the Dorn cycloaddition and the version of
Fu et al., alkynes bearing an electron-withdrawing group
proved to be most reactive. Ethyl propiolate (2a) gave the
expected adduct 3a in high yield and high regioselectivity
(Table 3, entry 1). Propargylic ketones such as 2b were also
good dipolarophiles under these conditions, giving the corre-
sponding diketo bicycle 3b in high yield (Table 3, entry 2).
The latter was however slightly lower than with propiolates
(Table 3, entry 2 versus entry 1). Nevertheless, a single
isomer was also detected in this case, that is, the regioselec-
tivity of this CuI-zeolite catalyzed cycloaddition is high. The
corresponding propargylic alcohol 2c did not give the ex-
pected adduct, even after prolonged reaction time (Table 3,
entry 3). To be sure that this lack of transformation was not
due to some size discrimination by the zeolite, the simplest
methyl propargyl ether (2d) was used under the same condi-
tions (Table 3, entry 4). Since no reaction took place in this
case and hyperconjugation slightly decreases the electron
density on the alkyne, such CuI-zeolite-catalyzed cycloaddi-
tion clearly requires acetylenic derivatives bearing strongly
electron withdrawing groups.
Figure 2. Efficiency of Cu-zeolite-catalyzed cycloaddition in dependence
on zeolite Si/Al ratio.
Since this ratio is linked to the number of acidic sites, and
thus to the number of copper ions in the zeolites, such corre-
lation could correspond to the accessibility of the reagents
to copper ions. The activity of copper loaded in zeolites is
known to be dependent on its location within zeolite frame-
work.[16]
To check the extent of such electronic effects, we subject-
ed phenylacetylene (2e) and derivatives thereof bearing
electron-donating (2 f) or electron-withdrawing groups at
the para position (2g) to the same conditions. Parent com-
pound 2e and compound 2 f having an electron-donating
substituent did not react (Table 3, entries 5 and 6). Com-
pound 2e was also a poorly reactive alkyne under the condi-
tions of Fu et al.; it required heating and longer reaction
time and gave a mixture of diastereoisomers. In contrast, 4-
trifluoromethylphenylacetylene (2g) exhibiting an electron-
withdrawing group rapidly underwent cycloaddition in good
Catalyst recycling: An important and useful feature of any
heterogeneous catalyst is its recovery and recyclability. The
Cu-modified zeolites used in the present study could easily
be recovered through a simple filtration over Nylon mem-
brane. A simple washing process allowed the organic materi-
als and the zeolite to be recovered.
Recyclability was examined by performing the cycloaddi-
tion reaction between the azomethine ylide 1a and ethyl
propiolate (2a) several times with the same CuI-USY cata-
lyst. After each run, the catalyst was recovered by filtration
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Copper(I) Zeolite Catalysts
FULL PAPER
Table 3. CuI-zeolite catalyzed cycloaddition of pyrazolidinone ylide 1a with various alkynes 2.[a]
The mono-substituted (Z)-1-
benzylidene-5-methylpyrazol-3-
one ylide 1c also gave the ex-
pected adduct 3e. The yield
was, however, lower due to
some degradation of this adduct
Entry
1
Dipolarophile
t [h]
Yield [%][b,c]
Adduct
(Table 4,
entry 2
versus
entry 1). Interestingly, a single
3a regio- and diastereoisomer was
isolated. The NOESY correla-
tions revealed a syn relative ste-
reochemistry for the methyl
2a
2b
4
90
2
4
77
3b
and phenyl groups in this
adduct (Scheme 3). Such stereo-
chemical relationship in 3e sug-
gested propiolate addition anti
to the methyl group in 1c
(Scheme 3).
3
4
2c
2d
4
4
0[d]
0[d]
0[d]
0[d]
–
–
5
6
2e
2 f
48
4
–
–
The nature of the substituent
at the dipole end was varied in
order to explore the frontier or-
bital control typical of uncata-
lyzed [3+2] cycloadditions.
Benzaldehyde derivatives bear-
ing electron-donating or -with-
drawing groups were thus con-
densed with 5,5-dimethylpyra-
zol-3-one to give a series of pyr-
azol-3-one ylides with variously
substituted phenyl groups at the
1-position.
7
2g
4
68
8
9
2h
2i
48
48
0[f]
0[f]
–
–
Halogenated derivatives 1d
[a] Reactions performed with 1 equiv of 1a, 1.2 equiv of 2, and 5 mol% CuI-USY,[15] in 2 mL of toluene at
608C. [b] Yields of isolated pure product. [c] Only one regioisomer was formed and isolated unless otherwise
noted. [d] No further transformation on prolonged reaction time, and the starting materials were recovered.
[e] The starting materials were essentially recovered. [f] Decomposition occurred, and unidentified byproducts
were formed.
and 1e reacted as readily as
their parent compound 1a to
yield the corresponding adducts
3 f and 3g in the same reaction
time and with similar high
yields (Table 4, entries 3 and 4,
yield (Table 3, entry 7 versus entries 5 and 6). However, two
regioisomers were produced, of which the major one 3c was
that solely observed in the preceding reactions (Table 3,
entry 7 versus entries 1 and 2). The two isomers 3c and 4
could be easily distinguished by 1H NMR spectroscopy,
through the multiplicity of their vinylic and benzylic pro-
tons.
Disubstituted alkynes 2h and 2i could not be transformed
into the corresponding bicyclic heterocycles, and only degra-
dation products formed after prolonged reaction time
(Table 3, entries 8 and 9).
In a second series of experiments, various pyrazol-3-one
ylides 1b–j were treated with the most reactive alkyne
under our conditions, that is, ethyl propiolate (2a; see
Table 3) in the presence of CuI-USY as catalyst (Table 4).
The unsubstituted (Z)-1-benzylidenepyrazol-3-one ylide
(1b) proved to be as reactive as its disubstituted analogue
1a and gave the expected adduct with ethyl propiolate (3d)
over 4 h and in high yield (Table 4, entry 1).
versus Table 1, entry 1). Interestingly, the fluorinated com-
pound having the more electron-withdrawing group gave
the highest yield, while the less electronegative chloride
gave the lowest (Table 4, entry 3 versus 4), and this suggests
a correlation between reaction efficiency and the electronic
properties of the substituent. This effect was confirmed by
the reaction of compounds bearing electron-donating groups
of increasing strength. The para-methoxyphenyl derivative
1 f indeed gave the expected cycloadduct 3h, but in lower
yield than achieved with the halogenophenyl derivatives 1d
and 1e (Table 4, entry 5 versus entries 3 and 4). The para-
aminophenyl derivative 1g proved far less reactive and only
approximately one-third of the starting material was con-
verted within the same duration, giving the corresponding
adduct 3i in modest yield (Table 4, entry 6).
These results clearly showed the influence of electronic
effects on the CuI-zeolite-catalyzed cycloaddition of pyrazol-
3-one ylides. The more electron-withdrawing the substituent
at the dipole end, the more efficient the reaction and the
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P. Pale, J. Sommer et al.
Table 4. CuI-USY-catalyzed cycloaddition of various 1 with ethyl propio-
late.[a]
Scheme 3. NOESY correlations establishing the relative stereochemistry
of 3e and suggesting possible transition states.
Entry
1
Dipolarophile
Yield [%][b,c]
Adduct
80
better the yield over the same reaction time (Table 4, en-
tries 3–6). However, an experiment carried out with the
meta-methoxyphenyl-substituted ylide 1h revealed that such
electronic influence might not be the sole parameter.
Indeed, 1h reacted as effectively as its para-substituted ana-
logue 1 f, despite the weaker electronic effect of the me-
thoxy group at that position (Table 4, entry 7 versus
entry 5).
Pyrazol-3-one ylides 1i and 1j substituted by alkyl group
at the dipole end also gave the corresponding adducts 3k
and 3l (Table 4, entries 8 and 9). Under the same conditions,
these 1-alkylidenepyrazol-3-one ylides reacted almost the
same as the methoxyphenyl-substituted derivative 1 f, as ex-
pected from a dipole bearing a slightly electron donating
group (Table 4, entry 8 versus entry 5). In the case of cyclo-
hexyl derivative 1j, some decomposition occurred and led
to a reduced yield of the adduct and to side products
(Table 4, entry 9).
1b
1c
1d
3d
3e
3 f
2
3
4
5
6
7
8
9
63
90
82
1e
1 f
1g
1h
3g
3h
3i
67
Mechanism: As for other copper(I)-catalyzed [3+2] cycload-
ditions, copper acetylides have been postulated as inter-
mediates.[9–11] Whether the mechanism of the present cop-
per(I)-zeolite catalyzed Dorn cycloaddition is similar could
easily be checked through experiments with deuterated al-
kynes. With such starting materials, no deuterium should be
recovered in the adduct if copper acetylides are involved.
Ethyl deuteropropriolate (2j) was thus prepared and
treated with ylide 1a in the presence of a catalytic amount
of CuI-USY. The bicyclic heterocycle 3a was obtained with
a yield similar to the one previously obtained (see Table 3,
entry 1), but no deuterium could be found in this adduct
[Scheme 4, Eq. (1)]. This result is in favor of acetylide for-
mation during the course of the reaction, as are the results
obtained with disubstituted alkynes.
However, H/D exchange in ethyl deuteropropriolate prior
to the cycloaddition could not be excluded in zeolites.
Indeed, copper(I)-USY prepared at 3508C still contains ap-
proximately 20% of protons in its active sites. Therefore,
these residual acidic protons could be responsible for some
H/D exchange with relatively labile protons.
To check this hypothesis, 2j was subjected to the same
conditions but without any dipole. Only a slight decrease in
deuterium content was observed [Scheme 4, Eq. (3)], that is,
H/D exchange occurred to an extent which corresponds to
the amount of protons remaining in CuI-USY.
30[d,e]
70
3j
63
1i
1j
3k
3l
50[f]
[a] Reactions performed with 1 equiv of 1, 1.2 equiv of 2a, and 5 mol%
CuI-USY[15] in 2 mL of toluene at 608C. [b] Yields of isolated pure prod-
uct. [c] Only one regioisomer was formed and isolated. [d] No further
transformation on prolonged reaction time. [e] The starting materials
were essentially recovered. [f] Decomposition occurred, and unidentified
byproducts were formed.
Further, 2j was again treated with ylide 1a but in the
presence of deuterated copper(I) zeolite.[18] No H/D ex-
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Copper(I) Zeolite Catalysts
FULL PAPER
allacycle, which could evolve to a bicyclic vinyl copper spe-
cies, which on hydrolysis yields the adduct 3. Other routes,
such as nucleophilic addition of the azomethine ylide to the
propiolate unit in A, B, or C, which should also give E, can
not be ruled out at this stage.
Conclusion
We have shown for the first time that copper(I)-modified
zeolites can be used as catalysts for [3+2] cycloaddition of
pyrazol-3-one ylides with alkynes. This heterogeneous
method mild
offers
and
efficient
access
to
tetrahydropyrazoloACHTUNTGERN[NNUG 1,2-a]pyrazol-3-ones with a reasonably
Scheme 4. Cycloadditions with deuterated ethyl propriolate catalyzed by
either regular copper(I) zeolite (a) or deuterated copper(I)-zeolite (b).
wide scope, tolerates various functional groups, and gives
high regioselectivity. Moreover, this heterogeneous cop-
per(I)-modified zeolite catalyst can be reused six times with-
out significant loss of activity. Experiments with labeled ma-
terials suggested a mechanism involving a copper acetylide
as intermediate.
change can occur on 2j if the starting zeolite is already deu-
terated. The deuterium label should thus be retained during
the reaction if no other process occurs, but should disappear
if acetylide is formed. CuI-USY obtained from a deuterated
zeolite.[18] catalyzed the cycloaddition as well as regular CuI-
USY, but loss of deuterium was observed [Scheme 4,
Eq. (2)].
Experimental Section
These results clearly showed that the mechanism of the
copper-zeolite catalyzed cycloaddition of azomethine imines
is similar to those other copper-catalyzed cycloadditions,
and probably involves a copper acetylide.[9–11] The copper
acetylide (B in Scheme 5) is probably produced from the ini-
tial p complex A through hydrogen (deuterium) abstraction.
The base able to do so could be the azomethine ylide 1, but
not the zeolite oxygen atoms, since 2j was mostly recovered
in the presence of zeolite alone [see Scheme 4, Eq. (3)]. The
thus-formed copper acetylide would then interact with the
azomethine ylide, most probably through the negatively
charged nitrogen atom, giving cuprate-like complex (C).
This would then rearrange to a putative six-membered met-
General: All starting materials were commercial and were used as re-
ceived; pyrazolidin-3-ones 1a–j were prepared according to known pro-
cedures (see Supporting Information for details).[19] The reactions were
monitored by thin-layer chromatography on silica plates (silica gel 60
F254, Merck) by using UV light and p-anisaldehyde for visualization.
Column chromatography was performed on silica gel 60 (0.040–
0.063 mm, Merck) with ethyl acetate/cyclohexane as eluent. Evaporation
of solvents was conducted under reduced pressure below 308C unless
otherwise noted. Melting points were measured in open capillary tubes
and are uncorrected. IR spectra were recorded with a Perkin-Elmer
FTIR 1600 spectrometer (KBr disk). 1H and 13C NMR spectra were re-
corded on Bruker Avance 300 or 400 spectrometers. Chemical shifts are
reported relative to residual solvent as an internal standard (CDCl3:
7.26 ppm for 1H and 77.0 ppm for 13C; CD3OD: 3.31 ppm for 1H and
49.15 ppm for 13C). Carbon multiplicities were determined by DEPT135
experiments. Electron impact (EI) and electrospray ionization (ESI) low/
high-resolution mass spectra (MS) were obtained from the mass spec-
trometry department of the Service Commun dꢀAnalyses, Institut de
Chimie, Strasbourg.
Preparation of CuI-USY and other CuI zeolites: Commercial NH4-USY
was loaded in an oven and heated at 5508C for 4 h giving H-USY. 1 g of
H-USY and 475 mg of CuCl (1.1 equiv) were mixed in a mortar and
charged into a closed reactor. Heating the mixture of powders at 3508C
for 3 d under a nitrogen flow quantitatively yielded CuI-USY. The same
procedure was applied to other zeolites.[14] Such modified zeolites have
been characterized.[14]
General procedure for CuI-zeolite catalyzed [3+2] cycloaddition of
azides and terminal alkynes: Pyazolidin-3-one ylide
1 (0.4 mmol,
1.0 equiv) and then alkyne 2 (0.48 mmol, 1.2 equiv) were added to a sus-
pension of CuI-USY (7 mg, 0.05 equiv)[15] in 2 mL of toluene. After 4 h of
stirring at 608C (unless otherwise stated), the mixture was cooled to
room temperature, and the catalyst was removed by filtration over Nylon
membrane (0.20 mm). Solvent evaporation provided the resulting crude
product. Column chromatography was performed when necessary.
Ethyl 6,7-dihydro-7,7-dimethyl-5-oxo-1-phenyl-1H,5H-pyrazoloACHTUNGTRENNUNG[1,2-a]pyr-
azole-2-carboxylate (3a): Yellow oil, 90% yield. 1H NMR (CDCl3): d=
7.52 (d, J=1.5 Hz, 1H), 7.46–7.43 (m, 2H), 7.37–7.27 (m, 2H), 5.45 (d,
J=1.5 Hz, 1H), 4.13–3.98 (m, 2H), 2.86 (d, J=15.9 Hz, 1H), 2.37 (d, J=
15.9 Hz), 1.24 (s, 3H), 1.15 (t, J=7.0 Hz, 3H), 1.14 ppm (s, 3H);
Scheme 5. Proposed mechanism for copper(I)-zeolite-catalyzed cycload-
dition of azomethine ylide with activated alkyne.
Chem. Eur. J. 2009, 15, 2810 – 2817
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www.chemeurj.org
2815

P. Pale, J. Sommer et al.
13C NMR (CDCl3): d=166.6, 166.4, 142.0, 129.2, 128.3, 127.8, 127.7,
117.3, 64.5, 64.4, 60.3, 49.4, 24.9, 19.0, 14.0 ppm; FTIR (neat): 3556, 3074,
2979, 2937, 1686, 1596, 1544, 1502, 1455, 1404, 1374, 1355, 1318, 1275,
1252, 1222, 1208, 1169, 1115, 1094, 1039, 1025, 994, 976, 919 cmÀ1; HRMS
(ESI): m/z: calcd for C17H20N2O3: 323.1366 [M+Na+]; found: 323.1372.
1602, 1573, 1541, 1497, 1454, 1384, 1367, 1322, 1211, 1174, 1089, 1029,
1015, 978, 934 cmÀ1; HRMS (ESI): m/z: calcd for C17H19ClN2O3: 373.0729
[M+K+]; found: 373.0887.
Ethyl
pyrazolo
6,7-dihydro-1-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-1H,5H-
AHCTUNGTREG[NNUN 1,2-a]pyrazole-2-carboxylate (3h): Yellow oil, 67% yield.
6-Isobutyryl-3,3-dimethyl-5-phenyl-2,3-dihydropyrazolo
G
pyrazol-
1H NMR (CDCl3): d=7.49 (d, J=1.5 Hz, 1H), 7.36 (d, J=8.7 Hz, 2H),
6.87 (d, J=8.7 Hz, 2H), 5.43 (d, J=1.5 Hz, 1H), 4.12–3.97 (m, 2H), 3.80
(s, 3H), 2.85 (d, J=15.9 Hz, 1H), 2.37 (d, J=15.6 Hz, 1H), 1.40 (s, 3H),
1.23 (s, 3H), 1.16 ppm (t, J=7.2 Hz, 3H); 13C NMR (CDCl3): d=166.2,
163.7, 159.1, 134.1, 128.9, 117.4, 113.6, 64.2, 63.9, 60.3, 55.1, 49.4, 26.8,
1(5H)-one (3b): Yellow oil, 77% yield. M.p. 1298C; 1H NMR (CDCl3):
d=7.50 (d, J=1.5 Hz, 1H), 7.42–7.39 (m, 2H), 7.34–7.24 (m, 3H), 5.51
(d, J=1.5 Hz, 1H), 2.93–2.85 (m, 2H), 2.38 (d, J=15.6 Hz, 1H), 1.21 (s,
3H), 1.15 (s, 3H), 1.04 (d, J=6.6 Hz, 3H), 0.98 ppm (d, J=6.9 Hz, 3H);
13C NMR (CDCl3): d=200.0, 167.3, 142.1, 128.3, 128.0, 127.6, 125.1, 64.5,
49.3, 37.0, 24.9, 19.7, 18.9, 18.4 ppm; FTIR (neat): 3081, 3058, 3029, 2965,
2930, 2871, 1719, 1674, 1638, 1578, 1534, 1495, 1464, 1455, 1394, 1374,
1363, 1339, 1310, 1289, 1271, 1211, 1151, 1120, 1099, 1084, 1043, 1029,
1008, 988, 943 cmÀ1; HRMS (ESI): m/z: calcd for C18H22N2O2: 321.1573
[M+Na+]; found: 321.1555.
24.9, 19.9, 14.0 ppm; FTIR (neat): n˜
= 3079, 2964, 2933, 1728, 1686,
1600, 1511, 1459, 1439, 1409, 1374, 1358, 1324, 1282, 1245, 1224, 1200,
1169, 1119, 1097, 1034, 1001, 979, 930 cmÀ1; HRMS (ESI): m/z: calcd for
C18H22N2O4: 353.1472 [M+Na+]; found: 353.1462.
Ethyl 1-(4-diethylaminophenyl)-6,7-dihydro-7,7-dimethyl-5-oxo-1H,5H-
pyrazoloACHTUNTRGNEU[GN 1,2-a]pyrazole-2-carboxylate (3i): Yellow oil, 30% yield.
3,3-Dimethyl-5-phenyl-6-(4-trifluoromethylphenyl)-2,3-dihydropyrazolo-
1H NMR (CDCl3): d=7.47 (d, J=1.5 Hz, 1H), 7.21 (d, J=8.7 Hz, 2H),
6.62 (d, J=8.4 Hz, 2H), 5.36 (d, J=1.5 Hz, 1H), 4.14–3.99 (m, 2H), 3.31
(q, J=7.1 Hz, 4H), 2.85 (d, J=15.6 Hz, 1H), 2.35 (d, J=15.6 Hz, 1H),
1.21–1.11 ppm (m, 15H); 13C NMR (CDCl3): d=166.6, 163.9, 147.4,
128.9, 128.6, 128.4, 117.7, 111.4, 64.3, 64.0, 60.2, 49.5, 44.2, 24.9, 19.0, 14.1,
12.6 ppm; FTIR (neat): n˜ = 2968, 2927, 2869, 1721, 1697, 1596, 1571,
1518, 1454, 1412, 1381, 1370, 1356, 1319, 1286, 1254, 1230, 1191, 1167,
1150, 1116, 1089, 1035, 1005, 978, 940 cmÀ1; HRMS (ESI): m/z: calcd for
C21H29N3O3: 394.2101 [M+Na+]; found: 394.2026.
ACHTUNGTRENNUNG
[1,2-a]pyrazol-1(5H)-one (3c): Yellow oil, 49% yield. 1H NMR (CDCl3):
d=7.42 (m, 10H), 5.66 (d, J=1.5 Hz, 1H), 2.90 (d, J=15.6 Hz, 1H), 2.39
(d, J=15.6 Hz, 1H), 1.32, (s, 3H), 1.17 ppm (s, 3H); 13C NMR (CDCl3):
d=164.1, 141.3, 135.8, 131.1, 128.9, 128.2, 127.4, 125.4, 125.3, 124.4, 119.1,
66.0, 64.1, 63.6, 50.0, 49.8, 29.4, 25.2, 19.5 ppm; FTIR (neat): n˜ = 2975,
2930, 1713, 1667, 1617, 1557, 1495, 1445, 1410, 1371, 1321, 1235, 1162,
1108, 1064, 1016, 959, 923 cmÀ1
; HRMS (ESI): m/z: calcd for
C21H19F3N2O: 411.1081 [M+K+]; found: 411.1242.
3,3-Dimethyl-5-phenyl-7-(4-trifluoromethylphenyl)-2,3-dihydropyrazolo-
A
Ethyl
pyrazolo
6,7-dihydro-1-(3-methoxyphenyl)-7,7-dimethyl-5-oxo-1H,5H-
ACHTUNGTREN[NUNG 1,2-a]pyrazole-2-carboxylate (3j): Yellow oil, 70% yield.
[1,2-a]pyrazol-1(5H)-one (4): Yellow oil, 19% yield. 1H NMR (CDCl3):
d=7.72–7.26 (m, 9H), 5.44 (d, J=2.4 Hz, 1H), 2.39 (d, J=2.1 Hz, 1H),
3.03 (d, J=15.3 Hz, 1H), 2.45 (d, J=15.3 Hz, 1H), 1.36 (s, 3H), 1.17 ppm
(s, 3H); 13C NMR (CDCl3): d=165.6, 142.2, 130.2, 128.7, 128.3, 128.2,
127.5, 127.4, 125.8, 124.9, 116.1, 107.7, 64.2, 62.7, 50.9, 26.9, 20.4 ppm;
FTIR (neat): n˜ = 2976, 2928, 1707, 1667, 1619, 1555, 1484, 1444, 1410,
1370, 1320, 1215, 1162, 1107, 1063, 1016, 959 cmÀ1; HRMS (ESI): m/z:
calcd for C21H19F3N2O: 373.1522 [M+H+]; found: 373.1550.
1H NMR (CDCl3): d=7.51 (d, J=1.8 Hz, 1H), 7.26–7.21 (m, 1H), 7.03–
6.99 (m, 2H), 6.83–6.79 (m, 1H), 5.43 (d, J=1.5 Hz, 1H), 4.13–3.98 (m,
2H), 3.80 (s, 3H), 2.85 (d, J=15.6 Hz, 1H), 2.47 (d, J=15.6 Hz, 1H),
1.22 (S, 3H), 1.15 ppm (t, J=14.4 Hz, 6H); 13C NMR (CDCl3): d=166.5,
163.6, 159.0, 143.6, 129.2, 129.0, 120.2, 117.1, 113.5, 113.1, 64.4, 60.3, 55.2,
49.3, 24.9, 19.0, 14.0 ppm; FTIR (neat): n˜ = 2976, 2935, 2836, 1695, 1599,
1544, 1489, 1463, 1435, 1384, 1362, 1318, 1258, 1223, 1202, 1174, 1150,
1118, 1097, 1038, 1009, 951 cmÀ1
C18H22N2O4: 353.1472 [M+Na+]; found: 353.1449.
; HRMS (ESI): m/z: calcd for
Ethyl 6,7-dihydro-5-oxo-1-phenyl-1H,5H-pyrazoloACTHNUGTRNEUNG[1,2-a]pyrazole-2-car-
boxylate (3d): Yellow oil, 80% yield. 1H NMR (CDCl3): d=7.51–7.52
(m, 1H), 7.39–7.25 (m, 5H), 5.14 (s, 1H), 4.13–3.97 (m, 2H), 3.43–3.35
(m, 1H), 3.05–3.01 (m, 1H), 2.96–2.84 (m, 1H), 2.79–2.71 (m, 1H), 1.13–
1.10 ppm (m, 3H); 13C NMR (CDCl3): d=164.3, 163.3, 138.3, 128.7,
128.5, 128.4, 128.2, 118.3, 73.4, 60.6, 52.0, 36.1, 14.3 ppm.
Ethyl 6,7-dihydro-7,7-dimethyl-5-oxo-1-pentyl-1H,5H-pyrazoloACHTUNGTRENNUNG[1,2-a]pyr-
azole-2-carboxylate (3k): Yellow oil, 63% yield. 1H NMR (CDCl3): d=
7.42 (d, J=1.5 Hz), 4.42–4.38 (m, 1H), 4.22–4.19 (m, 2H), 3.11–3.06 (m,
1H), 2.79 (d, J=15.6 Hz, 1H), 2.28 (d, J=15.6 Hz, 1H), 1.72 (s, 3H),
1.66–1.58 (m, 2H), 1.35–1.25 (m, 7H), 1.03 (s, 3H), 0.90–0.85 ppm (m,
3H); 13C NMR (CDCl3): d=171.0, 168.9, 131.4, 116.1, 65.1, 60.6, 60.3,
48.8, 35.5, 31.7, 24.9, 24.4, 22.5, 18.2, 14.2 ppm; FTIR (neat): n˜ = 2957,
2931, 2871, 1699, 1606, 1543, 1466, 1405, 1362, 1332, 1253, 1203, 1173,
Ethyl 6,7-dihydro-7-methyl-5-oxo-1-phenyl-1H,5H-pyrazoloACHTUGNTERN[UNGN 1,2-a]pyra-
1
zole-2-carboxylate (3e): Yellow solid, m.p. 92–938C, 63% yield. H NMR
(CDCl3): d=7.46–7.23 (m, 5H+1H), 5.14 (d, J=1.6 Hz, 1H), 4.10–3.94
(qd, J=7,1 Hz, 11 Hz, 2H), 3.41 (qdd, J=6, 6.2, 12.1 Hz, 1H), 2.72–2.54
(m, 2H), 1.10 (t, J=7.1 Hz, 3H), 1.05 ppm (d, J=6 Hz, 3H); 13C NMR
(CDCl3): d?166.17, 163.45, 140.96, 128.84, 128.3, 128.09, 127.97, 117.82,
117.6, 63.58, 60.35, 42.94, 17.43, 14.04 ppm; FTIR (neat): n˜ = 3075, 2971,
2928, 1693, 1596, 1429, 1302, 1245, 1184, 1102, 1012, 957, 928, 899, 867,
843 cmÀ1; HRMS (ESI): m/z: calcd for C16H18N2O3: 309.1215 [M+Na+];
found: 309.1365.
1118, 1097, 1081, 1023, 948 cmÀ1
C16H26N2O3: 317.1836 [M+Na+]; found: 317.1842.
; HRMS (ESI): m/z: calcd for
Ethyl 1-cyclohexyl-6,7-dihydro-7,7-dimethyl-5-oxo-1H,5H-pyrazolo
pyrazole-2-carboxylate (3l): Yellow oil, 50% yield. M.p. 998C; 1H NMR
(CDCl3): d=7.44 (s, 1H), 4.18–4.13 (m, 4H), 2.73 (d, J=15.3 Hz, 1H),
2.20 (d, J=15.3 Hz, 1H), 1.70–1.67 (m, 2H), 1.61–1.58 (m, 2H), 1.47–1.44
(m, 2H), 1.26–1.16 (m, 8H), 1.08–1.03 (m, 3H), 0.92 ppm (s, 3H);
13C NMR (CDCl3): d=170.9, 164.2, 133. 2, 114.1, 65.8, 65.4, 48.1, 41.3,
30.2, 26.4, 26.3, 26.2, 26.1, 24.9, 17.6, 14.2 ppm; FTIR (neat): n˜ = 3085,
2926, 2852, 1735, 1684, 1603, 1410, 1383, 1371, 1354, 1329, 1315, 1299,
ACHTUNGTRENNUNG[1,2-a]-
Ethyl 1-(2-fluorophenyl)-6,7-dihydro-7,7-dimethyl-5-oxo-1H,5H-pyrazolo-
ACHTUNGTRENNUNG[1,2-a]pyrazole-2-carboxylate (3 f): Yellow solid, 90% yield. M.p 1048C;
1H NMR (CDCl3): d=7.59 (d, J=1.5 Hz, 1H), 7.49–7.43 (m, 1H), 7.28–
7.23 (m, 1H), 7.18–7.13 (m, 2H), 7.07–7.00 (m, 1H), 5.86 (d, J=1.2 Hz),
4.13–3.98 (m, 2H), 2.83 (d, J=15.9 Hz, 1H), 2.39 (d, J=15.6 Hz, 1H),
1.28 (s, 3H), 1.17 (s, 3H), 1.11 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3): d=
166.2, 163.3, 161.9, 158.6, 129.9, 129.2, 124.4, 116.2, 115.3, 115.0, 64.4,
60.4, 57.0, 49.3, 26.8, 24.6, 19.1, 13.9 ppm; FTIR (neat): n˜ = 2978, 2932,
1697, 1603, 1556, 1489, 1440, 1384, 1362, 1322, 1288, 1256, 1223, 1204,
1172, 1119, 1094, 1035, 1010, 937 cmÀ1; HRMS (ESI): m/z: calcd for
C17H19FN2O3: 341.1272 [M+Na+]; found: 341.1226.
1287, 1266, 1257, 1223, 1207, 1173, 1117, 1103, 1030, 1000, 976, 923 cmÀ1
;
HRMS (ESI): m/z: calcd for C17H26N2O3: 329.1836 [M+Na+]; found:
329.1803.
Ethyl
pyrazolo
1-(4-chlorophenyl)-6,7-dihydro-7,7-dimethyl-5-oxo-1H,5H-
ACHTUNGTRENNUNG
1H NMR (CDCl3): d=7.50 (d, J=1.2 Hz, 1H), 7.42–7.15 (m, 4H), 5.44
(d, J=1.2 Hz, 1H), 4.14–4.00 (m, 2H), 2.87 (d, J=15.6 Hz, 1H), 2.40 (D,
J=15.6 Hz, 1H), 1.23 (s, 3H), 1.17 (t, J=7.2 Hz, 3H), 1.13 ppm (s, 3H);
13C NMR (CDCl3): d=166.2, 163.7, 140.6, 133.6, 129.2, 138.5, 116.8, 64.3,
63.9, 60.4, 49.3, 24.9, 19.0, 14.0 ppm; FTIR (neat): n˜ = 2979, 2932, 1699,
Acknowledgements
A.S.S.S. and M.K. thank the Loker Institute for financial support. The au-
thors gratefully acknowledge financial support from the CNRS and the
French Ministry of Research.
2816
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ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 2810 – 2817

Copper(I) Zeolite Catalysts
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Received: October 23, 2008
Published online: February 3, 2009
Chem. Eur. J. 2009, 15, 2810 – 2817
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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