Combining in situ generated chiral silicon Lewis acid and chiral Bronsted acid catalysts for [3+2] cycloadditions: Cooperative catalysis as a convenient enantioselective route to pyrazolidines

Article abstract of DOI:10.1002/adsc.201200293

A facile enantioselective synthesis of chiral pyrazolidines via a [3+2] cycloaddition reaction, involving a BINOL-derived phosphoric acid and an in situ generated BINOL phosphate-derived silicon Lewis acid, which may act cooperatively, has been developed.

Full text of DOI:10.1002/adsc.201200293

UPDATES
DOI: 10.1002/adsc.201200293
Combining in situ Generated Chiral Silicon Lewis Acid and
Chiral Brønsted Acid Catalysts for [3+2]Cycloadditions:
Cooperative Catalysis as a Convenient Enantioselective Route to
Pyrazolidines
Olga V. Serdyuk,a Alexandru Zamfir,a Frank Hampel,a and Svetlana B. Tsogoevaa,*
a
Department of Chemistry and Pharmacy, Chair of Organic Chemistry I, University of Erlangen-Nuremberg, Henkestrasse
42, 91054 Erlangen, Germany
Fax : (+49)-(0)9131-85-26865; phone: (+49)-(0)9131-85-22541; e-mail: tsogoeva@chemie.uni-erlangen.de
Received: April 8, 2012; Revised: July 11, 2012; Published online: October 10, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200293.
Abstract: A facile enantioselective synthesis of
chiral pyrazolidines via a [3+2]cycloaddition reac-
tion, involving a BINOL-derived phosphoric acid
and an in situ generated BINOL phosphate-derived
silicon Lewis acid, which may act cooperatively, has
been developed.
Keywords:
ACHTUNGTRENNUNG[3+2]cycloaddition; enantioselective
synthesis; organocatalysis; pyrazolidines; silicon
catalysts
Figure 1. Pyrazolines and pyrazolidines as subunits of bioac-
tive compounds and drugs.
Introduction
Pyrazolidine and pyrazoline heterocycles are ubiqui-
tous in pharmaceutical compounds. They are widely Lewis acid catalysts.[11] Recently, it was reported that
used as antidepressants,[1] acyltransferase inhibitors,[2] Cu
ACHTNUTRGNE(UNG OTf)2 can catalyze the cycloaddition of fluorinat-
analgesic[3] and antimicrobial agents.[4] Some of them ed hydrazones with ethynyl ketones.[12] Leighton and
show antitumor,[5] or anticonvulsant[6] activities and co-workers described an asymmetric intermolecular
are used in agriculture as arthropodicidal agents[7] [3+2] acylhydrazone-enol ether cycloaddition using
(Figure 1). Representing attractive synthetic targets, 1.5 equiv. of a chiral pseudoephedrine-derived silane
these heterocycles are of particular interest for organ- Lewis acid.[13] In 2009 Mꢀller and List showed[14] that
ic chemists.
[3+2]Cycloadditions of hydrazones to olefins pro- merization of a,b-unsaturated hydrazones to give pyr-
vide a direct access to pyrazolidines and pyrazo- azolines in high yields and enantioselectivities.
lines.[8,9] Much effort has been devoted to the develop-
Recently, we have demonstrated for the first time
chiral Brønsted acids efficiently catalyze the cycloiso-
ACHTUNGTRENNUNG
ment of catalytic versions of this reaction. In 2002, it that the [3+2]cycloaddition reaction between N-acyl-
was reported by Kobayashi et al. that Lewis acids ef- hydrazones and cyclopentadiene can be successfully
fectively promote this transformation.[10] For example, performed in high yields (up to 99%), with a diaste-
in the presence of a stoichiometric amount of reoselectivity of up to 98:2 dr by using catalytic
BF3·OEt2 or a catalytic amount of Zr
ACHTUNGRTEN(NUGN OTf)4 and amounts of TMSOTf (trimethylsilyl triflate) as a readi-
Hf
ACHTUNGTRENNUNG
can be obtained in good yields. Later, an asymmetric Nonetheless, identification of enantioselective metal-
version of the [3+2]cycloaddition has been devel- free catalyst systems for this useful intermolecular re-
oped using ZrACHTUNGTRENNUNG(OTf)4/BINOL derivatives as chiral action remains an important challenge.
Adv. Synth. Catal. 2012, 354, 3115 – 3121
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3115

Olga V. Serdyuk et al.
UPDATES
Inspired by the proven ability of silicon Lewis acids Results and Discussion
to serve as effective catalysts in this reaction,[15] and
by the fact that BINOL phosphates[16] can enantiose- First, we undertook a systematic investigation of sol-
lectively catalyze the cycloisomerization of a,b-unsa- vents and reaction temperature for the model reac-
turated hydrazones[14] we envisioned to achieve an tion of N-benzoylhydrazone 2a with cyclopentadiene
enantioselective intermolecular [3+2] cycloaddition using the combination of chiral BINOL phosphate 1a
of hydrazones to olefins through combining an achiral and Ph2SiCl2 as a catalytic system.
silicon Lewis acid catalyst with chiral BINOL phos-
phates 1a–f (Figure 2 and Figure 3).
Our screening experiments demonstrated that tolu-
ene was the most suitable among the studied solvents
Herein, we wish to report our studies, aimed at the in terms of the observed stereoselectivities (entry 3,
development of a new and easily accessible silicon Table 1). Decreasing the temperature from room tem-
Lewis acid catalytic system for the enantioselective perature to À208C led to an improvement in the
[3+2]cycloaddition reaction between N-benzoylhy- enantioselectivity from 40% to 80% ee, but resulted
drazones and cyclopentadiene, providing a convenient in lower yield (entry 3 vs. entry 2).
and facile process for the synthesis of pyrazolidines
under metal-free conditions in good yields, high enan- BINOL phosphate 1a and Ph2SiCl2. While 1a itself
tioselectivities and diastereoselectivities. showed low reactivity and moderate enantioselectivity
Next, we tested an assumed synergism between the
Compared with those advancements achieved with (47% ee, 99:1 dr, entry 1, Table 2) and the weak
chiral Brønsted acid organocatalysts,[16] silicon-based Lewis acid additive Ph2SiCl2 alone was inactive in the
Lewis acid enantioselective catalysis finds itself still in catalysis under these reaction conditions (entry 2), the
the early stages.[17–19] Undoubtedly, however, chiral sil- combination of both components resulted in the prod-
icon Lewis acids as enantioselective catalysts hold sig- uct with low yield, but fairly good enantioselectivity
nificant potential in the broad area of Lewis acid cat- and diastereoselectivity (80% ee, 96:4 dr, entry 3,
alysis. Very recently, Schreiner and co-workers have Table 2). Most likely this might be explained by the
reported a new and interesting class of Lewis acid cat- fact, that weak silicon Lewis acids can be activated,
alysts based on the combination of achiral thiourea besides using Lewis bases,[21] also by connection to
and SiCl4 for the stereospecific rearrangement of ep- a strongly electron-withdrawing group,[22] which is
oxides to quaternary carbaldehydes.[20] Thus, our new represented by the BINOL-derived phosphoric acid
catalytic system, generated in situ from chiral moiety in our system (Figure 2).
BINOL-derived phosphoric acid and achiral halosi-
To further improve the outcome of the reaction, we
lane, might contribute to the rare examples of asym- screened several other commercially available Lewis
metric catalysis by in situ formed chiral silane species. acid additives in combination with 1a. While BBr3,
PhSiCl3, and TMSOTf provided good yields of 56–
64%, low enantioselectivities were observed (3–32%
ee, entries 4–6). Thus, the originally applied combina-
tion of Ph2SiCl2 and 1a was confirmed as the most op-
Table 1. ACHTUNGTRENNUNG[3+2]Cycloaddition reaction of hydrazone 2a with cyclopentadiene using 1a/Ph2SiCl2 as a catalytic system.
Entry
Solvent
T [8C]
Yield [%][a]
syn/anti[b]
ee [%][c] syn
1
2
3
4
5
DCM
toluene
toluene
chlorobenzene
m-xylene
À10
r.t.
À20
À20
À20
46[d]
37
18
33
36
n.d.
30
40
80
72
69
95:5
96:4
98:2
97:3
[a]
Yield of the isolated product.
The dr was determined by HPLC (Daicel Chiralpak IA).
Enantiomeric excess was determined by HPLC (Daicel Chiralpak IA).
11 mol% of 1a was used.
[b]
[c]
[d]
3116
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 3115 – 3121

Combining in situ Generated Chiral Silicon Lewis Acid and Chiral Brønsted Acid Catalysts
Table 2. Optimization of the catalytic system.
Entry
Catalyst [mol%]
Additive [mol%]
T [8C]
Yield [%][a]
syn/anti[b]
ee [%][c] syn
1
2
3
4
5
6
7
8
1a (15)
–
–
À20
À20
À20
À20
À15
À15
À15
À15
À15
À15
À15
À15
À15
À15
13
99:1
–
47
–
80
3
Ph2SiCl2 (10)
Ph2SiCl2 (10)
BBr3 (10)
n.r.
18
1a (15)
1b (12)
1a (30)
1a (30)
1a (15)
1a (30)
1a (30)
1a (30)
1a (30)
1a (20)
1a (30)
1a (30)
96:4
97:3
84:16
89:11
96:4
92:8
99:1
98:2
93:7
93:7
92:8
91:9
56[d]
64
PhSiCl3 (15)
TMSOTf (15)
Ph2SiCl2 (30)
Ph2SiCl2 (30)
Ph2SiCl2 (20)
Ph2SiCl2 (15)
Ph2SiCl2 (10)
Ph2SiCl2 (15)
Ph2SiCl2(15)
Ph2SiCl2(15)
32
24
43
57
70
82
59
43
82
62
59
64
69
62
62
47
9
10
11
12
13
14
56
41[e]
64[f]
[a]
Yield of the isolated product.
The dr was determined by HPLC (Daicel Chiralpak IA).
Enantiomeric excess was determined by HPLC (Daicel Chiralpak IA).
The reaction was performed for 18 h.
MS 4 ꢂ were added to the reaction mixture.
[b]
[c]
[d]
[e]
[f]
50 mol% of H2O was added to the reaction mixture.
timal and was used for further studies concerning the
influence of co-catalysts ratio on the reaction out-
come. We noticed an improvement of the enantiose-
lectivity upon lowering the amount of Ph2SiCl2 with
respect to the amount of 1a (entry 10 vs. 7–9). The re-
action in toluene at À158C, in the presence of
30 mol% of 1a and 15 mol% of Ph2SiCl2 resulted in
62% yield, 82% ee and 98:2 dr (entry 10). Interesting-
ly, while addition of 4 ꢂ MS to the reaction mixture
has not influenced the enantioselectivity (entry 13 vs.
Figure 3. Screened BINOL phosphates.
entry 10), a significant decrease in the enantioselectiv- phosphate 1a was the best choice and gave the prod-
ity (from 82% to 62%, entry 14 vs. entry 10) was uct in 62% yield and 82% ee (entry 1). The catalyst
noted upon addition of water to the reaction mixture. 1d (entry 4) provided the product with slightly higher
Our further studies were commenced with the yield (64%), however, in much lower enantioselectivi-
screening of different BINOL phosphates 1a–1g ty (30% ee).
(Figure 3) readily available in our group.[16f,19] The re-
With the selected catalyst system 1a/Ph2SiCl2 and
sults obtained (Table 3), demonstrate that BINOL reaction conditions established, a variety of hydra-
zones were then evaluated as substrates and the re-
sults are summarized in Table 4. To our delight, most
of the reactions can be performed in good yields (53–
80%), high enantioselectivities and excellent diaste-
reoselectivities (82–95% ee, up to 98:2 dr, entries 1–6,
Table 4). The exception was the experiment using hy-
drazone with R1 =CO2Et, R2 =4-NO2C6H4, where the
product was isolated with 60% yield and in only 48%
ee (entry 7). Notably, while [3+2]cycloaddition reac-
Figure 2. Design of new chiral silicon-derived catalysts.
tions of N-benzoylhydrazones bearing different alkyl
Adv. Synth. Catal. 2012, 354, 3115 – 3121
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3117

Olga V. Serdyuk et al.
UPDATES
Table 3. Screening of BINOL phosphates 1a–1g.
Entry
Catalyst
Yield [%][a]
syn/anti[b]
ee [%][c]syn
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
1g
62
<1
44
64
34
98:2
95:5
97:3
92:8
70:30
96:4
–
82
15
5
30
12
2
30
n.r.
–
[a]
Yield of the isolated product.
[b]
[c]
Figure 4. Determination of the absolute configuration by X-
ray crystal structure analysis of 3f-syn.
The dr was determined by HPLC (Daicel Chiralpak IA).
Enantiomeric excess was determined by HPLC (Daicel
Chiralpak IA).
using BINOL phosphate/Ph2SiCl2 as
a catalytic
rests (R1 =Et, i-Bu, CH2CH2Ph) resulted in the for- system revealed that the reaction was slow and pro-
mation of the product in good to high yields and ceeded sluggishly under the standard reaction condi-
enantioselectivities (entries 1–6), in the case of the tions. Further studies with vinyl ethers are, therefore,
substrate with R1 =Ph the reaction did not proceed required to elaborate suitable reaction conditions and
(entry 8), most probably due to steric reasons.
to develop a silicon-based catalytic system providing
The absolute configuration (SSS) of the major dia- the desired chiral cycloaddition products.
stereomer of the [3+2]cycloaddition products has
Obviously, the catalytic system is generated from
been determined by X-ray crystal structure analysis of BINOL phosphate and Ph2SiCl2 in situ by exchanging
the pyrazolidine 3f-syn (Figure 4).[24]
one of the two chlorine atoms: the second one re-
Additional attempts to promote the cycloaddition mains as a leaving group (Figure 2), which might
between N-benzoylhydrazone 2a and selected vinyl eliminate upon catalyst interaction with hydrazone.
ethers (tert-butyl vinyl ether and propyl vinyl ether) The assumption that the presence of the leaving
Table 4. Scope of hydrazones.
Entry
Product
R1
R2
Yield [%][a]
syn/anti[b]
ee [%][c] syn
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
–
Et
Et
i-Bu
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CO2Et
Ph
4-NO2C6H4
4-BrC6H4
4-NO2C6H4
Ph
4-NO2C6H4
4-BrC6H4
4-NO2C6H4
4-NO2C6H4
62
53
80
72
61
54
60
–
98:2
96:4
96:4
96:4
97:3
98:2
91:9
–
82
84
88
95
86
95
48
–
[a]
Yield of the isolated product.
The dr was determined by HPLC (Daicel Chiralpak IA, IB, AS).
Enantiomeric excess was determined by HPLC (Daicel Chiralpak IA, IB, AS).
[b]
[c]
3118
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 3115 – 3121

Combining in situ Generated Chiral Silicon Lewis Acid and Chiral Brønsted Acid Catalysts
Scheme 1. 31P NMR and 29Si NMR studies of the reaction of 1a with Ph2SiCl2.
group in the in situ generated catalyst is required for
Based on 31P and 29Si NMR experiments, X-ray
the formation of the cycloaddition product, is sup- studies and our previous DFT computations of
ported by the observation that no reaction occurs TMSOTf catalyzed [3+2]cycloaddition reactions[15a]
using the combination of 1a with Ph3SiCl as a catalytic we propose a plausible transition state structure (TS
system.
1) for this reaction, demonstrating the interaction of
The in situ formation of O-silylated BINOL phos- the in situ formed catalyst 1a’ with hydrazone in
phate species is indicated by 31P NMR studies of both a monodentate fashion (Scheme 2a). However, the in-
the BINOL phosphate 1a and the 2:1 mixture of 1a teraction of catalyst 1a’ with hydrazone in a bidentate
with Ph2SiCl2 stirred for 1 hour at room temperature fashion (in analogy to the report of Leighton[13a]) is
before NMR measurement (Scheme 1). The major also reasonable (Scheme 2b). Both transition state
signal corresponds to free BINOL phosphate 1a and structures might provide the products with the same
the new signal that appeared at À12.011 ppm might stereochemistry.
be assigned the structure 1a’.
Because of the bifunctional character of the phos-
We also performed 29Si NMR experiments under phoric acid group in BINOL phosphate (Lewis base/
conditions similar to those used in the synthetic pro- Brønsted acid), the dual role of the additional BINOL
cedure. Upon mixing BINOL phosphate 1a and phosphate molecule could be imagined: while the
Ph2SiCl2 in a 2:1 ratio in CDCl3 we observed only one P=O moiety acts as a Lewis base and might coordi-
signal at À33.864 ppm. The 29Si NMR signal shifted nate to the HCl generated in the reaction system
upfield by nearly 40 ppm from +6.815 ppm in free (preventing non-enantioselective catalysis by HCl),
[23]
Ph2SiCl2 to À33.864 ppm in the in situ formed sili- the Brønsted acidic part is supposed to coordinate to
con compound 1a’ (Scheme 1). The observed signal at the hydrazone and to additionally stabilize the pro-
À33.864 ppm lies in the region for a four-coordinate posed transition state structure (TS 1 and TS 2,
silicon species.[25]
Scheme 2).
Scheme 2. Proposed transition state structures demonstrating the possible role of an additional molecule 1a.
Adv. Synth. Catal. 2012, 354, 3115 – 3121
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3119

Olga V. Serdyuk et al.
UPDATES
Scheme 3. Postulated mechanisms for the [3+2]cycloaddition reaction by using BINOL phosphate alone (catalytic cycle A)
and applying BINOL phosphate/Ph2SiCl2 (2:1) as a catalytic system (catalytic cycle B).
While in principle, two reaction pathways are possi- sis will find applications for other important asymmet-
ble in the [3+2]cycloaddition of the hydrazones to ric transformations and might become a powerful tool
olefins,[11b] one – a stepwise pathway, and the second – in organic synthesis.
a [3+2] concerted pathway, we suggest here a concert-
Further studies focusing on the full scope of this
ed mechanism based on our previous DFT computa- and related pericyclic reactions and other organic
tions of a related system using an achiral silicon cata- transformations using this new facile approach are
lyst (Scheme 2).[15a] Notably, the concerted pathway currently underway.
reported by Kobayashi and co-workers in their zirco-
nium-catalyzed enantioselective [3+2]cycloaddition
of hydrazones to external olefins[11b] further supports Experimental Section
our suggested concerted mechanism.
Since BINOL phosphate 1a itself can also give the General Procedure for the [3+2] Cyloaddition
product (and with the same absolute configuration as between Hydrazones and Cyclopentadiene
that obtained with 1a/Ph2SiCl2 system), albeit with
To a solution of BINOL phosphate 1a (60 mg, 0.0798 mmol,
modest results (13% yield, 47% ee, 99:1 dr, entry 1,
30 mol%) in toluene (2 mL) was added SiCl2Ph2 (8.4 mL,
Table 2), we propose here two catalytic cycles for
0.00398 mmol, 15 mol%) and the mixture was stirred for 1 h
both BINOL phosphate catalysis (cycle A, Scheme 3)
and a more efficient cooperative silicon-Lewis acid/
Brønsted acid catalysis (cycle B, Scheme 3), demon-
strating the advantages of 1a/Ph2SiCl2 catalytic system
over BINOL phosphate 1a itself.
at room temperature. The reaction mixture was then cooled
to À158C, and hydrazone 2a (60 mg, 0.2715 mmol) and
freshly distilled cyclopentadiene (400 mL) were added. After
stirring for 72 h at À158C, the reaction mixture was
quenched by the addition of saturated aqueous NaHCO3
(10 mL) and extracted with CH2Cl2 (3ꢃ20 mL). The com-
bined organic layers were dried (MgSO4), the solvent was
removed under reduced pressure, and the residue purified
by silica gel column chromatography (EtOAc-PE, 1:4) to
afford the product 3a; yield: 48 mg (0.1673 mmol, 62%).
Conclusions
In conclusion, we have successfully developed the
enantioselective [3+2]cycloaddition reaction between
different N-benzoylhydrazones and cyclopentadiene,
catalyzed by a combination of Brønsted acid with
chiral silicon Lewis acid, easily generated in situ from
Brønsted acid and Ph2SiCl2. This metal-free transfor-
mation provides a simple access to pyrazolidines in
up to 80% yields, up to 95% ee and 98:2 dr. We be-
lieve that the cooperative catalysis system involving
silicon-Lewis acid catalysis and Brønsted acid cataly-
Supporting Information
General remarks, characterization data, determination of
the absolute configuration, copies of the NMR spectra and
HPLC chromatograms are available in the Supporting Infor-
mation.
3120
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 3115 – 3121

Combining in situ Generated Chiral Silicon Lewis Acid and Chiral Brønsted Acid Catalysts
Leighton, Adv. Synth. Catal. 2006, 348, 2431–2436;
c) K. Tran, P. J. Lombardi, J. L. Leighton Org. Lett.
Acknowledgements
2008, 10, 3165–3167.
We are grateful to the Deutsche Forschungsgemeinschaft
(DFG) and the “Dr. Hertha & Helmut Schmauser-Stiftung”
for generous research support. We also thank Felix Held for
the preparation of two BINOL phosphates.
[14] S. Mꢀller, B. List, Angew. Chem. 2009, 121, 10160–
10163; Angew. Chem. Int. Ed. 2009, 48, 9975–9978.
[15] a) A. Zamfir, S. Schenker, W. Bauer, T. Clark, S. B.
Tsogoeva, Eur. J. Org. Chem. 2011, 3706–3709; b) A.
Zamfir, S. B. Tsogoeva, Synthesis 2011, 1988–1992.
[16] For selected reviews on BINOL phosphate catalysis,
see: a) T. Akiyama, Chem. Rev. 2007, 107, 5744–5758;
b) M. Terada, Chem. Commun. 2008, 4097–4112; c) D.
Kampen, C. M. Reisinger, B. List, Top. Curr. Chem.
2010, 291, 395–456; d) A. Zamfir, S. Schenker, M.
Freund, S. B. Tsogoeva, Org. Biomol. Chem. 2010, 8,
5262–5276; e) M. Rueping, A. Kuenkel, I. Atodiresei,
Chem. Soc. Rev. 2011, 40, 4539–4549; for selected
BINOL phosphate-catalyzed reactions from our labora-
tory, see: f) C. Baudequin, A. Zamfir, S. B. Tsogoeva,
Chem. Commun. 2008, 4637–4639.
[17] a) C. Chuit, R. J. P. Corriu, C. Reye, J. C. Young, Chem.
Rev. 1993, 93, 1371–1448; b) R. R. Holmes, Chem. Rev.
1996, 96, 927–950; c) S. Rendler, M. Oestreich, Synthe-
sis 2005, 1727–1747; d) O. Sereda, S. Tabassum, R. Wil-
helm, Top. Curr. Chem. 2009, 291, 349–393.
[18] E. B. Rowland, G. B. Rowland, E. Rivera-Otero, J. C.
Antilla, J. Am. Chem. Soc. 2007, 129, 12084–12085.
[19] A. Zamfir, S. B. Tsogoeva, Org. Lett. 2010, 12, 1, 188–
191.
References
[1] Y. R. Prasad, A. L. Rao, L. Prasoona, K. Murali, P. R.
Kumar, Bioorg. Med. Chem. Lett. 2005, 15, 5030–5034.
[2] T.-S. Jeong, K. S. Kim, S.-J. An, K.-H. Cho, S. Lee,
W. S. Lee, Bioorg. Med. Chem. Lett. 2004, 14, 2715–
2717.
[3] A. Gꢀrsoy, S¸. Demirayak, G. Capan, K. Erol, K. Vural,
Eur. J. Med. Chem. 2000, 35, 359–364.
[4] A. ꢄzdemir, G. Turan-Zitouni, Z. A. Kaplancikli, G.
Revial, K. Gꢀven, Eur. J. Med. Chem. 2007, 42, 403–
409.
[5] Z. Brozozowski, F. Sa˛czewski, M. Gdaniec, Eur. J.
Med. Chem. 2000, 35, 1053–1064.
[6] a) M. J. Kornet, R. J. Garrett, J. Pharm. Sci. 1979, 68,
377; b) Z. ꢄzdemir, H. B. Kandilici, B. Gꢀmꢀs¸el, ꢅ.
Calis¸, A. A. Bilgin, Eur. J. Med. Chem. 2007, 42, 373–
379.
[7] C. R. Harrison, G. P. Lahm, Patent WO 91/11438.
[8] For examples of [3+2]cycloaddition of hydrazones
with olefins under acidic conditions, see: a) T. Shimizu,
Y. Hayashi, S. Ishikawa, K. Teramura, Bull. Chem. Soc.
Jpn. 1982, 55, 2450–2455; b) T. Shimizu, Y. Hayashi, M.
Miki, K. Teramura, J. Org. Chem. 1987, 52, 2277–2285.
[9] For selected examples of [3+2] cycloaddition of hydra-
zones with olefins under thermal conditions, see: a) R.
Grigg, J. Kemp, N. Thompson, Tetrahedron Lett. 1978,
19, 2827–2830; b) R. Grigg, M. Dowling, M. W. Jordan,
V. Sridharan, Tetrahedron 1987, 43, 5873–5886.
[10] S. Kobayashi, R. Hirabaysahi, H. Shimizu, H. Ishitani,
Y. Yamashita, Tetrahedron Lett. 2003, 44, 3351–3354.
[11] a) S. Kobayashi, H. Shimizu, Y. Yamashita, H. Ishitani,
J. Kobayashi, J. Am. Chem. Soc. 2002, 124, 13678–
13679; b) Y. Yamashita, S. Kobayashi, J. Am. Chem.
Soc. 2004, 126, 11279–11282.
[20] R. Hrdina, C. E. Mꢀller, R. C. Wende, K. M. Lippert,
M. Benassi, B. Spengler, P. R. Schreiner, J. Am. Chem.
Soc. 2011, 133, 7624–7627.
[21] For selected recent examples, see: a) S. E. Denmark,
G. L. Beutner, Angew. Chem. 2008, 120, 1584; Angew.
Chem. Int. Ed. 2008, 47, 1560- 1638; b) R. Hrdina, F.
Opekar, J. Roithovꢆ, M. Kotora, Chem. Commun.
2009, 2314–2316.
[22] A. D. Dilman, S. L. Ioffe, Chem. Rev. 2003, 103, 733–
772.
[23] U. Herzog, J. Prakt. Chem. 2000, 342, 379–388.
[24] CCDC 894515 (3f-syn) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
[25] J. D. Kennedy, W. McFarlane, in: Multinuclear NMR,
(Ed.: J. Mason), Plenum Press, New York, 1987, Chap-
ter 11, p 308.
[12] H. Xie, J. Zhu, Z. Chen, S. Li, Y. Wu, Synthesis 2011,
2767–2774.
[13] a) S. Shirakawa, P. J. Lombardi, J. L. Leighton, J. Am.
Chem. Soc. 2005, 127, 9974–9975; b) K. Trana, J. L.
Adv. Synth. Catal. 2012, 354, 3115 – 3121
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3121