Enantioselective phase-transfer catalysis: Synthesis of pyrazolines

Article abstract of DOI:10.1002/anie.201002485

All paired up: Under catalytic phase-transfer conditions the formation of a chiral ion pair between quininium cation 1 and hydrazine anion 2 led to an enantioselective aza-Michael cyclocondensation domino reaction to furnish pyrazolines. A convenient one-pot protocol allowed exchange of the functional group (R1) on the nitrogen atom.

Full text of DOI:10.1002/anie.201002485

Communications
DOI: 10.1002/anie.201002485
Organocatalysis
Enantioselective Phase-Transfer Catalysis: Synthesis of Pyrazolines**
Olivier Mahꢀ, Isabelle Dez, Vincent Levacher, and Jean-Franꢁois Briꢂre*
The development of asymmetric catalytic reactions, as cost-
effective and environmentally friendly methodologies, is a
response to the increased demand of pharmaceutically
relevant chiral aza-heterocycles.[1] In this context, the D2-
pyrazolinyl platform is the core structure of many bioactive
ingredients, and among them are the recurring 3,5-diaryl-
pyrazoline architectures 3 (Scheme 1),[2] which have a polar
group on N1.[3] However, an efficient enantioselective syn-
thesis of this type of 4,5-dihydropyrazoles remains elusive.
3,5-diaryl pyrazolines. The organocatalytic asymmetric syn-
thesis of N-aryl pyrazolines was pioneered by List and Mꢀller
by making use of an elegant 6 p electrocyclization.[9] This
recent achievement paves the way for the development of
original transition-metal-free synthetic strategies that are
suited to the elaboration of pharmaceutically relevant chiral
heterocycles.
To provide efficient access to the chiral nonracemic 3,5-
diarylpyrazoline 3 (Scheme 1), bearing a polar group on N1
[usually an electron-withdrawing group (EWG)], we envis-
aged a domino aza-Michael addition/cyclocondensation reac-
tion of electron-poor hydrazine anions with chalcones cata-
lyzed by a chiral quaternary ammonium salt.[10] We assumed
that an irreversible (nonracemizing) conjugate addition of
deprotonated acylhydrazines would be secured by the sub-
sequent imine bond formation.[11] However, the formation of
an effective chiral ion pair between an amide anion and an
ammonium salt through cation exchange (M+/R4N+)
remained questionable, but was required to prevent a racemic
background process. Thus far, phase-transfer catalysis (PTC)
has elicited robust organocatalytic strategies for the asym-
Scheme 1. Organocatalytic strategy using chiral ammonium/amide ion
pairs.
À
metric construction of C C bonds from C anions and, to a
À
The first catalytic enantioselective construction of pyrazo-
lines, which was reported in 2000, proceeds through 1,3-
dipolar cycloaddition reactions of acrylamides by means of
Lewis acidic magnesium complexes.[4] The subsequently
developed asymmetric approaches were dominated by or-
ganometallic strategies which encompass [2+3] cycloaddi-
tions of either diazoalkane dipoles[5] or nitrile imine dipole
precursors, as well as others.[6,7] Alternatively, Kanemasa and
Yanagita described a metal-promoted aza-Michael cyclo-
condensation cascade using electron-rich N-arylhydrazines to
give exclusively 3-pyridyl-4-aryl pyrazolines, albeit with
moderate enantioselectivity.[8] This example, to our knowl-
edge, constitutes the only attempt to construct nonracemic
lesser extent, C X bonds from anionic O and S nucleo-
philes.[12] Nonetheless, the examples of asymmetric PTC
approaches for C N bond formation using anionic N-
À
nucleophilic species are rare.[10,12,13] In the 1970s, Juliꢁ et al.
pioneered the kinetic resolution of chiral tertiary alkyl
bromides by using potassium phthalimide nucleophiles
under the influence of cinchonium-derived alkaloids albeit
with modest selectivities.[14] Later in 1996, preliminary inves-
tigations from Prabhakar and co-workers triggered a series of
studies dealing with the asymmetric aziridination reactions of
enones by O-substituted hydroxylamide anions,[15a–d] and then
later extended to N-chloro-N-sodio carbamate.[15e] Recently, a
useful intramolecular enantioselective conjugate addition of
deprotonated indoles to an acrylate was achieved under PTC
conditions.[16] We describe herein an unprecedented asym-
metric synthesis of pyrazolines under PTC reaction conditions
by making use of the R2NÀ/R4N+ ion pairing mode of
activation.[17]
[*] O. Mahꢀ, Dr. V. Levacher, Dr. J.-F. Briꢁre
CNRS UMR COBRA, INSA et Universitꢀ de Rouen, FR 3038
IRCOF (Research Institute in Fine Organic Chemistry)
rue Tesniꢁre, BP 08, 76131 Mont Saint Aignan (France)
Fax: (+33)2-3552-2962
We first carried out a set of reactions between chalcone
(2a) and N-tert-butyloxycarbonyl hydrazine 1a (1.1 equiv) in
the presence of potassium carbonate (solid–liquid phase-
transfer conditions) and various commercially or easily
available chiral ammonium salts derived from cheap cinchona
alkaloids (Table 1).[12c] Pleasingly, 10 mol% of N-benzyl
quininium 4a furnished (S)-(À)-pyrazoline 3a with a promis-
ing 67% ee albeit in 31% yield. Subsequent attempts
revealed that the presence of water (liquid–liquid phase-
transfer conditions with 4a; Table 1 < xtabr1, entry 2) and the
use of cinchonidinium salt 4b were detrimental to the
enantiomeric excess. Interestingly, the introduction of an
E-mail: jean-francois.briere@insa-rouen.fr
Dr. I. Dez
UMR CNRS 6507, ENSICaen-Universitꢀ de Caen, FR3038
Laboratoire de Chimie Molꢀculaire et Thio-organique
Caen (France)
[**] We gratefully acknowledge financial support from the Rꢀgion Haute-
Normandie and the CRUNCH network (Centre de Recherche
Universitaire Normand de Chimie), as well as the Ministꢁre de la
Recherche and CNRS (Centre National de la Recherche Scientifi-
que).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002485.
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Chemie
Table 1: Optimization of the reaction.
shows that a polar functional group at the ortho position of
the benzylic substructure is required; this polar group (e.g., N-
oxide) is likely to accept hydrogen bonds which in turn results
in improved yields and ee values. Nevertheless, catalysts 4k
and 4l containing a pyridine ring resulted in a less enantio-
selective reaction (see the Supporting Information for further
details).[18]
To investigate the scope of the reaction, we examined the
EWG on the hydrazine (R1CONHNH2) in the presence of
catalyst 4a (Table 2). Although the N-benzoyl hydrazine
Entry
4
R3
R4
Ar
Base/T
[8C]
Yield ee
[%][a] [%][b]
1
2
3
4
5
6
7
8
4a OMe
4a OMe
4b
H
H
H
Ph
Ph
Ph
K2CO3/40 31
67
K2CO3/40 20[c] 57
H
K2CO3/40 11
K2CO3/40 17
Cs2CO3/20 55
Cs2CO3/20 15
Cs2CO3/20 58
Cs2CO3/20 38
Cs2CO3/20 46
Cs2CO3/20 72
Cs2CO3/20 80
Cs2CO3/20 54
Cs2CO3/20 48
48
Table 2: Optimization with various hydrazines R1CONHNH2 1.[a]
4c OMe allyl Ph
20 (R)[d]
73
4a OMe
4d OMe
4e OMe
4 f OMe
4g OMe
4h OMe
4i OMe
4j OMe
4k OMe
4l OMe
H
H
H
H
H
H
H
H
H
H
Ph
anthracenyl
4-MeOC6H4
4-CF3C6H4
4-FC6H4
12 (R)[d]
56
54
61
79
80
68
24
65
9
10
11
12
13
14
2-FC6H4
2-MeOC6H4
2-MeC6H4
2-pyridyl
2-pyridyl-N-oxide Cs2CO3/20 84
[a] Yield of pyrazine 3a determined by NMR methods using an internal
standard. [b] Determined by HPLC analysis using a chiral stationary
phase. [c] Toluene/H2O (75:25) used as solvent. [d] Absolute config-
uration determined by comparison to analogue 6a; see Ref. [21].
Entry
Cat.
R1
Solvent/T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4i
Ph
Me
OEt
OBn
OtBu
OtBu
OtBu
OtBu
OtBu
OtBu
toluene/RT
toluene/RT
toluene/RT
toluene/RT
toluene/RT
toluene/0
toluene/À20
THF/0
0
–
9
26
26
73 (S)
78 (S)
23 (S)
92 (S)
92 (R)
93 (S)[e]
86
74
60
55
55
45
80
78
77
allylic functional group on the alcohol at C9 (4c) or using the
bulkier anthracenyl derivative 4d led to an reversal of the
enantioselectivity and low-yielding reactions. Apparently, the
suitable organization of the amide/ammonium ion pair that
À
leads to efficient chirality transfer during the C N bond
9
4m
4i
THF/0
THF/0
formation requires the presence of a free alcohol at C9.
Futhermore, the steric hindrance at the benzylic moiety of the
quinuclidinium structure appeared to be a limiting structural
feature as exemplified by the catalyst 4d. At this stage, it was
found that the use of cesium carbonate instead of potassium
carbonate improved the yields (from 31% to 55% for catalyst
4a) while allowing the lowering of the reaction temperature
from 408C to 208C (67% to 73% ee for catalyst 4a). Then, we
turned our attention to electronic effects and tested catalysts
having para-substituted benzylic rings (4e–4g), but disap-
pointing results were obtained. Recently, Jew, Park, and co-
workers pioneered ortho-substituted benzyl cinchona deriv-
atives such as 4h as potent catalysts for glycine alkylation.[18]
Such catalysts were successfully exploited by Ricci and co-
workers, who used ortho-methoxy benzyl ammonium salts
such as 4i in several elegant PTC processes.[19] In our hands,
the enantiomeric excesses were improved from 73% ee with
quininium 4a to 79% ee with ortho-fluorobenzyl compound
4h, and a faster reaction was achieved such that pyrazoline 3a
was isolated in 72% yield after 24 hours. The best results
(80% ee) were obtained with quininium salt 4i, which
possesses a free alcohol and an ortho-methoxybenzyl motif.
In this regard, structure–activity relationships were examined
and revealed that the 2-methyl-substituted catalyst 4j fur-
nished only 68% ee, thereby excluding a simple steric
influence on selectivity. The comparison of the activity
between the 2-pyridyl 4k and 2-pyridyl-N-oxide 4l derivatives
10[d]
[a] Reaction conditions: chalcone 2a (0.5 mmol), hydrazine
1
(1.1 equiv), Cs2CO3 (1.3 equiv), and 10 mol% of catalyst 4 for 24 h.
[b] Yield of pyrazoline 3a determined by NMR methods using an internal
standard. [c] Determined by HPLC analysis using a chiral stationary
phase. [d] Carried out with chalcone 2a (2 mmol), 2 mol% of catalyst 4i
and 0.5 equivalents of Cs2CO3 for 87 h giving 70% yield of the isolated
product after column chromatography (43% yield in 24 h). [e] Greater
than 99% ee after one recrystallization in EtOAc/petroleum ether (1:3).
Bn=benzyl.
(Table 2, entry 1) did not yield the pyrazoline product 3a, the
N-acetyl derivative (Table 2, entry 2) smoothly reacted with
chalcone 2a to give the corresponding pyrazoline in 86%
yield, but low selectivity was measured. The bulky N-Boc
hydrazine was the only carbamate derivative (Table 2,
entries 3–5) to achieve a significant ee value in its reaction,
thereby showing the subtle influence of both the steric
hindrance and pKa value of the hydrazine nucleophiles upon
these asymmetric aza-Michael reactions. The enantiomeric
excesses were slightly improved at 08C (Table 2, entry 6), but
a lower temperature was detrimental to the reaction (Table 2,
entry 7). Consequently, by using the more competent ortho-
methoxy quininium catalyst 4i (see the Supporting Informa-
tion) in THF at 08C, the efficient formation of pyrazoline 3a
was observed in 80% yield with 92% ee (Table 2, entry 8).
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Communications
Table 4: One-pot protecting-group exchange.
Most importantly, the pseudo-enantiomeric effect was fully
countered by means of using 10% of the quinidinium catalyst
4m (Table 2, entry 9), which allowed the construction of (R)-
3a. We also demonstrated that on a 2 mmol scale only 0.5
equivalents of Cs2CO3 and 2 mol% of catalyst 4i (Table 2,
entry 10) were needed to maintain the high enantioselectivity
(93% ee), but the reaction required 87 hours to reach
completion. As a practical issue for the synthesis of chiral
drugs, a virtually enantiopure pyrazoline 3a could be
obtained after one recrystallization (Table 2, entry 10).
We evaluated these user-friendly and cost-effective orga-
nocatalytic conditions by applying them to reactions of
chalcone derivatives (2) with a quasi-stoichiometric amount
of 1a (Table 3). Pyrazolines 3 having various aryl (Table 3,
Entry
Product
R1’
Yield [%][a]
Selectivity[b]
1
2
3
4
6a
6b
6c
6d
Ts
Ac
Bz
86
99
99
93
> 99% ee (À)
> 99% ee (À)
> 99% ee (À)
> 99% de[c]
camphor sulfonyl
[a] Yield of product isolated after column chromatography. [b] Deter-
mined by HPLC analysis using a chiral stationary phase. [c] Determined
by 1H NMR analysis. Bz=benzoyl, Ts=4-toluenesulfonyl.
Table 3: Scope of the enantioselective synthesis of pyrazolines.[a]
entries 1–3) and diastereoisomeric 6d (Table 4, entry 4) was
realized, without any racemization, starting from the enan-
tioenriched pyrazoline 3a (see Table 2, entry 10). Considering
the usual chemical and configurational instability of 1H-
pyrazolines through oxidative degradation pathways,[11] this
achievement is noteworthy. The formation of an ammonium
intermediate 5 is likely and prevents any decomposition.
Pleasingly, the resulting product 6a (Table 4, entry 1) was
crystalline and the absolute configuration at C5 of the
pyrazoline ring was determined to be S as confirmed by X-
ray diffraction methods.[21]
With the ortho-fluorobenzyl ammonium catalyst 4h Jew,
Park, and co-workers demonstrated, by using X-ray crystal
diffraction, that a molecule of water was bound between the
oxygen atom on C9 and the ortho-fluorine atom on the benzyl
moiety.[18] The authors proposed that preorganization of the
obtained complex leads to improvement of the chiral
induction. In our case, however, hydrated conditions yielded
a drop in the ee values.[22] We suppose instead that both OH
and OMe functional groups of quininium catalyst 4i are
synergistically involved in a hydrogen-bond network around
the nucleophilic hydrazine anion of 1a, thus providing a
useful chiral platform for the selection of the prochiral enone
faces en route to an effective asymmetric synthesis of
pyrazolines (see the Supporting Information).[23] This hypoth-
esis is currently under investigation.
Entry
Base
Ar1
Ar2
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
Cs2CO3
K3PO4
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
77
71
72
62
89
52
66
60
92 (À)
90 (À)
90 (À)
92 (À)
92 (À)
94 (À)
87 (À)
91 (À)
92 (À)
89 (+)
88 (À)
89 (À)
91 (À)
78 (À)
4-MeOC6H4
4-FC6H4
4-FC6H4
2-MeOC6H4
2-MeOC6H4
2-thienyl
2-thienyl
3,4-ClC6H3
Ph
Ph
Ph
Ph
Ph
9
Ph
40 (62)[d]
60
70
62
61
46
10
11
12
13
14
4-MeOC6H4
4-ClC6H4
2-MeC6H4
3-MeOC6H4
2-thienyl
[a] Reactions were performed on a 0.5 mmol scale of chalcones 1 with 1.1
equivalent of hydrazine 1a. [b] Yield of isolated product after column
chromatography. [c] Determined by HPLC analysis using a chiral sta-
tionary phase. [d] Yield determined by NMR analysis of the crude
reaction mixture using an internal standard.
entries 1–6 and 9) and heterocyclic (Table 3, entries 7 and 8)
substituents at C3 were formed with more than 90% ee. As a
general trend, it was found that K3PO4 slightly improved the
enantiomeric excesses relative to those obtained with Cs2CO3
(Table 3, entries 4, 6, and 8), but the reactions were slower
and the yields were lower after the same reaction time
(24 hours). The ortho, meta, and para substitution on the aryl
rings at C5 were well tolerated even though a slight drop in
the ee values was measured (Table 3, entries 10–13). The
thienyl heterocycle led to a lower enantiomeric excess
(Table 3, entry 14).[20]
In conclusion, we developed an original and straightfor-
ward enantioselective synthesis of 3,5-diaryl pyrazolines,
biorelevant aza-heterocycles, by using phase-transfer organ-
ometallic methodology. The discovery that an N-ortho-
methoxybenzyl quininium salt leads to a useful chiral
ammonium/amide ion pair from N-acylhydrazines in this
process has prompted investigations of its utility for other
asymmetric transformations.
Received: April 26, 2010
Revised: June 23, 2010
Published online: August 16, 2010
The use of 1a was key to the success of this enantiose-
lective synthesis of the 3,5-diaryl pyrazolines, but the method-
ology is restricted to the formation of N-Boc derivatives.
Nevertheless, we achieved a practical one-pot protecting-
group exchange by making use of the acid lability of the N-
Boc group, thereby extending the scope of this methodology
(Table 4). A straightforward construction of 6a–c (Table 4,
Keywords: asymmetric synthesis · heterocycles ·
.
Michael addition · organocatalysis · phase-transfer catalysis
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Chemie
moto, K. Maruoka, Angew. Chem. 2008, 120, 9608; Angew.
[1] a) J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org.
Biomol. Chem. 2006, 4, 2337; b) V. Farina, J. T. Reeves, C. H.
Senanayake, J. J. Song, Chem. Rev. 2006, 106, 2734.
[2] Reviews on pyrazolines: a) A. Lꢂvai, J. Heterocycl. Chem. 2002,
39, 1; b) S. Kumar, S. Bawa, S. Drahu, R. Kumar, H. Gupta,
Recent Pat. Anti-Cancer Drug Discovery 2009, 4, 154; c) M.
Kissane, A. R. Maguire, Chem. Soc. Rev. 2010, 39, 845; d) C.-H.
Kꢀchenthal, W. Maison, Synthesis 2010, 5, 719.
[3] Representative bioactive 3,5-diarylpyrazolines: a) J. R. Goodell,
F. Puig-Basagoiti, B. M. Forshey, P.-Y. Shi, D. M. Ferguson, J.
Med. Chem. 2006, 49, 2127; b) P.-L. Zhao, F. Wang, M.-Z. Zhang,
Z.-M. Liu, W. Huang, G.-F. Yang, J. Agric. Food Chem. 2008, 56,
10767; c) C. D. Cox, M. J. Breslin, B. J. Mariano, P. J. Coleman,
C. A. Buser, E. S. Walsh, K. Hamilton, H. E. Huber, N. E. Kohl,
M. Torrent, Y. Yan, L. C. Kuod, G. D. Hartman, Bioorg. Med.
Chem. Lett. 2005, 15, 2041; d) F. Chimenti, A. Bolasco, F. Manna,
D. Secci, P. Chimenti, O. Befani, P. Turini, V. Giovannini, B.
Mondovi, R. Cirilli, F. La Torre, J. Med. Chem. 2004, 47, 2071;
e) A. Sahoo, S. Yabanoglu, B. N. Sinha, G. Ucar, A. Basu, V.
Jayaprakash, Bioorg. Med. Chem. Lett. 2010, 20, 132.
[4] S. Kanemasa, T. Kanai, J. Am. Chem. Soc. 2000, 122, 10710 and
references cited therein for previous related diastereoselective
methodologies. For preliminary discussions, see: K. V. Gothelf,
K. A. Jørgensen, Chem. Rev. 1998, 98, 863.
[5] [2+3] cycloadditions with diazoalkanes: a) T. Kano, T. Hashi-
moto, K. Maruoka, J. Am. Chem. Soc. 2006, 128, 2174; b) M. P.
Sibi, L. M. Standley, T. Soeta, Org. Lett. 2007, 9, 1553; c) L. Gao,
G.-S. Hwang, M. Y. Lee, D. H. Ryu, Chem. Commun. 2009, 5460.
[6] [2+3] cycloadditions with nitrilimines: a) M. P. Sibi, L. M.
Stanley, C. P. Jasperse, J. Am. Chem. Soc. 2005, 127, 8276;
b) M. P. Sibi, L. M. Standley, T. Soeta, Adv. Synth. Catal. 2006,
348, 2371.
Chem. Int. Ed. 2008, 47, 9466. For examples of racemic PTC aza-
Michael reaction, see: a) L. W. Xu, L. Li, C.-G. Xia, S.-L. Zhou,
J.-W. Li, X.-X. Hu, Synlett 2003, 2337; b) J. Lee, M.-H. Kim, S.-S.
Jew, H.-G. Park, B.-S. Jeong, Chem. Commun. 2008, 1932; c) M.
Mꢂnard, V. Dalla, Synlett 2005, 95.
[14] S. Juliꢁ, A. Ginebreda, J. Guixer, A. Tomꢁs, Tetrahedron Lett.
1980, 21, 3709, and references cited therein.
[15] a) J. Aires-de-Sousa, A. M. Lobo, S. Prabhakar, Tetrahedron
Lett. 1996, 37, 3183; b) J. Aires-de-Sousa, S. Prabhakar, A. M.
Lobo, A. M. Rosa, M. J. S. Gomes, M. C. Corvo, D. J. Williams,
A. J. P. White, Tetrahedron: Asymmetry 2001, 12, 3349; c) R.
Fioravanti, M. G. Mascia, L. Pellacani, P. A. Tardella, Tetrahe-
dron 2004, 60, 8073; d) E. Murugan, A. Siva, Synthesis 2005, 12,
2022; e) S. Minakata, Y. Murakami, R. Tsuruoka, S. Kitanaka,
M. Komatsu, Chem. Commun. 2008, 6363. Except in refer-
ence [15c] the creation of a stereogenic center occurred during
the ring-closing step of the aziridination reaction so that a chiral
enolate/ammonium ion pair is involved during the stereoselec-
tive event instead of an amide/ammonium one.
[16] a) M. Bandini, A. Eichholzer, M. Tragni, A. Umani-Ronchi,
Angew. Chem. 2008, 120, 3282; Angew. Chem. Int. Ed. 2008, 47,
3238.
[17] Selected review on organocatalysis: a) Special issue on organo-
catalysis: B. List, Chem. Rev. 2007, 107, 5413; b) Enantioselective
Organocatalysis (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2007;
c) S. Bertelsen, K. A. Jørgensen, Chem. Soc. Rev. 2009, 38, 2178,
and references cited therein.
[18] M.-S. Yoo, B.-S. Jeong, J.-H. Lee, H.-G. Park, S.-S. Jew, Org. Lett.
2005, 7, 1129, and references cited therein.
[19] a) O. Marianacci, G. Micheletti, L. Bernardi, F. Fini, M. Fochi, D.
Pettersen, V. Sgarzani, A. Ricci, Chem. Eur. J. 2007, 13, 8338;
b) R. D. Momo, F. Fini, L. Bernardi, A. Ricci, Adv. Synth. Catal.
2009, 351, 2283, and references cited therein.
[20] The present methodology did not furnish pyrazoline derivatives
from aliphatic ketones. For instance, the trans-1-phenyl-2-buten-
1-one mainly dimerized and gave a little of the aza-Michael
product resulting from the conjugate addition of the primary
amine of the tert-butylcarbazate. For precedent, see: F.-Y.
Zhang, E.-J. Corey, Org. Lett. 2004, 6, 3397.
[21] CCDC 773701 contains the supplementary crystallographic data
of pyrazoline (S)-(À)-6a 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. The
absolute configurations of the remaining pyrazolines as levo
(À) isomer were assigned (S) by analogy to 6a. The only one
exception to this rule is 5-(4-methoxyphenyl)-3-phenyl-pyrazo-
line (Table 2, entry 10).
[7] [2+3] cycloadditions of hydrazones: Y. Yamashita, S. Kobayashi,
J. Am. Chem. Soc. 2004, 126, 11279.
[8] a) H. Yanagita, S. Kanemasa, Heterocycles 2007, 71, 699; b) for
the first catalytic asymmetric aza-Michael reactions of hydra-
zines to afford pyrazolidinones, see: M. P. Sibi, T. Soeta, J. Am.
Chem. Soc. 2007, 129, 4522. For an alternative use of hydrazones
in aza-Michael reactions, see: c) D. Perdicchia, K. A. Jørgensen,
J. Org. Chem. 2007, 72, 3565; d) S. Gogoi, C.-G. Zhao, D. Ding,
Org. Lett. 2009, 11, 2249.
[9] S. Mꢀller, B. List, Angew. Chem. 2009, 121, 10160; Angew.
Chem. Int. Ed. 2009, 48, 9975.
[10] Review on organocatalytic aza-Michael reactions: a) D. Enders,
C. Wang, J. X. Liebich, Chem. Eur. J. 2009, 15, 11058; b) P. R.
Krishna, A. Sreeshailam, R. Srinivas, Tetrahedron 2009, 65, 9657.
[11] For previous studies from our laboratory using guanidines in an
aza-Michael mechanism for racemic products, see: O. Mahꢂ, D.
Frath, I. Dez, F. Marsais, V. Levacher, J.-F. Briꢃre, Org. Biomol.
Chem. 2009, 7, 3648, and references cited therein.
[22] The ortho-fluorobenzyl catalyst 4h with K2CO3 at 408C gave
pyrazoline 3a in 72% ee in toluene and 57% ee in a mixture of
toluene/H2O (75:25).
[12] Reviews on PTC: a) T. Ooi, K. Maruoka, Angew. Chem. 2007,
119, 4300; Angew. Chem. Int. Ed. 2007, 46, 4222; b) K. Maruoka,
T. Hashimoto, Chem. Rev. 2007, 107, 5656; c) S.-S. Jew, H.-G.
Park, Chem. Commun. 2009, 7090.
[23] For insight into role of the hydrogen bonds with ammonium
PTC, see: E. Gomez-Bengoa, A. Linden, R. Lꢄpez, I. Mfflgica-
Mendiola, M. Oiarbide, C. Palomo, J. Am. Chem. Soc. 2008, 130,
7955.
À
[13] An example of alternative C N bond formation with electro-
philic amine reagents under PTC: R. He, X. Wang, T. Hashi-
Angew. Chem. Int. Ed. 2010, 49, 7072 –7075
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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