A proof of concept: 2-pyrazolines (4,5-dihydro-1H-pyrazoles) can be used as organocatalysts via iminium activation

Article abstract of DOI:10.2174/1570178613666160815163117

Background: In the field of asymmetric aminocatalysis, chiral catalysts derived from azoles (five-membered heterocycles containing exclusively N atoms) play an important role. Surprisingly, all the catalysts used for enamine and/or iminium ion activation derive from pyrrole or imidazole. We decided to test if other reduced azole derivatives could be used as organocatalysts and particularly in aminocatalysis via iminium ion activation. The azole derivatives that came naturally to mind are the 3,5-disubstituted 2-pyrazolines (also called 4,5-dihydro-1H-pyrazoles). Methods: We synthesized racemic 3,5-diphenyl-2-pyrazoline, separated both enantiomers by chiral-HPLC on a Lux-Cellulose-4 column (heptane/ethanol 70:30 as mobile phase), determined the absolute configuration of their hydrochloride salts (pyrazolinium) by the combined use of experimental rotatory power and B3LYP/6-311++G(d,p) theoretical calculations and use one the enantiomers, the R, as the catalyst. Results: We have demonstrated that the enantiopure (R)-3,5-diphenyl-2-pyrazoline is able to catalyze the Michael addition of 1-(4-nitrophenyl)propan-2-one to cinnamaldehyde and crotonaldehyde via iminium activation. Conclusion: This is the first example of activation of both types of enals, aliphatic and aromatic, via pyrazolinium salts and opens new possibilities to the design of other type of chiral organocatalysts than the traditional pyrrole and imidazole derivatives.

Full text of DOI:10.2174/1570178613666160815163117

Send Orders for Reprints to reprints@benthamscience.ae
Letters in Organic Chemistry, 2016, 13, 414-419
414
RESEARCH ARTICLE
ISSN: 1570-1786
eISSN: 1875-6255
Impact
Factor:
0.664
A Proof of Concept: 2-Pyrazolines (4,5-Dihydro-1H-pyrazoles)
Can Be Used as Organocatalysts via Iminium Activation
BENTHAM
S
CIENCE
Eduardo Rodrigo1, M. Belén Cid1*, Christian Roussel2, Nicolas Vanthuyne2*, Felipe Reviriego3,
Ibon Alkorta3* and José Elguero3
2
1Department of Organic Chemistry, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain; Aix-
3
Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France; Instituto de Química
Médica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
Abstract: Background: In the field of asymmetric aminocatalysis, chiral catalysts
derived from azoles (five-membered heterocycles containing exclusively N atoms)
play an important role. Surprisingly, all the catalysts used for enamine and/or imin-
ium ion activation derive from pyrrole or imidazole. We decided to test if other re-
duced azole derivatives could be used as organocatalysts and particularly in amino-
catalysis via iminium ion activation. The azole derivatives that came naturally to
mind are the 3,5-disubstituted 2-pyrazolines (also called 4,5-dihydro-1H-pyrazoles).
A R T I C L E H I S T O R Y
Methods: We synthesized racemic 3,5-diphenyl-2-pyrazoline, separated both enanti-
omers by chiral-HPLC on a Lux-Cellulose-4 column (heptane/ethanol 70:30 as mo-
Received: January 26, 2016
Revised: May 10, 2016
bile phase), determined the absolute configuration of their hydrochloride salts (pyra-
Accepted: June 24, 2016
zolinium) by the combined use of experimental rotatory power and B3LYP/6-311++G(d,p) theoretical
DOI:
calculations and use one the enantiomers, the R, as the catalyst.
10.2174/15701786136661608151631
17
Results: We have demonstrated that the enantiopure (R)-3,5-diphenyl-2-pyrazoline is able to catalyze
the Michael addition of 1-(4-nitrophenyl)propan-2-one to cinnamaldehyde and crotonaldehyde via imin-
ium activation.
Conclusion: This is the first example of activation of both types of enals, aliphatic and aromatic, via
pyrazolinium salts and opens new possibilities to the design of other type of chiral organocatalysts than
the traditional pyrrole and imidazole derivatives.
Keywords: Absolute configuration, DFT calculations, 4,5-dihydro-1H-pyrazoles, Michael addition, organocatalysis, Pyra-
zolines.
1. INTRODUCTION
iminium ion catalysis, the most frequent catalysts were
MacMillan's imidazolidinone-based catalysts (6 [8] and 7
[9]). These catalysts were later also applied in SOMO cataly-
sis and enamine catalysis, yet they had been designed mostly
for iminium ion catalysis. Nowadays, these catalysts are still
being widely used; see for example [4].
In the field of asymmetric aminocatalysis [1], chiral cata-
lysts derived from azoles (five-membered heterocycles con-
taining exclusively N atoms) [2] play an important role. Sur-
prisingly, all the catalysts used for enamine and/or iminium
ion activation derive from pyrrole or imidazole. Fig. (1)
gathers some of the most employed chiral catalysts in imin-
ium and enamine activation.
To our knowledge, the use of imidazolines derivatives in
aminocatalysis (covalent catalysis involving iminium or
enamine activation) has not been described so far. Although
4 has been used as catalyst in a Friedel-Crafts type reaction,
it implied a non-covalent catalysis by hydrogen-bond [5].
Nowadays, the most popular catalysts in iminium and
enamine activation are probably the diarylprolinol silyl
ethers 2 [4] and 3 [5], which have resulted from proline (1)
evolution (for general reviews on the use of silyl diarylproli-
nol ethers as catalysts see [3]). However, at the early times in
We decided to test if other reduced azole derivatives
could be used as organocatalysts and particularly in amino-
catalysis via iminium ion activation. For a review of iminium
activation, see [12] and for our previous experience in imin-
ium activation see [13].
*Address correspondence to these authors at the Department of Organic
Chemistry, Universidad Autónoma de Madrid, Cantoblanco, E-28049
Madrid, Spain E-mail: belen.cid@uam.es; Aix-Marseille Université, Cen-
trale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France;
E-mail: nicolas.vanthuyne@univ-amu.fr; Instituto de Química Médica,
CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain; Tel: +3491 258 75 16;
Fax: +34 91 564 48 53; E-mail: ibon@iqm.csic.es
2. RESULTS AND DISCUSSION
The azole derivatives that came naturally to mind are the
3,5-disubstituted 2-pyrazolines (Fig. 2). Although several
1875-6255/16 $58.00+.00
© 2016 Bentham Science Publishers

A Proof of Concept: 2-Pyrazolines (4,5-Dihydro-1H-pyrazoles)
Letters in Organic Chemistry, 2016, Vol. 13, No. 6 415
O
N
H
N
H
N
H
N
H
pyrrolidine-
derivatives
pyrroline-
pyrrolididone-
pyrrole-
derivatives
derivatives
derivatives
No examples
No examples
OTMS
Ar
CO2H
N
N
H
1
Ar
H
2, Ar = Ph
3, Ar = 3,5-(CF3)2C6H3
O
N
N
N
N
N
H
N
H
N
H
N
H
imidazoline-
derivatives
imidazole-
derivatives
imidazolidine-
derivatives
imidazolidinone-
derivatives
O
Me
Me
O
Me
Ar
Ar
N
N
N
N
N
Id
Me
Me
Cl–
tBu
Cl–
Bn
Bn
N
N
N
N
H
N N
H
H H
H H
H
4
6
5
7
Id
Fig. (1). Examples of chiral organocatalysts derived from pyrrole or imidazole: 1 [6], 2 [7], 3 [8], 4 [5], 5 [9], 6 [10] and 7 [11].
R5
Ph
Ph
R3
H
Ph
H
N
N
N
N
Ph
Ph
H
N
N
N
N
9
8
pyrazole-
derivatives
3,5-disubstituted
1H-2-pyrazolines
This work
Fig. (2). 3,5-Diphenyl-2-pyrazoline (9) proposed as aminocatalyst.
enantioselective syntheses have been reported [14], this kind
of compounds is usually prepared as racemates, for instance
1,3,5-triphenyl-2-pyrazoline (8) (see later) [15]. Due to sim-
plicity reasons in its synthesis [16], 3,5-diphenyl-2-
pyrazoline (9) was chosen as tentative catalyst.
substituent. The Michael reaction/aldol reaction/ dehydration
sequence provided 5-substituted 6-(4-nitrophenyl)-2-
cyclohexen-1-ones 16 in good yields and complete diastereo-
selectivity.
Therefore, in order to test the catalytic possibilities of 9
via iminium activation, we have selected the Michael reac-
tion between 1-(4-nitrophenyl)propan-2-one (14) and both
cinnamaldehyde (21a) and crotonaldehyde (21b) as model
reactions (Schemes 2 and 3). Firstly, a preliminary study of
reactivity of the racemic catalyst was performed (Scheme 2).
The use of the hydrochloride (rac)-9.HCl led only to the
diethoxyacetal of cinnamaldehyde, and no Michael addition
was observed. Nevertheless, when the free base 9 was liber-
ated (by treatment with an aqueous solution of saturated
K2CO3 followed by extraction with Et2O) and the reaction
was carried out in the presence of benzoic acid, the corre-
sponding Michael adducts 15a of cinnamaldehyde were ob-
tained, although with low conversions. Under the same con-
ditions, no reaction was observed after 24 h when crotonal-
dehyde (21b) was used.
Several facts supported the viability of the use of com-
pound 9 in iminium activation processes. Firstly, it is known
that 2-pyrazolines protonate on N1 [17]. Also, 10, 11 and
some other iminium derivatives bearing the pyrazoline moi-
ety have been isolated (12 and 13 [18]) (Fig. 3). The X-ray
structures of 10-12 were reported in the CSD under the code
names of PYZOLC, VIDKUO and UPIPUT, respectively
[19].
We demonstrated that a p-nitrophenyl group converts
acetone in an excellent and versatile nucleophile in the Mi-
chael addition to α,β-unsaturated aldehydes via iminium ac-
tivation using catalysts 2 and 3 (Scheme 1) [13c]. The ad-
ducts were obtained with good yields and variable enantiose-
lectivities according to the aromatic or aliphatic nature of the

416 Letters in Organic Chemistry, 2016, Vol. 13, No. 6
Rodrigo et al.
Ph
Ph
Ph
B
Me
Me
Me
Me
Cl–
Me
Me
N
N
N
N
N
N
N
N
Cl–
=
H H
H H
1/2 SnCl6
13
H
Me
Me
11
10
12
F
Fig. (3). Different salts derived from 2-pyrazolines.
Our previous work:
a)
OTMS
Ar
N
H
Ar
3
R
O2N
O2N
Ar = 3,5-(CF3)2C6H3-
R
OTMS
Ar
N
b) DBU
+
Ar
c) p-TsOH
O
O
O
14
21
16
R
de > 98%, ee up to 96%
Yields 56-80%
Polysubstituted
2-aryl cyclohexanones
Scheme (1). Previous work as model reaction [13b].
Ph
N
Ph
N
O2N
O2N
(rac)-9
H
O
R
+
(20 mol %)
H
PhCO2H (20 mol%)
24 h, EtOH, rt
R
O
O
Me
O
Me
21a, R = Ph
21b
15a
14
, R = Ph, Conv.: 38%
, R = Me
15b, R = Me, Conv.: 0%
Scheme (2). Preliminary study of Michael reactivity with catalyst 9.
We confirmed that the reaction does not occur in the ab-
sence of the catalyst after 24 h in the case of cinnamaldehyde
(21a). Consequently, although the conversion was not very
high, the formation of the adduct 15a (as a mixture of di-
astereoisomers) demonstrated that pyrazoline 9 was able to
activate the enal via iminium activation. This result
prompted us to prepare 9 in enantiomerically pure form by
chromatographic separation of both enantiomers and evalu-
ate its possibilities in enantioselective catalysis.
our experiments, we employed the first eluted sample, which
had a rotatory power value of [α]D –109.
Lux-Cellulose-4
Heptane/ethanol 70/30
Compound 9
Compound 9 was analyzed by chiral HPLC on a Lux-
Cellulose-4 column (heptane/ethanol 70:30 as mobile phase,
UV 220 nm, 1 mL·min-1, 25°C, see Fig. 4). Compound 9
proved to be not very stable; therefore the separation had to
be done on the corresponding hydrochloride. At preparative
scale, 9.HCl was injected on a Lux-Cellulose-4 column
(250 x 10 mm), with hexane/ethanol (70/30) with 0.01 % of
triethylamine as mobile phase and 5 mL·min–1 as flow-rate.
Each enantiomer was collected separately, in a flask contain-
ing ethanol with aqueous hydrochloric acid to avoid its de-
composition, by formation of the hydrochloride. After
evaporation of the solvents, each enantiomer of 9.HCl was
obtained as a mixture with triethylamine hydrochloride. In
UV 220nm
polarimeter
0
1
2
3
4
5
6
7
8
9
min
Fig. (4). Analytical chiral HPLC chromatogram of 9.

A Proof of Concept: 2-Pyrazolines (4,5-Dihydro-1H-pyrazoles)
Letters in Organic Chemistry, 2016, Vol. 13, No. 6 417
To determine the absolute configuration of 9, first we
calculated, using the Gaussian 09 facilities, at the B3LYP/6-
311++G(d,p) level, the static [α]D of one of the enantiomers
of 1,3,5-triphenyl-2-pyrazoline (8) in CH2Cl2 that is equal to
–547, the experimental value being –424 (1.3 times greater).
Then, we calculated the (S)-enantiomer of 9.HCl and ob-
tained [α]D = +260. Thus, the first eluted compound is the
(R)-9. Here the ratio is ~2.4, much larger than 1.3 but the
hydrochloride 9.HCl is a mixture containing about 50 %
to obtain the corresponding adduct 15b (Scheme 3). The
transformation of the adducts 15 into the corresponding cy-
clohexenones 16 was necessary to determine the enantiose-
lectivity of the process by HPLC. After cyclization, epimeri-
zation of the benzylic position towards the most stable anti
cyclohexanone occurs [13]. Although the enantiomeric ex-
cess of 16a [derived form cinnamaldehyde (21a)] was rather
low (8 %), the cyclohexenone 16b derived from the aliphatic
enal 21b could be obtained with a preliminary promising 28
% ee.
1
(determined by H NMR) of triethylamine hydrochloride,
thus the ratio becomes comparable.
The (S,S) stereochemistry of the final products 16 was
determined by comparison with a HPLC sample we had from
our previous works, whose configuration was unequivocally
determined by X-ray diffraction [13b]. This configuration
agreed with a steric controlled mechanism (which seems
reasonable in the absence of a stereodirecting substituent)
and the formation of the (Z)-iminium. The attack of the nu-
cleophile would take place through the less hindered face,
opposite to one of the phenyl group. This is in accordance
The liberated catalyst (R)-9 was employed in the stereo-
selective Michael addition. In order to get higher conver-
sions, some small changes were performed compared to the
preliminary experiments carried out with the racemic cata-
lyst. In the case of the aromatic aldehyde 21a, just longer
reaction times led to higher conversions. In the case of the
aliphatic aldehyde 21b, an increase of the catalyst loading as
well as the use of a combination of additives were mandatory
Ph
N
Ph
(R)-9
O2N
O2N
R
N
H
O
+
H
Additive, time
EtOH, rt
14
15
R
O
O
Me
O
Me
21a, R = Ph,
1) DBU (40 mol%)
THF, 6 h
Conditions: Catalyst (20 mol%)
PhCO2H (20 mol%), 96 h
2) p-TsOH, toluene
reflux, 4 h
21b, R = Me,
Conditions: Catalyst (40 mol%)
PhCO2H (40 mol%), TBAB (1 equiv.), 120 h
O2N
R
O
16a, R = Ph, Yield = 53%, ee = 8%
16b, R = Me, Yield = 58%, ee = 28%
Scheme (3). (R)-3,5-Diphenyl-2-pyrazoline (9) as organocatalyst.
Scheme (4). Proposed mechanism of formation of 16.

418 Letters in Organic Chemistry, 2016, Vol. 13, No. 6
Rodrigo et al.
CH3
CH3
R
CH3
N
N
N
H
N
N
N
H
N
H
N
H
17
18
19
20
Fig. (4). Formulas of 17-20.
with the proposed one when using catalysts 2-7 [3c]
(Scheme 4).
flash column chromatography (hexane/ethyl acetate 4:1)
to afford the corresponding cyclohexenones [16a, R = Ph
(79 %); 16b, R = Me, (81 %)].
In conclusion, we have demonstrated that enantiopure
(R)-4,5-dihydro-3,5-diphenyl-1H-pyrazole (9) can be used as
chiral organocatalyst in Michael addition via iminium activa-
tion. The replacement of the 5-phenyl group by more elec-
tron-withdrawing and bulkier groups should increase the
reactivity of the catalyst and the enantioselectivity of the
process, for instance, compounds 17 [20] and 18 [21] (Fig. 4).
On the same way, the introduction of a supplementary 5-
methyl substituent [5-methyl-3,5-diphenyl-2-pyrazoline
(19)] [22] or a 4,4-dimethyl one [4,4-dimethyl-3,5-diphenyl-
2-pyrazoline (20)] could prevent the catalyst from oxidation,
increasing its stability. Note that many N-H pyrazolines have
been reported as stable compounds, amongst them 17 and 18.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
We thank the Spanish Government (CTQ-2012-35957).
E.R. thanks the Spanish Ministry of Science for a predoctoral
fellowship. This work has been supported by the Spanish
Ministerio de Economía y Competitividad (CTQ2015-
63997-C2-2-P) and Comunidad Autónoma de Madrid
(S2013/MIT-2841, Fotocarbon). Computer, storage and
other resources from the CTI (CSIC) are gratefully acknowl-
edged. Dedicated to Prof. José Luis García Ruano, mentor
and friend, on the occasion of his retirement
EXPERIMENTAL
Experimental Procedure for Michael Addition to Cin-
namaldehyde (21a, R = Ph) and Crotonaldehyde (21b, R
= Me)
SUPPLEMENTARY MATERIAL
Free base (R)-9 (20 mol% for 21a and 40 mol% for 21b),
the corresponding aldehyde 21 (0.75 mmol) and the additives
[20 mol % PhCO2H for 21a, and 40 mol % PhCO2H and 1
equiv of TBAB (tetrabutylammonium bromide) for 21b]
were dissolved in EtOH (1.5 mL) and the mixture was stirred
at room temperature for 5 min, whereupon the nucleophile
14 (26.8 mg, 0.15 mmol) was added to the solution. The so-
lution was stirred at room temperature 96 and 120 h for 21a
(R = Ph) and 21b (R = Me) respectively. Whereupon, the
solvent was removed under reduced pressure and the crude
purified by flash column chromatography (hexane/ethyl ace-
tate 4:1) to afford the corresponding Michael adducts 15.
The yields for 15a (13.6 mg, 68 %) and 15b (12.1 mg, 72 %)
were calculated based on the recovered starting material
(brsm).
More detailed experimental procedure for the chiral
HPLC, separation of catalyst 9 and Michael addition, NMR
spectra and data of compounds 15 and 16 as well as compu-
tational details.
Supplementary material is available on the publisher’s
web site along with the published article.
REFERENCES
[1]
(a) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Asymmet-
ric Aminocatalysis - Gold Rush in Organic Chemistry. Angew.
Chem., Int. Ed., 2008, 47, 6138-6171. (b) Nielsen, M.; Worgull, D.;
Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen, K. A. Mecha-
nisms in aminocatalysis. Chem. Commun. (Cambridge, U. K.)
2011, 47, 632-649. (c) Asymmetric Organocatalysis in Science of
Synthesis, ed. List, B.; Maruoka, K. Thieme Chemistry, New York
USA, 2012. (d) Organocatalysis in Comprehensive Chirality, ed.
Yamamoto, H.; Carreira, E. M. Elsevier, Oxford UK, 2012, vol. 6.
(e) Pellisier, H. Recent Developments in Asymmetric Organocata-
lysis. RSC Publishing, Cambridge, 2010. (f) Comprehensive Enan-
tioselective Organocatalysis, ed. Dalko, P. I. Wiley-VCH, Wein-
heim, Germany, 2013.
Experimental Procedure to Prepare Cyclohexenones 16
The previously obtained Michael adduct 15 was dis-
solved in 0.5 mL of THF and DBU (1,8-diazabicyclo
[5.4.0]undec-7-ene, 0.4 equiv) was added to the solution.
The mixture was stirred at room temperature until comple-
tion of the reaction (6 h). Then, it was filtered through a
short pad of silica to remove the DBU eluting with EtOAc.
The solvent was evaporated under reduced pressure and the
crude was redissolved in 1 mL of toluene. p-TsOH (0.2
equiv) was added to the solution and the mixture was heated
and vigorously stirred at 120 ºC for 4 h. The solvent was
removed under reduced pressure and the crude purified by
[2]
[3]
Schofield, K.; Grimmett, M. R.; Keene, B. R. T. The Azoles, Cam-
bridge University Press, Cambridge, 1976.
(a) Mielgo, A.; Palomo, C. α,α-Diarylprolinol ethers: new tools for
functionalization of carbonyl compounds. Chem.-Asian J. 2008, 3,
922-948. (b) Xu, L.-W.; Li, L.; Shi, Z.-H. Asymmetric synthesis
with silicon-based bulky amino organocatalysts. Adv. Synth. Catal.,
2010, 352, 243-279. (c) Jensen, K. L.; Dickmeiss, G.; Jiang, H.;
Albrecht, L.; Jørgensen, K. A. The diarylprolinol silyl ether system:
a general organocatalyst. Acc. Chem. Res., 2012, 45, 248-264.
Lelais, G.; MacMillan, D. W. C. Modern strategies in organic ca-
talysis: the advent and development of iminium activation. Ald-
[4]

A Proof of Concept: 2-Pyrazolines (4,5-Dihydro-1H-pyrazoles)
Letters in Organic Chemistry, 2016, Vol. 13, No. 6 419
richimica Acta., 2006, 39, 79-87. (b) Uria, U.; Vicario, J. L.; Badía,
D.; Carrillo, L. Organocatalytic enantioselective aza-Michael reac-
tion of nitrogen heterocycles and α,β-unsaturated aldehydes. Chem.
Commun. (Cambridge, U.K.) 2007, 2509-2511.
alkenyl Fischer carbene complexes with diazomethane derivatives:
preparation and synthetic applications of enantiomerically pure Δ2-
pyrazolines. Chem. Eur. J., 1999, 5, 883-896. (b) Illa, O.; Muray,
E.; Amsallem, D.; Moglioni, A. G.; Gornitzka, H.; Branchadel, V.;
Baceiredo, A.; Ortuño, R. M. A comparative study on the 1,3-
dipolar cycloadditions of diazomethane and bis(diisopropylamino)
phosphinodiazomethane to chiral electron-deficient olefins: reactiv-
ity and diastereoselectivity. Tetrahedron: Asymmetry, 2002, 13,
2593-2603. (c) Müller, S.; List, B. Catalytic asymmetric 6π-
electrocyclization: accessing highly substituted optically active 2-
pyrazolines via diastereoselective alkylations. Synthesis, 2010,
2171-2178. (d) Campbell, N. R.; Sun, B.; Singh, R. P.; Deng, L.
Cinchona alkaloid-catalyzed enantio-selective amination of α,β-
unsaturated ketones: an asymmetric approach to Δ2-pyrazolines.
Adv. Synth. Catal., 2011, 353, 3123-3128. (e) Zhang, Z.; Wang, D.;
Wei, Y.; Shi, M. Facile synthesis of 2-pyrazolines and α,β-diamino
ketones via regioselective ring-opening of hydrazone-tethered az-
iridines. Chem. Commun. (Cambridge, U.K.), 2012, 48, 9607-9609.
(f) Mahé, O.; Dez, I.; Levacher, V.; Brière, J.-F. Enantioselective
synthesis of bio-relevant 3,5-diaryl pyrazolines. Org. Biomol.
Chem., 2012, 10, 3946-3954.
(a) Elguero, J.; Claramunt, R. M.; Shindo, Y.; Mukai, M.; Roussel,
C.; Chemlal, A.; Djafri, A. Chemical behaviour of Δ2-pyrazolines
in acidic media: protonation, cis-trans isomerization, and C5 epi-
merization. Chem. Scripta, 1987, 27, 283-288. (b) Vanthuyne, N.;
Roussel, C.; Naubron, J.-V.; Jagerovic, N.; Morales Lázaro, P.;
Alkorta, I.; Elguero, J. Determination of the absolute configuration
of 1,3,5-triphenyl-4,5-dihydropyrazole enantiomers by a combina-
tion of VCD, ECD measurements, and theoretical calculations.
Tetrahedron: Asymmetry, 2011, 22, 1120-1124.
Aubagnac, J.-L.; Bouchet, P.; Elguero, J.; Jacquier, R.; Marzin, C.
Recherches dans la serie des azoles. XXII. Intervention des dou-
blets p des azotes sur les constantes de couplage dans le cycle pyra-
zoline-2. J. Chim. Phys., 1967, 64, 1649-1655.
Elguero, J.; Jacquier, R. Recherches dans la série des azoles. Proto-
nation des pyrazolines-2. Tetrahedron Lett., 1965, 6, 1175-1179.
Nassimbeni, L. R.; Stephen, A. M.; Van Schalkwyk, T. G. D. Ge-
ometry of the iminium moiety. I. Structure of pyrazolinium salts
and an N-isopropylidene derivative. Acta Crystallogr., Sect. C:
Cryst. Struct. Commun., 1991, C47, 141-146.
Allen, F. H. The Cambridge Structural Database: a quarter of a
million crystal structures and rising. Acta Crystallogr. Sect. B:
Struct. Sci. Cryst. Eng. Mater., 2002, B58, 380-388.
Azarifar, D.; Shaebanzadeh, M. Synthesis and characterization of
new 3,5-dinaphthyl substituted 2-pyrazolines and study of their an-
timicrobial activity. Molecules, 2002, 7, 885-895.
Dawane, B. S.; Vibhute, Y. B.; Konda, S. G.; Mali, M. R. Synthesis
of some new 3-(substituted phenyl)-5-(9-anthryl)-2-pyrazolines, 1-
phenyl-3-(substituted phenyl)-5-(9-anthryl)-2-pyrazolines and 2-(9-
anthryl) -4-(substituted phenyl)-1,5-benzothiazepines as antibacte-
rial agents. Asian J. Chem., 2008, 20, 4199-4204.
Landgrebe, J. A.; Kirk, A. G. Group migrations of carbene centers.
Pyrolysis of the sodium salts of α-arylisobutyrophenone tosylhy-
drazones. J. Org. Chem., 1967, 32, 3499-3506.
[5]
[6]
Takizawa, S.; Hirata, S.; Murai, K.; Fujioka, H.; Sasai, H. C3-
Symmetric chiral trisimidazoline-catalyzed Friedel-Crafts (FC)-
type reaction. Org. Biomol. Chem., 2014, 12, 5827-5830.
(a) Hajos, Z. G.; Parrish, D. R. Asymmetric synthesis of bicyclic
intermediates of natural product chemistry. J. Org. Chem., 1974,
39, 1615-1621. (b) Eder, U.; Sauer, G. Wiechert, R. New type of
asymmetric cyclization to optically active steroid CD partial struc-
tures. Angew. Chem. Int. Ed. Engl., 1971, 10, 496-497. (c) List, B.;
Lerner, R. A.; Barbas III, C. F. Proline-catalyzed direct asymmetric
aldol reactions. J. Am. Chem. Soc., 2000, 122, 2395-2396.
Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Diphenylprolinol
silyl ethers as efficient organocatalysts for the asymmetric Michael
reaction of aldehydes and nitroalkenes. Angew. Chem. Int. Ed.
Engl., 2005, 44, 4212-4215.
Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Enantioselective organocatalyzed α sulfenylation of aldehydes.
Angew. Chem. Int. Ed. Engl., 2005, 44, 794-797.
Prieto, A.; Halland, N.; Jørgensen, K. A. Novel imidazolidine-
tetrazole organocatalyst for asymmetric conjugate addition of ni-
troalkanes. Org. Lett., 2005, 7, 3897-3900.
(a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. New strate-
gies for organic catalysis: the first highly enantioselective organo-
catalytic Diels-Alder reaction. J. Am. Chem. Soc., 2000, 122, 4243-
4244. (b) Beeson, T. D.; MacMillan, D. W. C. Enantioselective or-
ganocatalytic α-fluorination of aldehydes. J. Am. Chem. Soc., 2005,
127, 8826-8828.
Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. Enantioselective
organocatalytic hydride reduction. J. Am. Chem. Soc., 2005, 127,
32-33.
Erkkilä, A.; Majnder, P.; Pihko, P. M. Iminium catalysis. Chem.
Rev., 2007, 107, 5416-5470.
[7]
[8]
[9]
[15]
[16]
[10]
[11]
[12]
[13]
[17]
[18]
(a) Cid, M. B.; Duce, S.; Morales, S.; Rodrigo, E.; García Ruano, J.
L. Nitrophenylacetonitriles as versatile nucleophiles in enantiose-
lective organo-catalytic conjugate additions. Org. Lett., 2010, 12,
3586-3589. (b) Duce, S.; Jorge, M.; Alonso, I.; García Ruano, J. L.;
Cid, M. B. An organocatalytic approach to enantiomerically en-
riched α-arylcyclo-hexenones and cyclohexanones. Org. Biomol.
Chem. 2011, 9, 8253-8260. (c) Duce, S.; Mateo, A.; Alonso, I.;
García Ruano, J. L.; Cid, B. Role of quaternary ammonium salts as
[19]
[20]
[21]
a
new additives in the enantioselective organocatalytic β-
benzylation of enals. Chem. Commun. (Cambridge, U. K.) 2012,
48, 5184-5186. (d) Duce, S.; Jorge, M.; Alonso, I.; García Ruano,
J. L.; Cid, B. p-Nitrophenyl ethylthioester in enantioselective or-
ganocatalytic Michael additions: different behaviour of β-aryl and
β-alkyl enals. Eur. J. Org. Chem. 2013, 7067-7075; (e) Morales, S.;
Guijarro, F. G.; García Ruano, J. L.; Cid, B. A general aminocata-
lytic method for the synthesis of aldimines. J. Am. Chem. Soc.
2014, 136, 1082-1089.
[22]
[14]
(a) Barluenga, J.; Fernández-Marí, F.; Viado, A. L.; Aguilar, E.;
Olano, B.; García-Granda, S.; Moya-Rubiera, C. First highly regio-
and diastereoselective [3+2] cycloaddition of chiral nonracemic
DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Edito-
rial Department reserves the right to make minor modifications for further improvement of the manuscript.