Organocatalytic enantioselective pyrazol-3-one addition to maleimides: Reactivity and stereochemical course

Article abstract of DOI:10.1039/c2ob06553c

The enantioselective synthesis of pyrazol-3-ones has not been extensively studied in organic synthesis. Here in we report the first asymmetric addition of pyrazolones to maleimides catalyzed by bifunctional thiourea catalysts.

Full text of DOI:10.1039/c2ob06553c

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 1645
www.rsc.org/obc
PAPER
Organocatalytic enantioselective pyrazol-3-one addition to maleimides:
Reactivity and stereochemical course†
Andrea Mazzanti,a Teresa Calbet,b Merce Font-Bardia,b Albert Moyanoc and Ramon Rios*c,d
Received 9th September 2011, Accepted 28th November 2011
DOI: 10.1039/c2ob06553c
The enantioselective synthesis of pyrazol-3-ones has not been extensively studied in organic synthesis.
Here in we report the first asymmetric addition of pyrazolones to maleimides catalyzed by bifunctional
thiourea catalysts.
dicarbonyl compounds to maleimides by Bartoli and Melchiorre
Introduction
and up to the most recently reported schemes for oxazolone or
Pyrazolones1 are important structural motifs in several bio-
benzofuranone addition to maleimides, maleimides have shown
logically active compounds: antibacterials,2 antifungals,3 anti-
a great utility in the synthesis of complex and highly functiona-
inflammatories,4 CCR3 antagonists,5 and antitumor6 and
anti-ischemic7 drugs. Pyrazol-3-ones have been found to inhibit
CD80; strongly inhibit protease-resistant prion protein accumu-
lation, cytokines, and p38 kinases; and even exhibit multidrug
resistance modulation (Scheme 1).8 Despite their importance,
however, only few asymmetric methodologies have been devel-
oped for the synthesis of chiral pyrazolones. Similar heterocycles
have attracted more interest for organic chemists, such as oxi-
ndoles,9 benzofuranones,10 and oxazolones;11 however, very
recently, there has been growing activity in the development of
new asymmetric methodologies for the synthesis of chiral
pyrazol-2-ones.
For example, in 2010, Yuan and co-workers reported a highly
diastereo- and enantioselective pyrazol-3-one addition to
nitroalkenes using bifunctional thioureas as catalysts.12 Our
research group has developed different methodologies for the
synthesis of spiropyrazol-3-ones, via a Michael–Michael–aldol
cascade reaction, with excellent results (Scheme 2).13
lized structures.15
On the basis of these previous reports and our experience in
organocatalysis,16 we envisioned achieving easy access to highly
functionalized chiral pyrazolones via an unprecedented
Michael17 reaction between 4-alkyl-pyrazol-3-ones and
maleimides.
Results and discussion
To our delight, when pyrazol-3-one 1a was treated with malei-
mide 2a in toluene at room temperature in the presence of cata-
lyst III, the desired addition product was obtained in good yields
and high diastereoselectivity.
Next, we decided to optimize the reaction conditions to obtain
an enantioselective version of the reaction. As shown in Table I,
In 2011, Feng and co-workers developed a scheme for amin-
ation of pyrazol-3-ones via nucleophilic attack of diazodicarbox-
ylates catalyzed by Gd salts. The final compounds were obtained
in excellent yields and enantioselectivity.14
Maleimides have been extensively used in organocatalysis as
Michael acceptors. Since the first report on the addition of 1,3-
aDepartment of Organic Chemistry “A. Mangini”, University of
Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
bDepartament de Cristalografia, Mineralogia i Dipòsits Minerals,
Universitat de Barcelona, Martí i Franqués s/n, 08028 Barcelona, Spain
cDepartment of Organic Chemistry, Universitat de Barcelona, Martí i
Franqués 1-11, 08028 Barcelona, Spain
dICREA Pg. Lluís Companys 23, 08010 Barcelona, (Spain). E-mail:
ríos.ramon@icrea.cat; Fax: (+34)933397878
†Electronic supplementary information (ESI) available: NMR spectra
and HPLC traces. See DOI: 10.1039/c2ob06553c
Scheme 1 Biologically active pyrazolone derivatives.
Org. Biomol. Chem., 2012, 10, 1645–1652 | 1645
This journal is © The Royal Society of Chemistry 2012

View Article Online
enantioselectivity decreased (entries 2, 3, and 6); and when
DMSO or DMF was used as the solvent, only traces of the final
product were obtained. However, in all the examples, the diaster-
eoselectivity was excellent, although the enantioselectivity was
highly dependent on the nature of the catalyst: the best enantio-
selectivity was obtained with Takemoto thiourea18 (entry 1,
Table 1); chiral bases such as quinine, quinidine, and Sharpless’
ligand can catalyze the reaction, albeit with low enantioselectiv-
ity (entries 7–14; Table 1). Surprisingly, decreases in temperature
did not increase the enantioselectivity or greatly increase the
reaction time (entry 15; Table 1).
After the optimized reaction conditions had been identified,
we shifted our focus to the scope of the reaction. First, we per-
formed the reaction with different maleimides.
As shown in Table 2, the substituent at the N position in the
maleimide has great influence on stereoselectivity. In all the
examples, the final adducts were obtained in excellent yields.
However, when N-aliphatic maleimides were used, the stereose-
lectivity decreased dramatically (entries 7, 8; Table 2). In
addition, N-(4-substituted-aryl) maleimides afforded the final
products in excellent diastereoselectivity and moderate-to-good
enantioselectivity (entries 1–6, 9; Table 2). Finally, N-(2-substi-
Scheme 2 Enantioselective reactions with pyrazol-3-ones.
Table 1 Screening conditionsa
Entry
Solvent
Catalyst
Conversionb
d.r.c
e.e.d
1
2
3
4
5
6
7
8
toluene
CHCl3
AcOEt
DMSO
DMF
III
III
III
III
III
III
I
II
100%
100%
100%
traces
traces
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
>10 : 1
>10 : 1
>10 : 1
>10 : 1
>10 : 1
>10 : 1
>10 : 1
>10 : 1
>10 : 1
>10 : 1
>10 : 1
>10 : 1
>10 : 1
>10 : 1
>10 : 1
80%
52%
30%
0%
2%
THF
28%
46%
12%
−52%
52%
15%
2%
0%
−17%
65%
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
quinine (IV)
quinine (IV)
(DHQ)2PYR (VI)
(DHQD)2PHAL(VII)
(DHQD)2AQN(VIII)
(DHQ)2PYR (IX)
III
10
11
12
13
14
15e
a 1.0 equiv. of pyrazol-3-one 1a, 1.5 equiv of maleimide 2a in 1 mL of toluene in presence of 10 mol% catalyst were stirred at room temperature for
1
1
14 h. b Determined by HNMR of the crude reaction. c Determined by HNMR of the crude reaction. d Determined by chiral HPLC e Reaction run at
−20 °C, 96 h.
the reaction was performed in different solvents with chiral bases
and bifunctional thiourea as catalysts.
The reaction is efficiently catalyzed by bases or bifunctional
catalysts, reaching full conversion to the final compounds in
14 h. When CHCl3, AcOEt, or THF was used, the
tuted-aryl) maleimides achieved high enantioselectivity (entries
10 and 11; Table 2, but with low diastereoselectivity. This
suggests a strong π-interaction between the aryl group of the
maleimide and the bistrifluoromethyl benzene ring of the
catalyst.
1646 | Org. Biomol. Chem., 2012, 10, 1645–1652
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 2 Maleimide scopea
Table 3 Pyrazol-3-one scopea
R1
R2
Product
Yield (%)b
d.r.c
e.e.d
Entry
R
Product
Yield (%)b
d.r.c
e.e.d
Entry
1
2
Ph
3a
3b
84
83
>10 : 1
7 : 1
80%
60%
1
2
3
4
5
6
7
8
9
Et
3a
3m
3n
3o
3p
3q
3r
3s
84
82
86
74
85
88
85
90
89
>10 : 1
>10 : 1
>10 : 1
1.5 : 1
1.6 : 1
10 : 1
>10 : 1
>10 : 1
>10 : 1
80%
64%
79%
86%/n.d
53%/n.d
n.d.
55%
66%
Me
Me
Me
Bn
Bn
iPr
iPr
Ph
3
4
5
6
3c
3d
3e
3f
78
88
92
79
10 : 1
10 : 1
10 : 1
10 : 1
50%
40%
84%
38%
3t
37%
a 1.0 equiv. of pyrazol-3-one 1a–e, 1.5 equiv of maleimide 2a, e, j, k in
1 mL of toluene in presence of 10 mol% catalyst III were stirred at room
temperature for 14 h. b Isolated yield. c Determined by 1HNMR of the
crude reaction. d Determined by chiral HPLC
7
8
3g
3h
93
92
3 : 1
1 : 1
18%/74%
42%/80%
the anomalous dispersion method19 is precluded. The relative
configuration derived from X-ray analysis is 3R*,4S*(C8 and
C13 respectively).
9
3i
3j
88
83
10 : 1
50%
For this reason, the absolute configuration (AC) was assigned
by means of chiroptical methods.20 In the present case, theoreti-
cal calculations of Electronic Circular Dichroism (ECD) and
Vibrational Circular Dichroism (VCD) spectra were carried out
by means of the TD-DFT and DFT methods. These techniques
have been successfully employed many times to assign the AC
of organic molecules.14,21 Compound 3a was selected instead of
3c, because it misses the heavy bromine atom that would
lengthen the calculation times. Taking into account the relative
configuration and the conformation observed in the X-Ray struc-
ture of 3c, a conformational search was carried out using the
Monte Carlo approach and the MMFF94 molecular mechanics
force field.22 All conformations within a 5 kcal mol−1 windows
were then optimized using DFT23 at the B3LYP/6-31G(d)
level.24 For each stationary point the harmonic vibrational fre-
quencies were calculated at the same level to confirm their stab-
ility (no imaginary frequencies were observed), and to evaluate
the free energy of each conformation by thermochemistry correc-
tions. After DFT minimization, the MMFF structures clustered
in nine conformations (a–i) (Table 4). due to the relative disposi-
tion of the two rings (C8–C13 bond) and to the position of the
ethyl group. (C8–C10 bond, see Fig. 1).
These corresponded to the possible orientation of the pyrazo-
lone ring with respect to the maleimide ring (C16–C13–C8–C7
dihedral angle, see Fig. 1) integrated with the three dispositions
of the ethyl group (C13–C8–C10–C11 dihedral). Each confor-
mation is labelled with respect to these dihedral angles in
Table 4.
Comfortably, the conformation corresponding to that observed
in the solid state of 3c is calculated to be the most stable if the
ZPE uncorrected energy is taken into account, and the second
most stable in the ZPE-corrected free energy scale, with a small
difference with the best structure (Fig. 2).
10
2.5 : 1
90%/n.d.
11
3l
87
1.5 : 1
87%/n.d.
a 1.0 equiv. of pyrazol-3-one 1a, 1.5 equiv of maleimide 2a–l in 1 mL of
toluene in presence of 10 mol% catalyst III were stirred at room
temperature for 14 h. b Isolated yield. c Determined by 1HNMR of the
crude reaction. d Determined by chiral HPLC.
Next, we decided to explore the scope of the reaction in terms
of the pyrazolone moiety. As shown in Table 3, the reaction
affords the final products in good yields in all the examples.
However, the stereoselectivity of the reaction seems to be very
dependent of the bulkiness at the C-5 position of the pyrazolone.
In fact, increasing the steric hindrance of the pyrazolone ring
decreases the enantioselectivity of the reaction dramatically
(entries 1, 2, 5, 7, 9; Table 3). As observed previously, substi-
tution of groups of the maleimide has considerable influence on
the stereoselectivity of the reaction: when 2-substituents were
placed on the aryl ring of the maleimide, the diastereoselectivity
decreased and the enantioselectivity increased.
The relative configuration of compound 3c was determined by
means of X-ray crystallography. Unfortunately, it crystallizes in
the centrosymmetric C2/c space group and any attempt to crys-
tallize a single enantiomer from the enantioenriched mixture
gave good crystals containing the racemate. For this reason the
X-ray data yield the relative stereochemistry of the two chiral
carbons and suitable information about the molecular confor-
mation whereas the assignment of the absolute configuration by
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1645–1652 | 1647

View Article Online
Table 4 Calculated ZPE-uncorrected internal energies (E) and ZPE-
corrected free energies (G°) of the conformations of 3a (in kcal mol−1
,
B3LYP/6-31G(d) level). Populations percentages (Pop, %) are calculated
assuming Boltzmann statistics at T = 25 °C
Conf.
Descriptorsa
E
G°
Pop (%)
a
b
c
d
e
f
g
h
i
a, a
0.076
0.000
0.605
1.766
2.413
5.173
7.278
9.559
10.439
0.000
0.287
0.975
2.097
3.065
5.199
7.586
9.899
10.722
55 (34b)
33 (49b)
10 (14b)
2 (3b)
—
—
—
—
—
−g, a
a, +g
−g,−g
−g,+g
a,−g
+g, a
+g,+g
+g, −g
a Anti (a) and gauche ( g) conformations are labelled with respect to the
C16–C13–C8–C7 and C13–C8–C10–C11 dihedral angles (first and
second descriptor, respectively). b Based on total energy.
Fig. 3 Top: Calculated ECD spectra for the four conformations of
compound 3a, using CAM-B3LYP/6-311+G(d,p). Vertical scale is Δε,
horizontal scale is the wavelength (in nm). Bottom: experimental ECD
spectrum of 3a (in black, using (R,R)-TUC III) and simulated spectra
(blue and red for the total energy and free energy ratios, respectively)
assuming 3S,4R absolute configuration. The vertical scale is in Δε (L
mol−1 cm−1). The simulated spectra were red-shifted by 3 nm and verti-
cally scaled to match the experimental trace.
experimental Δε has been accordingly scaled to obtain the spec-
trum of the enantiopure compound. Because of the distance
between the phenyl chromophores and to the presence of the car-
bonyl moieties, the intensity of the spectrum is rather limited,
and shifted to the low wavelengths region of the UV spectrum,
where the absorbance of the solvents become very strong. For
this reason the sample was prepared using far-UV HPLC grade
acetonitrile, and the spectrum could be reliably recorded down to
190 nm. Calculation of the Electronic Circular Dichroism spectra
were carried out using the TD-DFT CAM-B3LYP27/6-311+G(d,p)
//B3LYP/6-31G(d) and assuming 3S,4R, absolute configuration.
Electronic excitation energies and rotational strengths have been
calculated for the four populated conformations of 3a (Table 4),
and the rotational strength were calculated in both the length and
velocity representation. The resulting values were very similar,
thus the errors due to basis set incompleteness should be con-
sidered very small.28 To cover the 170–400 nm range (see
Fig. 3), 65 transitions were calculated for each conformation The
ECD spectra were then obtained by applying a 0.5 eV Gaussian
shaped line width.29
The shapes of the calculated spectra for the four conformation
a–d are very similar, albeit with different relative intensities of
the Cotton effects. This feature limits the effects due to any error
in the determination of the relative population, that could modify
the intensity of the spectrum, but it should not heavily influence
the pattern of the weighted spectra. The weighted ECD spectra
were obtained taking into account the 54 : 33 : 10 : 2 and the
34 : 49 : 14 : 3 population ratio determined starting from the cal-
culated free energies or from the uncorrected total energies at the
B3LYP/6-31G(d) level, and assuming Boltzmann statistics at
Fig. 1 X-Ray structure of compound 3c.
Fig. 2 3D views of the two most stable conformations of compound
3a. The X-ray structure of 3c is also reported (right).
The good agreement of the calculated with the experimental
structure shows that the theoretical approach can reliably tackle
the conformational analysis of these compounds. Assuming a
2 kcal mol−1 limit,25 the DFT optimization suggest that only
four conformations should be populated, whereas the energies of
the remaining five are too high. Therefore, despite the apparent
flexibility, these molecules should be considered quite rigid, with
well-defined conformational preferences. This finding greatly
enhances the reliability of the chirooptical methods, being the
correct scan of the potential energy surface and the evaluation of
the relative energies of the conformations their main weakness.26
The experimental ECD spectrum of 3a was obtained on
an enantioenriched sample (80% e.e. by HPLC) and the
1648 | Org. Biomol. Chem., 2012, 10, 1645–1652
This journal is © The Royal Society of Chemistry 2012

View Article Online
interactions between the N-arylmaleimide substituent and the
(3,5-bistrifluoromethyl)phenyl moiety of the catalyst play a key
role in determining the preferred orientation of the maleimide.
Conclusions
In summary, we have been developed the first enantioselective
addition of pyrazolones to maleimides. The reaction is efficiently
catalyzed by bifunctional thiourea catalysts and affords the final
compounds in excellent yields, moderate-to-excellent diastereos-
electivity, and good enantioselectivity. Moreover we ascertained
the absolute configurations of adducts 3 by chiroptical tech-
niques (ECD and VCD) coupled with DFT calculations.
Fig. 4 comparison of the calculated VCD spectra for the a–d confor-
mations (coloured traces) and experimental VCD spectrum (black line)
of the carbonyl stretching region. Calculations at the CAM-B3LYP/
6-311+G(d,p) level. The experimental spectrum was recorded in CCl4.
Experimental Section
General Procedure: In a small vial, pyrazolone 1a (50 mg,
0.25 mmol, 1 equiv.), maleimide 2a (65 mg, 0.375 mmol, 1.5
equiv) and catalyst III (12 mg, 10 mol%) in 1 mL of toluene
were stirred at room temperature overnight. The crude mixture
1
was monitored by H NMR and after completion the crude was
purifies by column chromatography, affording 79 mg of com-
pound 3a (84% yield).
1
Fig. 5 Proposed transition state.
3a: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.86
(d, J = 7.7 Hz, 2H), 7.45–7.35 (m, 5H), 7.25–7.15 (m, 3H), 3.37
(dd, J = 5.7 Hz, J′ = 9.6 Hz, 1H), 3.23 (dd, J = 5.7 Hz, J′ = 18.3
Hz, 1H), 2.96 (dd, J = 9.6 Hz, J′ = 18.3 Hz, 1H), 2.21 (s, 3H),
2.11 (q, J = 7.4 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13C NMR
(CDC3, 100 MHz) δ (ppm): 175.8, 175.1, 174.3, 161.8, 138.7,
132.7, 130.5, 130.3, 130.2, 127.6, 126.9, 120.5, 60.0, 44.6,
31.6, 28.2, 15.8, 9.4. HRMS (ESI): calcd. for [M+H]+
(C22H22N3O3) requires 376.1656, found 376.1659. HPLC (Chir-
alpak IA, n-hexane: i-PrOH = 80 : 20, λ = 220 nm, 1.0 mL
min−1): tR = 13.1, 17.5 min. [α]D25 −40.3 (c 0.8, CHCl3, e.e. =
80%).
+25 °C (Fig. 3). Both the simulated spectra with the two differ-
ent population ratio are in good agreement with the experimental
one, and the sequence and relative intensities of the Cotton
effects are correctly reproduced. The 3S,4R, configuration should
be therefore assigned to compound 3a.
However, the intensity of the ECD spectrum is rather weak,
and a cross-check of the assignment by an independent approach
is strongly advisable.30 Compound 3a bears three carbonyl
moiety that exhibit strong IR bands. For this reason the
Vibrational Circular Dichroism spectrum (VCD) of 3a was
acquired in CCl4 solution (4 cm−1 spectral resolution, 10 000
scans). The most intense bands of the VCD spectrum are indeed
the carbonyl stretching bands, that show two signals with oppo-
site phase. Calculations of the Vibrational Circular Dichroism
spectra were carried out using the same CAM-B3LYP31/6-
311+G(d,p) level employed in the simulation of the ECD spec-
trum, within the harmonic approximation32 and assuming the
same 3S,4R absolute configuration. The simulations of the four
spectra of conformers a–d in the carbonyl region are shown in
Fig. 4, together with the experimental trace (in black). All the
calculations correctly simulate the negative band, and the simu-
lations obtained for conformations a and c simulate also the
positive band at lower wavenumbers. Taking into account that
both the chiroptical approaches (ECD and VCD) yield the same
results, the 3S,4R absolute configuration can be reliably assigned
to compound 3a when (R,R)-TUC III was used as catalyst.
The stereochemical course of the pyrazolone-maleimide
Michael reaction catalyzed by the bifunctional thiourea (R,R)-I
can be easily accounted for within the working mechanistic
hypothesis schematized by the transition state depicted in Fig. 5.
The low enantioselectivity and diastereoseelctivities obtained
with N-alkyl-substituted maleimides suggest that π-stacking
1
3b: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.85,
(d, J = 7.7 Hz, 2H), 7.42–7.38 (n, 2H), 7.24–7.18 (m, 1H), 7.08,
(d, J = 8.7 Hz, 2H), 6.91, (d, J = 8.9 Hz, 2H), 3.79 (s, 3H), 3.34
(dd, J = 5.6 Hz, J′ = 9.3 Hz, 1H), 3.30–3.15 (m, 1H), 2.93 (dd, J
= 9.3 Hz, J′ = 18.0 Hz, 1H), 2.19 (s, 3H), 2.15–2.05 (m, 2H),
0.82 (t, J = 7.3 Hz, 3H). 13C NMR (CDC3, 100 MHz) δ (ppm):
176.1, 175.5, 174.4, 161.9, 161.0, 138.8, 130.3, 129.3, 129.0,
128.9, 126.9, 120.5, 116.0, 115.9, 115.9, 60.0, 56.9, 44.6, 31.5,
28.2, 15.9, 9.5. HRMS (ESI): calcd. for [M+H]+ (C23H24N3O4)
requires 406.1761, found 406.1769. HPLC (Chiralpak IB, n-
hexane: i-PrOH = 80 : 20, λ = 254 nm, 1.0 mL min−1): tR
=
21.9, 31.4 min.
1
3c: White solid. H NMR (CDCl3, 400 MHz) δ (ppm): 7.85,
(d, J = 8.6 Hz, 2H), 7.53, (d, J = 8.7 Hz, 2H), 7.43–7.37 (m,
2H), 7.25–7.18 (m, 1H), 7.07, (d, J = 8.7 Hz, 2H), 3.40–3.20
(m, 2H), 2.96 (dd, J = 9.0 Hz, J′ = 17.7 Hz, 1H), 2.20 (s, 3H),
2.13–2.00 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13C NMR (CDC3,
100 MHz) δ (ppm): 138.8, 133.8, 130.4, 129.2, 127.0, 120.5,
59.8, 44.8, 31.5, 28.3, 15.8, 9.4. HRMS (ESI): calcd. for
[M+H]+ (C22H21BrN3O3) requires 454.0761, found 454.0766.
HPLC (Chiralpak IB, n-hexane: i-PrOH = 80 : 20, λ = 254 nm,
1.0 mL min−1): tR = 13.1, 18.4 min.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1645–1652 | 1649

View Article Online
1
3d: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.95,
390.1812 found 390.1807. HPLC (Chiralpak IB, n-hexane:
i-PrOH = 95 : 5, λ = 254 nm, 1.0 mL min−1): 15.9, 16.7, 20.9,
22.1 min.
(d, J = 8.5 Hz, 2H), 7.84, (d, J = 8.6 Hz, 2H), 7.37–7.23 (m,
4H), 7.23–7.17 (m, 1H), 3.43–3.33 (m, 2H), 2.99 (dd, J = 10.5
Hz, J′ = 19.2 Hz, 1H), 2.21 (s, 3H), 2.13–2.00 (m, 2H), 0.83 (t,
J = 7.4 Hz, 3H). 13C NMR (CDC3, 100 MHz) δ (ppm): 175.3,
174.7, 174.2, 161.9, 138.5, 135.6, 130.2, 130.1, 128.3, 127.8,
127.6 (m, CF3), 126.9, 120.3, 59.5, 44.7, 31.3, 28.2, 15.6, 9.4.
HRMS (ESI): calcd. for [M+H]+ (C23H21F3N3O3) requires
444.1530, found 444.1523. HPLC (Chiralpak IA, n-hexane:
i-PrOH = 80 : 20, λ = 254 nm, 1.0 mL min−1): tR = 12.0,
16.0 min.
1
3i: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.85
(d, J = 7.7 Hz, 2H), 7.45–7.35 (m, 3H), 7.23–7.18 (m,2H), 7.13
(d, J = 8.6 Hz, 2H), 3.39–3.24 (m, 2H), 2.96 (dd, J = 9.1 Hz, J′
= 18.3 Hz, 1H), 2.20 (s, 3H), 2.18–2.04 (m, 2H), 0.83 (m, 3H).
13C NMR (CDC3, 100 MHz) δ (ppm): 175.6, 174.9, 174.3,
161.9, 147.6, 144.7, 138.7, 137.8, 136.0, 130.8, 130.7, 130.4,
130.3, 128.9, 127.0, 59.8, 44.8, 32.3, 31.5, 28.3, 15.8, 9.5.
HRMS (ESI): calcd. for [M+H]+ (C22H21ClN3O3) requires
410.1266 found 410.1275. HPLC (Chiralpak IB, n-hexane:
i-PrOH = 90 : 10, λ = 254 nm, 1.0 mL min−1): tR = 24.6,
39.3 min.
1
3e: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.85
(d, J = 7.7 Hz, 2H), 7.40 (t, J = 7.7 Hz, 2H), 7.23–7.18 (m, 1H),
7.00 (d, J = 9.1 Hz, 2H), 3.33 (dd, J = 5.6 Hz, J′ = 9.3 Hz, 1H),
3.11–3.01 (m, 1H), 3.00–2.85 (m, 1H), 2.93 (s, 6H), 2.18 (s,
3H), 2.17–2.00 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H). 13C NMR
(CDC3, 100 MHz) δ (ppm): 176.4, 175.9, 174.5, 161.9, 151.9,
138.8, 130.3, 128.3, 126.9, 120.6, 113.8, 60.4, 44.5, 41.8, 31.6,
28.2, 16.0, 9.5. HRMS (ESI): calcd. for [M+H]+ (C26H33N4O3)
requires 449.2547 found 449.2558. HPLC (Chiralpak IA,
1
3j: White scum (mixture of diastereomers). H NMR (CDCl3,
400 MHz) δ (ppm): 7.90–7.85 (m, 4H), 7.45–7.35, (m, 4H),
7.30–7.15 (m, 8H), 7.02–6.96 (m, 1H), 6.88–6.84 (m, 1H), 3.75
(dd, J = 5.4 Hz, J′ = 18.0 Hz, 1H), 3.43–3.34 (m, 2H),
3.25–3.16 (m, 1H), 3.05–2.93 (m, 2H), 2.24 (s, 3H), 2.21 (s,
3H), 2.15–2.05 (m, 1H), 2.11 (s, 3H), 1.95–1.85 (m, 1H), 1.77
(s, 3H). 13C NMR (CDC3, 100 MHz) δ (ppm): 175.8, 175.6,
175.5, 175.2, 174.4, 174.3, 162.6, 161.9, 139.0, 137.3, 132.6,
132.5, 131.9, 131.1, 131.0, 130.3, 130.2, 129.2, 129.0, 128.5,
128.2, 127.0, 126.7, 120.5, 120.3, 60.2, 59.0, 45.4, 44.8, 31.9,
31.1, 28.8, 28.3, 19.1, 18.9, 16.0, 15.6, 9.5, 9.4. HRMS (ESI):
calcd. for [M+H]+ (C23H24N3O3) requires 390.1812 found
390.1801. HPLC (Chiralpak IB, n-hexane: i-PrOH = 90 : 10, λ =
254 nm, 1.0 mL min−1): 24.3, 38.1 min.
n-hexane: i-PrOH = 85 : 15, λ = 254 nm, 1.0 mL min−1): tR
=
44.4, 63.7 min.
1
3f: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.86
(d, J = 7.8 Hz, 2H), 7.42–7.36 (m, 2H), 7.22–7.18 (m, 2H),
7.04, (d, J = 8.1 Hz, 2H), , 3.34 (dd, J = 5.5 Hz, J′ = 9.4 Hz,
1H), 3.22–3.12 (m, 1H), 2.93 (dd, J = 9.4 Hz, J′ = 18.1 Hz, 1H),
2.33 (s, 3H), 2.18 (s, 3H), 2.12–2.08 (m, 2H), 0.81 (t, J = 7.5
Hz, 3H). 13C NMR (CDC3, 100 MHz) δ (ppm): 176.0, 175.4,
174.4, 162.0, 140.3, 138.8, 131.3, 131.2, 130.3, 127.9, 127.5,
127.5, 126.9, 120.5, 60.0, 44.7, 31.6, 28.2, 22.6, 15.9, 9.5.
HRMS (ESI): calcd. for [M+H]+ (C23H24N3O3) requires
390.1812 found 390.1817. HPLC (Chiralpak IA, n-hexane:
i-PrOH = 80 : 20, λ = 254 nm, 1.0 mL min−1): tR = 14.0,
19.5 min.
1
3l: White scum (mixture of diastereomers). H NMR (CDCl3,
400 MHz) δ (ppm): 7.90–7.85 (m, 4H), 7.42–7.35, (m, 4H),
7.25–7.00 (m, 8H), 3.62 (dd, J = 5.6 Hz, J′ = 18.5 Hz, 1H),
3.50–3.30 (m, 3H), 3.07–2.90 (m, 3H), 2.64 (dd, J = 6.5 Hz,
J′ = 18.5 Hz, 1H), 2.50–2.40 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H),
2.19 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.00–1.85 (m, 1H), 1.84
(s, 3H). 13C NMR (CDC3, 100 MHz) δ (ppm): 175.4, 175.3,
175.1, 174.7, 174.5 174.3, 162.6, 160.2, 139.0, 137.6, 137.4,
136.7, 136.7, 131.3, 131.2, 130.9, 130.4, 130.2, 130.2, 130.0,
129.9, 129.9, 129.7, 126.9, 126.7, 120.5, 120.3, 61.2, 58.9,
45.4, 44.9, 32.7, 31.1, 28.9, 27.3, 22.0, 19.4, 19.2, 19.1, 19.0,
16.4, 15.6, 9.6, 9.4. HRMS (ESI): calcd. for [M+H]+
(C25H28N3O3) requires 418.2125 found 418.2121. HPLC (Chir-
alpak IB, n-hexane: i-PrOH = 90 : 10, λ = 254 nm, 1.0 mL
min−1): 16.8, 21.6 min.
3g: White scum (mixture of diastereomers). 1H NMR (CDCl3,
400 MHz) δ (ppm): 7.90–7.80 (m, 4H), 7.45–7.10, (m, 2H),
7.00–6.95 (m, 2H), 3.40–3.30 (m, 1H), 3.25–3.20 (m, 1H),
2.90–2.75 (m, 2H), 2.00 (s, 3H), 2.00–1.95 (m, 1H), 1.95 (s,
3H), 1.92–1.70 (m, 2H), 0.80–0.75 (m, 6H). 13C NMR (CDC3,
100 MHz) δ (ppm): 176.2, 176.0, 175.4, 174.5, 174.3, 162.4,
160.3, 139.0, 138.6, 130.3,1130.3, 130.2, 130.0, 129.9, 129.9,
129.7, 129.6, 129.4, 129.3, 129.0, 126.9, 126.0, 61.4, 60.4,
60.0, 59.6, 44.5, 44.1, 32.4, 31.1, 28.5, 27.3, 16.1 15.6, 9.6, 9.5.
HRMS (ESI): calcd. for [M+H]+ (C23H24N3O3) requires
390.1812 found 390.1807. HPLC (Chiralpak IB, n-hexane:
i-PrOH = 85 : 15, λ = 254 nm, 1.0 mL min−1): tR = 14.0.5, 17.0,
21.4, 28.4 min.
1
3m: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.83
(d, J = 7.6 Hz, 2H), 7.45–7.35 (m, 5H), 7.25–7.15 (m, 3H), 3.35
(dd, J = 5.8 Hz, J′ = 9.7 Hz, 1H), 3.23–3.18 (m, 1H), 2.96 (dd, J
= 9.7 Hz, J′ = 18.1 Hz, 1H), 2.23 (s, 3H), 1.56 (s, 3H). 13C
NMR (CDC3, 100 MHz) δ (ppm): 175.6, 174.8, 174.7, 163.0,
138.6, 132.4, 130.2, 130.0, 129.9, 127.3, 126.5, 120.0, 54.4,
44.5, 31.3, 20.7, 15.3. HRMS (ESI): calcd. for [M+H]+
(C21H20N3O3) requires 362.1499, found 362.1489. HPLC (Chir-
alpak IB, n-hexane: i-PrOH = 80 : 20, λ = 254 nm, 1.0 mL
min−1): tR = 16.9, 19.3 min.
3h: White scum (mixture of diastereomers). 1H NMR (CDCl3,
400 MHz) δ (ppm): 7.90–7.80 (m, 4H), 7.44–7.16, (m, 22H),
7.13–7.06 (m, 2H), 7.01–6.94 (m, 2H), 6.54 (s, 1H), 6.47 (s,
1H), 3.42–3.10 (m, 3H), 2.87–2.76 (m, 2H), 2.42–2.35 (m, 1H),
2.04 (s, 3H), 1.95 (s, 3H), 3.25–3.20 (m, 1H), 2.90–2.75 (m,
2H), 2.00 (s, 3H), 2.10–1.90 (m, 4H), 2.00–1.95 (m, 1H), 1.95
(s, 3H), 0.77 (m, 6H). 13C NMR (CDC3, 100 MHz) δ (ppm):
176.2, 176.0, 175.4, 174.6, 174.3, 162.4, 160.3, 138.7, 138.6,
138.2, 130.4, 130.3, 130.0, 129.9, 129.8, 129.7, 129.7, 129.6,
129.4, 129.2, 129.0, 126.9, 126.8, 120.5, 120.2, 61.4, 60.4,
60.0, 59.6, 44.5, 44.1, 32.4, 31.1, 28.5, 27.3, 16.1, 15.7, 9.6,
9.5. HRMS (ESI): calcd. for [M+H]+ (C23H24N3O3) requires
1
3n: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.86
(d, J = 8.7 Hz, 2H), 7.42–7.36 (m, 2H), 7.22–7.17 (m, 1H), 7.01
(d, J = 8.9 Hz, 2H), 6.69 (d, J = 8.9 Hz, 2H), 3.31 (dd, J = 5.7
Hz, J′ = 9.2 Hz, 1H), 3.08–2.08 (m, 2H), 2.94 (s, 6H), 2.20 (s,
3H),1.61 (s, 3H). 13C NMR (CDC3, 100 MHz) δ (ppm): 176.5,
175.8, 175.2, 163.3, 152.0, 139.0, 130.3, 128.7, 128.3, 126.7,
1650 | Org. Biomol. Chem., 2012, 10, 1645–1652
This journal is © The Royal Society of Chemistry 2012

View Article Online
121.1, 120.5, 113.9, 113.8, 55.1, 44.6, 41.9, 31.7, 21.0, 15.8.
HRMS (ESI): calcd. for [M+H]+ (C23H25N4O3) requires
405.1921 found 405.1919. HPLC (Chiralpak IB, n-hexane:
i-PrOH = 85 : 15, λ = 254 nm, 1.0 mL min−1): tR = 60.9,
65.8 min.
requires 433.2234 found 433.2240. HPLC (Chiralpak IA,
n-hexane: i-PrOH = 90 : 10, λ = 254 nm, 1.0 mL min−1): tR
=
28.8, 62.6 min.
1
3t: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.93
(d, J = 7.7 Hz, 2H), 7.48–7.10 (m, 13H), 3.99 (dd, J = 4.7 Hz, J′
= 9.5 Hz, 1H), 3.36 (dd, J = 4.7 Hz, J′ = 18.5 Hz, 1H), 2.92 (dd,
J = 9.5 Hz, J′ = 18.5 Hz, 1H), 2.20 (s, 3H). 13C NMR (CDC3,
100 MHz) δ (ppm): 175.9, 175.4, 174.2, 162.7, 138.9, 135.6,
132.9, 131.3, 131.2 130.7, 130.6, 130.5, 130.4, 130.4, 130.2,
128.3, 127.9, 127.8, 127.7, 127.1, 120.8, 63.5, 44.2, 32.9, 15.8.
HRMS (ESI): calcd. for [M+H]+ (C29H29N4O3) requires
481.2234 found 481.2228. HPLC (Chiralpak IB, n-hexane:
i-PrOH = 90 : 10, λ = 254 nm, 1.0 mL min−1): tR = 47.6,
65.4 min.
3o: White scum (mixture of diastereomers). 1H NMR (CDCl3,
400 MHz) δ (ppm): 7.90–7.80 (m, 4H), 7.45–7.15, (m, 12H),
7.01–6.99 (m, 1H), 6.89–6.86 (m, 1H), 3.73 (dd, J = 5.2 Hz, J′
= 18.1 Hz, 1H), 3.40–3.30 (m, 2H), 3.22–3.12 (m, 1H),
3.05–2.95 (m, 2H), 2.27 (s, 3H), 2.24 (s, 3H), 2.12 (s, 3H), 1.90
(s, 3H), 1.63 (s, 3H), 1.53 (s, 3H). 13C NMR (CDC3, 100 MHz)
δ (ppm): 176.7, 175.4, 175.1, 164.0, 139.2, 137.4, 136.8, 132.7,
132.6, 131.9, 131.1, 131.0, 130.5, 130.4, 130.2, 129.3, 129.0,
128.5, 128.2, 126.9, 126.7, 120.5, 120.3, 53.7, 46.6, 44.9, 31.9,
31.2, 21.6, 21.1, 19,1, 18.9, 15.7, 15.3. HRMS (ESI): calcd. for
[M+H]+ (C22H22N3O3) requires 376.1656 found 376.1661.
HPLC (Chiralpak IB, n-hexane: i-PrOH = 80 : 20, λ = 254 nm,
1.0 mL min−1): 21.4, 28.0 min.
Standard UV absorption spectra were recorded at 25 °C in
acetonitrile. ECD spectra of 3a were recorded at 24 °C on a
JASCO J-810 spectrapolarimeter in far-UV HPLC grade aceto-
nitrile solutions (1 × 10−4 M), using a path length of 0.2 cm.
Spectra were recorded in the range 190-400 nm; reported Δε
3p: White scum (mixture of diastereomers). 1H NMR (CDCl3,
400 MHz) δ (ppm): 7.61–7.53 (m, 4H), 7.45–7.30, (m, 6H),
7.20–7.10 (m, 14H), 7.06–6.96 (m, 4H), 3.80 (s, 3H), 3.75–3.70
(m, 1H), 3.64 (s, 3H), 3.60–3.50 (m, 3H), 3.42–3.35 (m, 2H),
3.06–2.96 (m, 3H), 2.85–2.75 (m,1H), 2.29 (s, 3H), 2.25 (s,
3H). 13C NMR (CDC3, 100 MHz) δ (ppm): 176.2, 176.0, 174.9,
174.8, 174.2, 174.1, 161.0, 156.0, 138.5, 135.2, 135.0, 132.5,
132.5, 130.7, 130.6, 130.5, 130.4, 130.2, 129.9, 129.9, 129.1,
129.0, 127.1, 127.0, 122.4, 121.5, 121.1, 121.0, 62.1, 61.5,
57.3, 56.9, 44.4, 44.1, 41.0, 40.8, 32.4, 32.3, 16.8, 16.6. HRMS
(ESI): calcd. for [M+H]+ (C28H26N3O4) requires 468.1918 found
468.1921. HPLC (Chiralpak IB, n-hexane: i-PrOH = 80 : 20, λ =
254 nm, 1.0 mL min−1): 23.2, 27.8 min.
values are expressed as L mol−1 cm−1
.
VCD spectra of 3a were recorded on a single-PEM BioTools
CHIRAL-IR2X spectrometer using a 4 cm−1 resolution. Spectra
were recorded in CCl4 solution (6 mg in 0.3 mL, 0.053 M) in a
BaF2 cell with a pathlenght of 100 μm. 10000 scans were col-
lected (3.5 h). The spectra were calibrated using the internal cali-
bration files, based on the spectra of α-pinene. Baseline artefacts
were corrected by subtracting the VCD spectrum of the pure
CCl4 solvent in the same 100 μm cell to the spectrum of the
compound.
Acknowledgements
1
3q: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.53
(d, J = 8.7 Hz, 2H), 7.36–7.28 (m, 2H), 7.21–7.00 (m, 8H), 6.72
(d, J = 9.0 Hz, 2H), 3.58 (d, J = 13.1 Hz, 1H), 3.53–3.48 (m,
1H), 3.38 (d, J = 13.1 Hz, 1H), 3.05–2.91 (m, 2H), 2.96 (s, 6H),
2.23 (s, 3H). 13C NMR (CDC3, 100 MHz) δ (ppm): 176.7,
175.7, 174.3, 161.0, 152.1, 128.5, 135.1, 130.7, 130.3, 130.0,
129.2, 128.4, 127.2, 121.2, 113.9, 61.7, 44.2, 41.9, 41.0, 32.1,
16.9. HRMS (ESI): calcd. for [M+H]+ (C29H29N4O3) requires
481.2234 found 481.2228.
We thank the Spanish Ministry of Science and Innovation
(MICINN) for financial support (Project AYA2009-13920-C02-
02). A. Mazzanti thanks the University of Bologna (RFO funds
2008).
Notes and references
1 For an excellent book about the chemistry of pyrazol-3-ones, see:Pyrazol-
3-ones. Part IV: Synthesis and Applications, G. Varvounis, in Adv.
Heterocyclic Chem., A. R. Katritzky (Ed.); Academic Press Inc, 2009,
Vol. 98, p. 143.
2 (a) K. Sujatha, G. Shanthi, N. P. Selvam, S. Manoharan, P. T. Perumal
and M. Rajendran, Bioorg. Med. Chem. Lett., 2009, 19, 4501;
(b) D. Costa, A. P. Marques, R. L. Reis, J. L. F. C. Lima and
E. Fernandes, Free Radical Biol. Med., 2006, 40, 632.
3 S. Bondock, R. Rabie, H. A. Etman and A. A. Fadda, Eur. J. Med.
Chem., 2008, 43, 2122.
4 R. N. Brogden, Drugs, 1986, 32, 60.
5 C. Pégurier, P. Collart, P. Danhaive, S. Defays, M. Gillard, F. Gilson,
T. Kogej, P. Pasau, N. Van Houtvin, M. Van Thuyne and B. Van Keulen,
Bioorg. Med. Chem. Lett., 2007, 17, 4228.
6 J. S. Casas, E. E. Castellano, J. Ellena, M. S. Garcia-Tasende, M.
L. Peres-Paralle, A. Sanchez, A. Sanchez-Gonzalez, J. Sordo and
A. Touceda, J. Inorg. Biochem., 2008, 102, 33.
1
3r: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.84
(d, J = 7.6 Hz, 2H), 7.50–7.30 (m, 5H), 7.20–7.14 (m, 3H), 3.62
(dd, J = 7.5 Hz, J′ = 7.5 Hz, 1H), 3.00–2.90 (m, 2H) 2.64–2.54
(m, 1H), 2.20 (s, 3H), 1.14 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 7.3
Hz, 3H). 13C NMR (CDC3, 100 MHz) δ (ppm): 176.3, 175.4,
174.6, 161.7, 138.9, 133.0,130.8, 130.5, 130.4, 127.8, 127.1,
120.7, 62.9, 42.2, 32.9, 31.9, 19.1, 17.8, 17.5. HRMS (ESI):
calcd. for [M+H]+ (C23H24N3O3) requires 390.1812 found
390.1819. HPLC (Chiralpak IA, n-hexane: i-PrOH = 90 : 10, λ =
254 nm, 1.0 mL min−1): tR = 15.6, 29.3 min.
1
3s: White scum. H NMR (CDCl3, 400 MHz) δ (ppm): 7.84
(d, J = 8.8 Hz, 2H), 7.42–7.36 (m, 2H), 7.22–7.17 (m, 1H), 7.01
(d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.9 Hz, 2H), 3.60 (dd, J = 6.9
Hz, J′ = 8.5 Hz, 1H), 2.98–2.80 (m, 2H), 2.94 (s, 6H),
2.66–2.56 (m, 1H), 2.17 (s, 3H), 1.17 (d, J = 6.3 Hz, 3H), 0.99
(d, J = 7.0 Hz, 3H). 13C NMR (CDC3, 100 MHz) δ (ppm):
176.8, 176.0, 174.6, 161.8, 152.1, 138.9, 130.5, 130.4, 128.5,
127.1, 121.3, 120.7, 114.0, 113.9, 63.1, 42.0, 41.9, 32.7, 31.9,
19.2, 17.8, 17.4. HRMS (ESI): calcd. for [M+H]+ (C25H29N4O3)
7 T. W. Wu, L. H. Zeng, J. Wu and K. P. Fung, Life Sci., 2002, 71, 2249.
8 (a) Y. L. Janin, Bioorg. Med. Chem., 2007, 15, 2479; (b) M. T. Gutierrez-
Lugo and C. J. Bewley, J. Med. Chem., 2008, 51, 2606;
(c) I. R. Matthews, PCT Int. Appl. WO 46679 (2005); (d) A. Kimata,
H. Nakagawa, R. Ohyama, T. Fukuuchi, S. Ohta, T. Suzuki and
N. Miyata, J. Med. Chem., 2007, 50, 5053.
9 (a) G. Bencivenni, L. Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaioli, M.
P. Song, G. Bartoli and P. Melchiorre, Angew. Chem., Int. Ed., 2009, 48,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1645–1652 | 1651

View Article Online
7200; (b) Q. Wei and L.-Z. Gong, Org. Lett., 2010, 12, 1008; (c) W.-
B. Chen, Z.-J. Wu, Q.-L. Pei, L.-F. Cun, X.-M. Zhang and W.-C. Yuan,
Org. Lett., 2010, 12, 3132; (d) K. Jiang, Z.-J. Jia, S. Chen, L. Wu and Y.-
C. Chen, Chem.–Eur. J., 2010, 16, 2852; (e) K. Jiang, Z. J. Jia, X.
A. Yin, L. Wu and Y. C. Chen, Org. Lett., 2010, 12, 2766.
A. N. L. Batista, J. S. Mota, Q. B. Cass, M. J. Kato, V. S. Bolzani,
T. B. Freedman, S. N. López, M. Furlan and L. A. Nafie, J. Org. Chem.,
2011, 76, 2603; (c) F. Pesciaioli, P. Righi, A. Mazzanti, G. Bartoli and
G. Bencivenni, Chem.–Eur. J., 2011, 17, 2842; (d) A. Lattanzi,
A. Scettri, R. Zanasi, F. J. Devlin and P. J. Stephens, J. Org. Chem.,
2010, 75, 2179; (e) S. Abbate, A. Ciogli, S. Fioravanti, F. Gasparrini,
G. Longhi, L. Pellacani, E. Rizzato, D. Spinelli and P. A. Tardella,
Eur. J. Org. Chem., 2010, 6193; (f) L. Lunazzi, M. Mancinelli,
A. Mazzanti and M. Pierini, J. Org. Chem., 2010, 75, 5927;
(g) G. Mazzeo, E. Giorgio, R. Zanasi, N. Berova and C. Rosini, J. Org.
Chem., 2010, 75, 4600; (h) G. Pescitelli, S. Di Pietro, C. Cardellicchio,
M. Annunziata, M. Capozzi and L. Di Bari, J. Org. Chem., 2010, 75,
1143; (i) D. Jacquemin, E. A. Perpète, I. Ciofini, C. Adamo, R. Valero,
Y. Zhao and D. G. Truhlar, J. Chem. Theory Comput., 2010, 6, 2071;
( j) C. Gioia, F. Fini, A. Mazzanti, L. Bernardi and A. Ricci, J. Am.
Chem. Soc., 2009, 131, 9614; (k) P. J. Stephens, J. J. Pan, F. J. Devlin
and J. R. Cheeseman, J. Nat. Prod., 2008, 71, 285. For Reviews see:
(l) G. Bringmann, T. Bruhn, K. Maksimenka and Y. Hemberger,
Eur. J. Org. Chem., 2009, 2717; (m) G. Bringmann, T. A. M. Gulder,
M. Reichert and T. Gulder, Chirality, 2008, 20, 628; (n) N. Berova, L. Di
Bari and G. Pescitelli, Chem. Soc. Rev., 2007, 36, 914; (o) G. Pescitelli,
L. Di Bari and N. Berova, Chem. Soc. Rev., 2011, 40, 4603, DOI:
10.1039/c1cs15036g in press.
10 C. Cassani, X. Tian, E. C. Escudero-Adan and P. Melchiorre, Chem.
Commun., 2011, 47, 233.
11 For an exhaustive review of organocatalytic reactions with oxazolones
see: (a) A.-N. R. Alba and R. Rios, Chem.–Asian J., 2011, 6, 720 and
references therein.
12 Y.-H. Liao, W.-B. Chen, Z.-J. Wu, X.-L. Du, L.-F. Cun, X.-M. Zhang and
W.-C. Yuan, Adv. Synth. Catal., 2010, 352, 827.
13 (a) A.-N. R. Alba, A. Zea, G. Valero, T. Calbet, M. Font-bardia,
A. Mazzanti, A. Moyano and R. Rios, Eur. J. Org. Chem., 2011, 1318;
(b) A. Zea, A.-N. R. Alba, A. Mazzanti, A. Moyano and R. Rios, Org.
Biomol. Chem., 2011, 9, 6519.
14 (a) Z. Yang, Z. Wang, S. Bai, X. Liu, L. Lin and X. Feng, Org. Lett.,
2011, 13, 596. For a related works in the synthesis of chiral pyrazol-3-
ones see: (b) S. Gogoi and C.-G. Zhao, Tetrahedron Lett., 2009, 50,
2252; (c) S. Gogoi, C.-G. Zhao and D. Ding, Org. Lett., 2009, 11, 2249;
(d) Z. Wang, Z. Yang, D. Chen, X. Liu, L. Lin and X. Feng, Angew.
Chem., Int. Ed., 2011, 50, 4928; (e) S. Muramulla and C.-G. Zhao, Tetra-
hedron Lett., 2011, 52, 3905.
15 Some examples of organocatalytic uses of maleimides: (a) G. Bartoli,
M. Bosco, A. Carlone, A. Cavalli, M. Locatelli, A. Mazzanti, P. Ricci,
L. Sambri and P. Melchiorre, Angew. Chem., Int. Ed., 2006, 45, 4966;
(b) G.-L. Zhao, Y. Xu, H. Sunden, L. Eriksson, M. Sayah and
A. Cordova, Chem. Commun., 2007, 734; (c) A.-N. R. Alba, G. Valero,
T. Calvet, M. Font-Bardia, A. Moyano and R. Rios, Chem.–Eur. J., 2010,
16, 9884.
16 For a non exhaustive list of our previous works in organocatalysis see:
(a) G. Valero, A.-N. Balaguer, A. Moyano and R. Rios, Tetrahedron
Lett., 2008, 49, 6559; (b) X. Companyó, G. Valero, L. Crovetto,
A. Moyano and R. Rios, Chem.–Eur. J., 2009, 15, 6564;
(c) X. Companyó, M. Hejnová, M. Kamlar, J. Vesely, A. Moyano and
R. Rios, Tetrahedron Lett., 2009, 50, 5021; (d) X. Companyó, A.-
N. Balaguer, F. Cárdenas, A. Moyano and R. Rios, Eur. J. Org. Chem.,
2009, 3075; (e) A.-N. R. Alba, X. Companyó, G. Valero, A. Moyano and
R. Rios, Chem.–Eur. J., 2010, 16, 5354; (f) X. Companyó, A. Zea, A.-N.
R. Alba, A. Mazzanti, A. Moyano and R. Rios, Chem. Commun., 2010,
46, 6953; (g) G. Valero, J. Schimer, I. Cisarova, J. Vesely, A. Moyano
and R. Rios, Tetrahedron Lett., 2009, 50, 1943.
17 For excellent reviews on the topic of 1,4-conjugate additions see:
(a) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; (b) D. Almasi,
D. A. Alonso and C. Najera, Tetrahedron: Asymmetry, 2007, 18, 299;
(c) S. Sulzer-Mosse and A. Alexakis, Chem. Commun., 2007, 3123; (d) J.
L. Vicario, D. Badia and L. Carrillo, Synthesis, 2007, 2065.
18 For the first report for the use of Takemoto’s catalyst see: T. Okino,
Y. Hoashi and Y. J. Takemoto, J. Am. Chem. Soc., 2003, 125, 12672. For
an exceptional review: H. Miyabe and Y. Takemoto, Bull. Chem. Soc.
Jpn., 2008, 81, 785.
22 MMFF94 conformational search, Titan 1.0.5, Wavefunction Inc
23 Gaussian 09, Revision A.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg,
M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida,
T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery
Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand,
K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,
M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross,
V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,
R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B. Foresman,
J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian, Inc., Wallingford CT,
2009
24 (a) A. D. Becke, J. Chem. Phys., 1993, 98, 5648; (b) C. Lee, W. Yang
and R. G. Parr, Phys. Rev. B, 1988, 37, 785; (c) P. J. Stephens, F.
J. Devlin, C. F. Chabalowski and M. J. Frisch, J. Phys. Chem., 1994, 98,
11623.
25 The 2 kcal mol−1 limit corresponds to a population of about 3% at
+25 °C. The, simulated spectrum corresponding to this population cannot
influence the shape of the spectra weighted on the populated
conformations.
26 M. Kwit, M. D. Rozwadowska, J. Gawroski and A. Grajewska, J. Org.
Chem., 2009, 74, 8051.
27 T. Yanai, D. Tew and N. Handy, Chem. Phys. Lett., 2004, 393, 51–57.
28 P. J. Stephens, D. M. McCann, F. J. Devlin, J. R. Cheeseman and
M. J. Frisch, J. Am. Chem. Soc., 2004, 126, 7514.
19 A. F. Peerdeman, A. J. van Bommel and J. M. Bijvoet, Nature, 1951,
168, 271. For a review on the use of X-ray Crystallography for the deter-
mination of the absolute configuration see: H. D. Flack and
G. Bernardinelli, Chirality, 2008, 20, 681.
29 Gaussview 5.0.9, Semichem Inc., 2009.
30 (a) P. L Polavarapu, Chirality, 2008, 20, 664–672; (b) P. J. Stephens, J.
J. Pan, F. J. Devlin, K. Krohn and T. Kurtn, J. Org. Chem., 2007, 72,
3521.
31 T. Yanai, D. Tew and N. Handy, Chem. Phys. Lett., 2004, 393, 51.
32 P. J. Stephens, J. Phys. Chem., 1985, 89, 748–752; P. J. Stephens, C.
S. Ashvar, F. J. Devlin, J. R. Cheeseman and M. J. Frisch, Mol. Phys.,
1996, 89, 579.
20 For
a perspective on chiroptical methods see a dedicated issue:
P. L. Polavarapu, L. A. Nafie and N. Berova (Ed.), Chirality, 2009, 21,
E1–E312.
21 (a) M. Woźnica, A. Butkiewicz, A. Grzywacz, P. Kowalska, M. Masnyk,
K. Michalak, R. Luboradzki, F. Furche, H. Kruse, S. Grimme and
J. Frelek, J. Org. Chem., 2011, 76, 3306; (b) J. M. Batista Jr.,
1652 | Org. Biomol. Chem., 2012, 10, 1645–1652
This journal is © The Royal Society of Chemistry 2012