Highly stereoselective synthesis of spiropyrazolones

Article abstract of DOI:10.1002/ejoc.201001452

The synthesis of spiro compounds through a Michael-Michael-aldol reaction is reported. The reaction affords spiropyrazolone derivatives in good yields, in almost diastereo- and enantiopure form, and is catalyzed by diphenylprolinol derivatives. The reacti

Full text of DOI:10.1002/ejoc.201001452

FULL PAPER
DOI: 10.1002/ejoc.201001452
Highly Stereoselective Synthesis of Spiropyrazolones
Andrea-Nekane R. Alba,[a] Alex Zea,[a] Guillem Valero,[a] Teresa Calbet,[b]
Merce Font-Bardía,[b] Andrea Mazzanti,[c] Albert Moyano,[a] and Ramon Rios*[a,d]
Dedicated to Carmen Nájera on the occasion of her 60th birthday
Keywords: Diastereoselectivity / Enantioselectivity / Michael addition / Organocatalysis / Spiro compounds
The synthesis of spiro compounds through a Michael–
Michael–aldol reaction is reported. The reaction affords spi-
ropyrazolone derivatives in good yields, in almost diastereo-
and enantiopure form, and is catalyzed by diphenylprolinol
derivatives. The reaction showed strong nonlinear effects.
Remarkably, when a catalyst with 70% ee is used, the reac-
tion still affords the final spiro compound in almost diastereo-
and enantiopure form.
motifs. In the last year, several research groups have re-
ported asymmetric organocatalytic methodologies for the
synthesis of spiro compounds based in the unique structure
of oxindoles. For example, Melchiorre reported in 2009 the
synthesis of spirooxindoles starting from methylene oxind-
oles by using an organocatalytic cascade reaction promoted
by primary or secondary amines.[5] Subsequently, similar
structural motifs have been built in an enantioselective fash-
ion through [4+2] cycloaddition,[6] [3+2] cycloaddition,
Knoevenagel/Michael cyclization,[7] [2+2+2] cyclization,[8]
and a quadruple domino reaction.[9]
Very recently, fascinated by the synthesis of spiro com-
pounds, our research group has developed a multicompo-
nent cascade reaction between oxindoles and enals that af-
fords the corresponding cyclohexenes in excellent yields and
stereoselectivities (Scheme 1).[10] We have shown that this
methodology can be applied to different heterocycles, such
as benzofuranones,[11] oxazolines, or pyrazolones.
Introduction
The synthesis of natural products with very complex
scaffolds and well-defined three-dimensional structure is
currently one of the goals of organic chemists.[1] This com-
plexity is generally correlated with stereospecificity in the
biological properties. Finding cost-effective, atom-economic
and sustainable methodologies that can be used to build
complex structures in a stereocontrolled fashion, if possible
in a catalytic way, is thus crucial for the chemical com-
munity.
In this context, organocatalysis and, in particular,
organocascade reactions, have emerged as powerful tools
for these complex syntheses.[2] For example, in 2007,
Jørgensen and co-workers reported a powerful triple dom-
ino asymmetric reaction between malononitrile and unsatu-
rated aldehydes that relied on a Michael–Michael–aldol re-
action to construct cyclohexene in excellent yields and
enantioselectivities, but only in moderate to good diastereo-
selectivities.[3] In 2009, Enders and co-workers employed the
same concept starting from nitromethane and unsaturated
aldehydes, with similar results.[4]
One of the most difficult examples of the synthesis of
complex structures is the asymmetric construction of spiro
[a] Department de Química Orgànica, Universitat de Barcelona,
Martí i Franqués 1–11, 08028 Barcelona, Spain
rios.ramon@icrea.cat
http://www.runam.host22.com
[b] Departament de Cristalografia, Mineralogia i Dipòsits
Minerals, Universitat de Barcelona,
Scheme 1. Synthesis of spirooxindoles reported by our group.[10]
Martí i Franqués s/n, 08028 Barcelona, Spain
[c] Dipartimento di Chimica Organica “A. Mangini”Alma Mater
Studiorum – Università di Bologna
Pyrazolones are constituents of several useful intermedi-
ates for medicinal drugs,[12] and have a wide range of ap-
proved biological and pharmaceutical activities, such as an-
algesic and antipyretic properties,[13] antiischemic effects,[14]
antiinflammatory,[13a] antiviral,[15] antitumor,[16] antibacte-
Viale Risorgimento 4, 40136 Bologna, Italy
[d] ICREA,
Passeig Lluis Companys 23, 08010 Barcelona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001452.
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Highly Stereoselective Synthesis of Spiropyrazolones
rial[17] and other useful properties (Figure 1).[18] Numerous be noted that the use of benzoic acid is crucial for the for-
pyrazolone derivatives are also used in the dye industry[19] mation of these spiro compounds; without the addition of
and as anticorrosives.[20]
acid, the reaction does not work, probably because of retro-
Michael reactions previously reported. We then screened
several catalysts and acids; the best catalyst was catalyst
II (Table 1, entry 2). Proline did not catalyze the reaction,
probably due to its poor solubility in toluene (Table 1, entry
1). Catalyst III, which is commonly used in similar method-
ologies, and catalyst IV both resulted in very slow reactions,
affording only trace amounts of product after 14 h (Table 1,
entries 3 and 4). Remarkably, the use of different acids did
not result in any difference in the reaction; o-fluorobenzoic
acid, o-nitrobenzoic acid, and p-nitrobenzoic acid (Table 1,
entries 4, 5, and 6) all gave the same results: full conversion
after 14 h and total diastereo- and enantioselectivity.
Figure 1. Biologically active pyrazolone derivatives.
Table 1. Catalyst screening.[a]
However, despite their wide use in pharmaceutical chem-
istry, there are few reports on the synthesis of chiral pyraz-
olones. Only very recently, Yuan and co-workers developed
an elegant asymmetric organocatalytic pyrazolone addition
to nitroalkenes catalyzed by bifunctional thiourea catalysts
(Scheme 2).[21]
Entry Cat. Acid
Conv. [%][b] dr[b]
ee [%][c]
1
2
3
4
5
6
7
I
C6H5CO2H
C6H5CO2H
C6H5CO2H
C6H5CO2H
o-FC6H4CO2H
o-NO2C6H4CO2H
p-NO2C6H4CO2H
0
–
–
Scheme 2. Organocatalytic pyrazolone addition to nitroalkenes re-
ported by Yuan.[21]
II
III
IV
II
II
II
100
Ͻ10
Ͻ10
100
100
100
Ͼ25:1
n.d.
n.d.
Ͼ25:1
Ͼ25:1
Ͼ25:1
Ͼ99
n.d.
n.d.
Ͼ99
Ͼ99
Ͼ99
Based on these previous reports and on our experience
in organocatalysis,[22] we envisioned an easy entry to chiral
spiropyrazolones through a double Michael addition fol-
lowed by an aldol-dehydration process.
[a] Reagents and conditions: 1a (0.25 mmol, 1.0 equiv.), 2a
(0.60 mmol, 1.2 equiv.), catalyst I–IV (0.05 mmol, 0.2 equiv.), acid
(0.05 mmol, 0.2 equiv.), toluene (1 mL), 14 h. [b] Determined by 1H
NMR spectroscopy. [c] Determined by chiral HPLC analysis.
Results and Discussion
We disclosed that pyrazolones could react with unsatu-
rated aldehydes through a Michael–Michael–aldol conden-
sation to furnish the desired spirocyclic compounds
(Scheme 3).
With this catalytic system in hand, we tested the reaction
in different solvents. The reaction worked in other solvents,
such as ethyl acetate (EtOAc) and chloroform (CHCl3), al-
beit with lower conversions and diastereoselectivities
(Table 2, entries 2 and 5).
Having thus identified the optimal catalyst and solvent,
we then studied the scope of the reaction with a variety
of α,β-unsaturated aldehydes, and found that the reaction
worked with both aliphatic and aromatic unsaturated alde-
hydes with excellent yields (Table 3, entries 1, 2, and 3).
Aromatic enals rendered the final spiro compounds with
excellent diastereo- and enantioselectivities. On the other
Scheme 3. Proposed reaction.
To our delight, when pyrazolone 1a was treated with cinn- hand, aliphatic enals gave lower diastereoselectivities. The
amaldehyde (2a) in the presence of catalyst II (20%) and reaction tolerated several functional groups, such as CN,
benzoic acid (20%) in toluene, the reaction rendered only NO2, or halogens (Table 3, entries 4, 5, and 6) without any
one product, in diastereo- and enantiopure form. It should loss of diastereo- or enantioselectivity.
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R. Rios et al.
FULL PAPER
Table 2. Solvent screening.[a]
Table 4. Pyrazolone scope.[a]
R1
3a Me Ph
R2
Yield [%][b] dr[c]
ee [%][d]
Entry
Solvent
Conv. [%][b]
dr[b]
ee [%][c]
Entry Ar
3
1
2
3
4
5
6
toluene
EtOAc
MeOH
DMSO
CHCl3
Et2O
100
100
Ͻ10
Ͻ10
100
100
Ͼ25:1
5:1
n.d.
n.d.
13:1
11:1
Ͼ99
Ͼ99
n.d.
n.d.
Ͼ99
Ͼ99
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
55
Ͼ25:1:0:0
7:1:0:0
Ͼ99
99
Ͼ99
99
97
93
–
–
–
–
3i Et
3j Et
3k Et
3l Et
3m Et
3n tBu Ph
3o Ph Ph
3p CF3 Ph
3q CF3 Me
p-CNC6H4 72
p-BrC6H4
CO2Et
Ph
51
58
74
64
n.r.[e]
n.r.[e]
n.r.[e]
n.r.[e]
68
20:1:0:0
20:1:0:0
Ͼ25:1:0:0
6.5:1:0:0
–
–
–
–
Ͼ25:1:0:0
5:1:0:0
Ͼ25:1:0:0
7:1:0:0
Me
[a] Reagents and conditions: 1a (0.25 mmol, 1.0 equiv.), 2a
(0.60 mmol, 1.2 equiv.), catalyst II (0.05 mmol, 0.2 equiv.), benzoic
acid (0.05 mmol, 0.2 equiv.), solvent (1 mL), 14 h. [b] Determined
by 1H NMR spectroscopy. [c] Determined by chiral HPLC analysis.
9
10
11
12
13
14
p-CF3C6H4 3r Me Ph
p-CF3C6H4 3s Me CO2Et
Ͼ99
Ͼ99
Ͼ99
92
42
p-CF3C6H4 3t Me p-CNC6H4 84
p-CF3C6H4 3u Me Me 58
Table 3. Enal scope.[a]
[a] Reagents and conditions: 1a–f (0.25 mmol, 1.0 equiv.), 2a–e
(0.60 mmol, 1.2 equiv.), catalyst II (0.05 mmol, 0.2 equiv.), benzoic
acid (0.05 mmol, 0.2 equiv.), toluene (1 mL), 14 h. [b] After column
chromatography. [c] Determined by 1H NMR spectroscopy. [d] De-
termined by chiral HPLC analysis. [e] n.r. (no reaction).
The relative configuration of the spiropyrazolone 3a was
determined by means of NOE and NOESY NMR experi-
ments, as well as by X-ray diffraction analysis of a mono-
crystal (Figure 2). As can be seen, the relative configuration
between the two phenyl groups is, as expected, trans.
Entry
R
3
Yield [%][b] dr[c]
ee [%][d]
1
2
3
4
5
6
Ph
3a
3b
3c
3d
3e
3f
3g
3g
3h
55
80
63
52
48
68
73
60
51
Ͼ25:1:0:0
Ͼ99
99
Ͼ99
99
99
96
94
Ͼ99
Ͼ99
p-CNC6H4
p-BrC6H4
p-ClC6H4
CO2Et
Me
Et
Et
Bu
Ͼ25:1:0:0
Ͼ25:1:0:0
Ͼ25:1:0:0
Ͼ25:1:0:0
7:1:0:0
4.5:1:0:0
7:1:0:0
7:1:0:0
7
8[e]
9
[a] Reagents and conditions: 1a (0.25 mmol, 1.0 equiv.), 2a–h
(0.60 mmol, 1.2 equiv.), catalyst II (0.05 mmol, 0.2 equiv.), acid
(0.05 mmol, 0.2 equiv.), toluene (1 mL), 14 h. [b] Isolated yield. [c]
1
Determined by H NMR of the crude mixture. [d] Determined by
chiral HPLC analysis. [e] Reaction run at 4 °C.
When the reaction was conducted with different pyraz-
olones, to our delight, the final spiropyrazolones were af-
forded in diastereo- and enantiopure form when small ali-
phatic residues, such as ethyl groups, occupied position 3
of the pyrazolone ring (Table 4, entries 2–6). Remarkably,
substitution of the phenylic ring of the pyrazolone by a p-
(trifluoromethyl)phenyl group gave the final spiro com-
pounds in good yields and excellent diastereo- and enantio-
selectivities (Table 4, entries 11–14). However, when bulky
substituents, such as phenyl or tert-butyl (Table 4, entries
Figure 2. Crystal structure of 3a.
Unfortunately, compound 3a lacks the heavy atom re-
7 and 8), or highly electron-withdrawing groups, such as quired to confirm the absolute configuration assignment by
trifluoromethyl, occupied position 3 (Table 4, entries 9 and the Bijvoet method (the anomalous dispersion method).
10), no reaction was observed.
Therefore, the absolute configuration (AC) was assigned by
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Eur. J. Org. Chem. 2011, 1318–1325

Highly Stereoselective Synthesis of Spiropyrazolones
means of chiroptical methods.[23] In the present case, a theo- the ECD spectra were obtained by applying a 0.4 eV
retical calculation of the electronic circular dichroism Gaussian-shaped line width.[29] In order to cover the 170–
(ECD) spectra was carried out by means of the TD-DFT 400 nm range, 70 transition were calculated for each confor-
method, because this technique has been successfully em- mation.
ployed several times previously to predict ECD spectra and
to assign the AC of organic molecules.[24] Starting from the
relative configuration obtained by NMR analysis and X-ray
diffraction, a conformational search was carried out using
Monte Carlo searching together with the MMFF94 molec-
ular mechanics force field (as implemented in Titan 1.0.5,
Wavefunction Inc.). All conformations within a 5 kcal/mol
window were then optimized using DFT at the B3LYP/6-
31G(d) level,[25] and the harmonic vibrational frequencies
of each conformation were calculated at the same level to
confirm their stability (no imaginary frequencies observed),
and to evaluate the free energy of each conformation by
Figure 4. Calculated ECD spectra for the two conformations of
compound 3a. Vertical scale in Δε, horizontal scale in nm.
zero point energy (ZPE) correction. After DFT minimi-
zation, the MMFF structures clustered in two conforma-
tions (a and b), which differed in the disposition of the
CHO group (see Figure 3 and Table 5). The most stable
structure (a) corresponded to the conformation observed in
the solid state, and the energy of the second most stable
conformation (b) was remarkably higher (2.0 kcal/mol).
This means that the molecule is quite rigid, which is a fea-
ture that greatly enhances the reliability of the method, be-
cause the correct evaluation of the relative energy of each
conformation it generally the main weakness of this ap-
proach.
Although the shapes of the two spectra are different, in
both cases the cotton effects below 250 nm are positive, in-
dicating that the resulting weighted ECD spectrum is not
strongly influenced by the relative population of the confor-
mations. The final simulated ECD spectra was obtained by
taking into account the 96:4 population ratios determined
starting from the calculated free energies at the B3LYP/6-
31G(d) level, and assuming Boltzmann statistics (Figure 5).
The simulated spectrum was in good agreement with the
experimental data, and the 5S,6S,10R configuration could
thus be reliably assigned to compound 3a [when (R)-II cata-
lyst was used].
Figure 3. 3D view of the two most stable conformations of com-
pound 3a (energies in kcal/mol).
Figure 5. Experimental ECD spectrum (in black) [using (R)-II as
catalyst] and simulated spectrum (in gray) assuming 5S,6S,10R ab-
solute configuration. The vertical scale is in mdeg, and the simu-
lated spectrum has been scaled accordingly. The simulated spec-
trum has been red-shifted by 8 nm in order to match the experi-
mental trace.
Table 5. Calculated relative energies (E) and free energies (G) of the
conformations of 3a [in kcal/mol, B3LYP/6-31G(d) level]. Popula-
tions percentages (P) were calculated assuming Boltzmann statistics
at T = 25 °C.
Conf.
E
G
Pop. (ΔG)
Both relative and absolute configurations were in agree-
ment with related aminocatalytic conjugate additions pro-
moted by catalyst II.[10,11]
3a
a
b
0.0
2.4
0.00
2.0
96
4
Calculation of the ECD spectra of both conformations
Once the relative and the absolute configuration of the
were carried out using the TD-DFT-BH&HLYP/6- obtained spiropyrazolone was determined, we turned out
311+G(d,p)//B3LYP/6-31G(d) and TD-DFT-B3LYP/6- our attention to the mechanism of the reaction. We as-
311+G(d,p)//B3LYP/6-31G(d)
levels,[26]
assuming sumed that the reaction proceeds through a double Michael
5S,6S,10R absolute configuration (Figure 4).[27] Rotational addition–aldol condensation pathway, as shown in
strengths were calculated in both length and velocity repre- Scheme 4. We propose that the two Michael addition reac-
sentation. Because the resulting values were very similar, tions are reversible and that these additions proceed with
the errors due to basis set incompleteness were very good enantioselectivities but probably with poor diastereo-
small.[28] Electronic excitation energies and rotational selectivities in the first step. However, the quaternary car-
strengths were calculated for the two conformations, and bon formed in compound B is a pro-stereogenic center
Eur. J. Org. Chem. 2011, 1318–1325
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1321

R. Rios et al.
FULL PAPER
when the two pendant chains have the same absolute con- (ee) was used, the reaction afforded, remarkably, the final
figuration, and this compound would be desymmetrized by compound with a 2:1:1:0 diastereomeric ratio and with 78%
the last irreversible aldol reaction (Scheme 4). On the other ee for the major diastereomer. These data seem to support
hand, cyclization of the remaining diastereomers of B, lead- the proposed equilibria in the Michael additions steps and
ing to cis-isomers of the spiropyrazolone, is probably more in the aldol step. Moreover, the reaction renders the final
difficult, which explains the high diastereo- and enantio- compound in almost enantiopure form (98% ee) and with
selectivity of the process.
high diastereoselectivity (8:1:1:0 dr) using a catalyst with
only 50% ee.
Conclusions
We have developed a new methodology for the construc-
tion of spiropyrazolones based on organocatalysis. The fi-
nal products are obtained in good to excellent yields and in
a totally stereocontrolled fashion in several instances.
Moreover, we studied the nonlinear effects of the reaction,
which displayed amazing asymmetric amplification. Fur-
ther studies on the application of this reaction to total syn-
thesis, as well as biological evaluations of the resulting spi-
ropyrazolones, are ongoing in our laboratories.
Experimental Section
Scheme 4. Possible mechanism.
General: Chemicals and solvents were either purchased from com-
mercial suppliers (P.A. grade) or purified by standard techniques.
For thin-layer chromatography (TLC), silica gel plates Merck 60
To obtain experimental support for this proposed path-
way, the presence of nonlinear effects in this reaction were
studied (Figure 6 and Table 6). As illustrated in Figure 6,
the enantiomeric excess of the major product exhibits a
strong nonlinear dependence on the enantiomeric purity of
the catalyst. When catalyst II with 20% enantiomeric excess
F254 were used; compounds were visualized by irradiation with UV
light and/or by treatment with a solution of phosphomolybdic acid
(25 g), Ce(SO4)2·H2O (10 g) followed by heating. Flash chromatog-
raphy was performed with silica gel Merck 60 (particle size 0.063–
0.200 mm). 1H and 13C NMR spectra were recorded with Varian
UNITY INOVA-300 or Varian MERCURY-400 spectrometers.
Chemical shifts for protons are given in δ units relative to tet-
ramethylsilane (TMS) and are referenced to residual protons in the
NMR solvent (CDCl3: δ = 7.26 ppm). Chemical shifts for carbon
are given in δ units relative to TMS and are referenced to the car-
bon resonances in the solvent (CDCl3: δ = 77.0 ppm). Coupling
constants (J) are given in Hz. Chiral HPLC was carried out with
a LCP 5020 Ignos liquid chromatography pump with an LCD 5000
spectrophotometric detector.
General Procedure for the Synthesis of Spiropyrazolones: In a small
flask, pyrazolone 1a–e (0.25 mmol, 1.0 equiv.), enal 2a–h
(0.60 mmol, 1.2 equiv.), catalyst II (0.05 mmol, 0.2 equiv.), and
benzoic acid (0.05 mmol, 0.2 equiv.) in toluene (1 mL), were stirred
over 14 h. The crude material was purified by column chromatog-
raphy to afford 3a–u.
Compound 3a: Yield 58 mg (55%); white solid. 1H NMR
(400 MHz, CDCl3): δ = 9.51 (s, 1 H, CHO), 7.80–7.66 (m, 2 H,
ArH), 7.42–7.30 (m, 8 H, ArH), 7.23–7.09 (m, 6 H, ArH, CH),
4.20 (s, 1 H, CH), 3.57 (dd, J = 5.6, 11.5 Hz, 1 H, CH), 3.45–3.35
(m, 1 H, CH2), 2.96–2.87 (m, 1 H, CH2), 0.95 (s, 3 H, CH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 191.1, 150.3, 139.3, 138.5, 131.7,
131.6, 129.3, 128.9, 128.8, 128.5, 128.2, 127.9, 127.6, 127.6, 125.3,
45.3, 39.6, 31.5, 15.6 ppm. HRMS (ESI): calcd. for C28H25N2O2 [M
+ H]+ 421.1911; found 421.1912. HPLC (Chiralpak IB; n-hexane/
iPrOH, 95:5; λ = 254 nm; 1.0 mL/min): tR = 13.3, 27.0 min. IR:
Figure 6. Nonlinear plot.
Table 6. Nonlinear effects.[a]
ee (cat.) [%] Conv. [%][b] dr[b]
er[c]
Yield [%][d]
100
80
70
60
50
40
30
20
0
100
100
100
100
100
100
100
100
100
Ͼ25:1:0:0
Ͼ25:1:0:0
21:3:1:0
11:1:1:0
8:1:1:0
7:1:1:0
6:2:1:0
Ͼ99.9:0.1
99.2:0.8
99.1:0.9
99.1:0.9
99.1:0.9
96.3:3.7
90.0:10.0
88.8:11.2
n.d.
55
52
56
48
43
61
54
59
49
4:1:1:0
2:1:1:0
[a] Reagents and conditions: 1a (0.25 mmol, 1.0 equiv.), 2a
(0.60 mmol, 1.2 equiv.), catalyst II (0.05 mmol, 0.2 equiv.), benzoic
acid (0.05 mmol, 0.2 equiv.), toluene (1 mL), 14 h. [b] Determined
by 1H NMR spectroscopy. [c] Determined by chiral HPLC analysis
of the major diastereomer. [d] After column chromatography.
ν
= 703, 758, 1123, 1159, 1288, 135, 1454, 1595, 1651, 1687.
˜
max
[α]2D5 = +69.8 [c = 0.7, CHCl3, ee Ͼ99%, (R)-cat.].
Compound 3b: Yield 94 mg (80%); yellow scum. 1H NMR
(300 MHz, CDCl3): δ = 0.98 (s, 3 H, CH3), 2.99–2.89 (dt, J = 19.8,
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Highly Stereoselective Synthesis of Spiropyrazolones
4.8 Hz, 1 H, CH2), 3.46–3.35 (m, 1 H, CH2), 3.56–3.50 (dd, J = 1.89–1.82 (m, 2 H, CH2), 2.25 (s, 3 H, CH3), 2.60 (m, 1 H, CH2),
11.4, 5.4 Hz, 1 H, CH), 4.24 (s, 1 H, CH), 7.22–7.76 (m, 14 H,
2.75–2.72 (dd, J = 6.8, 4.4 Hz, 1 H, CH2), 2.80–2.78 (dd, J = 6.8,
ArH, CH), 9.51 (s, 1 H, CHO) ppm. 13C NMR (400 MHz, CDCl3): 4.4 Hz, 1 H, CH), 2.89–2.86 (t, J = 5.6 Hz, 1 H, CH), 7.02–7.00 (t,
δ = 16.1, 30.9, 40.0, 45.1, 58.8, 112.6, 112.7, 118.2, 118.3, 119.3,
126.0, 128.7, 129.2, 132.7, 132.8, 133.0, 133.1, 137.4, 137.8, 143.8,
144.2, 150.3, 159.7, 173.1, 191.7 ppm. HRMS (ESI): calcd. for
C30H22N4NaO2 [M + Na]+ 493.1634; found 493.1635. HPLC (Chi-
J = 3.6 Hz, 1 H, CH), 7.52–7.15 (m, 3 H, ArH), 7.82–7.81 (d, J =
7.6 Hz, 2 H, ArH), 9.51 (s, 1 H, CHO) ppm. 13C NMR (100 MHz,
CDCl3): δ = 11.7, 13.3, 17.5, 24.9, 25.9, 28.9, 34.4, 39.1, 59.0, 119.0,
125.1, 128.9, 130.4, 133.9, 138.1, 140.3, 150.9, 161.6, 174.0,
193.3 ppm. HRMS (ESI): calcd. for C40H48N4NaO4 [2M + Na]+
671.3578; found 671.3568. HPLC (Chiralpak IB; n-hexane/iPrOH,
ralpak IB; n-hexane/iPrOH, 90:10; λ = 254 nm; 1.0 mL/min): tR
=
18.2, 20.6 min; [α]2D5 = +51.7 [c = 0.7, CHCl3, ee 99%, (R)-cat.].
99.5:0.5; λ = 254 nm; 1.0 mL/min): tR = 30.0, 35.6 min; [α]2D5
–13.1 [c = 0.4, CHCl3, ee = 94%, (R)-cat.].
=
Compound 3c: Yield 91 mg (63%); yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 1.03 (s, 3 H, CH3), 2.94–2.84 (dt, J = 4.8, 19.5 Hz, 1
H, CH2), 3.40–3.29 (m, 1 H, CH2), 3.49–3.44 (dd, J = 11.4, 5.4 Hz,
1 H, CH), 4.14 (s, 1 H, CH), 6.96–6.99 (d, J = 8.7 Hz, 2 H, ArH),
7.60–7.19 (m, 9 H, ArH, CH), 7.77–7.75 (d, J = 7.5 Hz, 2 H, ArH),
8.11–8.08 (d, J = 7.2 Hz, 1 H, ArH), 9.49 (s, 1 H, CHO) ppm. 13C
NMR (400 MHz, CDCl3): δ = 16.1, 31.4, 39.3, 44.8, 59.0, 119.3,
122.2, 122.6, 125.7, 128.7, 129.1, 129.3, 129.5, 130.4, 132.0, 132.3,
132.6, 133.4, 133.9, 137.5, 137.6, 138.2, 138.3, 150.4, 160.9, 171.4,
173.7, 192.0 ppm. HRMS (ESI): calcd. for C28H23Br2N2O2 [M +
H]+ 577.0123; found 577.0121. HPLC (Chiralpak IB; n-hexane/
iPrOH, 90:10; λ = 254 nm; 1.0 mL/min): tR = 13.8, 16.4 min; [α]2D5
= +89.5 [c = 0.3, CHCl3, ee Ͼ 99%, (R)-cat.].
Compound 3d: Yield 64 mg (53%); white scum. 1H NMR
(400 MHz, CDCl3): δ = 1.03 (s, 3 H, CH3), 2.93–2.86 (dt, J = 20.0,
5.2 Hz, 1 H, CH2), 3.39–3.31 (m, 1 H, CH2), 3.50–3.46 (dd, J =
11.6, 5.6 Hz, 1 H, CH), 4.16 (s, 1 H, CH), 7.05–7.03 (d, J = 8.4 Hz,
2 H, ArH), 7.62–7.15 (m, 9 H, ArH, CH), 7.78–7.76 (d, J = 8.0 Hz,
2 H, ArH), 8.11–8.10 (d, J = 7.2 Hz, 1 H, ArH), 9.50 (s, 1 H,
CHO) ppm. 13C NMR (400 MHz, CDCl3): δ = 16.1, 31.4, 39.2,
44.7, 59.2, 119.4, 125.7, 128.7, 129.1, 129.7, 130.4, 133.1, 133.9,
134.1, 134.5, 137.0, 137.7, 138.4, 150.5, 160.9, 173.7, 192.1 ppm.
HRMS (ESI): calcd. for C28H23Cl2N2O2 [M + H]+ 489.1133; found
489.1131. HPLC (Chiralpak IB; n-hexane/iPrOH, 90:10; λ =
254 nm; 1.0 mL/min): tR = 12.0, 14.6 min; [α]2D5 = +46.5 [c = 0.4,
CHCl3, ee 99%, (R)-cat.].
Compound 3e: Yield 49 mg (53%); colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 9.75 (s, 1 H, CHO), 8.08–8.05 (m, 2 H,
ArH), 7.66–7.60 (m, 2 H, ArH), 7.49–7.40 (m, 2 H, ArH, CH),
4.56–4.30 (m, 4 H, COOCH2), 3.92 (s, 1 H, CH), 3.88 (dd, J = 6.1,
10.8 Hz, 1 H, CH), 3.56–3.46 (m, 1 H, CH2), 3.25–3.15 (m, 1 H,
CH2), 2.25 (s, 3 H, CH3), 1.56 (t, J = 7.1 Hz, 3 H, CH3), 1.39 (t, J
= 7.1 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 191.6,
172.0, 171.0, 170.1, 158.2, 150.6, 137.7, 136.6, 128.8, 125.3, 119.1,
62.2, 61.7, 52.4, 42.8, 39.7, 26.0, 14.6, 13.9, 13.9 ppm. HRMS
(ESI): calcd. for C44H48N4NaO12 [2M + Na]+ 847.3161; found
847.3158. HPLC (Chiralpak IC; n-hexane/iPrOH, 90:10; λ =
254 nm; 1.0 mL/min): tR = 20.0, 25.3 min; [α]2D5 = +107.7 [c = 1.25,
CHCl3, ee = 99%, (R)-cat.].
Compound 3f: Yield 50 mg (68%); colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 9.46 (s, 1 H, CHO), 7.86–7.81 (m, 2 H,
ArH), 7.40–7.33 (m, 2 H, ArH), 7.19–7.12 (m, 1 H, ArH), 6.95–
6.91 (m, 1 H, CH), 3.01 (q, J = 7.0 Hz, 1 H, CH), 2.68–2.60 (m, 2
H, CH2), 2.43–2.32 (m, 1 H, CH), 2.22 (s, 3 H, CH3), 1.24 (d, J =
7.0 Hz, 3 H, CH3), 0.90 (d, J = 6.7 Hz, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 192.9, 173.6, 161.2, 150.4, 128.7, 125.0,
118.8, 58.6, 32.4, 31.3, 26.8, 18.1, 16.5 ppm. HRMS (ESI): calcd.
for C18H21N2O2 [M + H]+ 297.1599; found 297.1599. HPLC (Chi-
ralpak IB; n-hexane/iPrOH, 98.5:1.5; λ = 254 nm; 1.0 mL/min): tR
= 21.9, 23.1 min; [α]2D5 = –23.0 [c = 0.85, CHCl3, ee = 96%, (R)-
cat.].
Compound 3h: Yield 49 mg (51%); yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 9.49 (s, 1 H, CHO), 7.84–7.81 (m, 2 H, ArH), 7.39–
7.33 (m, 2 H, ArH), 7.18–7.12 (m, 1 H, ArH), 6.98–6.95 (m, 1 H,
CH), 2.87 (dd, J1 = J2 = 5.6 Hz, 1 H, CH), 2.74 (ddd, J = 4.4, 6.6,
20.5 Hz, 1 H, CH), 2.61–2.50 (m, 1 H, CH2), 2.30–2.21 (m, 1 H,
CH2), 2.23 (s, 3 H, CH3), 1.78–1.67 (m, 1 H), 1.60–1.00 (m, 11 H),
0.90–0.85 (m, 6 H, 2ϫCH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 192.9, 173.8, 161.4, 150.3, 140.5, 137.9, 128.7, 124.9, 118.7, 59.6,
37.9, 32.7, 32.3, 31.4, 30.9, 29.1, 23.0, 22.6, 17.2, 14–0, 13.9 ppm.
HRMS (ESI): calcd. for C24H32N2NaO2 [M + Na]+ 403.2356;
found 403.2357. HPLC (Chiralpak IB, n-hexane/iPrOH = 99:1, λ
= 254 nm, 1.0 mL/min): tR = 8.8, 10.0 min; [α]2D5 = –5.3 [c = 0.4,
CHCl3, ee Ͼ 99%, (R)-cat.].
Compound 3i: Yield 87 mg (72%); colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 9.49 (s, 1 H, CHO), 7.82–7.77 (m, 2 H,
ArH), 7.62–7.64 (m, 2 H, ArH), 7.53–7.33 (m, 8 H, ArH, CH),
7.27–7.20 (m, 2 H, ArH), 4.21 (s, 1 H, CH), 3.55 (dd, J = 5.5,
11.3 Hz, 1 H, CH), 3.45–3.32 (m, 1 H, CH2), 3.00–2.88 (m, 1 H,
CH2), 1.40–1.10 (m, 2 H, CH2), 0.64 (t, J = 7.0 Hz, 3 H, CH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 191.5, 173.1, 163.4, 150.1, 144.1,
143.7, 137.7, 137.4, 132.8, 132.7, 132.5, 132.3, 129.0, 128.8, 128.4,
125.7, 119.0, 118.1, 118.0, 112.4, 58.6, 50.0, 39.9, 30.9, 22.8 ppm.
HRMS (ESI): calcd. for C31H25N4O2 [M + H]+ 485.1972; found
485.1979. HPLC (Chiralpak IB; n-hexane/iPrOH, 90:10; λ =
254 nm; 1.0 mL/min): tR = 64.8, 69.0 min; [α]2D5 = –117.4 [c = 1.3,
CHCl3, ee = 99%, (S)-cat.].
Compound 3j: Yield 75 mg (51%); colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 9.47 (s, 1 H, CHO), 7.84–7.79 (m, 2 H,
ArH), 7.54–7.37 (m, 5 H, ArH), 7.35–7.15 (m, 5 H, ArH, CH),
7.00–6.93 (m, 2 H, ArH), 4.12 (s, 1 H, CH), 3.48 (dd, J = 5.5,
11.4 Hz, 1 H, CH), 3.39–3.26 (m, 1 H, CH2), 2.94–2.83 (m, 1 H,
CH2), 1.43–1.20 (m, 2 H, CH2), 0.67 (t, J = 7.2 Hz, 3 H, CH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 193.1, 175.0, 165.9, 151.5, 139.5,
139.5, 138.8, 135.0, 134.4, 133.5, 133.4, 133.1, 1315, 130.5, 130.4,
130.2, 129.8, 126.7, 123.6, 123.2, 120.4, 60.2, 46.0, 40.5, 32.8, 24.0,
10.5 ppm. HRMS (ESI): calcd. for C29H25Br2N2O2 [M + H]+
591.0277; found 591.0284. HPLC (Chiralpak IB; n-hexane/iPrOH,
95:5; λ = 254 nm; 1.0 mL/min): tR = 14.6, 19.2 min; [α]2D5 = +117.2
[c = 1.0, CHCl3, ee Ͼ99%, (R)-cat.].
Compound 3k: Yield 62 mg (58%); yellow oil. 1H NMR (300 MHz.
CDCl3): δ = 9.49 (s, 1 H, CHO), 7.86 (d, J = 7.8 Hz, 2 H, ArH),
7.40–7.30 (m, 2 H, ArH), 7.20–7.10 (m, 2 H, ArH, CH), 4.30–4.00
(m, 4 H, 2ϫCH2), 3.65–3.55 (m, 2 H, 2ϫCH), 3.30–3.20 (m, 1 H,
CH2), 3.05–2.95 (m, 1 H, CH2), 2.19 (q, J = 7.2 Hz, 2 H, CH2),
1.33–1.25 (m, 6 H, 2ϫCH3), 1.13 (t, J = 7.1 Hz, 3 H, CH3) ppm.
13C NMR (100 MHz. CDCl3): δ = 193.1, 172.6, 171.7, 163.8, 152.0,
147.4, 141.6, 138.7, 130.2, 126.7, 120.5, 65.6, 63.2, 44.4, 41.1, 27.7,
+
23.1, 15.4, 15.3, 11.1 ppm. HRMS: calcd. for C23H27N2O6 [M +
H]+ 427.1864; found 427.1868. HPLC (Chiralpak IA; hexane/IPA,
95:5; λ = 254 nm–1; 1 mL/min): tR = 17.9, 57.0 min; [α]2D5 = +98.7
[c = 0.95, CHCl3, (R)-cat.].
Compound 3g: Yield 59 mg (73%); yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 0.97–0.91 (m, 6 H, 2ϫCH3), 1.57–1.46 (m, 2 H, CH2),
Eur. J. Org. Chem. 2011, 1318–1325
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1323

R. Rios et al.
Compound 3l: Yield 80 mg (74%); pale-yellow solid. 1H NMR 254 nm; 1.0 mL/min): tR = 26.0, 36.4 min; [α]2D5 = –68.9 [c = 0.4,
FULL PAPER
(400 MHz, CDCl3): δ = 9.51 (s, 1 H, CHO), 7.85 (dd, J = 8.8,
2.2 Hz, 2 H, ArH), 7.42–7.31 (m, 8 H, ArH), 7.23–7.09 (m, 6 H,
ArH, CH), 4.19 (s, 1 H, CH), 3.59 (dd, J = 5.7, 11.4 Hz, 1 H, CH),
3.44–3.35 (m, 1 H, CH2), 2.95–2.88 (m, 1 H, CH2), 1.39–1.29 (m,
2 H, CH2), 0.60 (t, J = 7.1 Hz, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 192.1, 174.2, 165.3, 150.4, 139.4, 138.5, 137.9, 133.6,
131.5, 130.1, 129.0, 128.9, 128.7, 128.4, 128.1, 127.8, 127.5, 125.1,
119.2, 59.3, 45.4, 39.7, 31.7, 22.4, 9.1 ppm. HRMS (ESI): calcd. for
C29H27N2O2 [M + H]+ 435.2067; found 435.2070. HPLC (Chi-
CHCl3, ee Ͼ99%, (R)-cat.].
Compound 3u: Yield 53 mg (58%); pale-yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 0.89–0.91 (d, J = 6.8 Hz, 3 H, CH3), 1.26–
1.24 (d, J = 7.2 Hz, 3 H, CH3), 1.46–1.44 (dd, J = 6.4, 3.2 Hz, 1
H, CH), 2.24 (s, 3 H, CH3), 2.43–2.37 (m, 1 H, CH2), 2.66–2.63
(m, 1 H, CH2), 3.05–2.99 (q, J = 7.2 Hz, 1 H, CH), 7.50–7.46 (t, J
= 8.0 Hz, 1 H, CH), 7.63–7.61 (d, J = 8.8 Hz, 2 H, ArH), 8.03–
8.01 (d, J = 8.4 Hz, 2 H, ArH), 9.47 (s, 1 H, CHO) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.8, 17.4, 18.3, 27.1, 31.4, 32.7, 59.1,
118.3, 126.2, 128.6, 130.3, 133.8, 140.7, 141.6, 150.4, 162.2, 174.1,
193.0 ppm. 19F NMR (282 MHz, CDCl3): δ = –59.3 (s, 3 F) ppm.
HRMS (ESI): calcd. for C19H20F3N2O2 [M + H]+ 365.1464; found
365.1471. HPLC (Chiralpak IB; n-hexane/iPrOH, 95:5; λ = 254 nm;
1.0 mL/min): tR = 9.5, 10.1 min; [α]2D5 = +12.1 [c = 0.46, CHCl3, ee
92%, (S)-cat.].
ralpak IB; n-hexane/iPrOH, 90:10; λ = 254 nm; 1.0 mL/min): tR
=
8.1, 13.9 min; [α]2D5 = –66.80 [c = 1.0, CHCl3, ee = 97.5%, (S)-cat.].
Compound 3m: Yield 50 mg (64%); yellow oil. 1H NMR (300 MHz.
CDCl3): δ = 9.46 (s, 1 H, CHO), 7.87 (d, J = 8.0 Hz, 2 H, ArH),
7.40–7.35 (m, 2 H, ArH), 7.20–7.10 (m, 1 H, ArH), 6.95–6.90 (m,
1 H, CH), 2.99 (q, J = 6.8 Hz, 2 H, 2ϫCH), 2.65–2.45 (m, 2 H,
CH2), 2.40–2.30 (m, 2 H, CH2), 1.38 (t, J = 6.8 Hz, 3 H, CH3),
1.22 (d, J = 6.8 Hz, 3 H, CH3), 0.87 (d, J = 6.2 Hz, 3 H, CH3) ppm.
13C NMR (100 MHz. CDCl3): δ = 194.2, 166.5, 151.7, 149.6, 142.9,
139.3, 130.0, 126.1, 120.0, 60.1, 33.7, 32.7, 28.2, 25.2, 19.5, 18.0,
CCDC-808508 (for 3a) contains the supplementary crystallo-
graphic data 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.
+
11.5 ppm. HRMS: calcd. for C19H23N2O2 [M + H]+ 311.1754;
found 311.1751. HPLC (Chiralpak IA; hexane/IPA, 97:3; λ =
254 nm–1; 1 mL/min): tR = 10.4, 14.2 min; [α]2D5 = +18.9 [c = 0.95,
CHCl3, (S)-cat.].
Supporting Information (see footnote on the first page of this arti-
cle): X-ray crystal structure determination data, NMR and HPLC
spectra.
Compound 3r: Yield 83 mg (68%); colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 0.97 (s, 3 H, CH3), 2.98–2.90 (dt, J = 20.4,
5.6 Hz, 1 H, CH2), 3.42–3.33 (m, 1 H, CH2), 3.60–3.56 (dd, J =
11.6, 6.0 Hz, 1 H, CH), 4.19 (s, 1 H, CH), 7.96–7.06 (m, 11 H,
ArH, CH), 7.98–7.96 (d, J = 8.8 Hz, 2 H, ArH), 8.12–8.10 (d, J =
8.0 Hz, 2 H, ArH), 9.51 (s, 1 H, CHO) ppm. 13C NMR (100 MHz,
CDCl3): δ = 15.9, 31.6, 39.9, 45.5, 59.7, 118.7, 126.2, 126.3, 127.7,
127.8, 128.3, 128.5, 128.7, 128.8, 129.2, 129.5, 130.4, 131.8, 133.9,
138.3, 138.6, 139.2, 140.7, 150.4, 162.5, 171.5, 174.6, 192.2 ppm.
19F NMR (282 MHz, CDCl3): δ = –65.2 (s, 3 F) ppm. HRMS
(ESI): calcd. for C29H24F3N2O2 [M + H]+ 489.1785; found
489.1784. HPLC (Chiralpak IB; n-hexane/iPrOH, 90:10; λ =
254 nm; 1.0 mL/min): tR = 10.8, 19.2 min; [α]2D5 = –88.9 [c = 0.75,
CHCl3, ee Ͼ99%, (S)-cat.].
Acknowledgments
We thank the Spanish Ministerio de Ciencia e Innovación (MIC-
INN) for financial support (project number AYA2009-13920-C02-
02). A.-N. R. A. and G. V. are also grateful to MICINN for their
pre-doctoral fellowships. A. M. thanks the University of Bologna
(RFO funds 2008). The authors thank Dr. Z. El-Hachemi for his
help with the DC spectra.
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Compound 3s: Yield 50 mg (42%); pale-yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 9.76 (s, 1 H, CHO), 8.26 (d, J = 8.8 Hz, 2
H, ArH), 7.88 (d, J = 8.8 Hz, 2 H, ArH), 7.51–7.47 (m, 1 H, CH),
4.60–4.30 (m, 4 H, 2ϫCH2), 3.94–3.87 (m, 2 H, 2ϫCH), 3.55–3.42
(m, 1 H, CH2), 3.29–3.17 (m, 1 H, CH2), 2.26 (s, 3 H, CH3), 1.56
(t, J = 7.2 Hz, 3 H, CH3), 1.39 (t, J = 7.1 Hz, 3 H, CH3) ppm.
19F NMR (282 MHz, CDCl3): δ = –62.2 (s, 3 F) ppm. 13C NMR
(100 MHz, CDCl3): δ = 191.5, 172.3, 171.0, 169.9, 159.0, 150.4,
134.5, 129.7, 129.2, 128.3, 127.7, 126.1, 126.0, 118.3, 62.3, 61.8,
46.4, 42.7, 39.7, 26.1, 14.6, 13.9, 13.9 ppm. HRMS (ESI): calcd. for
C23H24F3N2O6 [M + H]+ 481.1581; found 481.1588. HPLC (Chi-
ralpak IB; n-hexane/iPrOH, 90:10; λ = 254 nm; 1.0 mL/min): tR
=
7.3, 8.2 min; [α]2D5 = +75.8 [c = 1.0, CHCl3, ee Ͼ99%, (R)-cat.].
[8] K. Jiang, Z.-J. Jia, S. Chen, L. Wu, Y.-C. Chen, Chem. Eur. J.
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Compound 3t: Yield 113 mg (84%); pale-yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 1.00 (s, 3 H, CH3), 3.01–2.93 (dt, J = 20.4,
5.2 Hz, 1 H, CH2), 3.43–3.35 (m, 1 H, CH2), 3.56–3.52 (dd, J =
11.2, 5.6 Hz, 1 H, CH), 4.24 (s, 1 H, CH), 7.21–7.19 (d, J = 8.4 Hz,
2 H, ArH), 7.71–7.33 (m, 9 H, ArH, CH), 7.96–7.94 (d, J = 8.8 Hz,
2 H), 9.51 (s, 1 H, CHO) ppm. 13C NMR (100 MHz, CDCl3): δ =
16.1, 29.9, 30.8, 39.9, 45.0, 59.0, 112.7, 112.8, 118.0, 118.6, 126.4,
126.5, 128.5, 133.1, 137.7, 140.1, 143.4, 143.9, 150.1, 160.4, 173.4,
191.5 ppm. 19F NMR (282 MHz, CDCl3): δ = –61.8 (s, 3 F) ppm.
HRMS (ESI): calcd. for C31H22F3N4O2 [M + H]+ 539.1691; found
539.1689. HPLC (Chiralpak IB; n-hexane/iPrOH, 80:20; λ =
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1324
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1318–1325

Highly Stereoselective Synthesis of Spiropyrazolones
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Received: October 26, 2010
Published Online: January 26, 2011
Eur. J. Org. Chem. 2011, 1318–1325
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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