Highly enantioselective 1, 4-michael additions of nucleophiles to unsaturated aryl ketones with organocatalysis by bifunctional cinchona alkaloids

Article abstract of DOI:10.1002/ejoc.201000273

The development of general and efficient asymmetric organocatalytic additions of malononitrile and nitromethane to 1, 5-diarylpenta-2, 4-dien-1-ones (cinnamylideneacetophenones) catalyzed by cinchona organocatalysts is reported. The reactions afforded excellent enantioselectivities (up to 99%), high yields (up to 97%), and exclusive 1, 4-addition regioselectivities. The potential of these new enantioselective additions lies in the demonstration that organocatalysts bearing primary amino groups in combination with TFA provide effective catalytic systems for the activation of a broad range of aryl ketones under mild conditions to give compounds with high levels of enantioselectivity and yields.

Full text of DOI:10.1002/ejoc.201000273

FULL PAPER
DOI: 10.1002/ejoc.201000273
Highly Enantioselective 1,4-Michael Additions of Nucleophiles to Unsaturated
Aryl Ketones with Organocatalysis by Bifunctional Cinchona Alkaloids
Cristina G. Oliva,[a] Artur M. S. Silva,*[a] Diana I. S. P. Resende,[a] Filipe A. A. Paz,[b] and
José A. S. Cavaleiro[a]
Keywords: Asymmetric catalysis / Organocatalysis / Enantioselectivity / Regioselectivity / Ketones / Michael addition
The development of general and efficient asymmetric
organocatalytic additions of malononitrile and nitromethane
to 1,5-diarylpenta-2,4-dien-1-ones (cinnamylideneaceto-
phenones) catalyzed by cinchona organocatalysts is re-
ported. The reactions afforded excellent enantioselectivities
(up to 99%), high yields (up to 97%), and exclusive 1,4-ad-
dition regioselectivities. The potential of these new enantio-
selective additions lies in the demonstration that organocata-
lysts bearing primary amino groups in combination with TFA
provide effective catalytic systems for the activation of a
broad range of aryl ketones under mild conditions to give
compounds with high levels of enantioselectivity and yields.
Introduction
Asymmetric organocatalysis has emerged as a new and
powerful methodology for the catalytic production of enan-
tiomerically pure organic compounds and also as one of
the most rapidly growing and competitive research areas in
synthetic organic chemistry,[1] in particular with respect to
1,4-Michael additions.[2] Organocatalysis has attracted con-
siderable attention in chemistry in recent years because usu-
ally it uses nontoxic metal-free catalysts. This approach
might become valuable for the preparation of pharmaceuti-
cal compounds, in which metal contamination cannot be
tolerated.[3]
Small chiral organic molecules can function as catalyti-
cally active species; among them, cinchona alkaloids are
present in numerous biologically active and therapeutically
important molecules. In the last two decades, cinchona al-
kaloids have also become widely used as catalysts in asym-
metric syntheses, to give access to chiral building blocks of
high enantiopurity. In particular, the 9-amino-(9-deoxy)-
Figure 1. Structures of screened organocatalysts.
epi-cinchona alkaloids 1[2c,4] and the 9-thiourea-(9-deoxy)- neously (Figure 2). The catalysts 1 form ketiminium
epi-cinchona alkaloids 2[1e,5] (Figure 1) have been exten- ions[4c,4e,4j] and each possesses a Lewis base functionality.
sively used as organocatalysts in 1,4-Michael additions to The in situ generation of an iminium ion from a chiral ami-
α,β-unsaturated ketones.
nocatalyst and a carbonyl compound is thought to lower
The catalysts 1 and 2 were designed as bifunctional or- the LUMO energy in the system and is a powerful strategy
ganocatalysts, because both the electrophilic and the nucleo- for asymmetric transformations.[4a] The catalysts 2 syner-
philic components of a reaction can be activated simulta- gistically employ Brønsted acid and Lewis base function-
alities.[5j] Organic chemists have begun to appreciate the tre-
mendous potential offered by hydrogen bonding as a
mechanism for electrophile activation in small mole-
cules.[5f–5h] Hydrogen bonding with an electrophile serves to
decrease the electron density in this species, activating it
toward nucleophilic attack. This principle is frequently em-
ployed by nature’s catalysts (enzymes) for the acceleration
of a wide range of chemical processes.
[a] QOPNA, Departament of Chemistry, University of Aveiro,
3810-193 Aveiro, Portugal
Fax: +351-234-370084
E-mail: cgoliva@ua.pt
artur.silva@ua.pt
[b] CICECO, Departament of Chemistry, University of Aveiro,
3810-193 Aveiro, Portugal
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000273.
Eur. J. Org. Chem. 2010, 3449–3458
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. M. S. Silva et al.
FULL PAPER
Results and Discussion
The addition of malononitrile to 1,5-diphenylpenta-2,4-
dien-1-one (3a) in the presence of catalysts 1a or 2a was
investigated (Table 1). The initial reaction conditions in-
volved a solution of 3a (0.1 ) and the catalyst (20 mol-%).
Poor enantioselectivities were found when catalyst 1a and
benzoic acid were used (Entries 1 and 2), but the use of a
more acidic additive such as TFA increased the ee values
(Entries 3–9). Variation of the solvent had an influence in
the course of the reaction: THF (Entry 3) and CH2Cl2 (En-
try 4) gave acceptable levels of ee and moderate yields,
CHCl3 (Entry 5) and toluene (Entry 6) gave better yields
but worst levels of ee, CH3CN (Entry 7) gave an acceptable
ee but a poor yield, and CH3OH (Entry 8) gave a poor yield
and ee. The enantioselectivity was increased when the reac-
tion was carried out with exclusion of oxygen (Entry 9).
When the reaction was performed in the presence of cata-
lyst 2a poor enantioselectivities were obtained (Entries 10
and 11).
Figure 2. Activation of bifunctional cinchona alkaloids.
Several nucleophilic species capable of undergoing 1,4-
Michael additions to α,β-unsaturated ketones with catalysis
by cinchona alkaloids have been extensively reported. Such
species include C-nucleophiles (nitroalkanes,[4n,5b,5k,5m,6]
malononitrile,[4i,5e,7]
malonates,[5e,8]
α,α-dicyanoalk-
enes,[4a,4k] α-cyanosulfones,[9] 4-hydroxycoumarins,[4b] in-
doles,[4d,4g,10] cyanoacetates,[5i,11] ketones,[12] and 1-fluoro-
bis(phenylsulfonyl)methane[13]), N-nucleophiles,[4j,4m,14] O-
nucleophiles,[4f,15] and S-nucleophiles.[4h,16] Amongst these
nucleophiles, malononitrile and nitromethane represent ver-
satile functional compounds that can be chemically trans-
formed into a variety of functional useful compounds.
We have recently developed a new methodology for 1,4-
Michael additions of nitromethane to cinnamylideneaceto-
phenones (δ-aryl α,β,γ,δ-unsaturated aryl ketones)[5m] in the
presence of the 9-thiourea-9-(deoxy)-epi-hydroquinine 2a
with excellent levels of enantioselectivity and isolated yields,
as well as exclusive regioselectivities. α,β-Unsaturated aryl
ketones are a class of compounds that have been receiving
less attention than the corresponding alkyl ketones or alde-
hydes because the aromatic group can block the interaction
of the carbonyl group with the catalyst. In particular, few
organocatalytic examples of reactions of α,β-unsaturated
aryl ketones catalyzed by the primary amines 1 have been
reported.[4g–4i,4n] Only moderate levels of enantioselectivity
and yield have been obtained, which is probably due to the
fact that the generation of the corresponding iminium cat-
ions is unfavorable as a result of steric hindrance caused by
the aryl group.
Table 1. Catalyst and solvent screening for the conjugate addition
of malononitrile to 3a.[a]
Entry Catalyst Solvent
Additive
Yield [%][b] ee [%][c]
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
THF
CH2Cl2
THF
CH2Cl2
CHCl3
toluene
CH3CN
CH3OH
THF
PhCO2H
PhCO2H
TFA
TFA
TFA
TFA
TFA
TFA
52
56
60
49
85
70
20
19
51
68
78
27[d]
16[d]
82[d]
84[d]
69[d]
74[d]
71[d]
19[d]
90[d]
35[h]
43[h]
2[e]
3
4
5
6
7
8
9[f]
10[f]
11[f]
TFA
[g]
THF
CH2Cl2
–
[g]
–
[a] Reactions were carried out with a solution of 3a (0.1 , 15 mg,
0.064 mmol), catalyst 1a or 2a (20 mol-%, 0.013 mmol), a suitable
additive (40 mol-%, 0.026 mmol), and malononitrile (25.3 mg,
0.38 mmol) in solvent (0.64 mL) for 7 d at room temp. [b] Yield of
isolated products after chromatography. [c] Determined by chiral
HPLC with a Chiralpak IA column. [d] The S configuration was
assigned to the major enantiomer by chiral HPLC. [e] The reaction
was carried out for 2 d. [f] The reaction was carried out under ni-
trogen. [g] Without additive. [h] The R configuration was assigned
to the major enantiomer by chiral HPLC. TFA: trifluoroacetic
acid.
A number of additions of nitromethane to chalcones
have been achieved,[5b,5k,6a] but additions of nitromethane
to cinnamylideneacetophenones has been reported only
rarely.[5k] In this case only one example has been described:
for a δ-phenyl α,β,γ,δ-unsaturated N-acylpyrrole ketone,
with 54% yield and 94% ee. Until now, organocatalyzed
Michael additions of malononitrile to chalcones[4h,5e] have
been less well studied than those of nitromethane, and
moderate values of enantioselectivity and yield have been
achieved. To the best of our knowledge, no study of organo-
catalytic additions of malononitrile to cinnamylideneaceto-
phenones has yet appeared.
The 9-amino-(9-deoxy)-epi-hydroquinine 1a in combina-
tion with TFA has been shown to provide an effective cata-
In this communication we present general and efficient lytic system for the activation of the phenyl ketone 3a. Pre-
organocatalytic 1,4-Michael additions of malononitrile to sumably, the sterically less hindered primary amine group
different cinnamylideneacetophenones assisted by organo- in 1a reacts more readily with the ketone functionality of
catalysis by compounds of types 1 and 2. We have also ex- 3a than that in catalyst 2a, to initiate the iminium catalysis,
tended the scope of reactions between nitromethane and and the quinuclidine motif of hydroquinine can then bind
cinnamylideneacetophenones catalyzed by the organocata- to malononitrile, through hydrogen-bonding interactions,
lysts 2.
thereby activating the nucleophilic attack (Figure 3).
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Organocatalyzed Enantioselective Michael Additions
Table 2. Optimization of reaction conditions for asymmetric conju-
gate addition of malononitrile to 3a in the presence of catalysts 1a–
d.[a]
Entry
Catalyst
mol-%

Yield [%][b] ee [%][c]
Catalyst TFA
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
20
20
20
20
20
20
20
30
30
40
40
50
30
40
40
40
40
40
40
40
40
40
60
60
80
80
100
60
80
80
0.1
0.1
0.1
0.1
0.2
0.3
0.3
0.1
0.2
0.1
0.1
0.1
0.2
0.1
0.1
51
31
70
78
84
96
82
70
96
88
75
80
79
69
61
90
86
84
84
89
2[d]
3[e]
4[f]
5
Figure 3. Activation of the α,β,δ,γ-unsaturated phenyl ketone 3a
and malononitrile by the bifunctional catalyst 1a.
6
81
83
7[g]
8
88
9
90[h,i]
89
10
11[f]
83
The catalytic system and THF as solvent having been
selected, the influence of catalyst loading and molar con- 12
centration were investigated (Table 2). In a solution of the
substrate 3a (0.1 ) and catalyst (20 mol-%), increasing the
81
13
14
15
90[j]
77
48
amount of malononitrile produced a decrease in the yield
(Entry 2), whereas the yield was significantly increased by
increasing the temperature (Entry 3) and adding molecular
sieves (Entry 4). In these cases the ee values were accept-
able. Raising the molar concentration gave better yields
(Entries 5–7). Increasing of the catalyst loading, from 30%
(Entries 8 and 9) to 40% (Entries 10 and 11) and 50% (En-
try 12), was also investigated. Entry 9, in which a 0.3 
solution of 3a and 30% molar equivalent of catalyst 1a was
used, represents the best reaction conditions, with an excel-
lent yield (96%) and a high level of enantioselectivity
(90%). Recrystallization of the obtained compound led to
an increase in the ee value to 99%. The absolute configura-
[a] Reactions were carried out with 3a (15 mg, 0.064 mmol), cata-
lysts 1a–d, TFA, and malononitrile (25.3 mg, 0.38 mmol) in THF
for 7 d at room temp. under N2. [b] Yield of isolated products after
chromatography. [c] Determined by chiral HPLC with a Chi-
ralpak IA column. [d] Reaction was carried out with malononitrile
(60 mol-%). [e] Reaction was carried at 40 °C. [f] With molecular
sieves (4 Å,10 mg). [g] Reaction was carried out with malononitrile
(2 mol equiv.). [h] ee Ͼ 99% after recrystallization. [i] The absolute
configuration of (S)-4a was assigned by chiral HPLC and X-ray
analysis. [j] The (R)-4a configuration was confirmed by chiral
HPLC. TFA: trifluoroacetic acid.
Table 3. Scope of enantioselective 1,4-Michael additions of ma-
lononitrile to the 1,5-diarylpenta-2,4-dien-1-ones 3b–i catalyzed by
tion of (S)-4a was assigned by chiral HPLC and X-ray 1a.[a]
analysis. Different 9-amino-(9-deoxy)-epi-cinchona alka-
loids were also evaluated: i) 1b gave the opposite enanti-
omer (R)-4a in good yield (79%) and ee value (90%) (En-
try 13), whereas ii) catalysts 1c (Entry 14) and 1d (Entry 15)
did not improve the previous results.
Entry
3
R1
R2
4 [%][b]
ee [%][c]
The best protocol for obtaining high levels of enantio-
selectivity and yield now having been established, the scope
of the reaction for the different cinnamylideneaceto-
phenones 3b–i was investigated (Table 3).
1
2
3
4
5
6
7
8
3b
3c
3d
3e
3f
3g
3h
3i
H
H
CH3
OCH3
Cl
Br
F
CN
NO2
OCH3
H
H
H
H
H
H
4b (56)
4c (91)
4d (97)
4e (95)
4f (87)
4g (93)
4h (65)
4i (77)
80[d,e]
97[d]
84[d,f]
84[d]
The results show that the synthesis of the new (S,E)-2-(1-
oxo-1,5-diarylpent-4-en-3-yl)malononitriles 4b–i took place
efficiently with good enantioselectivities (80–97%). These
compounds were recrystallized with enantioselectivities
higher than 98%. The yields, however were influenced by
the nature and pattern of the substitution on the starting
materials (56–97%; see Table 3). When an electron-with-
drawing substitution was present in the para position of the
δ-aryl group (Entry 1), moderate yield and ee values were
found, possibly because the charge density decrease in the
α,β,γ,δ-unsaturated ketone system and the iminium cation
formation might be more unfavorable. When an electron-
donating group was present (Entry 2), a high enantio-
selectivity and a good yield were obtained. The yields and
90[d,f]
94[d,e]
92[d,f]
82[d]
[a] Reactions took place in the presence of 3b–i (0.128 mmol) and
catalyst 1a (30 mol-%, 12.3 mg, 0.038 mmol) dissolved in THF
(0.32 mL) under nitrogen. TFA (60 mol-%, 5.8 µL, 0.076 mmol)
and malononitrile (50.7 mg, 0.768 mmol) dissolved in THF
(0.32 mL) were next added. Reactions conditions: solution of 3b–i
(0.2 ) at room temp. for 7 d. [b] Yield of isolated products after
chromatography. [c] Determined by chiral HPLC with a Chi-
ralpak IA column. [d] The S configuration was confirmed by chiral
HPLC. [e] ee Ͼ 99% after recrystallization. [f] ee Ͼ 98% after
recrystallization.
ee values were good with a range of different substituents because the aryl groups exert great steric hindrance and cat-
present in the para position of the ketone aryl group (En- ion formation is unfavorable. We would like to emphasize
tries 3–8). It is noteworthy that aromatic ketones are a class that these asymmetric additions constitute the first example
of substrates not generally suitable for iminium activation, of the use of 9-amino-9-(deoxy)-epi-hydroquinine in combi-
Eur. J. Org. Chem. 2010, 3449–3458
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3451

A. M. S. Silva et al.
FULL PAPER
nation with TFA, and provide an effective catalytic system
for the activation of a broad range of cinnamylideneaceto-
phenones under mild conditions.
In our previous study on 1,4-Michael additions of nitro-
methane to cinnamylideneacetophenones,[5m] the reactions
were carried out in neat nitromethane, with solutions of the
substrates (0.3 ), and with catalyst 2a (30 mol-%; see Ex-
perimental Section – 2a was the best catalyst found after
the screening of chiral organocatalysts 1, 2, and a diarylpro-
linol silyl ether). The synthesis of the (R,E)-1,5-diaryl-3-(ni-
tromethyl)-5-pent-4-en-1-ones 5a–h (see Exp. Section) took
place with good levels of enantioselectivity (87–99%) and
moderate to excellent yields (19–97%). These reactions have
now been extended (Table 4) to the synthesis of the new
derivatives 5i–k (Entries 1–3) with good levels of enantio-
selectivity (84–94%) and yields (77–86%). These com-
pounds were recrystallized and their enantioselectivities
were increased up to 99%.
Figure 4. Schematic representation of the molecular units present
in compounds (S)-4a and (S)-5a. Non-hydrogen atoms are repre-
sented as thermal ellipsoids drawn at the 50% probability level and
hydrogen atoms as spheres with arbitrary radii.
Table 4. Enantioselective 1,4-Michael additions of nitromethane to
Conclusions
the 1,5-diarylpenta-2,4-dien-1-ones 3g–i organocatalyzed by 2a.[a]
In summary, we have developed the first general organo-
catalytic 1,4-Michael additions of malononitrile to different
1,5-diarylpenta-2,4-dien-1-ones in the presence of 9-amino-
9-(deoxy)-epi-hydroquinine and TFA. Excellent levels of
enantioselectivity (up to 99%) and isolated yields (up to
97%) have been achieved for a wide spectrum of substrates
and β-addition regioselectivities were obtained exclusively,
with no δ-addition being observed. We have also extended
the 1,4-Michael additions of nitromethane to 1,5-di-
arylpenta-2,4-dien-1-ones in the presence of 9-thiourea-9-
(deoxy)-epi-hydroquinine with good levels of enantio-
selectivity and isolated yields.
Entry
3
R
5 [%][b]
ee [%][c]
84[d,e]
91[d,f]
94[d,f]
1
2
3
3g
3h
3i
Br
F
CN
5i (77)
5j (81)
5k (86)
[a] Reactions took place with 3g–i (0.128 mmol) and catalyst 2a
(30 mol-%, 22.9 mg, 0.038 mmol) in nitromethane solution (0.3 ,
0.47 mL) under nitrogen for 7 d at room temp. [b] Yield of isolated
products after chromatography. [c] Determined by chiral HPLC
with a Chiralpak IA column. [d] The R configuration was con-
firmed by chiral HPLC. [e] ee Ͼ96% after recrystallization. [f] ee
Ͼ99% after recrystallization.
Experimental Section
General Methods: Melting points were determined with a Büchi
melting point apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded with Bruker 300 or 500 [300.13 MHz (1H),
75.47 MHz (13C) or 500.13 MHz (1H), 125.77 MHz (13C)] spec-
As shown earlier, treatment of 1,5-diphenylpenta-2,4-
dien-1-one (3a) with nitromethane in the presence of cata-
lyst 2a gave (R,E)-1,5-diphenyl-3-(nitromethyl)-5-pent-4-en-
1-one [(R)-5a],[5m] but the corresponding reaction in the
presence of the 9-thiourea-(9-deoxy)-epi-hydroquinidine 2b
led to the synthesis of the opposite enantiomer (S,E)-5a
with good yield (85%) and ee (92%). Recrystallization of
the obtained compound led to an increase in the ee value
to 99%. The absolute configuration of (S)-5a was assigned
by chiral HPLC and X-ray analysis.
1
trometers with TMS as internal reference. Data for H NMR are
recorded as follows: chemical shift (δ, ppm), multiplicity [s (singlet),
br. s (broad singlet), d (doublet), t (triplet), q (quartet), and m
(multiplet)], coupling constant [Hz], integration. Data for 13C
NMR are reported in terms of chemical shift (δ, ppm). Unequivo-
cal 1H assignments were made with aid of 2D COSY (1H/1H),
whereas 13C assignments were made on the basis of 2D HSQC (1H/
13C) and HMBC (delays for one-bond and long-range C,H cou-
plings were optimized for 145 and 7 Hz, respectively) experiments.
High-resolution mass spectra analyses (HRMS-ESI+) were per-
formed with a microTOF (focus) mass spectrometer. Ions were gen-
erated with an ApolloII (ESI) source. Ionization was achieved by
electrospray, with use of a voltage of 4500 V applied to the needle,
and a counter voltage between 100 and 150 V applied to the capil-
lary. High-resolution mass spectra analyses (HRMS-EI, 70 eV)
were measured with a VG Autospec M spectrometer. Elemental
analyses were obtained with a Carlo Erba 1108 CHNS analyzer.
Silica gel (60 F254, Merck) was used for TLC, and the spots were
detected with UV light (254 nm). Flash column chromatography
The crystal structures of compounds (S)-4a[17] and (S)-
5a[18] (Figure 4) were determined both to be in the chiral
orthorhombic P212121 space group (for details see Support-
ing Information). Although the absolute configurations of
the molecules could not be unequivocally determined solely
from the single-crystal X-ray diffraction data (due to the
presence only of light atoms in the compounds: i.e., Z Ͻ
Si), their determination was ensured by taking data from
the synthesis and the results of chiral HPLC separation into
consideration.
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Organocatalyzed Enantioselective Michael Additions
3
3
3
was carried out with silica gel 60 (Merck). Enantiomeric excesses
(ee values) were measured by chiral HPLC analysis with a Chi-
ralpak IA column (0.46ϫ25 cm). UV detection was monitored at
254 nm.
3Ј-H), 5.78 (ddd, Jtrans = 17.4, Jcis = 10.3, J = 7.3 Hz, 1 H, 10-
H), 5.02–4.94 (m, 2 H, 11-H), 4.70 (d, 3J = 9.6 Hz, 1 H, 9-H), 3.29–
3.14 (m, 2 H, 2-H, 6-H), 3.11–3.02 (m, 1 H, 8-H), 2.84–2.73 (m, 2
H, 2-H, 6-H), 2.28 (br. s, 3 H, 3-H, NH2), 1.60–1.50 (m, 3 H, 4-H,
3
3
3
5-H), 1.44–1.37 (m, 1 H, 7-H), 0.72 (ddd, J = 13.5, J = 9.0, J =
7.5 Hz, 1 H, 7-H) ppm. 13C NMR (75.47 MHz, CDCl3, 20 °C): δ
= 150.0 (C-2Ј), 148.4 (C-4Ј), 148.2 (C-4aЈ), 141.4 (C-10), 130.0 (C-
8Ј), 128.6 (C-6Ј), 127.5 (C-8aЈ), 126.1 (C-7Ј), 123.0 (C-5Ј), 119.3
(C-3Ј), 114.0 (C-11), 61.6 (C-9), 55.9 (C-2), 40.6 (C-6), 39.4 (C-8,
C-3), 27.7 (C-5), 27.2 (C-4), 25.7 (C-7) ppm. HRMS (ESI+): calcd.
for [C19H24N3 + H]+ 294.1963; found 294.1961.
Materials: Hydroquinine, hydroquinidine, quinine, chinchonidine,
diisopropyl azidocarboxylate, diphenyl phosphoryl azide, 3,5-bis-
(trifluoromethyl)phenyl isothiocyanate, nitromethane, malono-
nitrile, and trifluoroacetic acid (TFA) were purchased from Sigma–
Aldrich and used without other purification. The chinchona alka-
loids 1a,[5b] 2a,[5b] and 2b[19] and the 1,5-diarylpenta-2,4-dien-1-
ones 3a,[20a] 3b,[20b] 3c,[20b] 3d,[20a] 3e,[20a] 3f,[20c] and 3h[20a] were
prepared as described in the literature. THF was distilled from so-
dium/benzophenone prior to use.
General Procedure for the Synthesis of 3g and 3i: An aqueous solu-
tion of sodium hydroxide (60%, 25 mL) was slowly added to a
methanolic solution (30 mL) of the appropriate acetophenone
(5.0 mmol). After the solution had been cooled to room temp., cin-
namaldehyde (792 mg, 6.0 mmol) was added. The mixture was
stirred at room temperature for 20 h and was then poured into
water (100 mL), ice (100 g), and conc. hydrochloric acid (pH ad-
justed to ca. 2). The obtained solid was removed by filtration, dis-
solved in chloroform (50 mL), and washed with an aqueous solu-
tion of sodium hydrogen carbonate (5%, 30 mL). The organic layer
was collected and dried with anhydrous sodium sulfate, and the
solution was concentrated to dryness. The residue was purified by
silica gel column chromatography with dichloromethane as eluent.
Finally, the isolated compounds were recrystallized from ethanol.
General Procedure for the Preparation of the Primary Amine Cata-
lysts 1b–d: The appropriate hydroquinidine, quinine, or chinchonid-
ine (6.13 mmol) and triphenylphosphane (2.11 g, 7.35 mmol) were
dissolved in dry THF (30 mL) and the solution was cooled to 0 °C.
Diisopropyl azidocarboxylate (1.52 mL, 7.35 mmol) was added in
one portion. A solution of diphenyl phosphoryl azide (1.63 mL,
7.35 mmol) in dry THF (13 mL) was then added dropwise at 0 °C.
The mixture was allowed to warm to room temp. After having been
stirred for 12 h, the solution was heated at 50 °C for 2 h. Tri-
phenylphosphane (2.29 g, 7.97 mmol) was then added and heating
was maintained until the gas evolution had ceased (2 h). The solu-
tion was cooled to room temperature, water (0.7 mL) was added,
and the solution was stirred for 3 h. Solvents were removed in
vacuo and the residue was dissolved in CH2Cl2 (30 mL) and diluted
hydrochloric acid (10%, 30 mL). The aqueous phase was washed
with CH2Cl2 (3ϫ30 mL). The aqueous phase was then alkalinized
with an excess of concd. aqueous ammonia and washed with
CH2Cl2 (3ϫ30 mL). The CH2Cl2 solutions were dried with
Na2SO4 and concentrated. The concentrated organic phase was
purified by column chromatography on silica gel with elution with
EtOAc/MeOH/NH4OH (50:50:1) to afford the title compounds as
yellowish viscous oils.
(E,E)-1-(4-Bromophenyl)-5-phenylpenta-2,4-dien-1-one (3g):[20c] Yel-
low solid (1.39 g, 89% yield); m.p. 141–143 °C. 1H NMR
4
(300.13 MHz, CDCl3, 20 °C): δ = 7.85 (AAЈBBЈ, 3JAB = 8.4, JAAЈ
5
= 2.4, JABЈ = 1.7 Hz, 2 H, 2Ј,6Ј-H), 7.66–7.56 (m, 3 H, 3-H, 3Ј,5-
3
4
H), 7.51 (dd, J = 8.2, J = 1.7 Hz, 2 H, 2ЈЈ,6ЈЈ-H), 7.42–7.33 (m,
3
3 H, 3ЈЈ,5ЈЈ-H, 4ЈЈ-H), 7.05 (d, Jtrans = 14.5 Hz, 1 H, 2-H), 7.04–
7.03 (m, 2 H, 4-H, 5-H) ppm. 13C NMR (125.77 MHz, CDCl3,
20 °C): δ = 189.3 (C-1), 145.4 (C-3), 142.5 (C-4), 137.0 (C-1Ј), 136.0
(C-1ЈЈ), 131.9 (5Ј, C-3Ј), 129.9 (C-2Ј,6Ј), 129.4 (C-4ЈЈ), 128.9 (C-
3ЈЈ,5ЈЈ), 127.7 (C-4Ј), 127.4 (C-2ЈЈ,6ЈЈ), 126.8 (C-5), 124.8 (C-
2) ppm. HRMS (EI+): calcd. for [C17H13BrO + H]+ 313.0222;
found 313.0215. C17H13BrO calcd. C 65.19, H 4.18; found C 64.84,
H 3.86.
9-Amino-(9-deoxy)-epi-hydroquinidine (1b):[21] Yellow oil (1.7 g,
1
87% yield). H NMR (300.13 MHz, CDCl3, 20 °C): δ = 8.75 (d, 3J
3
= 4.5 Hz, 1 H, 2Ј-H), 8.04 (d, J = 9.2 Hz, 1 H, 8Ј-H), 7.63 (br. s,
3
3
4
1 H, 5Ј-H), 7.53 (d, J = 4.5 Hz, 1 H, 3Ј-H), 7.39 (dd, J = 9.2, J
4-[(E,E)-5-Phenylpenta-2,4-dienoyl]benzonitrile (3i):[20c,23] Yellow
solid (0.96 g, 74% yield); m.p. 138–140 °C. 1H NMR (300.13 MHz,
3
= 2.7 Hz, 1 H, 7Ј-H), 4.70 (d, J = 9.7 Hz, 1 H, 9-H), 3.97 (s, 3 H,
CH3), 3.11–2.94 (m, 4 H, 2-H, 6-H, 8-H), 2.70–2.64 (m, 1 H, 2-H),
1.54–1.34 (m, 6 H, 3-H, 4-H, 5-H, 10-H), 1.13–1.05 (m, 1 H, 7-H),
0.99–0.93 (ddt, 3J = 13.6, 3J = 7.4, 4J = 1.8 Hz 1 H, 7-H), 0.88 (t, 3J
= 7.2 Hz, 3 H, 11-H) ppm. HRMS (ESI+): calcd. for [C20H27N3O +
H]+ 326.2227; found 326.2223.
4
5
CDCl3, 20 °C): δ = 8.04 (AAЈBBЈ, 3JAB = 8.5, JAAЈ = 1.7, JABЈ
=
3
4
5
1.5 Hz, 2 H, 2Ј,6Ј-H), 7.79 (AAЈBBЈ, JBA = 8.5, JBBЈ = 1.7, JBAЈ
= 1.5 Hz, 2 H, 3Ј,5Ј-H), 7.63 (ddd, Jtrans = 14.8, 3J = 8.6, 4J =
3
1.9 Hz, 3-H), 7.50–7.53 (m, 2 H, 2ЈЈ,6ЈЈ-H), 7.42–7.35 (m, 3 H, 4ЈЈ-
H, 3ЈЈ,5ЈЈ-H), 7.06–6.99 (m, 3 H, 2-H, 4-H, 5-H) ppm. 13C NMR
(125.77 MHz, CDCl3, 20 °C): δ = 189.0 (C-1), 146.5 (C-3), 143.4
(C-4), 141.5 (C-1Ј), 135.8 (C-1ЈЈ), 132.4 (C-3Ј,5Ј), 129.6 (C-4ЈЈ),
128.9 (C-3ЈЈ,5ЈЈ), 128.7 (C-2Ј,6Ј), 127.4 (C-2ЈЈ,6ЈЈ), 126.5 (C-5),
124.3 (C-2), 118 (CN), 115.8 (C-4Ј) ppm. HRMS (ESI+): calcd. for
[C18H13NO + H]+ 260.1070; found 260.1068. C18H13NO calcd. C
83.37, H 5.05, N 4.40; found C 83.17, H 5.04, N 5.42.
9-Amino-(9-deoxy)-epi-quinine (1c):[22] Yellow oil (1.6 g, 82% yield).
3
1H NMR (300.13 MHz, CDCl3, 20 °C): δ = 8.74 (d, J = 4.4 Hz, 1
3
H, 2Ј-H), 8.03 (d, J = 9.2 Hz, 1 H, 8Ј-H), 7.65 (br. s, 1 H, 5Ј-H),
3
3
4
7.46 (d, J = 4.4 Hz, 1 H, 3Ј-H), 7.38 (dd, J = 9.2, J = 2.7 Hz, 1
3
3
3
H, 7Ј-H), 5.80 (ddd, Jtrans = 17.5, Jcis = 10.3, J = 7.5 Hz, 1 H,
10-H), 5.03–4.95 (m, 2 H, 11-H), 4.60 (d, J = 9.9 Hz, 1 H, 9-H),
3
3.95 (s, 3 H, CH3), 3.31–3.16 (m, 2 H, 2-H, 6-H), 3.12–3.04 (m, 1
H, 8-H), 2.84–2.74 (m, 2 H, 2-H, 6-H), 2.27 (br. s 1 H, 3-H), 2.18
(br. s, 2 H, NH2), 1.63–1.52 (m, 3 H, 4-H, 5-H), 1.46–1.38 (m, 1
General Procedure for Enantioselective Addition of Malononitrile to
Cinnamylideneacetophenones 3a–i
3
H, 7-H), 0.72 (ddt, J = 13.6, 3J = 7.4, 4J = 1.8 Hz 1 H, 7-H) ppm.
Synthesis of 4a–i: The 1,5-diarylpenta-2,4-dien-1-ones 3a–i
(0.128 mmol) and the amino catalysts 1a or 1b (12.3 mg,
0.038 mmol) were dissolved in THF (0.32 mL) under nitrogen.
Next, TFA (5.8 µL, 0.076 mmol) and malononitrile (50.7 mg,
0.768 mmmol) in THF (0.32 mL, 0.2 ) were added. The mixture
was stirred for 7 d at room temp. The resulting solution was con-
centrated to dryness, taken up in CH2Cl2, and purified by column
chromatography with elution with hexane/AcOEt (9:1). Finally the
HRMS (ESI+): calcd. for [C20H26N3O + H]+ 324.2070; found
324.2066.
9-Amino-(9-deoxy)-epi-cinchonidine (1d): Yellow oil (1.3 g, 73%
yield). 1H NMR (300.13 MHz, CDCl3, 20 °C): δ = 8.89 (d, 3J =
3
4
4.4 Hz, 1 H, 2Ј-H), 8.35 (br. s, 1 H, 5Ј-H), 8.14 (dd, J = 8.3, J =
1.2 Hz, 1 H, 8Ј-H), 7.70 (td, 3J = 8.3, 4J = 1.2 Hz, 1 H, 6Ј-H), 7.58
(td, J = 8.3, J = 1.2 Hz, 1 H, 7Ј-H), 7.53 (d, J = 4.4 Hz, 1 H,
3
4
3
Eur. J. Org. Chem. 2010, 3449–3458
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3453

A. M. S. Silva et al.
FULL PAPER
residues were crystallized from hexane/iPr2O to give the desire com-
pounds 4a–i.
(S,E)-2-(1-Oxo-1,5-diphenylpent-4-en-3-yl)malononitrile [(S)-4a]:[23]
This compound was produced with use of catalyst 1a. White solid
(36.9 mg, 96% yield); m.p. 80–82 °C (hexane/iPr2O). 1H NMR
2 JA B = 18.5, JB X = 8.1 Hz, 1 H, 2-H) ppm. 1 3 C NMR
(125.77 MHz, CDCl3, 20 °C): δ = 196.8 (C-1), 160.0 (C-4ЈЈ), 135.8
(C-1Ј), 135.7 (C-5), 134.1 (C-4Ј), 128.9 (C-3Ј,5Ј), 128.1 (C-2ЈЈ,6ЈЈ),
128.0 (C-2Ј,6Ј, C-1ЈЈ), 120.9 (C-4), 114.1 (C-3ЈЈ,5ЈЈ), 112.0 (CN),
111.6 (CN), 55.3 (OCH3), 40.1 (C-3), 39.8 (C-2), 27.7 (C-1ЈЈЈ) ppm.
HRMS (ESI)+: calcd. for [C21 H1 8N2O2 + H]+ 331.1441;
found 331.1439. HPLC (2-propanol/hexane 10:90, flow rate
0.70 mLmin–1, λ = 254 nm), retention time of (S)-4c 45.94 min,
retention time of (R)-4c 50.83 min (ee = 97%).
3
3
(300.13 MHz, CDCl3, 20 °C): δ = 7.97 (d, J = 7.3 Hz, 2 H, 2Ј,6Ј-
H), 7.64 (t, 3J = 7.3 Hz, 1 H, 4Ј-H), 7.51 (t, 3J = 7.3 Hz, 2 H, 3Ј,5Ј-
3
4
H), 7.42 (dt, J = 7.9, J = 1.5 Hz, 2 H, 2ЈЈ,6ЈЈ-H), 7.38–7.30 (m,
3
3 H, 3ЈЈ,5ЈЈ-H, 4ЈЈ-H), 6.42 (d, Jtrans = 15.7 Hz, 1 H, 5-H), 6.24
3
3
3
(dd, Jtrans = 15.7, J = 8.8 Hz, 1 H, 4-H), 4.59 (d, J = 4.7 Hz, 1
H, 1ЈЈЈ-H), 3.61–3.52 (m, 1 H, 3-H), 3.47–3.44 (m, 2 H, 2-H) ppm.
13C NMR (75.47 MHz, CDCl3, 20 °C): δ = 196.7 (C-1), 136.3 (C-
5), 135.7 (C-1Ј), 135.3 (C-1ЈЈ), 134.2 (C-4Ј), 128.9 (C-3Ј,5Ј), 128.7
(C-3ЈЈ,5ЈЈ), 128.6 (C-4ЈЈ), 128.1 (C-2Ј,6Ј), 126.8 (C-2ЈЈ,6ЈЈ), 123.2
(C-4), 112.0 (CN), 111.5 (CN), 40.0 (C-3), 39.6 (C-2), 27.5 (C-
1ЈЈЈ) ppm. MS (EI+): m/z (%) = 300.13 (0.51) [M]+·, 234.11 (6.08)
[M – 66]+, 180.07 (11.79) [M – 120]+, 153.06 (12.99) [M – 146]+,
115.06 (13.32) [M – 185]+, 105.06 (100) [M – 195]+, 77.04 (31.89)
[M – 223]+. HRMS (ESI+): calcd. for [C20H16N2O + H] 300.1263;
found 300.1257. C20H16N2O calcd. C 79.98, H 5.37, N 9.33; found
C 79.91, H 5.39, N 9.11. HPLC (2-propanol/hexane 10:90, flow
rate 0.7 mLmin–1, λ = 254 nm), retention time of (S)-4a 21.16 min,
retention time of (R)-4a 29.69 min (ee = 90%), after recrystalli-
zation (ee Ͼ 99%).
(S,E)-2-[1-(4-Methylphenyl)-1-oxo-5-phenylpent-4-en-3-yl]malono-
nitrile [(S)-4d]:[23] This compound was produced with use of cata-
lyst 1a. Yellow solid (38.1 mg, 97% yield); m.p. 78–79 °C (hexane/
1
3
iPr2O). H NMR (500.13 MHz, CDCl3, 20 °C): δ = 7.86 (d, J =
3
4
8.2 Hz, 2 H, 2Ј,6Ј-H), 7.41 (dt, J = 7.1, J = 1.8 Hz, 2 H, 2ЈЈ,6ЈЈ-
H), 7.36–7.33 (m, 2 H, 3ЈЈ,5ЈЈ-H), 7.31–7.28 (m, 3 H, 3Ј,5Ј-H, 4ЈЈ-
3
3
H), 6.78 (d, Jtrans = 15.7 Hz, 1 H, 5-H), 6.23 (dd, 3Jtrans = 15.7, J
3
= 9.0 Hz, 1 H, 4-H), 4.59 (d, J = 4.7 Hz, 1 H, 1ЈЈЈ-H), 3.57–3.51
(m, 1 H, 3-H), 3.44 (ABX, JAB = 18.3, JAX = 5.0 Hz, 1 H, 2-H),
2
3
2
3
3.40 (ABX, JAB = 18.3, JBX = 8.1 Hz, 1 H, 2-H), 2.43 (s, 3 H,
CH3) ppm. 13C NMR (125.77 MHz, CDCl3, 20 °C): δ = 196.3 (C-
1), 145.2 (C-4Ј), 136.2 (C-5), 135.3 (C-1ЈЈ), 133.3 (C-1Ј), 129.6 (C-
3Ј,5Ј), 128.7 (C-3ЈЈ,5ЈЈ), 128.6 (C-4ЈЈ), 128.2 (C-2Ј,6Ј), 126.8 (C-
2ЈЈ,6ЈЈ), 123.3 (C-4), 112.0 (CN), 111.5 (CN), 40.0 (C-3), 39.4 (C-
2), 27.5 (C-1ЈЈЈ), 21.7 (CH3) ppm. HRMS (ESI)+: calcd. for
[C21H18N2O + H]+ 315.1492; found 315.1490. HPLC (2-propanol/
hexane 10:90, flow rate 0.8 mLmin–1, λ = 254 nm), retention time
of (S)-4d 19.79 min, retention time of (R)-4d 32.38 min (ee = 84%),
after recrystallization (ee Ͼ 98%).
(R,E)-2-(1-Oxo-1,5-diphenylpent-4-en-3-yl)malononitrile [(R)-4a]:
This compound was produced with use of catalyst 1b. White solid
(30.4 mg, 79% yield). HPLC (2-propanol/hexane 10:90, flow rate
0.7 mLmin–1, λ = 254 nm), retention time of (S)-4a 21.27 min, re-
tention time of (R)-4a 28.92 min (ee = 90%).
(S,E)-2-[1-(4-Methoxyphenyl)-1-oxo-5-phenylpent-4-en-3-yl]malono-
nitrile [(S)-4e]:[23] This compound was produced with use of catalyst
1a. Yellow oil (40.2 mg, 95 % yield). 1H NMR (300.13 MHz,
(S,E)-2-[5-(4-Nitrophenyl)-1-oxo-1-phenylpent-4-en-3-yl]malono-
nitrile [(S)-4b]:[23] This compound was produced with use of cata-
lyst 1a. Yellow solid (24.7 mg, 56% yield); m.p. 154–156 °C (hex-
ane/iPr2O). 1H NMR (500.13 MHz, CDCl3, 20 °C): δ = 8.21
4
5
CDCl3, 20 °C): δ = 7.95 (AAЈBBЈ, 3JAB = 8.9, JAAЈ = 2.9, JABЈ
=
2.0 Hz, 2 H, 2Ј,6Ј-H), 7.43–7.29 (m, 5 H, 4ЈЈ-H, 2ЈЈ,6ЈЈ-H, 3ЈЈ,5ЈЈ-
H), 6.96 (AAЈBBЈ, JAB = 8.9, JBBЈ = 2.9, JAЈB = 2.0 Hz, 2 H,
3
4
5
3
4
5
(AAЈBBЈ, JAB = 8.8, JBBЈ = 2.3, JAЈB = 1.9 Hz, 2 H, 3ЈЈ,5ЈЈ-H),
3
3
3
3
3Ј,5Ј-H), 6.78 (d, Jtrans = 15.7 Hz, 1 H, 5-H), 6.23 (dd, Jtrans
=
7.98 (d, J = 7.8 Hz, 2 H, 2Ј,6Ј-H), 7.65 (t, J = 7.8 Hz, 1 H, 4Ј-
15.7, 3J = 8.9 Hz, 1 H, 4-H), 4.61 (d, 3J = 4.8 Hz, 1 H, 1ЈЈЈ-H),
3.89 (s, 3 H, OCH3), 3.58–3.49 (m, 1 H, 3-H), 3.42 (ABX, JAB
18.3, JBX = 5.1 Hz, 1 H, 2-H), 3.36 (ABX, JAB = 18.3, JAX
3
4
5
H), 7.57 (AAЈBBЈ, JAB = 8.8, JAAЈ = 2.3, JABЈ = 1.9 Hz, 2 H,
2
2ЈЈ,6ЈЈ-H), 7.52 (t, 3J = 7.8 Hz, 2 H, 3Ј,5Ј-H), 6.88 (d, Jtrans
=
3
=
=
3
2
3
15.8 Hz, 1 H, 5-H), 6.42 (dd, 3Jtrans = 15.8, 3J = 9.1 Hz, 1 H, 4-H),
7.8 Hz, 1 H, 2-H) ppm. 13C NMR (125.77 MHz, CDCl3, 20 °C): δ
= 195.1 (C-1), 164.3 (C-4Ј), 136.2 (C-5), 135.4 (C-1ЈЈ), 130.4 (C-
2Ј,6Ј), 128.8 (C-1Ј), 128.7 (C-3ЈЈ,5ЈЈ), 128.6 (C-4ЈЈ), 126.8 (C-
2ЈЈ,6ЈЈ), 123.4 (C-4), 114.0 (C-3Ј,5Ј), 112.1 (CN), 111.6 (CN), 55.6
(OCH3), 40.1 (C-3), 39.2 (C-2), 27.5 (C-1ЈЈЈ) ppm. HRMS (ESI)+:
calcd. for [C21H18N2O2 + H]+ 331.1441; found 331.1439. HPLC (2-
propanol/hexane 10:90, flow rate 1.2 mLmin–1, λ = 254 nm), reten-
tion time of (S)-4e 21.70 min, retention time of (R)-4e 37.62 min
(ee = 84%).
4.61 (d, 3J = 4.9 Hz, 1 H, 1ЈЈЈ-H), 3.65–3.60 (m, 1 H, 3-H), 3.50
2
3
2
(ABX, JAB = 18.3, JAX = 5.0 Hz, 1 H, 2-H), 3.47 (ABX, JAB
=
18.3, JBX = 7.8 Hz, 1 H, 2-H) ppm. 13C NMR (125.77 MHz,
CDCl3, 20 °C): δ = 196.3 (C-1), 147.6 (C-4ЈЈ), 141.5 (C-1ЈЈ), 135.6
(C-1Ј), 134.4 (C-4Ј), 134.3 (C-5), 129.0 (C-3Ј,5Ј), 128.1 (C-2Ј,6Ј),
128.0 (C-4), 127.5 (C-2ЈЈ,6ЈЈ), 124.1 (C-3ЈЈ,5ЈЈ), 111.7 (CN), 112.3
(CN), 40.0 (C-3), 39.3 (C-2), 27.3 (C-1ЈЈЈ) ppm. HRMS (ESI+):
calcd. for [C20H15N3O3 + Na]+ 368.1006; found 368.1005.
C20H15N3O3 calcd. C 69.56, H 4.38, N 12.17; found C 69.26, H
3.99, N 11.81. HPLC (2-propanol/hexane 20:80, flow rate
1.5 mLmin–1, λ = 254 nm), retention time of (S)-4b 17.72 min, re-
tention time of (R)-4b 22.88 min (ee = 80%) after recrystallization
(ee Ͼ 99%).
3
(S,E)-2-[1-(4-Chlorophenyl)-1-oxo-5-phenylpent-4-en-3-yl]malono-
nitrile [(S)-4f]:[23] This compound was produced with use of catalyst
1a. Yellow solid (37.2 mg, 87 % yield); m.p. 75–77 °C (hexane/
1
iPr2O). H NMR (500.13 MHz, CDCl3, 20 °C): δ = 7.91 (AAЈBBЈ,
4
5
(S,E)-2-[5-(4-Methoxyphenyl)-1-oxo-1-phenylpent-4-en-3-yl]malono-
nitrile [(S)-4c]:[23] This compound was produced with use of catalyst
1a. Yellow oil (38.4 mg, 91 % yield). 1H NMR (300.13 MHz,
3JAB = 8.7, JAAЈ = 2.4, JABЈ = 1.9 Hz, 2 H, 2Ј,6Ј-H), 7.48
3
4
5
(AAЈBBЈ, JAB = 8.7, JBBЈ = 2.4, JAЈB = 1.9 Hz, 2 H, 3Ј,5Ј-H),
3
4
7.41 (dt, J = 7.3, J = 2.0 Hz, 2 H, 2ЈЈ,6ЈЈ-H), 7.37–7.33 (m, 2 H,
3
4
CDCl3, 20 °C): δ = 7.97 (dt, J = 7.2, J = 1.8 Hz, 2 H, 2Ј,6Ј-H),
3ЈЈ,5ЈЈ-H), 7.30 (tt, 3J = 7.3, 4J = 2.0 Hz, 1 H, 4ЈЈ-H), 6.79 (d, 3Jtrans
3
4
3
4
3
3
7.63 (tt, J = 7.2, J = 1.8 Hz, 1 H, 4Ј-H), 7.50 (td, J = 7.2, J = = 15.7 Hz, 1 H, 5-H), 6.21 (dd, Jtrans = 15.7, J = 9.1 Hz, 1 H, 4-
1.8 Hz, 2 H, 3Ј,5Ј-H), 7.34 (AAЈBBЈ, 3JAB = 8.8, 4JAAЈ = 2.8, 5JABЈ H), 4.55 (d, 3J = 4.8 Hz, 1 H, 1ЈЈЈ-H), 3.58–3.53 (m, 1 H, 3-H),
3
4
2
3
= 2.0 Hz, 2 H, 2ЈЈ,6ЈЈ-H), 6.87 (AAЈBBЈ, JAB = 8.8, JBBЈ = 2.8,
3.45 (ABX, JAB = 18.7, JAX = 5.2 Hz, 1 H, 2-H), 3.40 (ABX,
5JAЈB = 2.0 Hz, 2 H, 3ЈЈ,5ЈЈ-H), 6.72 (d, Jtrans = 15.7 Hz, 1 H, 5- 2 JA B = 18.7, JB X = 8.2 Hz, 1 H, 2-H) ppm. 1 3 C NMR
3
3
3
3
3
H), 6.08 (dd, Jtrans = 15.7, J = 8.8 Hz, 1 H, 4-H), 4.55 (d, J = (125.77 MHz, CDCl3, 20 °C): δ = 195.5 (C-1), 140.8 (C-4Ј), 136.5
4.7 Hz, 1 H, 1ЈЈЈ-H), 3.82 (s, 3 H, OCH3), 3.57–3.48 (m, 1 H, 3- (C-5), 135.2 (C-1ЈЈ), 134.0 (C-1Ј), 129.5 (C-2Ј,6Ј), 129.3 (C-3Ј,5Ј),
H), 3.47 (ABX, 2JAB = 18.5, 3JAX = 4.7 Hz, 1 H, 2-H), 3.40 (ABX,
128.7 (C-3ЈЈ,5ЈЈ, C-4ЈЈ), 126.8 (C-2ЈЈ,6ЈЈ), 123.0 (C-4), 111.8 (CN),
3454
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3449–3458

Organocatalyzed Enantioselective Michael Additions
111.4 (CN), 39.9 (C-3), 39.6 (C-2), 27.5 (C-1ЈЈЈ) ppm. HRMS (ESI)
+: calcd. for [C20H15ClN2O + H]+ 335.0946; found 335.0944. HPLC
(2-propanol/hexane 10:90, flow rate 0.8 mLmin–1, λ = 254 nm), re-
tention time of (S)-4f 23.53 min, retention time of (R)-4f 35.14 min
(ee = 90%), after recrystallization (ee Ͼ 98%).
7 d at room temp. The resulting solution was concentrated and
purified by column chromatography with elution with hexane/
AcOEt (9:1). Finally the residues were crystallized from hexane/
AcOEt to afford the desire compounds 5a–k. Compounds (R)-5a
and (R)-5f have been described previously.[5m]
(S,E)-2-[1-(4-Bromophenyl)-1-oxo-5-phenylpent-4-en-3-yl]malono-
nitrile [(S)-4g]:[23] This compound was produced with use of cata-
lyst 1a. Yellow solid (45.1 mg, 93% yield); m.p. 98.6–100.3 °C (hex-
(S,E)-3-(Nitromethyl)-1,5-diphenylpent-4-en-1-one [(S)-5a]: This
compound was produced with use of catalyst 2b. White solid
1
(32.2 mg, 85% yield); m.p. 105–107 °C (hexane/AcOEt). H NMR
3
ane/iPr2O). 1H NMR (300.13 MHz, CDCl3, 25 °C): δ = 7.83 (300.13 MHz, CDCl3, 20 °C): δ = 7.96 (d, J = 7.5 Hz, 2 H, 2Ј,6Ј-
3
4
5
(AAЈBBЈ, JAB = 8.6, JAAЈ = 2.3, JABЈ = 1.9 Hz, 2 H, 2Ј,6Ј-H), H), 7.60 (t, 3J = 7.5 Hz, 1 H, 4Ј-H), 7.48 (t, 3J = 7.5 Hz, 2 H, 3Ј,5Ј-
3
4
5
3
7.65 (AAЈBBЈ, JAB = 8.6, JBBЈ = 2.3, JAЈB = 1.9 Hz, 2 H, 3Ј,5Ј-
H), 7.43–7.30 (m, 5 H, 2ЈЈ,6ЈЈ-H, 4ЈЈ-H, 3ЈЈ,5ЈЈ-H), 6.79 (d, Jtrans = 15.9 Hz, 1 H, 5-H), 6.17 (dd, Jtrans = 15.9, J = 8.6 Hz, 1 H, 4-
H), 7.34–7.21 (m, 5 H, 2ЈЈ,6ЈЈ-H, 3ЈЈ,5ЈЈ-H, 4ЈЈ-H), 6.58 (d, Jtrans
3
3
3
3
3
2
3
= 15.7 Hz, 1 H, 5-H), 6.21 (dd, Jtrans = 15.7, J = 9.0 Hz, 1 H, 4-
H), 4.72 (ABX, JAB = 12.2, JAX = 5.9 Hz, 1ЈЈЈ-H), 4.62 (ABX,
H), 4.54 (d, 3J = 4.8 Hz, 1 H, 1ЈЈЈ-H), 3.57–3.47 (m, 1 H, 3-H), 2JAB = 12.2, JBX = 7.4 Hz, 1 H, 1ЈЈЈ-H), 3.81–3.70 (m, 1 H, 3-H),
3
3.43–3.39 (m, 2 H, 2-H) ppm. 13C NMR (75.5 MHz, CDCl3,
25 °C): δ = 195.7 (C-1), 136.4 (C-5), 135.2 (C-1ЈЈ), 134.4 (C-1Ј),
132.2 (C-3Ј,5Ј), 129.5 (C-2Ј,6Ј), 128.7 (C-3ЈЈ,5ЈЈ, C-4ЈЈ), 126.8 (C-
3.30 (d, 3J = 6.5 Hz, 2 H, 2-H) ppm. 13C NMR (75.47 MHz,
CDCl3, 20 °C): δ = 197.0 (C-1), 136.5 (C-1Ј), 136.2 (C-1ЈЈ), 133.6
(C-4Ј), 133.4 (C-5), 128.8 (C-3Ј,5Ј), 128.6 (C-3ЈЈ,5ЈЈ), 128.1 (C-
2ЈЈ,6ЈЈ), 123.0 (C-4), 111.9 (CN), 111.5 (CN), 108.8 (C-4Ј), 39.8 (C- 2Ј,6Ј), 128.0 (C-4ЈЈ), 126.5 (C-4), 126.4 (C-2ЈЈ,6ЈЈ), 78.8 (C-1ЈЈЈ),
3), 39.6 (C-2), 27.5 (C-1ЈЈЈ) ppm. HRMS (ESI)+: calcd. for
[C20H15BrNO2 + H]+ 379.0440; found 379.0444. HPLC (2-propa-
nol/hexane 10:90, flow rate 0.9 mLmin–1, λ = 254 nm), retention
time of (S)-4g 24.63 min, retention time of (R)-4g 32.48 min (ee =
94%), after recrystallization (ee Ͼ 99%).
40.3 (C-2), 37.3 (C-3) ppm. HRMS (ESI+): calcd. for [C18H17NO3
+ H]+ 296.1281; found 296.1279. C18H17NO3 calcd. C 73.20, H
5.80, N 4.74; found C 73.17, H 5.82, N 4.79. HPLC (2-propanol/
hexane 10:90, flow rate 0.7 mLmin–1, λ = 254 nm), retention time
of (S)-5a 18.21 min, retention time of (R)-5a 20.63 min (ee = 92%),
after recrystallization (ee Ͼ 99%).
(S,E)-2-[1-(4-Fluorophenyl)-1-oxo-5-phenylpent-4-en-3-yl]malono-
nitrile [(S)-4h]:[23] This compound was produced with use of cata-
lyst 1a. Yellow solid (26.5 mg, 65% yield); m.p. 74–75 °C (hexane/
(R,E)-3-(Nitromethyl)-1,5-diphenylpent-4-en-1-one [(R)-5a]:[5m] This
compound was produced with use of catalyst 2a. HPLC (2-propa-
1
3
iPr2O). H NMR (300.13 MHz, CDCl3, 25 °C): δ = 8.01 (dd, J = nol/hexane 10:90, flow rate 0.7 mLmin–1, λ = 254 nm), retention
4
8.9, J = 5.3 Hz, 2 H, 2Ј,6Ј-H), 7.44–7.31 (m, 5 H, 2ЈЈ,6ЈЈ-H, 3Ј,5Ј-
time of (S)-5a 18.31 min, retention time of (R)-5a 20.70 min (ee =
92%), after recrystallization (ee Ͼ 99%).
H, 4ЈЈ-H), 7.18 (t, 3J = 8.6 Hz, 2 H, 3ЈЈ,5ЈЈ-H), 6.79 (d, Jtrans
=
3
15.7 Hz, 1 H, 5-H), 6.22 (dd, 3Jtrans = 15.7, 3J = 9.0 Hz, 1 H, 4-H),
(R,E)-3-(Nitromethyl)-5-(4-nitrophenyl)-1-phenylpent-4-en-1-one
[(R)-5b]: This compound was produced with use of catalyst 2a. Yel-
low solid (28.7 mg, 66% yield); m.p. 121–123 °C (hexane/AcOEt).
3
4.56 (d, J = 4.8 Hz, 1 H, 1ЈЈЈ-H), 3.62–3.56 (m, 1 H, 3-H), 3.44–
3.36 (m, 2 H, 2-H) ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C): δ
= 195.1 (C-1), 166.3 (d, 1J = 256.9 Hz, C-4Ј), 136.3 (C-5), 135.2
(C-1ЈЈ), 132.2 (d, 4J = 3.2 Hz, C-1Ј), 130.8 (d, 3J = 9.6 Hz, C-2Ј,6Ј),
1H NMR (500.13 MHz, CDCl3, 20 °C): δ = 8.16 (AAЈBBЈ, 3JAB
8.8, JBBЈ = 2.4, JABЈ = 1.9 Hz, 2 H, 3ЈЈ,5ЈЈ-H), 7.96 (dt, J = 8.0,
=
4
5
3
2
128.7 (C-3ЈЈ,5ЈЈ, C-4ЈЈ), 126.8 (C-2ЈЈ,6ЈЈ), 123.1 (C-4), 116.1 (d, J
3
4
4J = 1.3 Hz, 2 H, 2Ј,6Ј-H), 7.61 (tt, J = 8.0, J = 1.3 Hz, 1 H, 4Ј-
= 22.0 Hz, C-3Ј,5Ј), 111.9 (CN), 111.5 (CN), 39.9 (C-3), 39.5 (C-
2), 27.5 (C-1ЈЈЈ) ppm. HRMS: calcd. for [C20H15FN2O + H]+
319.1241; found 319.1244. HPLC (2-propanol/hexane 10:90, flow
rate 0.8 mLmin–1, λ = 254 nm), retention time of (S)-4h 20.12 min,
retention time of (R)-4h 28.07 min (ee = 92%), after recrystalli-
zation (ee Ͼ 98%).
3
4
H), 7.50 (td, J = 8.0, J = 1.3 Hz, 2 H, 3Ј,5Ј-H), 7.47 (AAЈBBЈ,
3JAB = 8.8, JAAЈ = 2.4, JABЈ = 1.9 Hz, 2 H, 2ЈЈ,6ЈЈ-H), 6.66 (d,
4
5
3Jtrans = 15.9 Hz, 1 H, 5-H), 6.38 (dd, Jtrans = 15.9, J = 8.5 Hz, 1
H, 4-H), 4.77 (ABX, 2JAB = 12.3, 3JAX = 5.6 Hz, 1 H, 1ЈЈЈ-H), 4.66
(ABX, 2JAB = 12.3, 3JBX = 7.6 Hz, 1 H, 1ЈЈЈ-H), 3.84–3.74 (m, 1 H,
3-H), 3.34 (d, 3J = 6.4 Hz, 2 H, 2-H) ppm. 13C NMR (125.77 MHz,
3
3
(S,E)-2-[1-(4-Cyanophenyl)-1-oxo-5-phenylpent-4-en-3-yl]malono- CDCl3, 20 °C): δ = 196.6 (C-1), 147.2 (C-4ЈЈ), 142.5 (C-1ЈЈ), 136.2
nitrile [(S)-4i]:[23] This compound was produced with use of catalyst
(C-1Ј), 133.8 (C-4Ј), 131.6 (C-5), 131.5 (C-4), 128.8 (C-3Ј,5Ј), 128.0
(C-2Ј,6Ј), 127.0 (C-2ЈЈ,6ЈЈ), 124.0 (C-3ЈЈ,5ЈЈ), 78.4 (C-1ЈЈЈ), 40.0 (C-
2), 37.3 (C-3) ppm. HRMS (ESI+): calcd. for [C18H16N2O5 + Na]
1
1a. Yellow oil (35.9 mg, 77% yield). H NMR (300 MHz, CDCl3,
4
5
25 °C): δ = 8.06 (AAЈBBЈ, 3JAB = 8.7, JAAЈ = 1.9, JABЈ = 1.5 Hz,
3
4
5
+
2 H, 2Ј,6Ј-H), 7.82 (AAЈBBЈ, JAB = 8.7, JBBЈ = 1.9, JAЈB
=
363.0951; found 363.0950. C18H16N2O5 calcd. C 63.52, H 4.74,
1.5 Hz, 2 H, 3Ј,5Ј-H), 7.43–7.26 (m, 5 H, 2ЈЈ,6ЈЈ-H, 3ЈЈ,5ЈЈ-H, 4Ј- N 8.23; found C 63.47, H 4.63, N 8.00. HPLC (2-propanol/hexane
3
3
H), 6.80 (d, 3Jtrans = 15.7 Hz, 1 H, 5-H), 6.20 (dd, Jtrans = 15.7, J
20:80, flow rate 1.5 mLmin–1, λ = 254 nm), retention time of (S)-
5b 19.46 min, retention time of (R)-5b 25.45 min (ee = 88%), after
recrystallization (ee Ͼ 99%).
3
= 8.9 Hz, 1 H, 4-H), 4.49 (d, J = 4.8 Hz, 1 H, 1ЈЈЈ-H), 3.61–3.54
(m, 1 H, 3-H), 3.49–3.39 (m, 2 H, 2-H) ppm. 13C NMR (75.5 MHz,
CDCl3, 25 °C): δ = 195.3 (C-1), 138.5 (C-1Ј), 136.7 (C-5), 135.0 (C-
1ЈЈ), 132.7 (C-3Ј,5Ј), 128.8 (C-4ЈЈ), 128.7 (C-3ЈЈ,5ЈЈ), 128.5 (C-2Ј,6Ј),
126.8 (C-3ЈЈ,5ЈЈ), 122.6 (C-4), 117.5 (CN), 117.3 (C-4Ј) 111.7 (CN),
111.3 (CN), 40.1 (C-3), 39.8 (C-2), 27.6 (C-1ЈЈЈ) ppm. HPLC (2-
propanol/hexane 10:90, flow rate 2.0 mLmin–1, λ = 254 nm), reten-
tion time of (S)-4i 22.17 min, retention time of (R)-4i 31.76 min (ee
= 82%).
(R,E)-5-(4-Methoxyphenyl)-3-(nitromethyl)-1-phenylpent-4-en-1-one
[(R)-5c]: This compound was produced with use of catalyst 2a.
Brown solid (37.9 mg, 91% yield); m.p. 74–75 °C (hexane/AcOEt).
3
4
1H NMR (500.13 MHz, CDCl3, 20 °C): δ = 7.95 (dt, J = 7.3, J
3
4
= 1.6 Hz, 2 H, 2Ј,6Ј-H), 7.60 (tt, J = 7.3, J = 1.6 Hz, 1 H, 4Ј-H),
7.48 (td, J = 7.3, J = 1.6 Hz, 2 H, 3Ј,5Ј-H), 7.26 (AAЈBBЈ, JAB
3
4
3
4
5
= 8.7, JAAЈ = 2.9, JABЈ = 2.0 Hz, 2 H, 2ЈЈ,6ЈЈ-H), 6.83 (AAЈBBЈ,
4
5
General Procedure for Enantioselective Addition of Nitromethane to
Cinnamylideneacetophenones 3a–k – Synthesis of 5a–k: The 1,5-di-
arylpenta-2,4-dien-1-ones 3a–k (0.128 mmol) and the thiourea cat-
alysts 2a or 2b (22.9 mg, 0.038 mmol) were dissolved in nitrometh-
ane (0.47 mL, 0.3 ) under nitrogen. The mixture was stirred for
3JAB = 8.7, JBBЈ = 2.9, JAЈB = 2.0 Hz, 2 H, 3ЈЈ,5ЈЈ-H), 6.51 (d,
3Jtrans = 15.9 Hz, 1 H, 5-H), 6.01 (dd, Jtrans = 15.9, J = 8.6 Hz, 1
3
3
H, 4-H), 4.71 (ABX, 2JAB = 12.1, 3JAX = 5.9 Hz, 1 H, 1ЈЈЈ-H), 4.59
2
3
(ABX, JAB = 12.1, JBX = 7.4 Hz, 1 H, 1ЈЈЈ-H), 3.79 (s, 3 H,
OCH3), 3.77–3.66 (m, 1 H, 3-H), 3.28 (d, 3J = 6.5 Hz, 2 H, 2-
Eur. J. Org. Chem. 2010, 3449–3458
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3455

A. M. S. Silva et al.
FULL PAPER
H) ppm. 13C NMR (125.77 MHz, CDCl3, 20 °C): δ = 197.2 (C-1),
7.2 Hz, 1 H, 1ЈЈЈ-H), 3.80–3.73 (m, 1 H, 3-H), 3.33 (d, 3J = 6.6 Hz,
159.5 (C-4ЈЈ), 136.5 (C-1Ј), 133.6 (C-4Ј), 132.9 (C-5), 128.9 (C-1ЈЈ), 1 H, 2-H) ppm. 13C NMR (125.77 MHz, CDCl3, 20 °C): δ = 202.9
128.7 (C-3Ј,5Ј), 128.0 (C-2Ј,6Ј), 127.6 (C-2ЈЈ,6ЈЈ), 124.2 (C-4), 114.0
(C-3ЈЈ,5ЈЈ), 78.9 (C-1ЈЈЈ), 55.3 (OCH3), 40.4 (C-2), 37.4 (C-3) ppm.
HRMS (ESI+): calcd. for [C19H19NO4 + H]+ 326.1387; found
(C-1), 162.6 (C-2Ј), 136.9 (C-4Ј), 136.0 (C-1ЈЈ), 133.8 (C-5), 129.6
(C-6Ј), 128.6 (C-3ЈЈ,5ЈЈ), 128.1 (C-4ЈЈ), 127.4 (C-1Ј), 126.4 (C-
2ЈЈ,6ЈЈ), 126.0 (C-4), 119.2 (C-5Ј), 118.8 (C-3Ј), 78.8 (C-1ЈЈЈ), 40.0
326.1385. C19H19NO4 calcd. C 70.14, H 5.89, N 4.31; found C (C-2), 37.1 (C-3) ppm. HRMS (ESI+): calcd. for [C18H17NO4 + Na]
+
70.43, H 5.80, N 3.98. HPLC (2-propanol/hexane 10:90, flow rate
1.2 mLmin–1, λ = 254 nm), retention time of (R)-5c 20.54 min (ee
Ͼ 99%).
334.1050; found 334.1049. HPLC (2-propanol/hexane 3:97, flow
rate 0.9 mLmin–1, λ = 254 nm), retention time of (S)-5g 28.49 min,
retention time of (R)-5g 31.50 min (ee = 90%).
(R,E)-1-(4-Methylphenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-one
[(R)-5d]: This compound was produced with use of catalyst 2a.
White solid (32.9 mg, 83 % yield); m.p. 140–141 °C (hexane/Ac-
OEt). 1H NMR (500.13 MHz, CDCl3, 20 °C): δ = 7.85 (d, 3J =
8.2 Hz, 2 H, 2Ј,6Ј-H), 7.34–7.22 (m, 7 H, 2ЈЈ,6ЈЈ-H, 3Ј,5Ј-H, 3ЈЈ,5ЈЈ-
(R,E)-1-(2-Aminophenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-one
[(R)-5h]: This compound was produced with use of catalyst 2a. Col-
1
orless oil (7.5 mg, 19%). H NMR (300.13 MHz, CDCl3, 20 °C): δ
3
= 7.70 (dd, 3J = 8.5, J = 1.4 Hz 1 H, 6Ј-H), 7.34–7.23 (m, 6 H,
4Ј-H, 2ЈЈ,6ЈЈ-H, 4ЈЈ-H, 3ЈЈ,5ЈЈ-H), 6.67–6.64 (m, 2 H, 3Ј-H, 5Ј-H),
3
3
3
H, 4Ј-H), 6.57 (d, Jtrans = 15.8 Hz, 1 H, 5-H), 6.17 (dd, Jtrans
=
=
6.57 (d, Jtrans = 15.8 Hz, 1 H, 5-H), 6.28 (br. s, 2 H, NH2), 6.17
2
3
15.8, 3J = 8.6 Hz, 1 H, 4-H), 4.72 (ABX, JAB = 12.1, JAX
(dd, 3Jtrans = 15.8, 3J = 8.6 Hz, 1 H, 4-H), 4.71 (ABX, 2JAB = 12.1,
2
3
2
3
3JAX = 5.6 Hz, 1 H, 1ЈЈЈ-H), 4.57 (ABX, JAB = 12.1, JBX
=
=
=
5.7 Hz, 1 H, 1ЈЈЈ-H), 4.61 (ABX, JAB = 12.1, JBX = 7.5 Hz, 1 H,
3
2
1ЈЈЈ-H), 3.78–3.71 (m, 1 H, 3-H), 3.27 (d, J = 6.7 Hz, 2 H, 2-H),
7.9 Hz, 1 H, 1ЈЈЈ-H), 3.78–3.71 (m, 1 H, 3-H), 3.27 (ABX, JAB
17.1, JAX = 6.0 Hz, 1 H, 2-H), 3.23 (ABX, JAB = 17.1, JBX
2.42 (s, 3 H, CH3) ppm. 13C NMR (125.77 MHz, CDCl3, 20 °C): δ
= 196.6 (C-1), 144.5 (C-4Ј), 136.2 (C-1ЈЈ), 134.0 (C-1Ј), 133.3 (C-
5), 129.4 (C-3Ј,5Ј), 128.6 (C-3ЈЈ,5ЈЈ), 128.2 (C-2Ј,6Ј), 128.0 (C-4ЈЈ),
126.6 (C-4), 126.4 (C-2ЈЈ,6ЈЈ), 78.8 (C-1ЈЈЈ), 40.2 (C-2), 37.4 (C-
3), 21.7 (CH3) ppm. HRMS (ESI+): calcd. for [C19H19NO3 + H]+
310.1438; found 310.1436. C19H19NO3 calcd. C 73.77, H 6.19, N
4.53; found C 73.81, H 6.20, N 4.50. HPLC (2-propanol/hexane
10:90, flow rate 0.7 mLmin–1, λ = 254 nm), retention time of (S)-
5d 19.32 min, retention time of (R)-5d 24.30 min (ee = 90%), after
recrystallization (ee Ͼ 99%).
3
2
3
7.1 Hz, 1 H, 2-H) ppm. 13C NMR (125.77 MHz, CDCl3, 20 °C): δ
= 195.6 (C-1), 152.5 (C-2Ј), 138.0 (C-1ЈЈ), 134.8 (C-4Ј), 133.2 (C-
5), 130.7 (C-6Ј), 128.6 (C-3ЈЈ,5ЈЈ), 127.9 (C-4ЈЈ), 126.9 (C-4), 126.4
(C-2ЈЈ,6ЈЈ), 118.4 (C-1Ј), 117.5 (C-5Ј), 116.0 (C-3Ј), 79.0 (C-1ЈЈЈ),
40.8 (C-2), 37.6 (C-3) ppm. HRMS (ESI+): calcd. for [C18H18N2O3
+ H]+ 311.1390; found 311.1389. HPLC (2-propanol/hexane 20:80,
flow rate 1.5 mL min–1, λ = 254 nm), retention time of (S)-5h
14.86 min, retention time of (R)-5h 18.19 min (ee = 87%).
(R,E)-1-(4-Bromophenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-one
[(R)-5i]: This compound was produced with use of catalyst 2a. Yel-
low solid (36.8 mg, 77% yield); m.p. 147–148 °C (hexane/AcOEt).
(R,E)-1-(4-Methoxyphenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-one
[(R)-5e]: This compound was produced with use of catalyst 2a.
Brown solid (33.7 mg, 81% yield); m.p. 101–103 °C (hexane/Ac-
3
1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.82 (AAЈBBЈ, JAB
=
1
OEt). H NMR (300.13 MHz, CDCl3, 20 °C): δ = 7.94 (AAЈBBЈ,
8.6, 4JAAЈ = 2.4, 5JABЈ = 1.9 Hz, 2 H, 2Ј,6Ј-H), 7.63 (AAЈBBЈ, 3JBA
= 8.6, JBBЈ = 2.4, JBAЈ = 1.9 Hz, 2 H, 3Ј,5Ј-H), 7.35–7.24 (m, 5
4
5
3JAB = 7.9, JAAЈ = 2.9, JABЈ = 2.0 Hz, 2 H, 2Ј,6Ј-H), 7.35–7.23
4
5
3
(m, 5 H, 4ЈЈ-H, 2ЈЈ,6ЈЈ-H, 3ЈЈ,5ЈЈ-H), 6.96 (AAЈBBЈ, JAB = 7.9,
3
H, 4ЈЈ-H, 2ЈЈ,6ЈЈ-H, 3ЈЈ,5ЈЈ-H), 6.58 (d, Jtrans = 15.8 Hz, 1 H, 5-
4JBBЈ = 2.9, 5JABЈ = 2.0 Hz, 2 H, 3Ј,5Ј-H), 6.57 (d, 3Jtrans = 15.8 Hz,
H), 6.15 (dd, Jtrans = 15.8, 3J = 8.6 Hz, 1 H, 4-H), 4.70 (ABX,
3
1 H, 5-H), 6.17 (dd, Jtrans = 15.8, 3J = 8.5 Hz, 1 H, 4-H), 4.72
3
2JAB = 12.1, JAX = 4.1 Hz, 1 H, 1ЈЈЈ-H), 4.61 (ABX, JAB = 12.1,
3
2
2
3
2
(ABX, JAB = 12.1, JAX = 5.9 Hz, 1 H, 1ЈЈЈ-H), 4.60 (ABX, JAB
= 12.1, 3JBX = 7.4 Hz, 1 H, 1ЈЈЈ-H), 3.88 (s, 3 H, OCH3), 3.81–3.68
(m, 1 H, 3-H), 3.24 (d, 3J = 6.6 Hz, 2 H, 2-H) ppm. 13C NMR
(75.47 MHz, CDCl3, 20 °C): δ = 195.5 (C-1), 163.8 (C-4Ј), 136.2
(C-1ЈЈ), 133.3 (C-5), 130.4 (C-2Ј,6Ј), 129.5 (C-1Ј), 128.5 (C-3ЈЈ,5ЈЈ),
127.9 (C-4ЈЈ), 126.7 (C-4), 126.4 (C-2ЈЈ,6ЈЈ), 113.9 (C-3Ј,5Ј), 78.9
(C-1ЈЈЈ), 55.5 (OCH3), 39.9 (C-2), 37.5 (C-3) ppm. HRMS (ESI+):
calcd. for [C19H19NO4 + H]+ 326.1387; found 326.1386.
C19H19NO4 calcd. C 70.14, H 5.89, N 4.31; found C 70.44, H 6.16,
N 3.99. HPLC (2-propanol/hexane 10:90, flow rate 1.2 mLmin–1,
λ = 254 nm), retention time of (S)-5e 21.55 min, retention time of
(R)-5e 28.04 min (ee = 92%), after recrystallization (ee Ͼ 99%).
3JBX = 7.1 Hz, 1 H, 1ЈЈЈ-H), 3.79–3.68 (m, 1 H, 3-H), 3.30 (ABX,
2JAB = 17.7, JAX = 6.5 Hz, 1 H, 2-H), 3.22 (ABX, JAB = 17.7,
3JBX = 6.3 Hz, 1 H, 2-H) ppm. 13C NMR (75.5 MHz, CDCl3,
25 °C): δ = 196.0 (C-1), 136.0 (C-1ЈЈ), 135.1 (C-1Ј), 133.6 (C-5),
132.1 (C-3Ј,5Ј), 128.9 (C-4Ј), 129.5 (C-2Ј,6Ј), 128.6 (C-3ЈЈ,5ЈЈ),
128.1 (C-4ЈЈ), 126.4 (C-2ЈЈ,6ЈЈ), 126.2 (C-4), 78.7 (C-1ЈЈЈ), 40.3 (C-
2), 37.2 (C-3) ppm. HRMS: calcd. for [C18H16NO3 + H]+ 374.0386;
found 374.0387. C18H16NO3 calcd. C 57.77, H 4.31, N 3.74; found
C 57.51, H 4.27, N 3.76. HPLC (2-propanol/hexane 10:90, flow
rate 0.9 mLmin–1, λ = 254 nm), retention time of (S)-5i 24.64 min,
retention time of (R)-5i 29.38 min (ee = 84 %), after recrystalli-
zation (ee Ͼ 96%).
3
2
(R,E)-1-(4-Chlorophenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-one
[(R)-5f]:[5m] HPLC (2-propanol/hexane 10:90, flow rate
0.7 mLmin–1, λ = 254 nm), retention times minor 24.31 min, reten-
tion times major 28.95 min (ee = 94%), after recrystallization (ee
Ͼ 99%).
(R,E)-1-(4-Fluorophenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-one
[(R)-5j]: This compound was produced with use of catalyst 2a. Yel-
low solid (32.4 mg, 81% yield); m.p. 80–82 °C (hexane/AcOEt). 1H
NMR (300.13 MHz, CDCl3, 25 °C): δ = 7.99 (dd, 3J = 9.0, 4J =
5.4 Hz, 2 H, 2Ј,6Ј-H), 7.35–7.24 (m, 5 H, 3Ј,5Ј-H, 2ЈЈ,6ЈЈ-H, 4ЈЈ-H),
(R,E)-1-(2-Hydroxyphenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-one 7.15 (t, 3J = 8.6 Hz, 2 H, 3ЈЈ,5ЈЈ-H), 6.58 (d, 3Jtrans = 15.9 Hz, 1 H,
3
3
[(R)-5g]: This compound was produced with use of catalyst 2a. Col-
5-H), 6.16 (dd, Jtrans = 15.9, J = 8.6 Hz, 1 H, 4-H), 4.71 (ABX,
1
3
2
orless oil (13.2 mg, 33%). H NMR (300.13 MHz, CDCl3, 20 °C): 2JAB = 12.1, JAX = 6.0 Hz, 1 H, 1ЈЈЈ-H), 4.62 (ABX, JAB = 12.1,
3
4
δ = 12.0 (s, 1 H, OH), 7.74 (dd, J = 8.2, J = 1.6 Hz, 1 H, 6Ј-H), 3JBX = 7.2 Hz, 1 H, 1ЈЈЈ-H), 3.80–3.68 (m, 1 H, 3-H), 3.30 (ABX,
7.50 (td, 3J = 8.2, 4J = 1.6 Hz, 1 H, 4Ј-H), 7.35–7.27 (m, 5 H,
2JAB = 17.8, JAX = 6.6 Hz, 1 H, 2-H), 3.24 (ABX, JAB = 17.8,
3
2
3
2ЈЈ,6ЈЈ-H, 4ЈЈ-H, 3ЈЈ,5ЈЈ-H), 7.00 (d, J = 8.2 Hz, 1 H, 3Ј-H), 6.93 3JBX = 6.5 Hz, 1 H, 2-H) ppm. 13C NMR (75.5 MHz, CDCl3,
3
1
(t, 3J = 8.2 Hz, 1 H, 5Ј-H), 6.59 (d, Jtrans = 15.9 Hz, 1 H, 5-H), 25 °C): δ = 195.4 (C-1), 166.0 (d, J = 255.8 Hz, C-4Ј), 136.1 (C-
3
2
6.14 (dd, 3Jtrans = 15.9, J = 8.5 Hz, 1 H, 4-H), 4.70 (ABX, JAB
=
=
1ЈЈ), 133.5 (C-5), 132.9 (d, 4J = 3.0 Hz, C-1Ј), 130.72 (d, 3J =
9.4 Hz, C-2Ј,6Ј), 128.6 (C-3ЈЈ,5ЈЈ), 128.0 (C-4ЈЈ), 126.4 (C-2ЈЈ,6ЈЈ),
3
2
3
12.2, JAX = 6.0 Hz, 1 H, 1ЈЈЈ-H), 4.61 (ABX, JAB = 12.2, JBX
3456
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3449–3458

Organocatalyzed Enantioselective Michael Additions
2
[2]
126.3 (C-4), 115.9 (d, J = 22.0 Hz, C-3Ј,5Ј), 78.7 (C-1ЈЈЈ), 40.2 (C-
a) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701–1716; b) T.
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Discov. Today 2007, 12, 8–27.
2), 37.3 (C-3) ppm. HRMS: calcd. for [C18H16FNO3 + H]+
314.1187; found 314.1186. C18H16FNO3 calcd. C 69.00, H 5.15, N
4.47; found C 68.98, H 5.15, N 4.51. HPLC (2-propanol/hexane
10:90, flow rate 0.9 mLmin–1, λ = 254 nm), retention time of (S)-
5j 20.34 min, retention time of (R)-5j 23.61 min (ee = 91%), after
recrystallization (ee Ͼ 99%).
[3]
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(R,E)-1-(4-Cyanophenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-one
[(R)-5k]: This compound was produced with use of catalyst 2a. Yel-
low solid (35.2 mg, 86% yield); m.p. 95–96 °C (hexane/AcOEt). 1H
NMR (300.13 MHz, CDCl3, 25 °C): δ = 8.04 (dd, 3J = 8.7, 4J =
1.7 Hz, 2 H, 2Ј,6Ј-H), 7.79 (dd, J = 8.7, J = 1.7 Hz, 2 H, 3Ј,5Ј-
H), 7.34–7.24 (m, 5 H, 2ЈЈ,6ЈЈ-H, 3ЈЈ,5ЈЈ-H, 4ЈЈ-H), 6.59 (d, Jtrans
3
4
3
3
3
= 15.9 Hz, 1 H, 5-H), 6.14 (dd, Jtrans = 15.9, J = 8.6 Hz, 1 H, 4-
H), 4.70 (ABX, JAB = 12.2, JAX = 6.3 Hz, 1 H, 1ЈЈЈ-H), 4.63
2
3
2
3
(ABX, JAB = 12.2, JBX = 6.8 Hz, 1 H, 1ЈЈЈ-H), 3.78–3.71 (m, 1
2
3
H, 3-H), 3.36 (ABX, JAB = 17.5, JAX = 6.7 Hz, 1 H, 2-H), 3.28
2
3
(ABX, JAB = 17.5, JBX = 6.5 Hz, 1 H, 2-H) ppm. 13C NMR
(75.5 MHz, CDCl3, 25 °C): δ = 195.8 (C-1), 139.2 (C-1Ј), 135.9 (C-
1ЈЈ), 133.9 (C-5), 132.6 (C-3Ј,5Ј), 128.6 (C-3ЈЈ,5ЈЈ), 128.4 (C-2Ј,6Ј),
128.2 (C-4ЈЈ), 125.8 (C-2ЈЈ,6ЈЈ), 125.5 (C-4), 117.7 (CN), 116.8 (C-
4Ј), 78.5 (C-1ЈЈЈ), 40.6 (C-2), 37.1 (C-3) ppm. HRMS: calcd. for
[C19H16N2O3 + H]+ 321.1234; found 321.1236. C19H16N2O3 calcd.
C 71.24, H 5.03, N 8.74; found C 70.94, H 5.02, N 8.75. HPLC (2-
propanol/hexane 10:90, flow rate 2.0 mLmin–1, λ = 254 nm), reten-
tion time of (S)-5k 19.69 min, retention time of (R)-5k 29.38 min
(ee = 94%), after recrystallization (ee Ͼ 99%).
[5]
CCDC-739751 [for (S)-4a] and CCDC-739750 [for (S)-5a] contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra, chiral HPLC analysis and X-ray
data.
Acknowledgments
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Thanks are due to the University of Aveiro, to the Fundação para
a Ciência e a Tecnologia (FCT) and the Fundo Europeu de Desen-
volvimento Regional (FEDER) for funding the Organic Chemistry
Research Unit and for financial support towards the purchase of a
single-crystal diffractometer. The authors are very grateful to Pro-
fessor Juan Carlos Carretero (Universidad Autonoma de Madrid,
Spain) for providing access and information on the use of chiral
HPLC columns and also to Dr. Fernando Domingues (Universid-
ade de Aveiro) for his assistance with HPLC determinations. One
of us (C. G. O.) thanks the FCT for a “Investigador Auxiliar” posi-
tion.
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Eur. J. Org. Chem. 2010, 3449–3458
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3457

A. M. S. Silva et al.
FULL PAPER
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[17] Further details on the single-crystal X-ray diffraction studies
are given as Supporting Information. This compound crys-
tallize as colorless prisms, in the orthorhombic P212121 space
group with Z = 4. Crystal data for (S)-4a: C20H16N2O, M =
300.35, T = 150(2) K, a = 5.65340(10) Å, b = 13.6153(4) Å, c
= 20.6207(6) Å, V = 1587.23(7) Å3, µ(Mo-Kα) = 0.079 mm–1,
Dc = 1.257 gcm–3, crystal size: 0.26ϫ0.08ϫ0.08 mm3. Of a
total of 19017 reflections collected, 2439 were independent
(Rint = 0.0242). Final R1 = 0.0345 [IϾ2σ(I)] and wR2 = 0.0851
[18]
Further details on the single-crystal X-ray diffraction studies
are given as Supporting Information. This compound crys-
tallizes as colorless prisms, in the orthorhombic P212121 space
group with Z = 4. Crystal data for (S)-5a: C18H17NO3, M =
295.33, T = 180(2) K, a = 5.6100(2) Å, b = 11.9959(3) Å, c =
23.0786(7) Å, V = 1553.12(8) Å3, µ(Mo-Kα) = 0.086 mm–1, Dc
= 1.263 gcm–3, crystal size: 0.26ϫ0.19ϫ0.16 mm3. Of a total
of 31462 reflections collected, 3376 were independent (Rint
=
0.0274). Final R1 = 0.0525 [IϾ2σ(I)] and wR2 = 0.1433 (all
data). Data completeness to θ = 33.15°, 99.6%. CCDC-739750.
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been kept for easier comprehension of the NMR spectroscopic
data.
Received: February 27, 2010
Published Online: May 11, 2010
3458
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3449–3458