Enantioselective conjugate addition of nitro compounds to α,β-unsaturated ketones: An experimental and computational study

Article abstract of DOI:10.1002/chem.201100241

A series of chiral thioureas derived from easily available diamines, prepared from α-amino acids, have been tested as catalysts in the enantioselective Michael additions of nitroalkanes to α,β-unsaturated ketones. The best results are obtained with the bi

Full text of DOI:10.1002/chem.201100241

FULL PAPER
DOI: 10.1002/chem.201100241
Enantioselective Conjugate Addition of Nitro Compounds to a,b-
Unsaturated Ketones: An Experimental and Computational Study
ACHTUNGTRENNUNG
Rubꢀn Manzano,[a] Josꢀ M. Andrꢀs,[a] Rosana ꢁlvarez,[b] Marꢂa D. Muruzꢃbal,[a]
ꢁngel R. de Lera,[b] and Rafael Pedrosa*[a]
Dedicated to Professor Rafael Suau, in Memoriam
Abstract: A series of chiral thioureas
derived from easily available diamines,
prepared from a-amino acids, have
been tested as catalysts in the enantio-
selective Michael additions of nitroal-
kanes to a,b-unsaturated ketones. The
best results are obtained with the bi-
functional catalyst prepared from l-
valine. This thiourea promotes the re-
action with high enantioselectivities
and chemical yields for aryl/vinyl ke-
tones, but the enantiomeric ratio for
alkyl/vinyl derivatives is very modest.
The addition of substituted nitrome-
thanes led to the corresponding ad-
ducts with excellent enantioselectivity
but very poor diastereoselectivity. Evi-
dence for the isomerization of the addi-
tion products has been obtained from
the reaction of chalcone with
[D3]nitromethane, which shows that
the final addition products epimerize
under the reaction conditions. The epi-
merization explains the low diastereo-
selectivity observed in the formation of
adducts with two adjacent tertiary
ies of the transition structures corre-
sponding to two alternative activation
modes of the nitroalkanes and a,b-un-
saturated ketones by the bifunctional
organocatalyst have been carried out at
the B3LYP/3-21G* level. The computa-
tions are consistent with a reaction
model involving the Michael addition
of the thiourea-activated nitronate to
the ketone activated by the protonated
amine of the organocatalyst. The enan-
tioselectivities predicted by the compu-
tations are consistent with the experi-
mental values obtained for aryl- and
alkyl-substituted a,b-unsaturated ke-
tones.
stereoACTHNUGRTNEUNGcenters. Density functional stud-
Keywords: density functional calcu-
lations · Michael addition · nitro-
AHCTUNGTRENNaGUN lkanes · organocatalysis · thioureas
Introduction
ACHTUNGTRENNUNG
The conjugate addition of nitroalkanes to electron-poor al-
kenes has attracted a great deal of interest during the last
years.[1] One of the most studied Michael acceptors are a,b-
unsaturated ketones, because the adducts obtained contain
interesting functionalities suitable for their further transfor-
mation into relevant products, such as pyrrolidines, aminoal-
kanes, and aminocarbonyl compounds. Organocatalytic
enantioselective conjugate addition of nitroalkanes to cyclic
and acyclic aliphatic a,b-unsaturated ketones has been ex-
tensively studied by using proline derivatives,[2] imid-
[a] Dr. R. Manzano, Dr. J. M. Andrꢀs, M. D. Muruzꢁbal,
Prof. Dr. R. Pedrosa
Centro de Innovaciꢂn en Quꢃmica y Materiales
Avanzados (CINQUIMA) and Departamento de Quꢃmica Orgꢁnica
Facultad de Ciencias, Universidad de Valladolid
Dr. Mergelina s/n, 47011 Valladolid (Spain)
Fax : (+34)983186324
E-mail: pedrosa@qo.uva.es
[b] Dr. R. ꢄlvarez, Prof. Dr. ꢄ. R. de Lera
Departamento de Quꢃmica Orgꢁnica, Facultad de Quꢃmica
Universidade de Vigo, Lagoas Marcosende
36310 Vigo (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100241.
Chem. Eur. J. 2011, 17, 5931 – 5938
ꢅ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5931

metal catalysis,[16] nickel- and cobalt-based complexes are
moderately enantioselective catalysts, and a lanthanum-
based complex has been described to be more selective, al-
though high catalyst loading is required.
We have recently described an easy and modular synthesis
of amino thioureas 1–7 derived from small 1,2-diamines,
readily obtained from natural and unnatural a-amino acids.
The best results in terms of enantioselectivity were ob-
tained with the valine and tert-leucine-derived thioureas 1
and 6 (Table 1, entries 1, 6). The analogous sec-leucine and
phenylalanine thioureas (4 and 5) achieved only moderate
enantioselectivity (entries 4, 5), as well as urea 2, although
the latter required a longer reaction time (entry 2). The
effect on the reaction of a modification on the thiourea sub-
stituent was studied by changing the 3,5-bis(trifluorome-
thyl)phenyl substituent to a pentafluorophenyl group in
thioACTHUNRTGNEUNGurea 3. When perfluorophenyl derivative 3 was used as a
catalyst, the product was obtained with low yield and mod-
erate enantioselectivity (entry 3). Interestingly, thiourea 7,
the regioisomer of 1, afforded the adduct with moderate
yield, but the product obtained was basically racemic
(entry 7), which indicated that the thiourea component of
the catalyst must be attached to the stereogenic carbon
atom to get good enantioselection.
A set of experiments were carried out to determine the
optimal reaction conditions, by studying the influence of pa-
rameters, such as temperature, solvent, and catalyst loading,
and the results are collected in Table 2.
These bifunctional organocatalysts are excellent promoters
of enantioselective nitro-Michael addition[17] and meso anhy-
dride desymmetrization.[18] Herein, we describe their utiliza-
tion as catalysts for the enantio- and diastereoselective addi-
tion of nitroalkanes and nitroesters to chalcones and other
a,b-unsaturated ketones.
Table 2. Optimization of parameters, such as solvent, temperature, and
catalyst loading.[a]
Entry Ketone
(R)
Catalyst
T
t
Product (yield
e.r.[c,d]
[8C] [h] [%])[b]
1
8a (H)
8a (H)
8a (H)
8a (H)
8a (H)
8a (H)
8a (H)
8b (Cl)
8b (Cl)
1
1
1
1
1
6
2
1
1
23
23
50
50
50
50
50
23
50
136 9a (73)
163 9a (43)
90 9a (89)
90 9a (68)
95:5
95:5
94:6
93:7
91:9
92:8
90:10
93:7
95:5
2[e]
3
Results and Discussion
4[f]
5[g]
6
9
9a (48)
Taking as a model the addition of nitromethane to unsubsti-
tuted chalcone 8a a preliminary catalyst screening was car-
ried out (Scheme 1). The reactions were performed neat
with five equivalents of nitroalkane and 10 mol% of cata-
lysts 1–7 at room temperature and the results are collected
in Table 1.
70 9a (90)
71 9a (100)
137 9b (15)
72 9b (100)
7[f]
8
9
[a] Reaction performed neat on a 0.3 mmol scale of chalcone 8 with
5 equiv of nitromethane and 10 mol% of catalyst. [b] Isolated yield after
flash chromatography. [c] Determined by chiral HPLC analysis. [d] The
absolute configuration was determined by comparing the specific optical
rotation of 9 with that of literature data. [e] 0.2 mL of toluene was used
as the solvent. [f] 5 mol% of catalyst. [g] Reaction performed under mi-
crowave irradiation.
Scheme 1. Organocatalyzed enantioselective Michael addition of nitro-
methane to chalcone.
When toluene was used as the solvent (Table 2, entry 2),
the enantioselectivity of the process was not altered, al-
though the reaction rate was appreciably reduced. When the
reaction temperature was raised to 508C (entries 3–5), the
reaction rate was significantly increased, although a slight
reduction in enantioselectivity was observed (compare en-
tries 1 and 3). However, it was necessary to perform the re-
action at 508C when p-chlorobenzylidene acetophenone
(8b; Scheme 2) was used as the Michael acceptor, due to its
insolubility in the reaction medium at room temperature,
which affected the efficiency of the process (entries 8–9). At
this point, a significant difference was observed between the
valine-derived thiourea and urea, as the latter is a more effi-
cient catalyst in terms of yield, but less selective (entry 7).
When the catalyst loading was reduced to 5 mol% (entry 4),
Table 1. Effects of the nature of the catalyst[a]
Entry
Catalyst
t [h]
Yield [%][b]
e.r.[c,d]
1
2
3
4
5
6
7
1
2
3
4
5
6
7
136
175
136
138
139
142
137
73
86
25
58
36
66
51
95:5
90:10
71:29
91:9
90:10
94:6
49:51
[a] Reaction performed neat on a 0.3 mmol scale of chalcone (8a) with
5 equiv of nitromethane and 10 mol% of catalyst 1–7 at RT. [b] Isolated
yield after flash chromatography. [c] Determined by chiral HPLC analy-
sis. [d] Absolute configuration was determined by comparing the specific
optical rotation of 9a with that of literature data.
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Addition of Nitro Compounds to a,b-Unsaturated Ketones
FULL PAPER
Table 3. Enantioselective Michael addition of nitromethane to a,b-unsa-
turated systems[a]
Entry
Catalyst
t [h]
Yield [%][b]
e.r.[c,d]
1
2
3
4
5
6
7
8b
8c
8d
8e
8 f
8g
8h
8h
8i
72
168
48
144
144
144
88
94
72
168
168
14
100
59
73
12
32
35
90
82
100
31
<5
60[f]
83[g]
n.r.
61
9b (95:5)
9c (92:8)
9d (90:10)
9e (90:10)
9 f (89:11)
9g (90:10)
9h (89:11)
9h (92:8)
9i (94:6)
9j (59:41)
n. d.
9’l (n.d.)
9l (57:43)
–
9n (90:10)
–
Scheme 2. Organocatalyzed enantioselective Michael addition of nitro-
methane to chalcones.
the reaction rate was slightly reduced although the enantio-
selectivity did not decrease. An experiment performed by
using microwave irradiation as a heat source showed no sig-
nificant improvement (entry 5). After 9 h of irradiation,
48% yield of product was obtained, but with lower enantio-
selectivity.
8[e]
9
10
11
12
13[e]
14
15
16
8j
8k
8l
8l
7
The substrate scope was explored under the optimized re-
action conditions (i.e., 5 equiv of nitromethane, neat,
10 mol% of 1 as catalyst, at 508C) in the enantioselective
Michael addition of nitromethane to aromatic and aliphatic
a,b-unsaturated ketones, and the results are summarized in
Scheme 3 and Table 3.
8m
8n
8o
144
168
168
n.r.
[a] Reaction performed neat on
a 0.3 mmol scale of chalcone with
5 equiv of nitromethane and 10 mol% of catalyst 1a at 508C. [b] Isolated
yield after flash chromatography. [c] Determined by chiral HPLC analy-
sis. [d] The absolute configuration was determined by comparing the spe-
cific optical rotation of 9 with that of literature data. [e] Reaction at
238C. [f] Double addition (1,4+1,2) product 9’l was isolated. [g] 1,2-Ad-
dition product 9l was isolated. n.r.=no reaction; n.d.=not determined.
No appreciable changes were observed when the reaction
was carried out on (E)-1-phenylbut-2-en-1-one (8h), with a
methyl group instead of an aryl substituent b to the carbonyl
group. Ketone 8h reacted with nitromethane under the de-
scribed conditions leading to 9h in excellent yield and with
a good enantiomeric ratio (e.r.; 89:11), whereas the ratio of
enantiomers increased to 92:8 when the reaction was carried
out at ambient temperature (Table 3, entries 7, 8). The
changes on the substituent directly bonded to the carbonyl
group (R2) had a more dramatic effect on the yield and
enantioselectivity of the reaction. Thus, whereas (E)-1-(4-
chlorophenyl)-3-phenylprop-2-en-1-one (8i) yielded the ad-
dition product 9i in quantitative yield and with very good
e.r. (94:6; entry 9), (E)-1-phenylbut-2-en-1-one (8j), regio-
isomer of 8h, gave the nitroketone 9j in low yield and with
very poor e.r. (entry 10). The more hindered isopropyl-sub-
stituted ketone 8k was unreactive under the described con-
ditions and only trace amounts of the addition product were
obtained after 168 h. However, 2-cyclohexenone (8n) under-
went the 1,4-addition of nitromethane with good enantiose-
lectivity (entry 15), but moderate yield because, in the de-
scribed conditions, some product resulting from a double-ad-
dition reaction was formed.
In an attempt to extend the substrate scope to other Mi-
chael acceptors, other than ketones, the reaction was per-
formed by using cinnamaldehyde (8l) and methyl cinnamate
(8m). In the case of the reaction with the aldehyde at 508C,
the main product was the double 1,4+1,2-addition adduct
9’l, but when the reaction was carried out at room tempera-
ture, the single 1,2 addition product 9l was obtained with
poor selectivity (Table 3, entries 12, 13). On the other hand,
the cinnamic ester remained unmodified even after 144 h of
heating at 908C (entry 14). Finally, the trisubstituted a-phe-
Scheme 3. Enantioselective Michael addition of nitromethane to a,b-un-
saturated systems catalyzed by thiourea organocatalyst 1.
We first studied the influence of the nature of R1 in the
reactivity and enantioselectivity of the process by reacting
arylidene acetophenones 8b–g in the described experimental
conditions (Table 3, entries 1–6). Important differences in
reactivity were observed depending on the electronic nature
and the size of R1. Ketones 8b and 8d, bearing an electron-
withdrawing group on the aromatic ring reacted faster and
in better yields than 8c, with an electron-donating substitu-
ent at the nucleus (entries 1–3). When bulkier aromatic (8e,
8 f) or heteroaromatic (8g) substituents were present in the
ketone (entries 4–6), the reaction rate decreased considera-
bly, especially for the 2-naphthyl derivative, although the
level of enantioselection was maintained. This fact may be
attributed to the low solubility of this ketone in nitrome-
thane, even at 508C. Interestingly, the best enantioselection
was observed for the reaction of compound 8b leading to
9b, but both the electronic nature of the substituent at the
ring or the size of the aromatic ring slightly affected the
stereoACHTUNGTRENNUNGselection, and the enantiomeric ratios are quite similar
for 9c–g.
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5933

R. Pedrosa et al.
nylchalcone (8o) was recovered unchanged after 168 h of re-
action at 508C (entry 16).
ingly, the reaction between chalcone (8a) and bromonitro-
methane (12) did not take place after seven days of stirring
at 508C (entry 6). The more reactive ethyl nitroacetate (13)
and 2-nitropropionate (14) afforded the addition products to
chalcone 8a with good to excellent yields, although the
enantioselectivity was significantly reduced (entries 7–8). A
slight improvement in the enantioselection was observed by
performing the reaction at room temperature (entries 9–10).
The absolute stereochemistry of 16i was determined by X-
ray diffraction analysis,[19] and extended to all the addition
products by analogy.
After exploring the scope and limitations of the method,
the study was extended to the simultaneous formation of
two stereocenters. To this aim different nitroalkanes and ni-
troesters were used as Michael donors and the results are
collected in Scheme 4 and Table 4.
An interesting fact observed from the results summarized
in Table 4 is that, as previously reported,[2e] much better dia-
stereoselection was obtained when trisubstituted nitropropi-
onate 14 (Table 4, entries 8 and 10) was used as the nucleo-
phile instead of secondary nitro derivatives (10–13) in the
addition reaction. Intrigued by this fact, we reacted
[D3]nitromethane with chalcone (8a) under two different re-
action conditions (Scheme 5).
Scheme 4. Enantioselective Michael addition of nitroalkanes and nitro-
esters to a,b-unsaturated systems.
Table 4. Diastereoselective and enantioselective Michael addition of ni-
trocompounds to chalcones catalyzed by thiourea organocatalyst 1.[a]
Entry Ketone Nitroalkane
t
Product (yield
d.r.[c] e.r.[d]
[h] [%])[b]
1
2
3
4
5
8a
8a
8b
8b
8i
10
11
10
11
11
120 15a (88)
47:53 92:8/
92:8
60:40 91:9/
96:4
50:50 93:7/
93:7
54:46 92:8/
89:11
120 16a (81)
72 15b (94)
92 16b (93)
50 16i (100)
168 n.r.
Scheme 5. Deuterium
[D3]nitromethane to chalcone catalyzed by thiourea organocatalyst 1.
labeling
in
the
Michael
addition
of
To our surprise, when the reaction was carried out at
508C in toluene as the solvent with one equivalent of deu-
teriated nitromethane, the 1H NMR spectra[19] of the re-
64:36 98:2/
91:9
6
7
8a
8a
12
13
–
–
AHCTUNGTREGaNNNU ction mixtures showed the product to be a mixture of tetra-
6
17a (100)
59:41 77:23/
81:19
74:26 74:26/
88:12
47:53 85:15/
85:15
71:29 77:23/
90:10
deuteriated nitro ketone [D4]9a (74–75%) and di-deuteriat-
ed [D2]9a (25–26%) at both a-positions of the nitro and car-
bonyl groups. The same experiment carried out in
[D3]nitromethane acting as reagent and solvent led to a mix-
ture of 91–92% of [D4]9a and 8–9% of [D2]9a. The incor-
poration of two deuterium atoms at the a-position to the
carbonyl group and one hydrogen atom at the a-position to
the nitro functionality is consistent with the epimerization of
the final nitro ketone[20] through enolization, which occurs
to the same extent, of both functional groups. This finding
could explain why the d.r. observed for the addition of ter-
8
8a
8a
8a
14
13
14
26 18a (75)
24 17a (90)
36 18a (85)
9[e]
10[e]
[a] Reaction performed neat on
a
0.3 mmol scale of chalcone with
5 equiv of nitroalkane or nitroester and 10 mol% of catalyst 1a at 508C.
[b] Isolated yield after flash chromatography. [c] Ratio of the 3R,4R/
3R,4S diastereomers determined by 1H NMR spectroscopic analysis of
the crude reaction mixture. [d] Determined for the 3R,4R and 3R,4S dia-
stereomers by chiral HPLC analysis. [e] Reaction run at 238C. n.r.=no
reaction.
AHCTUNGTREGtNNUN iary nitro derivatives was better than those obtained in the
additions of secondary ones, because the addition product in
the first case was unable to epimerize at the a-position to
the nitro group.
In an attempt to explain the enantioselectivity of the Mi-
chael reaction we carried out a computational study of the
Chalcone (8a) reacted with nitroethane (10) and nitropro-
pane (11) for 120 h (Table 4, entries 1, 2) leading to 15a and
16a, respectively, with very low diastereoselection but good
enantioselectivity. In the same way, 4-chlorobenzylideneace-
tophenone (8b) led to equimolar or near equimolar mix-
tures of diastereoisomers of 15b and 16b (entries 4, 5) when
treated with the same nitroalkanes, and (E)-1-(4-chloro-
phenyl)-3-phenylprop-2-en-1-one (8i) was transformed, in
poor diastereomeric ratio (d.r.) but excellent e.r., into the
adduct 16i by reaction with nitropropane (entry 5). Surpris-
À
enantiodetermining C C bond-formation step for the addi-
tion of the nitronate anion to three of the acceptors used in
the experiments, namely (E)-chalcone (8a), (E)-4-phenyl-
but-3-en-2-one (8j), and (E)-1-phenylbut-2-en-1-one (8h),
catalyzed by model thiourea 19 (Scheme 6). The complete
analysis of the alternative mechanistic channels requires the
computation of the transition structures[21] corresponding to
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Chem. Eur. J. 2011, 17, 5931 – 5938

Addition of Nitro Compounds to a,b-Unsaturated Ketones
FULL PAPER
energies of activation relative
to the starting ternary complex.
Regardless of the structure of
the ketones the mechanism
with the lowest activation
energy is the one involving the
bidentate interaction of the
donor nitronate with the thio-
AHCTUNGTERGuNNUN rea and the activation of the
carbonyl group by the protonat-
ed amine (the energies corre-
sponding to the species comput-
ed along mechanism 1 are col-
lected in the Supporting Infor-
mation).[24,25] For 8j, the lowest
activation energies correspond
to TS8 (10.2 kcalmolÀ1) closely
followed by TS5 (10.9 kcal
Scheme 6. Representative mechanisms (M1 and M2) used in the computational study of the Michael addition
of nitronate anion to a,b-unsaturated ketones (8a, 8h, and 8j; please note the change of descriptors for the
enantiotopic faces of 8a/8j and 8h).
the addition of a nitronate anion to both Re and Si enantio-
topic faces of the enones (8a, 8j, and 8h) adopting the (s)-
cis and (s)-trans conformations, following two alternative re-
action channels in which the chiral organocatalyst scaffold
19 plays alternative roles. Therefore, a total of 24 transition
structures were computed after building the initial nitronate
anion–thiourea–unsaturated ketone (8a, 8j, and 8h) ternary
complexes following the hydrogen-bonding activation
models proposed in the literature.[22,23] In mechanism 1, M1,
inspired in the original dual activation model of Takemo-
to,[22] the nitronate interacts with the protonated amine
while the ketone binds the thiourea. The alternative mecha-
nism 2, M2, involves the stabilization of the nitronate by the
thiourea and the activation of the ketone by the protonated
amine of the organocatalyst, as proposed in other systems
by Pꢁpai.[23] Scheme 6 depicts the bond-formation event for
the alternative mechanistic channels and Table 5 collects the
molÀ1), which lead to the S and R-enantiomers, respectively.
The predicted enantiomeric ratio for the enantiodetermining
reaction would be 28:72 (experimentally, a 41:59 ratio was
obtained, Table 3, entry 10). Differences in activation ener-
gies are more significant in the case of 8a and 8h, which
show values of 11.4, 13.6, 8.4, and 10.5 kcalmolÀ1 for TS1,
TS4, TS10, and TS11, respectively, for the two reaction
channels of lowest energy in M2. Following the Boltzman
distribution the approximately 2 kcalmolÀ1 difference com-
puted allows us to predict a 97:3 enantiomeric ratio of the
addition product, which closely approaches the experimental
values of 95:5 for 8a and 92:8 for 8h (Table 3, entries 1 and
8). In both cases, the theoretical study correctly predicts the
absolute configuration of the major enantiomer ((R)-9a and
(S)-9h; please note the change of priorities of the substitu-
ents for the stereocenters in products 9a and 9h), which is
also consistent with the experimental results. Moreover, the
inclusion of solvent effects on the reaction of ketone 8h pro-
vided identical results to those shown (see the Supporting
Information). Although a general stabilization of the ionic
species was observed, the preferred reaction channels and
the relative activation energies were not modified by the
solvent.
Examination of the computed structures of starting com-
plexes and transition states suggests a rationale for the dif-
ferent enantioselectivities experimentally obtained in the re-
actions of a,b-unsaturated ketones 8j and 8a/8h (Figure 1).
The ternary complexes for the preferred reaction channels
of the nitronate anion and 8j show no significant distortion
of the planarity of the unsaturated ketone and lead to the
addition product via TS8 and TS5 with similar activation en-
ergies (0.7 Kcal difference). In contrast, the reactive ternary
complexes are more destabilized with 8a and 8h in the (s)-
trans conformations due to the steric interactions of the aryl
group attached to the ketone. Since the transition states are
early for these Michael reactions, the destabilization is not
relieved in TS4 and TS11 with the ketone in the (s)-trans
conformation and therefore the reaction channels via the
(s)-cis conformations TS1 and TS10 are favored by 2.2 and
À
Table 5. Gibbs free energies for the C C bond-formation reactions of the ad-
dition of nitronate anion to a,b-unsaturated ketones 8a, 8h, and 8j catalyzed
by thiourea 19 along the mechanistic channel M2 of Scheme 6.[a]
Transition Ketone Conformation Enantiotopic Addition DG#[c] DDG#[d]
structure
face
product[b]
TS1
TS2
TS3
TS4
TS5
TS6
TS7
TS8
TS9
TS10
TS11
TS12
8a
8a
8a
8a
8j
8j
8j
8j
8h
8h
8h
8h
(s)-cis
(s)-cis
(s)-trans
(s)-trans
(s)-cis
Re
Si
Re
Si
Re
Si
Re
Si
Re
Si
Re
Si
(R)-9a
(S)-9a
(R)-9a
(S)-9a
(R)-9j
(S)-9j
(R)-9j
(S)-9j
(R)-9h
(S)-9h
(R)-9h
(S)-9h
11.4
20.3
15.4
13.6
10.9
17.5
12.5
10.2
16.2
8.4
0.0
8.9
4.0
2.2
0.7
7.3
2.3
0.0
7.8
0.0
2.1
3.8
(s)-cis
(s)-trans
(s)-trans
(s)-cis
(s)-cis
(s)-trans
(s)-trans
10.5
12.2
[a] All the calculations have been carried out at the B3LYP/3-21G* level.
[b] Configuration of the reaction product. [c] Energies (in kcalmolÀ1) relative
to the more stable ((s)-cis) starting hydrogen-bonded ternary complex of the
ketones. [d] Activation energies (in kcalmolÀ1) relative to the most favorable
transition structure.
Chem. Eur. J. 2011, 17, 5931 – 5938
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5935

R. Pedrosa et al.
À
Figure 1. Optimized geometries (B3LYP/6-31G*) for the two most favored transition structures characterized in the C C bond-formation reactions of ni-
tronate anions to a,b-unsaturated ketones 8h (TS10 and TS11) and 8j (TS5 and TS8) leading to enantiomers of the Michael addition products, catalyzed
À
by model thiourea. Selected geometric parameters (substrate dihedral angles and O H bond lengths) of the transition structures are shown and com-
pared to those of the starting ternary complexes (shown in brackets).
2.1 KcalmolÀ1, respectively, for 8a and 8h, leading to addi-
tion products with high enantioselectivities.
Conclusion
Finally, we extended the computational study to the con-
jugate addition reaction of the nitronate anion to chalcone
8a catalyzed by the bifunctional organocatalyst 1 used in
the experiments, which differs from model 19 by the pres-
ence of the two meta-CF3 substituents on the aryl ring. The
results, listed in Table 6, indicate that the substitution on the
aryl group of the catalyst does not substantially modify the
energies of activation and the stereoselectivity of the conju-
gate addition.
In summary, we have developed the enantio- and diastereo-
selective Michael addition of different nitro compounds to
a,b-unsaturated ketones catalyzed by thioureas derived
from a-amino acids. We have focused especially on the less
reactive chalcones, although acyclic and cyclic aliphatic
enones have been also used. We have explored the substrate
scope and the limitations of the method. Additionally, our
theoretical study suggests that this Michael addition cata-
lyzed by thioureas goes through a mechanism involving in-
teractions of the nitro group with the thiourea while the
ketone is activated by the protonated amine.
À
Table 6. Gibbs free energies for the C C bond-formation reactions of the ad-
dition of nitronate anions to a,b-unsaturated ketones 8a, 8h, and 8j catalyzed
Experimental Section
by thiourea 19 along the mechanistic channel M2 of Scheme 6.[a]
General remarks: 1H (300 or 400 MHz) and 13C NMR (75 MHz) spectra
were recorded in CDCl3. Chemical shifts for protons are reported in ppm
from tetramethylsilane with the residual CHCl3 resonance as internal ref-
erence. Chemical shifts for carbon atoms are reported in ppm from tetra-
methylsilane and are referenced to the carbon resonance of the solvent.
Data are reported as follows: chemical shift, multiplicity (s=singlet, d=
doublet, t=triplet, q=quartet, sp=septet, m=multiplet, br=broad),
coupling constants in Hertz, and integration. Specific rotations were mea-
sured by using a 5 mL cell with a 1 dm path length, a sodium lamp, and
concentration is given in g per 100 mL. Flash chromatography was car-
ried out by using silica gel (230–240 mesh). Chemical yields refer to pure
isolated substances. TLC analysis was performed on glass-backed plates
Transition Ketone Conformation Enantiotopic Addition DG#[c] DDG#[d]
structure
face
product[b]
TS13
TS14
TS15
TS16
8a
8a
8a
8a
(s)-cis
(s)-cis
(s)-trans
(s)-trans
Re
Si
Re
Si
(R)-9a
(S)-9a
(R)-9a
(S)-9a
12.8
22.6
17.4
15.2
0.0
9.8
4.6
2.4
[a] All the calculations have been carried out at the B3LYP/3-21G* level.
[b] Configuration of the reaction product. [c] Energies (in kcalmolÀ1) relative
to the starting more stable ((s)-cis) hydrogen-bond ternary complex of both
ketones. [d] Activation energies (in kcalmolÀ1) relative to the most favorable
transition structure.
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Addition of Nitro Compounds to a,b-Unsaturated Ketones
FULL PAPER
coated with silica gel 60 and an F254 indicator, and visualized by either
UV irradiation or by staining with I2 or phosphomolybdic acid solution.
Chiral HPLC analysis was performed by using a Daicel Chiralcel OD
column (250ꢆ4.6 mm) or Chiralpak AS-H or AD-H column (250ꢆ
4.6 mm). UV detection was monitored at 220 or 254 nm. Unless other-
wise indicated, all compounds were purchased from Aldrich and used as
received. Catalysts 1–7 were prepared according to the described proce-
dure (see Supporting Information).[17a] Chalcones 8e, 8 f, and 8g were
prepared according to literature procedures.[26]
R. S. Reddy, T. Shiraishi, M. Hirama, Tetrahedron 1997, 53, 11223–
11236.
[3] a) N. Halland, R. G. Hazell, K. A. Jørgensen, J. Org. Chem. 2002,
67, 8331–8338; b) A. Prieto, N. Halland, K. A. Jørgensen, Org. Lett.
2005, 7, 3897–3900; c) G. Szꢁntꢂ, P. Bombicz, A. Grꢇn, I. Kꢁdas,
Chirality 2008, 20, 1120–1126.
[4] a) S. V. Pansare, R. Lingampally, Org. Biomol. Chem. 2009, 7, 319–
324; b) A. P. Davis, K. J. Dempsey, Tetrahedron: Asymmetry 1995, 6,
2829–2840.
[5] T. Ooi, S. Takada, S. Fujioka, K. Maruoka, Org. Lett. 2005, 7, 5143–
5146.
[6] a) P. Li, Y. Wang, X. Liang, J. Ye, Chem. Commun. 2008, 3302–
3304; b) K. Mei, M. Jin, S. Zhang, P. Li, W. Liu, X. Chen, F. Xue, W.
Duan, W. Wang, Org. Lett. 2009, 11, 2864–2867.
[7] a) M. S. Taylor, D. N. Zalatan, A. M. Lerchner, E. N. Jacobsen, J.
Am. Chem. Soc. 2005, 127, 1313–1317; b) C. Palomo, R. Pazos, M.
Oiarbide, J. M. Garcꢃa, Adv. Synth. Catal. 2006, 348, 1161–1164.
[8] S. Colonna, H. Hiemstra, H. Wynberg, J. Chem. Soc. Chem.
Commun. 1978, 238–239.
[9] A. Sera, K. Takagi, H. Katayama, H. Yamada, K. Matsumoto, J.
Org. Chem. 1988, 53, 1157–1161.
[10] a) D. Y. Kim, S. C. Huh, Tetrahedron 2001, 57, 8933–8938; b) E. J.
Corey, F.-Y. Zhang, Org. Lett. 2000, 2, 4257–4259.
[11] a) B. Vakulya, S. Varga, A. Csꢁmpai, T. Soꢂs, Org. Lett. 2005, 7,
1967–1969; b) B. Vakulya, S. Varga, T. Soꢂs, J. Org. Chem. 2008, 73,
3475–3480.
[12] P. Suresh, K. Pitchumani, Tetrahedron: Asymmetry 2008, 19, 2037–
2044.
Typical procedure for the enantioselective Michael addition of nitrocom-
pounds to a,b-unsaturated ketones: Nitromethane (85 mL, 1.5 mmol) was
added to a mixture of a,b-unsaturated ketone 8a (62 mg, 0.3 mmol) and
catalyst 1 (12.0 mg, 0.03 mmol). The reaction mixture was stirred at 508C
until disappearance of the starting ketone (TLC). The volatiles were
evaporated in vacuo and the residue was purified by flash chromatogra-
phy (silica gel, hexane/ethyl acetate 20:1 to 8:1) to afford desired product
9a (76 mg, 0.27 mmol, 89%).
(R)-4-Nitro-1,3-diphenylbutan-1-one (9a): White solid; [a]2D5 =+19.0 (c=
0.9 in CHCl3, 95:5 e.r.); 1H NMR (300 MHz, CDCl3): d=3.43 (dd, J=
17.8, 7.5 Hz, 1H), 3.51 (dd, J=17.7, 6.4 Hz, 1H), 4.24 (ps quint, J=
7.1 Hz, 1H), 4.70 (dd, J=12.5, 8.0 Hz, 1H), 4.85 (dd, J=12.5, 6.6 Hz,
1H), 7.25–7.38 (m, 5H), 7.45–7.50 (m, 2H), 7.56–7.62 (m, 1H), 7.92–
7.94 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=39.1 (CH), 41.4
(CH2), 79.5 (CH2), 127.4 (2CH), 127.8 (CH), 127.9 (2CH), 128.6 (2CH),
129.0 (2CH), 133.5 (CH), 136.2 (C), 139.1 (C), 196.8 ppm (C); HPLC
(Chiralpak AS-H, hexane/isopropanol 90:10, 1.0 mLminÀ1, l=220 nm):
tR =23.5 (minor), 30.8 min (major); HRMS: m/z: calcd for C16H15NO3 +
Na+: 292.0950; found: 292.0948.
[13] M. T. Allingham, A. Howard-Jones, P. J. Murphy, D. A. Thomas,
P. W. R. Caulkett, Tetrahedron Lett. 2003, 44, 8677–8680.
[14] P. Bakꢂ, ꢄ. Szçllꢈsy, P. Bombicz, L. Tꢈke, Synlett 1997, 291–292.
[15] G. Sundararajan, N. Prabagaran, Org. Lett. 2001, 3, 389–392.
[16] a) K. Funabashi, Y. Saida, M. Kanai, T. Arai, H. Sasai, M. Shibasaki,
Tetrahedron Lett. 1998, 39, 7557–7558; b) C. Botteghi, S. Paganelli,
A. Schionato, C. Boga, A. Fava, J. Mol. Catal. 1991, 66, 7–21.
[17] a) J. M. Andrꢀs, R. Manzano, R. Pedrosa, Chem. Eur. J. 2008, 14,
5116–5119; b) R. Manzano, J. M. Andrꢀs, M. D. Muruzꢁbal, R. Pe-
drosa, Adv. Synth. Catal. 2010, 352, 3364–3372.
Computational details: All computations were performed by using the
Gaussian 03 software package.[27] To include electron correlation at an af-
fordable computational cost, DFT[28] was used by means of the Becke
three-parameter exchange functional and the nonlocal correlation func-
tional of Lee, Yang, and Parr (B3LYP).[29] The 3-21G* basis set was
chosen to compute the geometries, energies, and normal frequencies. Sta-
tionary points were characterized by means of harmonic analysis, and
transition states were confirmed by the relationship between nuclei
motion and the unique imaginary vibration frequency. Cartesian coordi-
nates and energies of all stationary points located are given in the Sup-
porting Information. Solvent effects were taken into account through
single-point energy calculations by using PCM (polarizable continuum
model) implemented in Gaussian 03 with CH3NO2 as model.[30]
[18] R. Manzano, J. M. Andrꢀs, M.-D. Muruzꢁbal, R. Pedrosa, J. Org.
Chem. 2010, 75, 5417–5420.
[19] See the Supporting Information.
[20] C. A. Kingsbury, J. Org. Chem. 1998, 63, 3838–3846.
[21] The bifunctional role of thiourea derivatives has recently been ex-
amined by computational methods: a) R. Zhu, D. Zang, J. Wu, C.
Liu, Tetrahedron: Asymmetry 2007, 18, 1655–1662; b) P. Hammar,
T. Marcelli, H. Hiemstra, F. Himo, Adv. Synth. Catal. 2007, 349,
2537–2548; c) K. N. Houk, P. H. Y. Cheog, Nature 2008, 455, 309–
313; d) S. J. Zuend, E. N. Jacobsen, J. Am. Chem. Soc. 2009, 131,
15358–15374; e) D. A. Yalalov, S. B. Tsogoeva, S. Schmatz, Adv.
Synth. Catal. 2006, 348, 826–832.
[22] T. Okino, Y. Hoashi, T. Furukuwa, X. Xu, Y. Takemoto, J. Am.
Chem. Soc. 2005, 127, 119–125.
[23] a) A. Hamza, G. Schubert, T. Soꢂs, I. Pꢁpai, J. Am. Chem. Soc.
2006, 128, 13151–13160; b) T. Marcelli, R. N. S. van der Haas, J. H.
van Maarseveen, H. Hiemstra, Angew. Chem. 2006, 118, 943–945;
Angew. Chem. Int. Ed. 2006, 45, 929–931.
[24] Similar conclusions have been reached in the computational model-
ing of the enantioselective addition of a-ketoester anions to nitro-
styrenes (B. Tan, Y. Lu, X. Zeng, P. J. Chua, G. Zhong, Org. Lett.
2010, 12, 2682–2685) and for the anions of malonates or diketones
to nitroolefins (D. Almasi, D. A. Alonso, E. Gꢂmez-Bengoa, C.
Nꢁjera, J. Org. Chem. 2009, 74, 6163–6168).
[25] In the intramolecular Michael addition of nitronate anions onto con-
jugated esters, an alternative model was computed featuring binding
of both the nitronate and the ester to the thiourea: W. J. Nodes,
D. R. Nutt, A. M. Chippindale, A. J. A. Cobb, J. Am. Chem. Soc.
2009, 131, 16016–16017.
Acknowledgements
We acknowledge financial support by the Spanish MICINN (Project
CTQ2008–03960/BQU) and Junta de Castilla y Leꢂn (Project GR 168).
R.M. and M.-D.M. also thank the MEC and J C y L, respectively, for pre-
doctoral fellowships. We thank the Centro de Supercomputaciꢂn de Gali-
cia (CESGA) for the generous allocation of computational resources.
[1] R. Ballini, G. Bosica, D. Fiorini, A. Palmieri, M. Petrini, Chem. Rev.
2005, 105, 933–972.
[2] a) S. Hanessian, V. Pham, Org. Lett. 2000, 2, 2975–2978; b) S. Ha-
nessian, S. Govindan, J. S. Warrier, Chirality 2005, 17, 540–543; c) S.
Hanessian, Z. Shao, J. S. Warrier, Org. Lett. 2006, 8, 4787–4790;
d) C. E. T. Mitchell, S. E. Brenner, S. V. Ley, Chem. Commun. 2005,
5346–5348; e) C. E. T. Mitchell, S. E. Brenner, J. Garcꢃa-Fortanet,
S. V. Ley, Org. Biomol. Chem. 2006, 4, 2039–2049; f) M. Malmgren,
J. Granander, M. Amedjkouh, Tetrahedron: Asymmetry 2008, 19,
1934–1940; g) S. B. Tsogoeva, S. B. Jagtap, Z. A. Ardamesova, V. N.
Kalikhevich, Eur. J. Org. Chem. 2004, 4014–4019; h) S. B. Tsogoeva,
S. B. Jagtap, Z. A. Ardamesova, Tetrahedron: Asymmetry 2006, 17,
989–992; i) M. Yamaguchi, T. Shiraishi, Y. Igarashi, M. Hirama, Tet-
rahedron Lett. 1994, 35, 8233–8236; j) M. Yamaguchi, Y. Igarashi,
[26] a) L. D. Chiaradia, A. Mascarello, M. Purificażo, J. Vernal, M. N. S.
Cordeiro, M. E. Zenteno, A. Villarino, R. J. Nunes, R. A. Yunes, H.
Chem. Eur. J. 2011, 17, 5931 – 5938
ꢅ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5937

R. Pedrosa et al.
Terenzi, Bioorg. Med. Chem. Lett. 2008, 18, 6227–6230; b) S. Liu,
L. S. Liebeskind, J. Am. Chem. Soc. 2008, 130, 6918–6919.
[27] Gaussian 03, Revision D.02, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgom-
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cio-
slowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaro-
mi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wall-
ingford CT, 2004..
ACHTUNGTRENNUNGery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S.
Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,
N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
[28] W. Kohn, L. J. Sham, Phys. Rev. 1965, 140, A1133.
[29] A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
[30] a) L. Onsager, J. Am. Chem. Soc. 1936, 58, 1486–1493; b) J. Tomasi,
M. Persico, Chem. Rev. 1994, 94, 2027–2094; c) J. Tomasi, B. Men-
nucci, R. Cammi, Chem. Rev. 2005, 105, 2999–3094.
Received: January 21, 2011
Published online: April 15, 2011
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Chem. Eur. J. 2011, 17, 5931 – 5938