Oxygen-chlorine interactions in the transition state of asymmetric Michael additions of carbonyl compounds to β-nitrostyrene

Article abstract of DOI:10.1016/j.tetasy.2014.05.002

An oxygen-chlorine interaction is reported in the transition state of the Michael addition of acetone to nitrostyrene catalyzed by enantioenriched monosulfonamides. The interaction between the oxygen from the nitro group and the chlorine at the ortho-posi

Full text of DOI:10.1016/j.tetasy.2014.05.002

Tetrahedron: Asymmetry 25 (2014) 997–1001
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Tetrahedron: Asymmetry
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Oxygen–chlorine interactions in the transition state of asymmetric
Michael additions of carbonyl compounds to b-nitrostyrene
José A. Romero a, Angélica Navarrate a, Felipe A. Servín a, Domingo Madrigal a, Andrew L. Cooksy b,
Gerardo Aguirre a, Daniel Chávez a, Ratnasamy Somanathan a,
⇑
a Centro de Graduados e Investigación del Instituto Tecnológico de Tijuana, Apartado Postal 1166, Tijuana, B.C. 22510, Mexico
b Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An oxygen–chlorine interaction is reported in the transition state of the Michael addition of acetone to
nitrostyrene catalyzed by enantioenriched monosulfonamides. The interaction between the oxygen from
the nitro group and the chlorine at the ortho-position of the sulfonamide moiety is supported by theoret-
ical calculations. Asymmetric Michael addition products catalyzed by monosulfonamides were obtained
in moderate yields and enantioselectivities.
Received 22 April 2014
Accepted 9 May 2014
Available online 18 June 2014
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Various classes of bifunctional organocatalysts have been
employed in Michael additions, such as thioureas, cinchona alka-
The catalytic Michael reaction is an important and well-studied
process for stereoselective carbon–carbon bond formation in
organic synthesis.1 In recent years, the field of asymmetric
organocatalytic Michael reactions has received widespread
attention.2 Among the reactions studied, the conjugate addition
loids, proline derivatives, and sulfonamides.4a Having a library of
enantioenriched monosulfonamides in hand,5 we turned our atten-
tion to using these ligands as organocatalysts in Michael additions.
Herein we report the use of enantioenriched mono-sulfonamides
derived from (1R,2R)-cyclohexanediamine as bifunctional
organocatalysts to promote the addition of carbonyl compounds
to b-nitrostyrene (Scheme 2).
of nitroalkanes to
carbonyl compounds to
interest (Scheme 1).3,4 The products obtained are direct precursors
a
,b-unsaturated systems and additions involving
a,b-unsaturated nitroalkenes are of great
to important structural moieties, such as
c
-aminocarbonyls,
O
O
2-pyrrolidones, and 2-piperidones.3a
NO2
NO2
R
NO2
R
R
EWG
RCH2NO2
O
R1
+
EWG
H2N
HN SO2
R
R1
O
NO2
Scheme 2. Michael addition of acetone to nitrostyrene catalyzed by chiral
+
R1
monosulfonamides.
NO2
R1
The sulfonamide organocatalyst acts as a weak hydrogen bond
donor, and at the same time contains a basic primary amino group
that can activate the nucleophilic reaction partner (in this case,
acetone) by generation of an enamine. Thus, the catalyst is pro-
posed to be bifunctional in the transition state of the reaction
(Fig. 1A).
Scheme 1. Michael addition of nucleophiles to
electron-withdrawing group.
a,b-unsaturated systems with an
⇑
Corresponding author. Tel.: +52 (664) 623 3772; fax: +52 (664) 623 4043.
E-mail address: rsomanathan@mail.sdsu.edu (R. Somanathan).
http://dx.doi.org/10.1016/j.tetasy.2014.05.002
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

998
J. A. Romero et al. / Tetrahedron: Asymmetry 25 (2014) 997–1001
going from the ortho-substituents R = H 1a–c and R = CH3 1d to
R = isopropyl 1e on the sulfonamide aryl ring, the reaction was
quenched. The bulky substituent in the sulfonamide (2,4,6-i-Pr3C6H2
in 1e) induced strong steric repulsions between nitrostyrene and
the substituted sulfonyl group, which diminishes the hydrogen
bonding interactions, and leads to a very slow reaction rate.
Furthermore, electron-withdrawing groups on the sulfonamide aryl
ring 1f–i had very little impact on the yield and enantioselectivity.
Based on this observation, our intention was to transform this
steric repulsion into an electronic attraction by replacing the iso-
propyl group with a proton donor group at the ortho position of
the sulfonamide aromatic ring. Our expectation was that both oxy-
gens of the nitro group would now be hydrogen-bonded to the
ligand (Fig. 1B). The double oxygen interaction might then stabilize
the transition state and enhance the enantioselectivity. An obvious
choice for group X is AOH. Thus, we synthesized the monosulfona-
mide 2 (Fig. 3), and tested it in the Michael addition of acetone to
nitrostyrene in toluene. The addition product was obtained with
excellent enantioselectivity (>98%), although only 33% yield. We
considered this low yield was perhaps due to the lack of solubility
of organocatalyst 2 in the solvent used in the reaction (toluene). As
predicted, changing the solvent to anhydrous polar aprotic DMSO,
led to a lower ee (40%), probably due to disruption of the hydrogen
bonding in the transition state.
O2
S
O2
S
HN
N
N
H
HN
enamine
H
-O
-O
N+
proton donor
X
N+
O
O
B
A
Figure 1. Proposed transition states in the Michael addition of acetone to
nitrostyrene.
In addition to the hydrogen donor interactions, we report, for
the first time, a novel OÁ Á ÁCl interaction and its participation in
the stabilization of the transition state for the Michael addition
reaction (Fig. 1B, X = Cl). Similar OÁ Á ÁCl interactions have been
reported in the X-ray crystal structure of 2,5-dichloro-1,4-benzo-
quinone (Fig. 2).6 Non-covalent interactions between electron-
deficient halogen compounds and Lewis bases (O, N) have gained
recognition as a useful class of interactions, similar to hydrogen
bonding, and have recently been christened ‘halogen bonds’.7 Sim-
ilar interactions have been reported for supramolecular assemblies
in medicinal chemistry and in crystalline assemblies.6,8–13
Cl
Cl
O
O
Cl
O2
H2N
HN
S
Cl
O
O
HO
Cl
2
Cl
Figure 2. OÁ Á ÁCl interaction in the 2,5-dichloro-1,4-benzoquinone crystal structure.
Figure 3. Monosulfonamide 2 with a phenolic OH as a proton donor.
2. Results and discussion
Looking for an alternate, more soluble functionalized sulfon-
amide, our literature search revealed a report by Allen et al. on
novel intermolecular interactions between halogens and oxygen
or nitrogen.6 The authors observed an intermolecular ClÁ Á ÁO inter-
action in the X-ray structure of 2,5-dichloro-1,4-benzoquinone,
similar to hydrogen bonding (Fig. 2). Their proposal was supported
by theoretical calculations, suggesting that a general halogen (Cl,
Br, I)-oxygen or nitrogen bond interaction could have bond energy
comparable to that of OÁ Á ÁH hydrogen bonding. More recently,
Jacobsen reported on an iodonium ion-nitrogen interaction in the
transition state leading to an enantioselective iodolactonization
reaction.16 This encouraged us to synthesize a series of ligands
with an o-chlorine substituent and apply them as organocatalysts
in the 1,4-addition reaction, with the idea that the OÁ Á ÁCl interac-
tion, seen in the benzoquinone crystal structure, would be mim-
icked in the transition state of the Michael addition shown in
Fig. 1B. Various halogenated monosulfonamides 3a–e were synthe-
sized from commercially available sulfonyl chlorides (Fig. 4) and
tested in the asymmetric addition of acetone to nitrostyrene. The
results are shown in Table 2.
Enantioenriched monosulfonamides 1a–1i were synthesized
using a previously reported method,14 and tested in the Michael
addition reaction. The results in Table 1 show an interesting effect:
Table 1
Monosulfonamides 1a–1i evaluated in the Michael addition of acetone to nitrosty-
renea
O
O
NO2
NO2
R3
O2
H2N
HN
1a 1i
S
R2
R1
catalyst
-
Catalyst
Yieldb (%)
eec (%)
1a) R1 = R2 = R3 = H
78
86
80
85
75
76
79
72
—
61
77
78
74
1b) R1 = R3 = H, R2 = CH3
1c) R1 = R3 = H, R2 = tert-butyl
1d) R1 = R2 = R3 = CH3
R5
R4
1e) R1 = R2 = R3 = isopropyl
1f) R1 = R3 = H, R2 = NO2
1g) R1 = R3 = H, R2 = CF3
1h) R1 = R3 = H, R2 = CN
1i) R1 = R3 = H, R2 = I
No product
O2
S
R3
78
85
80
86
H2N
HN
R1
R2
) R1 = R2 = Cl, R3 = R4 = R5 = H
3a
a
All entries are for 10 mol % in toluene over 5 days.
Yields were determined by HPLC with a Chiralpak AS-H column at 208 nm
3b) R1 = R3 = Cl, R2 = R4 = R5 = H
b
) R1 = R4 = Cl, R2 = R3 = R5 = H
3d) R1 = R5 = Cl, R2 = R3 = R4 = H
3e
3c
(hexane/i-PrOH75:25, 1 mL/min).
c
) R1 = R4 = Br, R2 = R3 = R5 = H
The enantiomeric excesses were determined by HPLC and the absolute con-
figuration was established as (R), and assigned by comparing the tR with literature
values.15
Figure 4. Halogenated monosulfonamides.

J. A. Romero et al. / Tetrahedron: Asymmetry 25 (2014) 997–1001
999
Table 2
Monosulfonamides 3a–3e evaluated in the Michael addition of acetone to
nitrostyrenea
Catalyst
Yieldb (%)
ee (%)c
3a
3b
3c
3d
3e
96
97
96
99
86
84
81
85
88
88
a
All entries are for 10 mol % in toluene over 5 days.
Yields were determined by HPLC with a Chiralpak AS-H column at 208 nm
b
(hexane/i-PrOH75:25, 1 mL/min).
c
The enantiomeric excesses were determined by HPLC and the absolute con-
figuration was established as (R), and assigned by comparing the tR with literature
values.15
Figure 5. Interaction between the sulfoxide oxygen and the o-hydrogen of the
dichlorophenyl group.
The results indicated a positive increase in the enantioselectiv-
ities (8–17%) and yields (8–26%) compared to the unsubstituted
benzene sulfonamide (Table 1, entry 1a and Table 2). Although
no dramatic enhancement in the enantioselectivities was seen, this
notable increasing trend led us to carry out theoretical calculations
on the transition states involving ligands 3a–d to probe the exper-
imental observations. Calculations using Gaussian 0917 were car-
ried out for monosulfonamides 3a–3d (also 2) using the B3LYP
density functional theory18 and the cc-pVDZ basis set.19
Table 3 shows the relevant atom–atom distances for the PRO-S
transition state with the organocatalyst 3a–3d (values for the
PRO-R was similar). The distance CAC was 1.93 Å, and NOAH was
1.966 to 2.044 Å.
N
NH
N
SO2
NH
H
SO2
H
O
-O
N+
-O
N+
Cl
Cl
O
Cl
B
A
Figure 6. Transition state of (A) PRO-S 3c; (B) PRO-R 3a.
With respect to organocatalyst 2, an evident NOÁ Á ÁHO interac-
tion was predicted by the DFT calculations, with a separation of
1.697 Å, and the NO-HN separation was predicted to be 2.42 Å
(Fig. 7). The DDG– of the transition state (S–R) was equal to
À3.29 kcal/mol. This result was in agreement with the high enanti-
oselectivity obtained experimentally.
Table 3
DFT computed distances (Å) of interactions in the PRO-S transition states and R–S
relative energies (kcal/mol) of Michael reactions
Catalyst
CAC
OAH
OACl
XAOSb
DDG– TS
3a
3b
3c
3d
1.93
1.93
1.94
1.93
1.966
2.009
2.025
2.044
3.470a
3.365
3.391
3.421
2.318
2.362
2.36
À0.670
À1.680
À3.105
À2.283
2.873
a
Interaction with Cl on R2.
X = H in 3a–3d and Cl in 3d.
b
The calculations predict a ClÁ Á ÁO interaction involving the nitro
group O-atom, with separation distances of 3.391 to 3.470 Å. The
energy of the interaction between the oxygen and the chlorine
was obtained by comparing the energies of the distinct transition
state conformers of 3c. By fixing several dihedral angles to separate
the O and Cl atoms by more than 5 Å, we estimated the energy of
the transition state in the absence of the O and Cl interaction. The
OÁ Á ÁCl interaction energy was estimated to be 2.32 kcal/mol in the
PRO-S TS by these means, and 1.61 kcal/mol in PRO-R TS. The
higher energy for the OÁ Á ÁCl interaction was found for the PRO-S
transition state, consistent with experimental results, where the
(S)-enantiomer is obtained in all Michael reactions that use sulfon-
amide organocatalysts 3a–3d containing a Lewis-acidic chlorine.
An interaction was also found between the sulfonamide and the
o-hydrogen (in the case of 3d with chlorine) of the benzenoid ring
of the sulfonamide (Table 3), with separation distances from 2.318
to 2.873 Å, with a roughly periplanar conformation (Fig. 5).
Two oxygen bonding interactions (OÁ Á ÁH and OÁ Á ÁCl), as shown
in Figure 6A, were found in the more favored PRO-S transition state
for all cases with organocatalyst 3a–3d, in contrast to a single
oxygen interaction with both H and Cl in the unfavored PRO-R
transition state as shown in Figure 6B, except for 3c.
Figure 7. NOÁ Á ÁHN and NOÁ Á ÁHO interaction distances in the transition state of 2.
Comparing the transition state in the thiourea-catalyzed
Michael addition, Tsogoeva et al. suggested from calculations that
the double hydrogen bonding of the two thiourea NHs to a single
NO2 oxygen is the favored transition state20 (Fig. 8A). Based on this
S
S
Ar
HN
Ar
N
H
N
H
HN
Ar
N
H
O
N
H
O
O
N
N
O
A
B
Figure 8. Transition states involving a thiourea organocatalyst, (A) favored; (B)
unfavored.20

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J. A. Romero et al. / Tetrahedron: Asymmetry 25 (2014) 997–1001
reasoning, the lack of enantioselectivity enhancement may be
explained by the double oxygen (NO2) bonding from the nitro
group to the NH and the chlorine of the ligands 3a–e (Fig. 6A),
which may not offer a favorable orientation of the alkene for nucle-
ophilic attack.21 This unfavorable orientation would affect the
enantioselectivity, but not the yield.
4.1.3. N-((1R,2R)-2-Aminocyclohexyl)-2,4-dichlorobenzenesulf-
onamide 3b
This compound was obtained as a white solid with a yield of
90% (3.7 g, 11.43 mmol). Mp 136 °C; IR: 3351, 3289 (NH2), 3099
(CAH, Ar), 2945, 2928 (CH, Alif), 2859 (CAC), 1573, 1555, 1457,
1373 (C@C, Ar), 1323, 1161 (SO2), 1076, 1040 (S@O), 836–815
(CACl) cmÀ1 1H NMR (600 MHz, CDCl3): d 8.05 (d, J = 8.4 Hz, 1H),
;
3. Conclusion
7.53 (d, J = 2.4 Hz, 1H), 7.39 (dd, J = 8.4, 2.4 Hz 1H), 3.2–2.7 (s,
3H, NH), 2.67 (m, 1H), 2.46 (m, 1H), 1.95 (m, 1H), 1.77 (m, 1H),
1.63 (m, 2H), 1.22 (m, 2H), 1.09 (m, 2H); 13C NMR (150 MHz,
CDCl3): d 139.3, 137.0, 132.6, 132.0, 131.4, 127.5, 60.9, 54.8, 35.3,
32.3, 24.9, 24.6; EIMS m/z: [M]+ 323 (1), 145 (30), 113 (91), 96
(100), 79 (51), 56 (70); Calcd for C12H16Cl2N2O2S: C, 44.59; H,
4.99. Found: C, 44.71; H, 5.12.
In conclusion, we have demonstrated an unprecedented exam-
ple of an OÁ Á ÁCl interaction in the transition state of the Michael
addition of acetone to a nitroolefin as catalyzed by bifunctional
monosulfonamides, providing Michael adducts in moderate yields
and enantioselectivities. Our finding is supported by theoretical
calculations. This subtle OÁ Á ÁCl attraction and similar interactions
may play a role in the future design of bifunctional or multifunc-
tional OÁ Á ÁCl organocatalysts.
4.1.4. N-((1R,2R)-2-Aminocyclohexyl)-2,5-dichlorobenzenesulf-
onamide 3c
This compound was obtained as a green solid with a yield of
4. Experimental section
60% (3.7 g, 11. 36 mmol). Mp 143 °C; [
IR: 3361, 3298 (NH2), 3094 (CAH, Ar), 2949 (CH, Alif), 2842
a
]
20 = À29 (c 1.1, MeOH);
D
4.1. General procedure for the preparation of the monosulfona-
mides
(ACA), 1582, 1451, 1441, 1376 (C@C, Ar), 1324, 1160 (SO2),
1074, 1041 (S@O), 827-678 (CACl) cmÀ1
;
1H NMR (600 MHz,
DMSO-d6): d 8.01 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.68
(dd, J = 8.4, 2.4 Hz 1H), 4.1 (s, 3H, NH), 2.7 (td,, 9.6, 4.2 Hz 1H),
2.44 (td, J = 9.6, 4.2 Hz, 1H), 1.75 (m, 2H), 1.55 (m, 2H), 1.24–0.98
(m, 4H); 13C NMR (150 MHz, DMSO-d6)): d 141.0, 133.9, 132.4,
130.3, 129.9, 60.5, 54.0, 33.9, 32.6, 24.9, 24.6; EIMS m/z: [M]+
323 (1), 145 (10), 113 (90), 96 (100), 79 (66), 56 (58), 43 (25); Calcd
for C12H16Cl2N2O2S: C, 44.59; H, 4.99. Found: C, 44.63; H, 5.03.
To a stirred solution of the L-tartrate salt of (R,R)-1,2-diaminocy-
clohexane (5.0 g, 18.9 mmol) in 35 mL of a 2 M NaOH solution,
were added 5.3 mL of NEt3 and 100 mL of CH2Cl2. The mixture
was cooled to 0 °C and a solution of the corresponding aryl-
sulfonylchoride (13 mmol) in 50 mL of CH2Cl2 was added drop-
wise. The mixture was allowed to warm to room temperature
and stirred overnight. The reaction mixture was extracted with a
2 M HCl solution (3 Â 100 mL). The aqueous phase was basified
with 2 M NaOH solution, and extracted with CH2Cl2 (3 Â 75 mL).
The solvent was removed under reduced pressure and the corre-
sponding product was purified by either column chromatography
over silica gel or recrystallization.
4.1.5. N-((1R,2R)-2-Aminocyclohexyl)-2,6-dichlorobenzenesulf-
onamide 3d
This compound was obtained as a white solid with a yield of
55% (2.2 g, 6.9 mmol). Mp 130 °C; [
IR: 3354, 3292 (NH2), 3031 (C-H, Ar), 2944, 2921 (CH, Alif), 2860
a
]
20 = À30 (c 0.84, CH2Cl2);
D
Monosulfonamides 1a–i were synthesized using a previously
reported method and the spectroscopic data were in good agree-
ment with those reported in the literature.14
(-C-C-), 1594, 1571, 1560, 1425 (C=C, Ar), 1331, 1165 (SO2),
1076, 1045 (S=O).cm-1 1H NMR (600 MHz, CDCl3): d 7.46 (d,
;
J=8.1 Hz, 2H), 7.33 (t, J = 8.1 Hz, 1H), 3.80-3.00 (s, 3H, NH), 2.90
(td, J=10.2, 3.8 Hz, 1H), 2.55 (td, J = 10.7, 3.8 Hz, 1H), 2.01 (m,
1H), 1.79 (m, 1H), 1.65 (m, 2H), 1.20 (m, 4H); 13C NMR
(150 MHz, CDCl3): d 136.5, 134.9, 132.2, 131.4, 60.8, 54.7, 35.0,
32.0, 24.8, 24.7; EIMS m/z: [M]+ 323 (7), 145 (20), 113 (92), 96
(100), 79 (45), 56 (64), 43 (45) ; Calcd. for C12H16Cl2N2O2S: C,
44.59; H, 4.99. Found: C, 44.60; H, 5.02.
4.1.1. N-((1R,2R)-2-Aminocyclohexyl)-3,5-dichloro-2-hydroxy-
benzenesulfonamide 2
This compound was obtained as a white solid with a yield of
69% (2.70 g, 7.9 mmol). Mp 304–305 °C, IR: 3372 (OH), 3213
(NH), 3027 (CAH, Ar), 2947 (CH, Alif), 1441 (C@C, Ar), 1298,
; d 7.25 (d,
1138 (SO2) cmÀ1 1H NMR (600 MHz, DMSO-d6):
J = 2.0 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 5.20 (br s, OH), 3.2 (m,
NH), 2.65 (m, 1H), 2.45 (m, 1H), 1.82 (m, 1H), 1.50 (m, 1H), 1.40–
1.00 (m, 6H); 13C NMR (150 MHz, DMSO-d6): d 161.9, 132.2,
127.4, 127.3, 126.5, 109.6, 53.2, 46.0, 34.0, 30.0, 24.5, 24.0; EIMS
m/z: [M]+ 338 (3), 177 (3), 133 (15), 113 (57), 96 (100), 56 (19).
4.1.6. N-((1R,2R)-2-Aminocyclohexyl)-2,5-dibromobenzenesulf-
onamide 3e
This compound was obtained as a white solid with a yield of
85% (3.6 g, 10.75 mmol). Mp 163 °C; [
IR: 3354, 3294 (NH2), 3092 (Ar-H), 2943 (CH, Alif), 2839 (CAC),
a
]
20 = À17 (c 6.1, MeOH);
D
1584, 1475, 1442, 1369 (C@C, Ar), 1323, 1159 (SO2), 1071, 1022
4.1.2. N-((1R,2R)-2-Aminocyclohexyl)-2,3-dichlorobenzenesulf-
onamide 3a
(S@O) cmÀ1 1H NMR (600 MHz, CDCl3): d 8.28 (d, J = 2.4 Hz, 1H),
;
7.58 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.4, 2.4 Hz 1H), 2.70 (m, 1H),
2.43 (m, 1H), 1.95 (m, 1H), 1.79 (m, 1H), 1.66 (m, 2H), 1.30–1.04
(m, 4H); 13C NMR (150 MHz, CDCl3): d 141.6, 136.4, 136.3, 133.9,
121.7, 118.6, 61.1, 54.9, 35.3, 32.3, 24.9, 24.7; EIMS m/z: [M]+
412 (1), 113 (92), 96 (100), 79 (19); Calcd for C12H16Br2N2O2S: C,
34.94; H, 3.9. Found: C, 34.90; H, 3.88.
This compound was obtained as a white solid with a yield of
44% (1.80 g, 5.57 mmol). Mp 98 °C, [
a]
D
20 = À20 (c 0.72, CH2Cl2),
IR: 3354, 3288 (NH2), 3081 (CAH, Ar), 2932 (CH, Alif), 2859
(CAC), 1591, 1436, 1400 (C@C, Ar), 1327, 1160 (SO2), 1090, 1048
(S@O), 914 (NH, tors), 834–706 (CACl) cmÀ1 1H NMR (600 MHz,
;
CDCl3): d 8.05 (d, J = 7.8 Hz, 1H), 7.66 (dd, J = 7.8 Hz, 1H), 7.37 (t,
J = 7.8 Hz 1H), 3.6–3.2 (m, 3H, NH), 2.81 (m, 1H), 2.62 (m, 1H),
2.02 (m, 1H), 1.70 (m, 1H), 1.65 (m, 1H), 1.59 (m, 1H), 1.20
(m, 3H), 1.10 (m, 1H); 13C NMR (150 MHz, CDCl3): d 140.6, 135.4,
134.3, 130.0, 129.3, 127.5, 60.3, 54.7, 34.6, 32.1, 24.8, 24.5;
EIMS m/z: [M]+ 297 (2), 267 (9), 189 (27), 113 (69), 96 (100), 43
(85); Calcd for C12H16Cl2N2O2S : C, 44.59; H, 4.99. Found: C,
44.66; H, 5.04.
4.2. Procedure for the addition of acetone to trans-b-nitrosty-
rene catalyzed by 1a–i, 2, and 3a–e
A mixture of trans-b-nitrostyrene (0.090 g, 0.6 mmol), organo-
catalyst (0.15 mmol), acetone (0.5 mL, 6 mmol), and toluene
(2 mL) in a 25 mL flask was stirred at room temperature for

J. A. Romero et al. / Tetrahedron: Asymmetry 25 (2014) 997–1001
1001
346, 1101–1105; (n) Rani, R.; Peddinti, R. K. Tetrahedron: Asymmetry 2010, 21,
2487–2492; (o) Rani, R.; Peddinti, R. K. Tetrahedron: Asymmetry 2010, 21,
775–779.
120 h. After the evaporation of the solvent under vacuum, the res-
idue was separated by flash chromatography over silica gel
(dichloromethane) to give (S)-5-nitro-4-phenylpentan-2-one as a
white solid. The enantiomeric excess was determined by HPLC
with Chiralpak AS-H column at 208 nm (hexane/i-PrOH 75:25,
1 mL/min); tR(major) = 13.7, tR(minor) = 19.1 min.
5. (a) Cortez, N. A.; Rodríguez-Apodaca, R.; Aguirre, G.; Parra-Hake, M.; Cole, T.;
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Acknowledgments
Our work in this area is supported by Consejo Nacional de
Ciencia y Tecnología (CONACyT Grant 128943), Dirección General
de Educación Superior Tecnológica (DGEST Grant 5152.13-P) and
PROMEP CA ITTIJ-CA-5. J.A.R., A.N., and F.A.S., acknowledge support
from CONACyT in the form of graduate scholarships.
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