Highly enantioselective and regioselective conjugate addition of nitromethane to 1,5-diarylpenta-2,4-dien-1-ones using bifunctional cinchona organocatalysts

Article abstract of DOI:10.1055/s-0029-1219576

A general and efficient asymmetric organocatalytic 1,4-Michael addition of nitromethane to 1,5-diarylpenta-2,4-dien-1-ones (cinnamylideneacetophenones) catalyzed by 9-thiourea-9-(deoxy)-epi-hydroquinine has been developed. The reactions afforded excellent enantioselectivities (up to 99%), high yields (up to 97%), and exclusive regioselectivity. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219576

LETTER
1123
Highly Enantioselective and Regioselective Conjugate Addition of
Nitromethane to 1,5-Diarylpenta-2,4-dien-1-ones Using Bifunctional Cinchona
Organocatalysts
Conjugate
Additi
r
on of
N
i
i
trometh
s
ane to 1,5
t
-
Diary
i
lpenta-
n
2, 4-dien-1-o
a
nes G. Oliva,a Artur M. S. Silva,*a Filipe A. A. Paz,b José A. S. Cavaleiroa
a
QOPNA, Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal
E-mail: cgoliva@ua.pt; E-mail: artur.silva@ua.pt
CICECO, Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal
b
Received 19 December 2009
Several electrophilic species can be suitable substrates for
1,4-Michael addition. Among them, a,b-unsaturated aryl
ketones constitute a class of compounds that has receive
less attention than the corresponding unsaturated alkyl ke-
Abstract: A general and efficient asymmetric organocatalytic 1,4-
Michael addition of nitromethane to 1,5-diarylpenta-2,4-dien-1-
ones (cinnamylideneacetophenones) catalyzed by 9-thiourea-9-
(deoxy)-epi-hydroquinine has been developed. The reactions af-
forded excellent enantioselectivities (up to 99%), high yields (up to tones or aldehydes because the aromatic group can block
97%), and exclusive regioselectivity.
the interaction of the carbonyl group with the catalyst. In
our investigation, we were concerned with d-aryl a,b,g,d-
unsaturated aryl ketones (cinnamylideneacetophenones),
compounds similar to chalcones but with an extra double
bond. Nitromethane represents a versatile nucleophile that
can be chemically transformed into a variety of function-
ally useful compounds. Addition of nitromethane to chal-
cones has been demonstrated5a,j,7 but the addition of
nitromethane to cinnamylideneacetophenones has re-
ceived scant attention.5j In this case only one example has
been described with d-phenyl-a,b,g,d-unsaturated N-
acylpyrrole ketone with 54% yield and 94% ee.
Key words: asymmetric catalysis, enantioselectivity, regioselec-
tivity, ketones
The 1,4-Michael addition of nucleophiles to electron-
deficient alkenes is one of the oldest and more useful
carbon–carbon bond-forming reactions.1 The key impor-
tance of this conjugate addition in organic synthesis has
led to the development of a great number of asymmetric
catalytic versions.2 The term asymmetric organocatalysis
covers a wide range of organic processes and methodolo-
gies providing efficient and environmentally friendly ac-
cess to enantiomerically pure compounds, including many
drugs and bioactive natural products, where the absence
of metals is required.3
In this communication we present a general and efficient
organocatalytic 1,4-Michael addition of nitromethane to
different cinnamylideneacetophenones catalyzed by orga-
nocatalysts 1–3. Our investigation began with the screen-
ing of chiral organocatalysts 1a,5a 2a,5a and 3 (Figure 1) to
promote a conjugate addition of nitromethane to 1,5-
diphenylpenta-2,4-dien-1-one (4a)8a under neat condi-
tions to obtain (E)-3-(nitromethyl)-1,5-diphenylpent-4-
en-1-one (5a, Table 1).
An attractive way to introduce chirality into a Michael ad-
dition is through the use of small chiral organic molecules.
In particular, 9-amino-(9-deoxy)-epi-cinchona alkaloids
1,4 9-thiourea-(9-deoxy)-epi-cinchona alkaloids 2,5 and
diarylprolinol silyl ether 36 (Figure 1) have been exten-
sively used as organocatalysts in 1,4-Michael addition to
a,b-unsaturated ketones.
R2
R2
F3C
N
CF3
N
R1
NH
H
N
OTMS
N
CF3
H
R1
NH2
S
N
CF3
CF3
F3C
N
1a R1 = OMe, R2 = Et
2a R1 = OMe, R2 = Et
3
1b R1 = OMe, R2 = CH=CH2
1c R1 = H, R2 = CH=CH2
2b R1 = OMe, R2 = CH=CH2
2c R1 = H, R2 = CH=CH2
Figure 1
SYNLETT 2010, No. 7, pp 1123–1127
x
x.
x
x.
2
0
1
0
Advanced online publication: 10.03.2010
DOI: 10.1055/s-0029-1219576; Art ID: D37409ST
© Georg Thieme Verlag Stuttgart · New York

1124
C. G. Oliva et al.
LETTER
Table 1 Catalyst Screening for the Addition of Nitromethane to 4aa
(entries 1–6) except in the case of the protic solvent meth-
anol (entry 7). However, yields were influenced by the
solvent; polar solvents such as MeOH (entry 7) or MeCN
(entry 4) gave poor yields; whereas less polar solvents
such as CH2Cl2 (entry 2), CHCl3 (entry 3), THF (entry 5),
or toluene (entry 6) gave rise to better yields. Dichlo-
romethane (entry 2) gave a result comparable with the
neat conditions (entry 1).
NO2
O
O
MeNO2
catalyst
Ph
Ph
Ph
Ph
4a
5a
Entry
1d
2d
3
Catalyst
Additive
PhCO2H
TFA
Yield (%)b ee (%)c
e
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
3
–
–
–
–
–
e
e
Table 2 Solvent Effect on the Organocatalyzed 1,4-Addition of
Nitromethane to 4aa
DMP
–
Entry
Catalyst
2a
Solvent
neat
Yield (%)b ee (%)c
4
DBU
77
51
83
33
60
56
40
0
1
2
3
4
5
6
7
56
50
42
19
39
39
23
93
90
92
90
90
86
76
5
DBU
13
4
2a
CH2Cl2
CHCl3
MeCN
THF
6f
DBU
2a
7
DMP
86
80
93
88
–
2a
8f
DMP
2a
g
9
–
2a
toluene
MeOH
10h
11
12
13
14
–
g
2a
e
PhCO2H
TFA
–
a Reactions were carried out at 0.1 M solution of 4a (15 mg, 0.064
mmol), 20 mol% of catalyst 2a (0.013 mmol), 20 mol% of adequate
additive (0.013 mmol), and nitromethane (5.4 mmol, 0.29 mL) in 0.35
mL of solvent at r.t. for 7 d under a nitrogen atmosphere.
b Yield of isolated products after chromatography.
e
3
–
–
e
3
DMP
–
–
3
DBU
98
0
c Determined by chiral HPLC using a Chiralpak IA column.
a Reactions were carried out using 4a (15 mg, 0.064 mmol), 20 mol%
of catalyst 1a, 2a, or 3 (0.013 mmol), 20 mol% of requisite additive
(0.013 mmol), and 0.1 M solution of nitromethane (0.64 mL) at r.t.
under a nitrogen atmosphere.
After selecting 9-thiourea-(9-deoxy)-epi-hydroquinine 2a
without any additive as the most efficient catalyst and ni-
tromethane as solvent, the influence of catalyst loading
and concentration conditions were investigated (Table 3).
We started at neat conditions with 20 mol% of catalyst 2a
in a 0.1 M solution of substrate. When the reaction tem-
perature was raised to 40 °C (entry 2) and molecular
sieves were added (entry 3), good ee and acceptable yields
were obtained. Increasing the molar concentration of sub-
strate (entries 4–6) improved the reaction yield and the
enantioselectivity was retained. The best reaction condi-
tions were achieved with 0.3 M solution of substrate and
30 mol% of catalyst (entry 7), resulting in excellent yield
(97%) and high enantioselectivity (96%). A recrystalliza-
tion of the material so obtained raised the ee to 99%. The
R-configuration was confirmed by single-crystal X-ray
diffraction data9 and this is in accordance with theoretical
studies developed by Soós and Pápai.10 Lowering the
reaction temperature to –10 °C did not improve the ee val-
ues (entry 8). Increasing the amount of catalyst to 40
mol% caused the ee values to decrease (entries 9, 10). Fi-
nally, we investigated the conjugate additions of ni-
tromethane to 4a with different epi-thiourea cinchona
alkaloids such as 2b5a and 2c11 (Figure 1), although poor
results were obtained (entries 11, 12).
b Yield of isolated products after chromatography.
c Determined by chiral HPLC using a Chiralpak IA column.
d Conditions: 40 mol% of additive.
e No reaction was observed.
f Reaction was carried out with 40 mol% of catalyst and additive.
g Without additive.
h Reaction was carried out without nitrogen atmosphere.
Enantioselectivity and yield varied significantly accord-
ing to the catalyst employed. No reaction was observed
with catalysts 1a (entries 1–3) and 3 (entries 11–13) and
with only DBU reaction occurred in a nonenantioselective
way (entries 4, 14). The main reason might be the fact that
nucleophile is not efficiently activated by 1a and 3. Poor
enantioselectivities were obtained for catalyst 2a in com-
bination with DBU (entries 5, 6). In contrast, the use of
trans-2,5-dimethylpiperazine as additive led to promising
results (entries 7, 8). In the absence of additive, catalyst 2a
afforded higher enantioselectivities (93%, entry 9) and
88% (entry 10). Therefore, this bifunctional thiourea
group seems to be the best catalytic system for the addi-
tion of nitromethane to cinnamylideneacetophenone (4a)
because the thiourea motif might be a very efficient tool
in this Michael addition.
With the established optimized conditions, the scope of
the reaction for different cinnamylideneacetophenones
4b–h8,12 was investigated (Table 4). Results show that the
Next we tested the influence of the solvent on the reaction,
with screening results summarized in Table 2. The varia-
tion of solvent had little effect on the enantioselectivity
Synlett 2010, No. 7, 1123–1127 © Thieme Stuttgart · New York

LETTER
Conjugate Addition of Nitromethane to 1,5-Diarylpenta-2,4-dien-1-ones
1125
Table 3 Optimization of Reaction Conditions for Asymmetric
Conjugate Addition of Nitrometane to 4a Using Catalysts 2a–ca
synthesis of new (R,E)-1,5-diaryl-3-(nitromethyl)-5-pent-
4-en-1-ones 5b–h13 took place with high levels of enanti-
oselectivity (87–99%) independent of the nature and posi-
tion of substituents. These compounds could be
recrystallized and their ee raised to 99%. However, the re-
action yield was influenced by the substitution on the aryl
rings (19–92%). Derivatives with electron-withdrawing
and electron-donating substitutents at the para position of
the d-aryl group were examined. When an electron-with-
drawing substitution was present (entry 1), a moderate
yield was obtained. This result can be explained by a
charge density decreasing in the a,b,g,d-unsaturated ke-
tone system, which implies that the hydrogen-bonding in-
teraction between the catalyst 2a and the carbonyl group
of 4b is more labile. When an electron-donating group
was present (entry 2), a high yield and enantioselectivity
were observed. In this case, the charge density increases
in the system and the hydrogen-bonding is stronger. Dif-
ferent substitutions present in the para position of the ke-
tone aryl group (entries 3–5), did not significantly affect
the enantioselectivity and isolated yield. ortho-Substitu-
tion in the aryl group proximal to the ketone decreased the
yield significantly (entries 6, 7). Presumably, the OH and
NH2 substituents can form intramolecular hydrogen bonds
to the ketone group and hinder the interaction between the
ketone and the catalyst.
Entry
2
Catalyst load Concentration Yield
ee
(mol%)
[M]
0.1
0.1
0.1
0.2
0.3
0.4
0.3
0.3
0.1
0.1
0.3
0.3
(%)b
56
77
65
65
78
87
97
82
60
70
64
74
(%)c
1
2d
3e
4
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
20
93
90
91
93
93
90
96f,g
93
87
85
91i
76i
20
20
20
5
20
6
20
7
30
8h
9
30
40
10e
11
12
40
30
30
a Reactions were carried out using 4a (15 mg, 0.064 mmol), catalyst
2a–c and nitromethane for 7 d under a nitrogen atmosphere.
b Yield of isolated products after chromatography.
c Determined by chiral HPLC using a Chiralpak IA column.
d Reaction was carried out at 40 °C.
The crystal structure of compound (R)-5a9 (Figure 2) was
found in the chiral orthorhombic P212121 space group.
Even though the absolute configuration of the molecules
could not be unequivocally determined using solely sin-
gle-crystal X-ray diffraction data (due to the presence of
only light atoms in the compounds, i.e., Z < Si), this was
e With 10 mg of 4 Å MS.
f >99% ee after recrystallization.
g The absolute configuration of (R)-5a was determined by chiral
HPLC and X-ray analysis.8
h Reaction was carried out at –10 °C.
i Configuration of (R)-5a was determined by chiral HPLC.
Table 4 Scope of the Enantioselective Addition of Nitromethane to 1,5-Diarylpenta-2,4-dien-1-ones 4b–h Organocatalyzed by 2aa
NO2
R1
O
R1
O
MeNO2
2a (30 mol%)
0.3 M, r.t., N2
R2
R3
R2
R3
4
5
Entry
4
R1
H
R2
H
R3
NO2
OMe
H
5 (yield, %)b
ee (%)c
88d,e
>99e
90d,e
93d,e
94d,e
90e
1
2
3
4
5
6
7
4b
4c
4d
4e
4f
5b (66)
5c (91)
5d (83)
5e (81)
5f (92)
5g (33)
5h (19)
H
H
H
Me
H
OMe
Cl
H
H
H
4g
OH
NH2
H
H
4h
H
H
87e
a Reactions carried out using 4b–h (0.128 mmol), 30 mol% of catalyst 2a (22.9 mg, 0.038 mmol) in 0.3 M solution of nitromethane (0.47 mL)
under nitrogen atmosphere for 7 d at r.t.
b Yield of isolated products after chromatography.
c Determined by chiral HPLC using a Chiralpak IA column.
d ee >99% after recrystallization.
e R-Configuration was determined by chiral HPLC.
Synlett 2010, No. 7, 1123–1127 © Thieme Stuttgart · New York

1126
C. G. Oliva et al.
LETTER
(3) Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T.
Drug Discovery Today 2007, 12, 8.
(4) (a) Xie, J. W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.;
Chen, Y. C.; Wu, Y.; Zhu, J.; Deng, J. G. Angew. Chem. Int.
Ed. 2007, 46, 389. (b) Xie, J. W.; Yue, L.; Chen, W.; Du,
W.; Zhu, J.; Deng, J. G.; Chen, Y. C. Org. Lett. 2007, 9, 413.
(c) Chen, W.; Du, W.; Duan, Y. Z.; Wu, Y.; Yang, S. Y.;
Chen, Y. C. Angew. Chem. Int. Ed. 2007, 46, 7667.
(d) Chen, W.; Du, W.; Yue, L.; Li, R.; Wu, Y.; Ding, L. S.;
Chen, Y. C. Org. Biomol. Chem. 2007, 5, 816. (e) Erkkila,
A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416.
(f) Carlone, A.; Bartoli, G.; Bosco, M.; Pesciaioli, F.; Ricci,
P.; Sambri, L.; Melchiorre, P. Eur. J. Org. Chem. 2007,
5492. (g) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.;
Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403.
(h) Ricci, P.; Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.;
Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49. (i) Li, X.
F.; Cun, L. F.; Lian, C. X.; Zhong, L.; Chen, Y. C.; Liao, J.;
Zhu, J.; Deng, J. G. Org. Biomol. Chem. 2008, 6, 349.
(j) Lu, X. J.; Deng, L. Angew. Chem. Int. Ed. 2008, 47,
7710. (k) Gogoi, S.; Zhao, C. G.; Ding, D. R. Org. Lett.
2009, 11, 2249. (l) Dong, L. T.; Lu, R. J.; Du, Q. S.; Zhang,
J. M.; Liu, S. P.; Xuan, Y. N.; Yan, M. Tetrahedron 2009,
65, 4124.
(5) (a) Vakulya, B.; Varga, S.; Csampai, A.; Soós, T. Org. Lett.
2005, 7, 1967. (b) Takemoto, Y. Org. Biomol. Chem. 2005,
3, 4299. (c) Connon, S. J. Chem. Eur. J. 2006, 12, 5418.
(d) Wang, J.; Li, H.; Zu, L. S.; Jiang, W.; Xie, H. X.; Duan,
W. H.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652.
(e) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2006, 45, 1520. (f) Doyle, A. G.; Jacobsen, E. N. Chem. Rev.
2007, 107, 5713. (g) Gu, C. L.; Liu, L.; Sui, Y.; Zhao, J. L.;
Wang, D.; Chen, Y. J. Tetrahedron: Asymmetry 2007, 18,
455. (h) Akiyama, T. Chem. Rev. 2007, 107, 5744.
(i) Connon, S. J. Chem. Commun. 2008, 2499. (j) Vakulya,
B.; Varga, S.; Soós, T. J. Org. Chem. 2008, 73, 3475.
(k) Lu, H.-H.; Wang, X.-F.; Yao, C.-J.; Zhang, J.-M.; Wu,
H.; Xiao, W.-J. .
Figure 2 Schematic representation of the molecular units present in
compound (R)-5a. Nonhydrogen atoms are represented as thermal el-
lipsoids drawn at the 50% probability level and hydrogen atoms as
spheres with arbitrary radii.
resolved by taking into consideration data from the syn-
thesis and results from chiral HPLC separation.
In summary, we have developed a general organocatalytic
1,4-Michael addition of nitromethane to different 1,5-dia-
rylpenta-2,4-dien-1-ones in the presence of 9-thiourea-9-
(deoxy)-epi-hydroquinine. Excellent levels of enantio-
meric excess (up to 99%) and isolated yields (up to 97%)
have been achieved for a wide range of substrates and ex-
clusive regioselectivity was obtained with no d-addition
being observed.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(6) (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
Rev. 2007, 107, 5471. (b) Lattanzi, A. Chem. Commun.
2009, 1452.
Acknowledgment
Thanks are due to the University of Aveiro, to ‘Fundação para a
Ciência e a Tecnologia’ and FEDER for funding the Organic Che-
mistry Research Unit and for the financial support towards the
purchase of the single-crystal diffractometer. The authors are very
grateful to Professor 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 (Uni-
versidade de Aveiro) for assistance in the HPLC determinations.
(7) (a) Sera, A.; Takagi, K.; Katayama, H.; Yamada, H.;
Matsumoto, K. J. Org. Chem. 1988, 53, 1157.
(b) Funabashi, K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.;
Shibasaki, M. Tetrahedron Lett. 1998, 39, 7557. (c) Corey,
E. J.; Zhang, F. Y. Org. Lett. 2000, 2, 4257. (d) Kim, D. Y.;
Huh, S. C. Tetrahedron 2001, 57, 8933.
(8) (a) Synthesis of 4a,d,e: Pinto, D. C. G. A.; Silva, A. M. S.;
Levai, A.; Cavaleiro, J. A. S.; Patonay, T.; Elguero, J. Eur.
J. Org. Chem. 2000, 2593. (b) Synthesis of 4b,c: Santos, C.
M. M.; Silva, A. M. S.; Cavaleiro, J. A. S.; Levai, A.;
Patonay, T. Eur. J. Org. Chem. 2007, 2877. (c) Synthesis of
4f: Resende, D. I. S. P.; Oliva, C. G.; Silva, A. M. S.; Paz, F.
A. A.; Cavaleiro, J. A. S. Synlett 2009, 115. (d)Synthesisof
4g: Silva, A. M. S.; Pinto, D. C. G. A.; Tavares, H. R.;
Cavaleiro, J. A. S.; Jimeno, M. L.; Elguero, J. Eur. J. Org.
Chem. 1998, 2031.
References and Notes
(1) Christoffers, J.; Baro, A. Angew. Chem. Int. Ed. 2003, 42,
1688.
(2) (a) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92,
771. (b) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
2004, 43, 5138. (c) Seayad, J.; List, B. Org. Biomol. Chem.
2005, 3, 719. (d) Guillena, G.; Ramon, D. J. Tetrahedron:
Asymmetry 2006, 17, 1465. (e) Almasi, D.; Alonso, D. A.;
Nájera, C. Tetrahedron: Asymmetry 2007, 18, 299.
(f) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(g) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107,
5656. (h) Dalko, P. I. Enantioselective Organocatalysis;
Wiley-VCH: Weinheim, 2007. (i) Maruoka, K. Org.
Process Res. Dev. 2008, 12, 679. (j)Melchiorre, P.;Marigo,
M.; Carlone, A.; Bartoli, G. Angew. Chem. Int. Ed. 2008, 47,
6138.
(9) Further details on the single-crystal X-ray diffraction studies
are given as Electronic Supporting Information. This
compound crystallized as colorless prisms, in the
orthorhombic P212121 space group with Z = 4.
Crystal Data for (R)-5a
C18H17NO3, M = 295.33, T = 150 (2) K, a = 5.59290 (10) Å,
b = 11.9990 (3) Å, c = 23.0093 (5) Å, V = 1544.14 (6) Å3,
m(MoKa) = 0.087 mm–1, Dc = 1.270 g cm–3, crystal size of
0.14 × 0.12 × 0.10 mm3. Of a total of 35216 reflections
collected, 2411 were independent (Rint = 0.0233). Final
Synlett 2010, No. 7, 1123–1127 © Thieme Stuttgart · New York

LETTER
Conjugate Addition of Nitromethane to 1,5-Diarylpenta-2,4-dien-1-ones
1127
R1 = 0.0360 [I > 2s(I)] and wR2 = 0.0969 (all data). Data
completeness to theta = 29.13°, 99.8%. Data have been
Selected Data for (R,E)-3-(Nitromethyl)-1,5-
diphenylpent-4-en-1-one [(R)-5a]
deposited at the Cambridge Crystallographic database:
CCDC 739749
(10) Hamza, A.; Schubert, G.; Soós, T.; Pápai, I. J. Am. Chem.
Soc. 2006, 128, 13151.
(11) Liu, T. Y.; Long, J.; Li, B. J.; Jiang, L.; Li, R.; Wu, Y.; Ding,
L. S.; Chen, Y. C. Org. Biomol. Chem. 2006, 4, 2097.
(12) Synthesis of (E,E)-1-(2-Aminophenyl)-5-phenylpenta-
2,4-dien-1-one (4h)
White solid (36.7 mg, 97% yield); 105–107 °C (hexane–
EtOAc). 1H NMR (300.13 MHz, CDCl3): d = 7.96 (d, 2 H,
3J = 7.5 Hz, H-2¢,6¢), 7.60 (t, 1 H, 3J = 7.5 Hz, H-4¢), 7.48 (t,
2 H, 3J = 7.5 Hz, H-3¢¢,5¢¢), 7.34–7.21 (m, 5 H, H-2¢¢,6¢¢, H-
3¢¢,5¢¢, H-4¢¢), 6.58 (d, 1 H, 3Jtrans = 15.9 Hz, H-5), 6.17 (dd,
1 H, 3Jtrans = 15.9 Hz, 3J = 8.6 Hz, H-4), 4.72 (ABX, 1 H,
2JAB = 12.2 Hz, 3JAX = 5.9 Hz, H-1A¢¢¢), 4.62 (ABX, 1 H,
2JAB = 12.2 Hz, 3JBX = 7.4 Hz, H-1B¢¢¢), 3.81–3.70 (m, 1 H,
H-3), 3.30 (d, 2 H, 3J = 6.5 Hz, H-2) ppm. 13C NMR (75.47
MHz, CDCl3): d = 197.0 (C-1), 136.5 (C-1¢), 136.2 (C-1¢¢),
133.6 (C-4¢), 133.4 (C-5), 128.8 (C-3¢,5¢), 128.6 (C-3¢¢,5¢¢),
128.1 (C-2¢,6¢), 128.0 (C-4¢¢), 126.5 (C-4), 126.4 (C-2¢¢,6¢¢),
78.8 (C-1¢¢¢), 40.3 (C-2), 37.3 (C-3) ppm. HRMS (ESI+): m/
z calcd for [C18H17NO3 + H]+: 296.1281; found: 296.1279.
Anal. Calcd for [C18H17NO3 + H]+: C, 73.20; H, 5.80; N,
4.74. Found: C, 73.17; H, 5.82; N, 4.79. HPLC (i-PrOH–
hexane = 10:90, flow rate 0.7 mL/min, l = 254 nm):
tR(minor) = 18.31 min; tR(major) = 20.70 min (ee = 96%),
after recrystallization (ee >99%).
Sodium hydride (265 mg, 11 mmol) was added to a solution
of 2¢-aminoacetophenone (675 mg, 5.0 mmol) in dry THF
(15.5 mL), and the mixture was cooled to r.t.
Cinnamaldehyde (792 mg, 6.0 mmol) in dry THF (20 mL)
was added, and the reaction mixture was stirred for 12 h and
then poured into a mixture of H2O (20 mL) and ice (20 g) and
acidified with HCl to pH ~2. The solid obtained was filtered,
taken up in CH2Cl2 and washed with H2O. The organic layer
was dried and concentrated, and the residue was purified by
silica gel column chromatography with a 1:1 mixture of light
PE–CH2Cl2 as eluent. The residue was recrystallized from
EtOH. Orange solid (573 mg, 46% yield); 113–114 °C. 1H
NMR (300.13 MHz, CDCl3): d = 7.79 (dd, 1 H, 3J = 8.5 Hz,
4J = 1.5 Hz, H-6¢), 7.58–7.48 (m, 3 H, H-3, H-2¢¢,6¢¢), 7.40–
Selected Data for (R,E)-1-(4-Chlorophenyl)-3-
(nitromethyl)-5-phenylpent-4-en-1-one [(R)-5f]
White solid (38.8 mg, 92% yield); 147–148 °C (hexane–
EtOAc). 1H NMR (300.13 MHz, CDCl3, 20 °C): d = 7.89
(AA¢BB ¢, 3JAB = 8.6, Hz, 4JAA¢ = 2.4 Hz, 5JAB¢ = 1.9 Hz, 2 H,
H-2¢,6¢), 7.46 (AA¢BB ¢, 3JAB = 8.6, Hz, 4JBB¢ = 2.4 Hz,
5JAB¢ = 1.9 Hz, 2 H, H-3¢,5¢), 7.32–7.24 (m, 5 H, H-3¢¢,5¢¢, H-
2¢¢,6¢¢, H-4¢¢), 6.58 (d, 3Jtrans = 15.8 Hz, 1 H, H-5), 6.15 (dd,
3Jtrans = 15.8 Hz, 3J = 8.5 Hz, 1 H, H-4), 4.71 (ABX,
2JAB = 12.1 Hz, 3JBX = 6.0 Hz, 1 H, H-1A¢¢¢), 4.61 (ABX,
2JAB = 12.1 Hz, 3JBX = 7.1 Hz, 1 H, H-1B¢¢¢), 3.79–3.68 (m,
1 H, H-3), 3.30 (dd, 2J = 17.7 Hz, 3J = 6.5 Hz, 1 H, H-2A),
7.25 (m, 4 H, H-3¢¢,5¢¢, H-4¢, H-4¢¢), 7.18 (d, 1 H, 3Jtrans
=
14.8 Hz, H-2), 7.08–6.94 (m, 2 H, H-4, H-5), 6.70–6.66 (m,
2 H, H-3¢, H-5¢), 6.31 (br s, 2 H, NH2) ppm. 13C NMR
(125.77 MHz, CDCl3): d = 191.7 (C-1), 150.9 (C-2¢), 143.0
(C-3), 140.7 (C-4), 136.3 (C-1¢¢), 134.2 (C-4¢), 130.9 (C-6¢),
129.0 (C-4¢¢), 128.8 (C-3¢¢,5¢¢), 127.2 (C-2¢¢,6¢¢, C-5), 126.5
(C-2), 119.1 (C-1¢), 117.3 (C-5¢), 115.9 (C-3¢) ppm.
(13) General Procedure for Enantioselective Addition of
Nitromethane to Cinnamylideneacetophenones 4a–h:
Synthesis of 5a–h
3.24 (dd, 2J = 17.7 Hz, 3J = 6.5 Hz, 1 H, H-2B) ppm. 13
C
1,5-Diarylpenta-2,4-dien-1-ones 4a–h (0.128 mmol) and
thiourea catalyst 2a (22.9 mg, 0.038 mmol) were dissolved
in nitromethane (0.47 mL) under a nitrogen atmosphere. The
mixture was stirred for 7 d at r.t. The resulting solution was
evaporated and purified by column chromatography eluting
with hexane–EtOAc (9:1). The purified material was
crystallized to obtain compounds 5a–h.
NMR (125.77 MHz, CDCl3, 20 °C): d = 195.8 (C-1), 140.1
(C-4¢), 136.0 (C-1¢¢), 134.7 (C-1¢), 133.6 (C-5), 129.4 (C-
2¢,6¢), 129.1 (C-3¢,5¢), 128.6 (C-3¢¢,5¢¢), 128.0 (C-4¢¢), 126.4
(C-2¢¢,6¢¢), 126.2 (C-4), 78.8 (C-1¢¢¢), 40.3 (C-2), 37.3 (C-3)
ppm. HRMS (ESI+): m/z calcd for [C18H16ClNO3 + Na]+:
352.0711; found: 352.0710. Anal. Calcd for [C18H16ClNO3 +
Na]+: C, 65.56; H, 4.89; N, 4.25. Found: C, 65.27; H, 4.92;
N, 4.21. HPLC (i-PrOH–hexane = 10:90, flow rate 0.7 mL/
min, l = 254 nm): tR(minor) = 24.31 min; tR(major) = 28.95
min (ee = 94%), after recrystallization (ee > 99%).
Synlett 2010, No. 7, 1123–1127 © Thieme Stuttgart · New York

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