Pyrrolidine-thioxotetrahydropyrimidinone as an efficient organocatalyst for the enantioselective Michael addition of cyclic ketones to nitrodienes

Article abstract of DOI:10.1016/j.tet.2012.07.078

Among the various Michael additions, the enantioselective reaction between cyclic ketones and nitrodienes has received little attention in comparison to the corresponding reaction with nitroolefins. A bifunctional organocatalyst consisting of the pyrrolidine moiety and a thioxotetrahydropyrimidinone ring successfully catalyzed this asymmetric transformation. The products of the reaction between various ketones and nitrodienes were obtained in high yields (up to 96%) with excellent diastereo- (up to >98:2 dr) and enantioselectivities (up to 99:1% er).

Full text of DOI:10.1016/j.tet.2012.07.078

Tetrahedron 68 (2012) 8630e8635
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Pyrrolidine-thioxotetrahydropyrimidinone as an efficient organocatalyst for the
enantioselective Michael addition of cyclic ketones to nitrodienes
*
Michail Tsakos, Maria Trifonidou, Christoforos G. Kokotos
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, 15771 Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Among the various Michael additions, the enantioselective reaction between cyclic ketones and nitro-
dienes has received little attention in comparison to the corresponding reaction with nitroolefins. A
bifunctional organocatalyst consisting of the pyrrolidine moiety and a thioxotetrahydropyrimidinone
ring successfully catalyzed this asymmetric transformation. The products of the reaction between various
ketones and nitrodienes were obtained in high yields (up to 96%) with excellent diastereo- (up to >98:2
dr) and enantioselectivities (up to 99:1% er).
Received 10 March 2012
Received in revised form 21 June 2012
Accepted 23 July 2012
Available online 31 July 2012
Keywords:
Michael addition
Organocatalysis
Ó 2012 Elsevier Ltd. All rights reserved.
Nitrodienes
Thioxotetrahydropyrimidinone
Asymmetric synthesis
Ar
1. Introduction
O
O
Among the various CeC bond-forming reactions in modern asym-
metric catalysis, the Michael additionpossesses a pivotal role.1 With the
recognition of organocatalysis as the third branch of asymmetric ca-
talysis, alongside transition metal complexes catalysis and bio-
catalysis,2,3 a significant increase in the number of studies concerning
Michael additions has been realized. Proline and proline derivatives
possess a prominent position among the organocatalysts utilized.4 The
five-membered secondary amine of the pyrrolidine ring enables the
activation of carbonyl compounds through the formation of enamine
intermediates, while incorporation of a chiral template provides extra
interactions or a bulky environment leading to enhanced selectivity.
The Michael reaction between carbonyl compounds and nitro-
styrenes has been extensively studied.5 In contrast, the use of
nitrodienes as the Michael acceptor remains an unexplored area of
research.6 Alexakis and co-workers succeeded in developing the
asymmetric Michael addition of aldehydes to nitrodienes,7 while
more recently, we and others have disclosed the asymmetric re-
action between aromatic methyl ketones with nitrodienes.6e,n,8
Although there are several examples demonstrating the conju-
gate addition of cyclohexanone to phenyl nitrodiene 2a,9 to the best
of our knowledge, only two reports study further the reaction be-
tween cyclic ketones and nitrodienes, with limited examples re-
garding the substrate scope (Scheme 1).8a,10
NO2
NO2 catalyst
+
Ar
3
X
S
X
N
1
2
N
N
H
Ph
OAc
O
H
N
H
S
Ph
F3C
N
COOH
N
H
AcO
AcO
NH
NH2
H
Ph
5
S
4
OAc
CF3
catalytic system reported by Xu10
catalyst reported by Ma8a
O
O
N
tBu-O
Ph
S
Ph
NH2
tBu-O
N
H
N
H
N
H
S
N
H
Ph
O
6
catalyst 7, this work
catalyst , this work
Scheme 1. Organocatalysts for the addition of cyclic ketones to nitrodienes.
Catalysts usually performing well in the reaction between methyl
ketonesandnitrodienessufferfrompoorcatalyticactivitywhencyclic
* Corresponding author. Tel.: þ30 210 7274281; fax: þ30 210 7274761; e-mail
address: ckokotos@chem.uoa.gr (C.G. Kokotos).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.078

M. Tsakos et al. / Tetrahedron 68 (2012) 8630e8635
8631
ketones replace methyl ketones.8a Thus, Ma and co-workers had to
alter the structural characteristics of their catalyst in order to find
catalyst 4 to perform well in the above mentioned reaction (Scheme
1).8a On the other hand, Xu and co-workers used a pyrrolidine-
derived catalyst in combination with a chiral thiourea additive as
a highly efficient catalytic system for the same transformation (cata-
lytic system 5, Scheme 1).10 The thiourea additive had a great impact
in both yield and selectivity of the reaction. During the preparation of
this manuscript, Wu and He presented a slight modification of Ma’s
catalyst as an efficient catalyst for this reaction.11
Table 1
Enantioselective Michael addition of cyclohexanone to phenyl nitrodiene using
catalyst 7
Ph
O
O
NO2
7
(10 mol%)
NO2
+
Ph
conditions
48 h
1a
2a
3a
On the basis of our own experience on organocatalytic Michael
additions5f,j,6n,12a,b and organocatalysis in general,12cee we initiated
our studies for the reaction between cyclohexanone (1a) and
phenyl nitrodiene (2a) utilizing catalyst 6, which was the catalyst of
choice for the Michael addition of methyl ketones to nitroolefins.6n
However, it became immediately obvious that the reaction suffered
from low yield and diastereoselectivity (13% yield, 70:30 dr, ꢀ99:1%
er). Therefore, taking into account the excellent catalytic activity of
the pyrrolidine-thioxotetrahydropyrimidinone 7 for the addition of
cyclic ketones to nitroalkenes,12b and for other difficult organo-
catalytic transformations,12d we hypothesized that this bifunctional
catalyst could activate cyclic ketones via enamine formation with
its secondary amine, and simultaneously nitrodienes via hydrogen
bonding. Moreover, one of our objectives was to extend the sub-
strate scope of this elegant protocol. The results of our study are
discussed in the present work.
Entry
Solvent
Toluene
Benzene
Xylene
Et2O
CH3CN
MeOH
DMSO
EtOAc
DCE
CHCl3
CH2Cl2
THF
Additives
Yielda (%)
erb (%)
drc
1
2
3
4
5
6
7
8
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA, H2O
4-NBA
93
84
79
92
91
94
85
90
91
95
92
94
96
Traces
98.5:1.5
97.5:2.5
97:3
97:3
98:2
96:4
92:8
97:3
98:2
98:2
98:2
96:4
97:3
d
98:2
97:3
82:18
96:4
96:4
95:5
93:7
97:3
95:5
97:3
96:4
96:4
95:5
d
9
10
11
12d
13
14e
Toluene
Toluene
d
4-NBA: 4-nitrobenzoic acid, DCE: 1,2-dichloroethane.
a
Isolated yield.
b
The enantiomeric ratio (er) was determined by chiral HPLC.
c
The diastereomeric ratio (dr) was determined by 1H NMR of the crude reaction
mixture.
2. Results and discussion
d
Reaction time 72 h.
e
Reaction time 6 days.
We initiated our studies using as a model reaction the addition
of cyclohexanone (1a) to phenyl nitrodiene (2a), in the presence of
catalyst 7 (10 mol %), 4-nitrobenzoic acid (10 mol %), and H2O
(2 equiv) as additives. Although nitrodiene 2a can be theoretically
were studied (entries 6e10, Table 3). 4-Methyl cyclohexanone
provided the product in high yield and enantioselectivity, but in
poor diastereoselectivity (entry 6, Table 3). This reaction generates
three stereogenic centers deriving from the desymmetrization of
the 4-substituted ketone. Although the two stereogenic centers
deriving from the conjugate addition seem to be excellently con-
trolled by the catalyst providing the product in an excellent syn
configuration, the third stereocenter at the 4-position of the six-
membered ring was not controlled since it seems to be too far
away from the catalytic center. Thus, only two diastereomers are
attacked in either the b- or d-position, only the 1,4-addition product
3a was obtained showcasing the regioselectivity of this reaction,
which is in accordance with literature.8,10 A screening of various
solvents revealed that both polar and non-polar solvents led gen-
erally to high yields and excellent diastereoselectivities and enan-
tioselectivities (entries 1e12, Table 1). Toluene was found to be the
best solvent in terms of yield and selectivity (entry 1, Table 1). In the
absence of water as additive, the reaction yield was maintained
high but the selectivity was very slightly decreased (entry 13, Table
1), while in the absence of both water and the acidic co-catalyst,
only traces of the product were obtained (entry 14, Table 1).
To further demonstrate the importance of the acidic counterpart
in the catalytic cycle, several Bronsted acids were tested in place of
4-nitrobenzoic acid (Table 2). 4-Cyanobenzoic acid, with a similar
pKa [pKa values in H2O of 4-nitrobenzoic acid (3.44), 4-
cyanobenzoic acid (3.55)], provided high selectivity but lower
yield (entry 1, Table 2), while weaker acids like benzoic and acetic
acid had a negative impact on both reactivity and enantioselectivity
(entries 2 and 3, Table 2). In the presence of a strong acid like TFA,
only traces of the product were obtained, probably due to salt
formation with the amine functionality of the catalyst (entry 4,
Table 2). Moreover, when the catalyst loading was decreased from
10 to 5 mol %, or the ratio of ketone to nitrodiene to 5:1, the reaction
turned sluggish (entries 5 and 6, Table 2).
Table 2
Effect of the acid additive on the Michael addition of cyclohexanone to phenyl
nitrodiene
Ph
O
O
NO2
7
(10 mol%)
NO2
+
Ph
toluene, 48 h
1a
2a
3a
Entry
Additives
Yielda (%)
erb (%)
drc
1
2
3
4-CBA, H2O
79
32
86
Traces
43
97.5:2.5
92:8
96.5:3.5
d
97:3
96:4
90:10
d
PhCOOH, H2O
AcOH, H2O
TFA, H2O
4-NBA, H2O
4-NBA, H2O
4
5d
6e
97:3
98:2
97:3
97:3
With optimal conditions in hand, we set out to test the scope
and limitations of our catalyst. A variety of substituted aromatic
nitrodienes (2bed) were utilized (entries 2e4, Table 3). All re-
actions with cyclohexanone provided the product almost as a single
diastereoisomer (dr >95:5). Electron-donating and electron-
withdrawing groups are well tolerated, affording the desired
products 3bed in high yields and excellent selectivities. When
nitrodiene 2e was used, the yield and the selectivity dropped
slightly (entry 5, Table 3). A variety of six-membered cyclic ketones
54
4-NBA: 4-nitrobenzoic acid, 4-CBA: 4-cyanobenzoic acid, AcOH: acetic acid, TFA:
trifluoroacetic acid.
a
Isolated yield.
b
The enantiomeric ratio (er) was determined by chiral HPLC.
c
The diastereomeric ratio (dr) was determined by 1H NMR of the crude reaction
mixture.
d
Catalyst (5 mol %) was used.
Ratio of ketone to nitrodiene 5:1.
e

8632
M. Tsakos et al. / Tetrahedron 68 (2012) 8630e8635
Table 3
obtained and their ratio reflects the diastereoselectivity at the 4-
position of the six-membered ring. When 4,4-disubstituted cyclo-
hexanones were employed, the product was obtained in lower
yields and varying selectivities (entries 7 and 8, Table 3). These
results highlight the fact that by adding substituents in the 4-
position of the six-membered ring, you are bound to have un-
desired steric repulsions that lead to lower yields and selectivities.
Tetrahydropyran-4-one and tetrahydrothiopyran-4-one proved to
be difficult substrates in the Michael reaction with phenyl nitro-
diene 2a and required higher catalyst loading in order to deliver the
products in good yields (entries 9 and 10, Table 3). Cycloheptanone
and cyclopentanone, which are known to be ‘difficult’ substrates in
enamine activation reactions and usually suffer from low yields and
selectivities, were also utilized with some success (entries 11 and
12, Table 3). Moreover, in order to broaden the scope of this
methodology, we investigated the reaction of cyclopentanone with
a variety of substituted nitrodienes (2aee, entries 12e16, Table 3).
In all cases, high to excellent yields, medium to high diaster-
eoselectivities, and high enantioselectivities were observed.
A plausible transition-state model is proposed in Fig.1. The secondary
amineofthepyrrolidineringactivatestheketonethroughtheformation
of an enamine intermediate. The s-trans conformation is preferred to the
s-cis, since it lacks the undesired steric repulsions the latter suffers from.
Simultaneously, the thioxotetrahydropyrimidinone ring of the catalyst
provides steric shielding as well as hydrogen bond interactions with the
nitro group of the nitrodiene, thus guiding the attack just from the one
face leading to high enantiocontrol. When R¼H, the product is provided
in high diastereo- and enantioselectivity. However, when steric bulki-
ness is added by placing one or two substituents at the 4-position of the
six-membered ring (RsH), then additional repulsions are created with
the backbone of the nitrodiene. When cyclic ketones of other size are
utilized, the conformation of the enamine is slightly modified leading to
lower levels of selectivity. Thus, we may predict that six-member ring
ketones bearing substituents at the 4-position, as well as five- or seven-
member ring ketones will not perform well in this transformation
leading to lower selectivities. On the other hand, six-member ketones
will provide the product in excellent yields and selectivities.
Enantioselective Michael reaction between cyclic ketones and nitrodienes using
catalyst 7a
Ar
R
O
O
NO2
NO2
7 (10 mol%)
4-NBA, H2O,
toluene, 48 h
+ Ar
R
n
n
3
1
2
Entry
1
Ketone
Ar, R
Yieldb (%)
erc (%)
drd
O
Ph, H (2a)
93 (3a)
98.5:1.5
98:2
2
o-NO2Ph, H (2b)
p-ClPh, H (2c)
p-MeOPh, H (2d)
Ph, Me (2e)
91 (3b)
92 (3c)
73 (3d)
80 (3e)
99:1
98:2
>98:2
96:4
>98:2
95:5
3
4e
5e
97.5:2.5
98:2
O
O
O
6
Ph, H (2a)
82 (3f)
98:2
58:42
90:10
7e,f
Ph, H (2a)
57 (3g)
90:10
8
Ph, H (2a)
73 (3h)
98:2
70:30
O
O
O
9e,f
Ph, H (2a)
Ph, H (2a)
74 (3i)
83 (3j)
96.5:3.5
73:27
97:3
O
O
O
N
N
R
O
N
10e,f
94:6
S
O
N
H
Ph
S
O
Ar
11
12
Ph, H (2a)
Ph, H (2a)
80 (3k)
90 (3l)
86.5:13.5
90:10
56:44
Fig. 1. Proposed transition-state of the model reaction.
3. Conclusions
O
93:7
In conclusion, pyrrolidine-thioxotetrahydropyrimidinone 7 was
found to be an excellent catalyst for the less-studied reaction be-
tween cyclic ketones and substituted nitrodienes. When cyclo-
hexanone was employed, excellent yields and selectivities were
obtained, while other cyclic ketones can be successfully utilized.
Efforts to further expand the utility of catalyst 7 are under way.
13
14
15e
16
o-NO2Ph, H (2b)
p-ClPh, H (2c)
p-MeOPh, H (2d)
Ph, Me (2e)
76 (3m)
90 (3n)
83 (3o)
93 (3p)
96:4
95:5
94:6
85:15
70:30
70:30
80:20
96.5:3.5
a
Reactions were performed using catalyst 7 (10 mol %), nitrodiene (0.1 mmol),
ketone (1 mmol), 4-nitrobenzoic acid (10 mol %), and H2O (2 equiv) in toluene
(0.25 mL) for 48 h at room temperature.
4. Experimental section
4.1. General information
b
Isolated yield.
c
The enantiomeric ratio (er) was determined by chiral HPLC.
d
The diastereomeric ratio (dr) was determined by 1H NMR of the crude reaction
mixture.
e
Organic solutions were concentrated under reduced pressure on
Reaction time 72 h.
f
€
20% catalyst loading was used.
a
Buchi rotary evaporator. Chromatographic purification of

M. Tsakos et al. / Tetrahedron 68 (2012) 8630e8635
8633
products was accomplished using forced-flow chromatography on
Merck Kieselgel 60 F254 230e400 mesh. Thin-layer chromatogra-
phy (TLC) was performed on aluminum-backed silica plates
(0.2 mm, 60 F254). Visualization of the developed chromatogram
was performed by fluorescence quenching using phosphomolybdic
propanol: 85:15, flow rate 0.8 mL/min, tR¼12.59 min (minor) and
19.70 min (major).
4.4.2. (S)-2-[(S,E)-1-Nitro-4-(2-nitrophenyl)but-3-en-2-yl]cyclohex-
20
anone (3b).8a Yellow oil (91%); [
a
]
D
ꢀ41.3 (c 1.0, CHCl3); 1H NMR
€
acid. Melting points were determined on a Buchi 530 hot stage
(200 MHz, CDCl3):
d
7.96 (d, J¼7.8 Hz, 1H, ArH), 7.61e7.36 (m, 3H,
apparatus and are uncorrected. IR spectra were recorded on
a Nicolet IR200 FT-IR spectrometer and are reported in terms of
frequency of absorption (cmꢀ1). 1H and 13C NMR spectra were
recorded on Varian Mercury (200 or 50 MHz) as noted, and are
internally referenced to residual solvent signals (CDCl3). Data for 1H
ArH), 6.96 (d, J¼15.7 Hz, 1H, ]CH), 6.01 (dd, J¼15.7, 9.4 Hz, 1H, ]
CH), 4.76e4.79 (m, 2H, CHHNO2), 3.49e3.31 (m, 1H, CH), 2.66e2.54
(m, 1H, COCH), 2.49e2.32 (m, 2H, COCHH), 2.28e2.04 (m, 2H, 2ꢂ
CHH), 1.98e1.89 (m, 1H, CHH), 1.80e1.47 (m, 3H, 3ꢂ CHH); 13C NMR
(50 MHz, CDCl3):
d 211.2, 147.3, 133.4, 132.5, 131.2, 130.2, 129.3,
NMR spectra are reported as follows: chemical shift (
d
ppm),
128.5, 124.5, 77.6, 51.5, 42.6, 41.9, 32.6, 28.1, 25.1; MS (ESI) m/z (%):
319 [MþH, (20)]þ; HPLC analysis: 99:1 er, >98:2 dr; Diacel
ChiralpakÒ OD-H column, hexane/2-propanol: 95:5, flow rate
0.8 mL/min, tR¼34.56 min (minor) and 36.46 min (major).
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quadruplet,
m¼multiplet, br s¼broad signal, br s m¼broad signal multiplet),
coupling constant, integration, and assignment. Diastereomeric
ratios were determined by 1H NMR spectra (200 MHz). Data for 13
C
NMR spectra are reported in terms of chemical shift (
d
ppm). Mass
4.4.3. (S)-2-[(S,E)-4-(4-Chlorophenyl)-1-nitrobut-3-en-2-yl]cyclo-
spectra were recorded on a Finnigan Surveyor MSQ Plus, with only
molecular ions and major peaks being reported with intensities
quoted as percentages of the base peak. High Performance Liquid
Chromatography (HPLC) was used to determine enantiomeric ex-
cesses and was performed on an Agilent 1100 Series apparatus
using ChiralpakÒ AD-H, OD-H, and AS-H columns. Optical rotations
were measured on a PerkineElmer 343 polarimeter. The configu-
ration of the products has been assigned either by comparison to
literature data or by analogy.
hexanone (3c).10 White solid (92%); mp 118e119 ꢁC [lit.: mp
20
125e126 ꢁC];10
CDCl3):
[
a]
ꢀ47.4 (c 1.0, CHCl3); 1H NMR (200 MHz,
D
d
7.26e7.24 (m, 4H, ArH), 6.44 (d, J¼15.8 Hz, 1H, ]CH), 5.99
(dd, J¼15.8, 9.5 Hz,1H, ]CH), 4.67 (dd, J¼11.9, 4.9 Hz,1H, CHHNO2),
4.55 (dd, J¼11.9, 8.4 Hz, 1H, CHHNO2), 3.41e3.25 (m, 1H, CH),
2.60e2.33 (m, 3H, COCH and COCHH), 2.20e2.04 (m, 2H, 2ꢂ CHH),
1.94e1.86 (m, 1H, CHH), 1.75e1.58 (m, 2H, 2ꢂ CHH), 1.53e1.39 (m,
1H, CHH); 13C NMR (50 MHz, CDCl3):
d 211.2, 134.6, 133.5, 133.1,
128.7, 127.6, 126.3, 77.9, 51.5, 42.6, 41.9, 32.6, 28.0, 25.0; MS (ESI) m/
z (%): 330 [MþNa, (100)]þ, 308 [MþH, (35)]þ; HPLC analysis: 98:2
er, 96:4 dr; Diacel ChiralpakÒ AD-H column, hexane/2-propanol:
95:5, flow rate 0.8 mL/min, tR¼30.07 min (minor) and 33.81 min
(major).
4.2. General procedure for the synthesis of nitrodienes
The nitrodienes used in this study were known compounds,
except nitrodiene 2e, which was prepared according to literature.6n
4.4.4. (S)-2-[(S,E)-4-(4-Methoxyphenyl)-1-nitrobut-3-en-2-yl]cyclo-
hexanone (3d).10 Yellow solid (73%); mp 136e137 ꢁC [lit.: mp
20
144e145 ꢁC];10
CDCl3):
[a
]
ꢀ61.8 (c 1.0, CHCl3); 1H NMR (200 MHz,
4.2.1. (2-Methyl-4-nitrobuta-1,3-dienyl)benzene (2e). Orange solid
(22% for two steps, E/Z mixture: 5:1); mp 85e86 ꢁC; 1H NMR
D
d
7.26 (d, J¼8.8 Hz, 2H, ArH), 6.82 (d, J¼8.8 Hz, 2H, ArH),
(200 MHz, CDCl3):
d
7.81 (d, J¼13.3 Hz, 1H, ]CH), 7.46e7.33 (m, 5H,
6.40 (d, J¼15.8 Hz, 1H, ]CH), 5.83 (dd, J¼15.8, 9.6 Hz, 1H, ]CH),
4.64 (dd, J¼11.8, 4.9 Hz, 1H, CHHNO2), 4.52 (dd, J¼11.8, 8.3 Hz, 1H,
CHHNO2), 3.77 (s, 3H, OCH3), 3.37e3.21 (m, 1H, CH), 2.57e2.29 (m,
3H, COCH and COCHH), 2.22e2.00 (m, 2H, 2ꢂ CHH), 1.93e1.79 (m,
1H, CHH), 1.73e1.55 (m, 3H, 3ꢂ CHH); 13C NMR (50 MHz, CDCl3):
ArH), 7.19 (d, J¼13.3 Hz, 1H, ]CH), 7.05 (s, 1H, ]CH), 2.08 (s, 3H,
CH3); 13C NMR (50 MHz, CDCl3):
d 144.4, 144.0, 137.2, 136.6, 135.7,
129.7, 128.8, 128.5, 14.1; MS (ESI) m/z (%): 190 [MþH, (20)]þ.
d
211.5, 159.3, 133.8, 128.9, 127.6, 123.2, 113.9, 78.2, 55.3, 51.6, 42.6,
4.3. General procedure for the Michael reaction between ke-
tones and nitrodienes
42.0, 32.6, 28.1, 25.0; MS (ESI) m/z (%): 326 [MþNa, (100)]þ, 304
[MþH, (60)]þ; HPLC analysis: 97.5:2.5 er, >98:2 dr; Diacel
ChiralpakÒ AD-H column, hexane/2-propanol: 95:5, flow rate
0.8 mL/min, tR¼41.35 min (minor) and 46.42 min (major).
To a stirring solution of catalyst 7 (0.01 mmol) in dry toluene
(0.25 mL), 4-nitrobenzoic acid (2 mg, 0.01 mmol) and H2O (4 mL,
0.20 mmol) were added. Nitrodiene (0.10 mmol) was added fol-
lowed by ketone (1.00 mmol). The reaction mixture was left stirring
for the stated time. The solvent was evaporated and the crude
product was purified using flash column chromatography eluting
with various mixtures of petroleum ether (40e60 ꢁC)/EtOAc to af-
ford the desired product.
4.4.5. (S)-2-[(R,E)-3-Methyl-1-nitro-4-phenylbut-3-en-2-yl]cyclo-
20
hexanone (3e). Colorless oil (80%); [
a
]
D
ꢀ40.6 (c 1.0, CHCl3); IR
(film) 2942, 2861, 1707, 1550, 1446, 1381, 1129, 745, 700 cmꢀ1
;
1H
NMR (200 MHz, CDCl3): 7.35e7.10 (m, 5H, ArH), 6.39 (s, 1H, ]CH),
d
4.82 (dd, J¼11.2, 4.2 Hz, 1H, CHHNO2), 4.42 (t, J¼11.2 Hz, 1H,
CHHNO2), 3.34 (td, J¼11.2, 4.2 Hz, 1H, CH), 2.54e2.32 (m, 3H, COCH
and COCHH), 2.14e1.99 (m, 2H, 2ꢂ CHH), 1.91e1.61 (m, 6H, 3ꢂ CHH
and CH3), 1.56e1.41 (m, 1H, CHH); 13C NMR (50 MHz, CDCl3):
4.4. Characterization of the products
d
212.0, 136.8, 132.6, 131.4, 128.9, 128.1, 126.7, 76.9, 49.8, 48.0, 42.7,
4.4.1. (S)-2-[(S,E)-1-Nitro-4-phenylbut-3-en-2-yl]cyclohexanone
33.0, 28.5, 24.9, 13.8; MS (ESI) m/z (%): 288 [MþH, (100)]þ; HRMS
exact mass calculated for [MþH]þ (C17H22NO3) requires m/z
288.1594, found m/z 288.1586; HPLC analysis: 98:2 er, 95:5 dr;
Diacel ChiralpakÒ AD-H column, hexane/2-propanol: 98:2, flow
rate 0.8 mL/min, tR¼30.46 min (minor) and 35.32 min (major).
(3a).8a White solid (93%); mp 120e122 ꢁC [lit.: mp 111e112 ꢁC];8a
20
[
a]
ꢀ63.2 (c 0.1, CHCl3); 1H NMR (200 MHz, CDCl3):
d 7.35e7.18
D
(m, 5H, ArH), 6.49 (d, J¼15.8 Hz, 1H, ]CH), 6.01 (dd, J¼15.8, 9.5 Hz,
1H, ]CH), 4.67 (dd, J¼11.9, 5.0 Hz, 1H, CHHNO2), 4.56 (dd, J¼11.9,
8.2 Hz, 1H, CHHNO2), 3.42e3.27 (m, 1H, CH), 2.60e2.30 (m, 3H,
COCH and COCHH), 2.21e2.03 (m, 2H, 2ꢂ CHH), 1.96e1.82 (m, 1H,
CHH), 1.73e1.54 (m, 3H, 3ꢂ CHH); 13C NMR (50 MHz, CDCl3):
4.4.6. (2S)-4-Methyl-2-[(S,E)-1-nitro-4-phenylbut-3-en-2-yl]cyclo-
hexanone (3f). Yellow oil (82%); [
a
]
20 ꢀ37.4 (c 1.0, CHCl3); IR (film)
D
d
211.2, 136.2, 134.4, 128.5, 127.9, 126.4, 125.6, 78.0, 51.6, 42.6, 41.9,
2924, 1708, 1550, 1448, 1380, 1131, 971, 747, 694 cmꢀ1
;
1H NMR
32.6, 28.1, 25.0; MS (ESI) m/z (%): 274 [MþH, (100)]þ; HPLC analysis:
(200 MHz, CDCl3):
d 7.33e7.25 (m, 5H, ArH), 6.56e6.43 (m, 1H, ]
98.5:1.5 er, 98:2 dr; Diacel ChiralpakÒ AS-H column, hexane/2-
CH), 6.27 (dd, J¼15.9, 9.1 Hz, 0.42H, ]CH), 5.92 (dd, J¼15.8, 9.5 Hz,

8634
M. Tsakos et al. / Tetrahedron 68 (2012) 8630e8635
0.58H, ]CH), 4.71e4.62 (m, 1H, CHHNO2), 4.54e4.40 (m, 1H,
CHHNO2), 3.46e3.27 (m, 0.58H, CH), 3.23e3.08 (m, 0.42H, CH),
2.72e2.34 (m, 3H, COCH and COCHH), 2.16e1.86 (m, 2H, 2ꢂ CHH),
1.84e1.61 (m, 2H, 2ꢂ CHH), 1.44e1.18 (m, 1H, CH), 1.09 (d, J¼6.8 Hz,
1.8H, CH3), 0.99 (d, J¼6.1 Hz, 1.2H, CH3); 13C NMR (50 MHz, CDCl3):
CDCl3):
d
7.40e7.19 (m, 5H, ArH), 6.54 (d, J¼15.8 Hz, 1H, ]CH), 5.93
(dd, J¼15.8, 9.7 Hz, 1H, ]CH), 4.69e4.43 (m, 2H, CHHNO2),
3.58e3.42 (m, 1H, CH), 3.06e2.65 (m, 7H, COCH, COCHH and 4ꢂ
SCHH); 13C NMR (50 MHz, CDCl3):
d 211.1, 136.5, 136.1, 129.6, 129.2,
127.8, 125.5, 78.1, 54.9, 45.8, 42.7, 35.9, 31.8; MS (ESI) m/z (%): 314
[MþNa, (50)]þ, 292 [MþH, (40)]þ; HPLC analysis: 94:6 er, 97:3 dr;
Diacel ChiralpakÒ AD-H column, hexane/2-propanol: 90:10, flow
rate 1.0 mL/min, tR¼23.26 min (minor) and 32.37 min (major).
d
212.3, 210.9, 136.0, 134.9, 134.8, 128.6, 128.5, 128.0, 126.5, 125.3,
124.9, 78.2, 78.0, 50.7, 48.5, 43.9, 42.3, 41.8, 39.8, 38.4, 37.6, 35.1,
33.8, 32.0, 26.5, 21.2, 19.3; MS (ESI) m/z (%): 288 [MþH, (100)]þ;
HRMS exact mass calculated for [MþH]þ (C17H22NO3) requires m/z
288.1594, found m/z 288.1587; HPLC analysis: 98:2 er, 58:42 dr;
Diacel ChiralpakÒ AS-H column, hexane/2-propanol: 95:5, flow rate
0.5 mL/min, tR¼25.49 min (minor) and 29.62 min (major).
4.4.11. (S)-2-[(S,E)-1-Nitro-4-phenylbut-3-en-2-yl]cycloheptanone
20
(3k). Yellow oil (80%); [
a
]
ꢀ47.8 (c 1.0, CHCl3); IR (film) 2922,
D
2856, 2358, 1697, 1549, 1448, 1378, 970, 748, 693 cmꢀ1
(200 MHz, CDCl3):
;
1H NMR
d
7.45e7.20 (m, 5H, ArH), 6.50 (d, J¼15.8 Hz, 1H,
4.4.7. (S)-4,4-Dimethyl-2-[(S,E)-1-nitro-4-phenylbut-3-en-2-yl]cy-
]CH), 6.13 (dd, J¼15.8, 9.5 Hz, 0.10H, ]CH), 5.98 (dd, J¼15.8,
8.9 Hz, 0.90H, ]CH), 4.72e4.45 (m, 2H, CHHNO2), 3.33e3.18 (m,
1H, CH), 2.79e2.70 (m, 1H, COCH), 2.61e2.39 (m, 2H, COCHH),
2.03e1.81 (m, 4H, 4ꢂ CHH), 1.62e1.13 (m, 4H, 4ꢂ CHH); 13C NMR
20
clohexanone (3g). Yellow oil (57%); [
a]
ꢀ22.5 (c 1.0, CHCl3); IR
D
(film) 2956, 2925, 2856, 1708, 1551, 1448, 1379, 970, 749, 694 cmꢀ1
;
1H NMR (200 MHz, CDCl3):
d
7.40e7.20 (m, 5H, ArH), 6.46 (d,
J¼15.8 Hz, 1H, ]CH), 6.25 (dd, J¼15.9, 9.1 Hz, 0.10H, ]CH), 5.99
(dd, J¼15.8, 9.5 Hz, 0.90H, ]CH), 4.68 (dd, J¼11.8, 5.2 Hz, 1H,
CHHNO2), 4.56 (dd, J¼11.8, 8.1 Hz, 1H, CHHNO2), 3.38e3.23 (m,
0.90H, CH), 3.16e3.02 (m, 0.10H, CH), 2.74e2.59 (m, 1H, COCH),
2.56e2.40 (m, 1H, COCHH), 2.33e2.22 (m, 1H, COCHH), 1.84e1.53
(m, 4H, 4ꢂ CHH), 1.19 (s, 3H, CH3), 0.99 (s, 3H, CH3); 13C NMR
(50 MHz, CDCl3): d 214.4, 136.1, 134.8, 128.6, 128.0, 126.4, 125.5,
78.0, 52.7, 43.8, 43.7, 29.7, 28.9, 28.7, 23.7; MS (ESI) m/z (%): 288
[MþH, (100)]þ; HRMS exact mass calculated for [MþH]þ
(C17H22NO3) requires m/z 288.1594, found m/z 288.1589; HPLC
analysis: 86.5:13.5 er, 90:10 dr; Diacel ChiralpakÒ AD-H column,
hexane/2-propanol: 98:2, flow rate 0.5 mL/min, tR¼46.79 min
(minor) and 54.49 min (major).
(50 MHz, CDCl3):
d 211.8, 136.2, 135.0, 134.3, 128.6, 127.9, 126.5,
125.6, 78.0, 47.1, 44.8, 41.7, 40.1, 38.9, 31.3, 31.0, 24.4; MS (ESI) m/z
(%): 302 [MþH, (100)]þ; HRMS exact mass calculated for [MþH]þ
(C18H24NO3) requires m/z 302.1751, found m/z 302.1744; HPLC
analysis: 90:10 er, 90:10 dr; Diacel ChiralpakÒ AD-H column, hex-
ane/2-propanol: 99:1, flow rate 0.4 mL/min, tR¼58.05 min (major)
and 66.82 min (minor).
4.4.12. (S)-2-[(S,E)-1-Nitro-4-phenylbut-3-en-2-yl]cyclopentanone
(3l).10 White solid (90%); mp 125e126 ꢁC [lit.: mp 122e123 ꢁC];8a
20
[a
]
ꢀ80.2 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3):
d 7.39e7.16
D
(m, 5H, ArH), 6.57e6.44 (m,1H, ]CH), 5.93 (dd, J¼15.8, 9.3 Hz,1H, ]
CH), 4.98e4.67 (m, 1.44H, CHHNO2), 4.54 (dd, J¼12.1, 9.0 Hz, 0.56H,
CHHNO2), 3.46e3.24 (m, 1H, CH), 2.42e1.96 (m, 5H, 5ꢂ CHH),
4.4.8. (S)-7-[(S,E)-1-Nitro-4-phenylbut-3-en-2-yl]-1,4-dioxaspiro
1.89e1.67 (m, 2H, 2ꢂ CHH); 13C NMR (50 MHz, CDCl3):
d 218.2,136.0,
20
[4.5]decan-8-one (3h). Yellow oil (73%); [
a]
ꢀ12.7 (c 1.0, CHCl3);
135.7, 134.6, 128.6, 128.1, 128.0, 126.5, 126.4, 124.4, 123.7, 77.9, 77.7,
50.1, 49.7, 42.7, 41.9, 39.2, 38.5, 27.4, 26.9, 20.8, 20.5; MS (ESI) m/z (%):
260 [MþH, (35)]þ; HPLC analysis: 93:7 er, 56:44 dr; Diacel
ChiralpakÒ AD-H column, hexane/2-propanol: 93:7, flow rate
1.0 mL/min, tR¼16.47 min (minor) and 20.57 min (major).
D
IR (film) 2961, 2360, 2340, 1714, 1551, 1436, 1379, 1130, 1042, 973,
695 cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d
7.41e7.07 (m, 5H, ArH),
6.53e6.42 (m,1H, ]CH), 6.23 (dd, J¼15.9, 9.2 Hz, 0.32H, ]CH), 5.97
(dd, J¼15.8, 9.5 Hz, 0.68H, ]CH), 4.83e4.43 (m, 2H, CHHNO2),
4.10e3.85 (m, 4H, 4ꢂ OCHH), 3.52e3.28 (m, 0.68H, CH), 3.18e3.05
(m, 0.32H, CH), 2.98e2.83 (m, 1H, COCH), 2.76e2.60 (m, 1H,
COCHH), 2.54e2.35 (m, 2H, COCHH and CHH), 2.19e1.79 (m, 3H, 3ꢂ
4.4.13. (S)-2-[(S,E)-1-Nitro-4-(2-nitrophenyl)but-3-en-2-yl]cyclo-
pentanone (3m). Yellow oil (76%); [
a
]
20 ꢀ51.8 (c 1.0, CHCl3); IR (film)
D
CHH); 13C NMR (50 MHz, CDCl3):
d
209.7, 209.5, 136.1, 135.4, 134.8,
2964, 2917, 2879, 1731, 1554, 1521, 1379, 1344, 1157, 969, 787,
128.5, 128.0, 126.5, 124.9, 124.1, 107.2, 107.0, 78.1, 77.9, 64.9, 64.7,
64.6, 47.8, 47.3, 43.8, 41.3, 39.0, 38.6, 38.5, 38.2, 34.7, 33.8; MS (ESI)
m/z (%): 332 [MþH, (100)]þ; HRMS exact mass calculated for
[MþH]þ (C18H22NO5) requires m/z 332.1492, found m/z 332.1483;
HPLC analysis: 98:2 er, 70:30 dr; Diacel ChiralpakÒ AD-H column,
hexane/2-propanol: 95:5, flow rate 0.7 mL/min, tR¼46.57 min
(minor) and 48.98 min (major).
740 cmꢀ1; 1H NMR (200 MHz, CDCl3):
d
7.97 (d, J¼8.2 Hz, 1H, ArH),
7.62e7.53 (m,1H, ArH), 7.48e7.38 (m, 2H, ArH), 7.05e6.91 (m,1H, ]
CH), 5.89 (dd, J¼15.7, 9.0 Hz,1H, ]CH), 5.05e4.90 (m,1H, CHHNO2),
4.72 (dd, J¼12.2, 5.8 Hz, 0.15H, CHHNO2), 4.62 (dd, J¼12.1, 9.2 Hz,
0.85H, CHHNO2), 3.48e3.30 (m,1H, CH), 2.48e2.01 (m, 5H, 5ꢂ CHH),
1.89e1.70 (m, 2H, 2ꢂ CHH); 13C NMR (50 MHz, CDCl3):
d 219.2, 218.3,
147.4, 133.4, 132.4, 131.9, 130.6, 130.2, 129.4, 129.1, 128.6, 124.6, 77.6,
77.5, 50.3, 49.5, 42.6, 41.8, 39.1, 38.4, 27.4, 27.3, 20.8, 20.4; MS (ESI) m/
z (%): 322 [MþNH4, (100)]þ, 305 [MþH, (10)]þ; HRMS exact mass
calculated for [MþH]þ (C15H17N2O5) requiresm/z 305.1132, found m/
z 305.1124; HPLC analysis: 96:4 er, 85:15 dr; Diacel ChiralpakÒ AD-H
column, hexane/2-propanol: 90:10, flow rate 1.0 mL/min,
tR¼32.82 min (minor) and 45.30 min (major).
4.4.9. (R)-2-[(S,E)-1-Nitro-4-phenylbut-3-en-2-yl]-tetrahydropyr-
ane-4-one (3i).10 White solid (74%); mp 124e125 ꢁC [lit.: mp
20
125e126 ꢁC];8a
CDCl3):
[
a]
ꢀ40.4 (c 1.0, CHCl3); 1H NMR (200 MHz,
D
d
7.33e7.25 (m, 5H, ArH), 6.57e6.43 (m, 1H, ]CH), 6.21 (dd,
J¼15.8, 9.4 Hz, 0.30H, ]CH), 5.93 (dd, J¼15.8, 9.7 Hz, 0.70H, ]CH),
4.78e4.61 (m, 1.30H, CHHNO2), 4.52 (dd, J¼12.1, 8.7 Hz, 0.70H,
CHHNO2), 4.23e4.10 (m, 2H, 2ꢂ OCHH), 3.83e3.33 (m, 3H, 2ꢂ
OCHH and CH), 2.88e2.34 (m, 3H, COCH and COCHH); 13C NMR
4.4.14. (S)-2-[(S,E)-4-(4-Chlorophenyl)-1-nitrobut-3-en-2-yl]cyclo-
20
pentanone (3n).10 Yellow oil (90%); [
a]
ꢀ19.3 (c 2.0, CHCl3); 1H
D
(50 MHz, CDCl3):
d
212.6, 137.1, 136.0, 135.2, 129.4, 128.7, 127.7,
NMR (200 MHz, CDCl3):
d
7.31e7.19 (m, 4H, ArH), 6.47 (d, J¼15.8 Hz,
126.5, 78.8, 52.5, 43.7, 33.6, 28.8, 25.5; MS (ESI) m/z (%): 298 [MþNa,
(100)]þ, 276 [MþH, (15)]þ; HPLC analysis: 96.5:3.5 er, 73:27 dr;
Diacel ChiralpakÒ AD-H column, hexane/2-propanol: 90:10, flow
rate 1.0 mL/min, tR¼26.75 min (minor) and 36.61 min (major).
0.30H, ]CH), 6.43 (d, J¼15.8 Hz, 0.70H, ]CH), 5.90 (dd, J¼15.8,
9.5 Hz,1H, ]CH), 4.90 (dd, J¼12.1, 5.5 Hz, 0.70H, CHHNO2), 4.82 (dd,
J¼12.2, 8.8 Hz, 0.30H, CHHNO2), 4.70 (dd, J¼12.2, 6.1 Hz, 0.30H,
CHHNO2), 4.52 (dd, J¼12.1, 9.2 Hz, 0.70H, CHHNO2), 3.44e3.24 (m,
1H, CH), 2.42e1.98 (m, 5H, 5ꢂ CHH),1.88e1.58 (m, 2H, 2ꢂ CHH); 13C
4.4.10. (S)-3-[(S,E)-1-Nitro-4-phenylbut-3-en-2-yl]-tetrahy-
NMR (50 MHz, CDCl3): d 219.0, 218.1, 134.5, 133.5, 128.7, 127.7, 127.6,
drothiopyran-4-one (3j).10 White solid (83%); mp 115e116 ꢁC [lit.:
125.1, 124.4, 77.6, 50.2, 49.7, 42.6, 41.9, 39.1, 38.4, 27.4, 26.9, 20.7,
20
mp 116e118 ꢁC];8a
[
a
]
ꢀ82.8 (c 1.0, CHCl3); 1H NMR (200 MHz,
20.4; MS (ESI) m/z (%): 316 [MþNa, (60)]þ, 294 [MþH, (20)]þ; HPLC
D

M. Tsakos et al. / Tetrahedron 68 (2012) 8630e8635
8635
analysis: 95:5 er, 70:30 dr; Diacel ChiralpakÒ AD-H column, hexane/
2-propanol: 95:5, flow rate 1.0 mL/min, tR¼30.19 min (minor) and
38.76 min (major).
47, 4638e4660; (e) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew.
Chem., Int. Ed. 2008, 47, 6138e6171; (f) Yu, X.; Wang, W. Chem.dAsian J. 2008, 3,
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243e279; (d) Panday, S. K. Tetrahedron: Asymmetry 2011, 22, 1817e1847; (e)
Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, L.; Jorgensen, K. A. Acc. Chem.
Res. 2012, 45, 248e264.
5. For selected examples on organocatalytic Michael reaction of ketones/alde-
hydes with nitroolefins, see: (a) Yalalov, D. A.; Tsogoeva, S. B.; Schwatz, S. Adv.
Synth. Catal. 2006, 348, 826e832; (b) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2006, 45, 6366e6370; (c) Brandes, S.; Niess, B.; Bella, M.;
Prieto, A.; Overgaard, J.; Jorgensen, K. A. Chem.dEur. J. 2006, 12, 6039e6052; (d)
Mandal, T.; Zhao, C.-G. Angew. Chem., Int. Ed. 2008, 47, 7714e7717; (e) Uehara,
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Kokotos, G. Adv. Synth. Catal. 2012, 354, 740e746.
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Commun. 2009, 833e835; (b) Zhang, X.-J.; Liu, S.-P.; Lao, J.-H.; Du, G.-J.; Yan, M.;
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656e662; (f) Dong, X.-Q.; Teng, H.-L.; Tong, M.-C.; Huang, H.; Tao, H.-Y.; Wang,
C.-J. Chem. Commun. 2010, 6840e6842; (g) Lu, A.; Liu, T.; Wu, R.; Wang, Y.;
Zhou, Z.; Wu, G.; Fang, J.; Tang, C. Eur. J. Org. Chem. 2010, 5777e5781; (h) He, P.;
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5034e5036; (j) Yang, W.; Du, D.-M. Adv. Synth. Catal. 2011, 353, 1241e1246; (k)
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Lu, A.; Wu, R.; Wang, Y.; Zhou, Z.; Wu, G.; Fang, J.; Tang, C. Eur. J. Org. Chem.
2010, 11, 2057e2061; (g) Chen, J.-R.; Fu, L.; Zou, Y.-Q.; Chang, N.-J.; Rong, J.;
Xiao, W.-J. Org. Biomol. Chem. 2011, 9, 5280e5287; (h) Lu, A.; Wu, R.; Wang, Y.;
Zhou, Z.; Wu, G.; Fang, J.; Tang, C. Eur. J. Org. Chem. 2011, 1, 122e127.
10. Li, Z.-B.; Luo, S.-P.; Guo, Y.; Xia, A.-B.; Xu, D.-Q. Org. Biomol. Chem. 2010, 8,
2505e2508.
4.4.15. (S)-2-[(S,E)-4-(4-Methoxyphenyl)-1-nitrobut-3-en-2-yl]cy-
clopentanone (3o).10 Yellow oil (83%); [
a
]
20 ꢀ92.4 (c 1.0, CHCl3); 1H
D
NMR (200 MHz, CDCl3):
d
7.24 (d, J¼8.8 Hz, 2H, ArH), 6.81 (d,
J¼8.8 Hz, 2H, ArH), 6.50e6.36 (m,1H, ]CH), 5.76 (dd, J¼15.7, 9.2 Hz,
1H, ]CH), 4.89 (dd, J¼12.0, 5.8 Hz, 1H, CHHNO2), 4.72 (dd, J¼12.2,
6.4 Hz, 0.30H, CHHNO2), 4.50 (dd, J¼12.0, 9.1 Hz, 0.70H, CHHNO2),
3.78 (s, 3H, OCH3), 3.47e3.22 (m, 1H, CH), 2.46e1.97 (m, 5H, 5ꢂ
CHH),1.90e1.60 (m, 2H, 2ꢂ CHH); 13C NMR (50 MHz, CDCl3):
d 219.5,
218.5, 159.4, 135.1, 134.0, 128.7, 127.7, 127.6, 121.9, 121.1, 113.9, 78.0,
77.9, 55.3, 50.1, 49.7, 42.8, 41.9, 39.3, 38.5, 27.4, 26.8, 20.8, 20.5; MS
(ESI) m/z (%): 290 [MþH, (100)]þ; HPLC analysis: 94:6 er, 70:30 dr;
Diacel ChiralpakÒ AD-H column, hexane/2-propanol: 90:10, flow
rate 1.0 mL/min, tR¼27.08 min (minor) and 35.24 min (major).
4.4.16. (S)-2-[(R,E)-3-Methyl-1-nitro-4-phenylbut-3-en-2-yl]cyclo-
pentanone (3p). Colorless oil (93%); [
a
]
20 ꢀ82.1 (c 1.0, CHCl3); IR (film)
D
2972, 2877, 1731, 1551, 1445, 1382, 1155, 1130, 920, 875, 749, 697 cmꢀ1
;
1H NMR (200 MHz, CDCl3):
d 7.40e7.12 (m, 5H, ArH), 6.36 (s,1H, ]CH),
5.36 (dd, J¼12.0, 4.4 Hz, 1H, CHHNO2), 4.93e4.80 (m, 0.20H, CHHNO2),
4.65e4.48 (m, 0.80H, CHHNO2), 3.48e3.35 (m, 0.20H, CH), 3.14e3.01
(m, 0.80H, CH), 2.47e2.26 (m, 2H, 2ꢂ CHH), 2.23e1.95 (m, 3H, 3ꢂ CHH),
1.87e1.55 (m, 5H, 2ꢂ CHH and CH3); 13C NMR (50 MHz, CDCl3):
d 219.6,
218.5, 136.8, 136.7, 134.3, 132.9, 131.1, 129.8, 128.9, 128.1, 126.8, 126.7,
76.4, 76.1, 50.0, 49.2, 47.4, 47.2, 38.7, 28.8, 27.2, 20.5, 20.3, 16.2, 13.2; MS
(ESI) m/z (%): 296 [MþNa, (75)]þ, 274 [MþH, (35)]þ; HRMS exact mass
calculated for [MþH]þ (C16H20NO3) requires m/z 274.1438, found m/z
274.1430; HPLC analysis: 96.5:3.5 er, 80:20 dr; Diacel ChiralpakÒ OD-H
column, hexane/2-propanol: 95:5, flow rate 0.8 mL/min, tR¼33.71 min
(major) and 41.64 min (minor).
Supplementary data
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.07.078.
References and notes
1. For reviews on organocatalytic Michael reactions, see: (a) Almasi, D.; Alonso, D.
A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299e365; (b) Tsogoeva, S. B. Eur.
J. Org. Chem. 2007, 1701e1716; (c) Vicario, J. L.; Badia, D.; Carillo, L. Synthesis
2007, 2065e2092; (d) Roca-Lopez, D.; Sadaba, D.; Delso, I.; Herrera, R. P.; Tejero,
T.; Merino, P. Tetrahedron: Asymmetry 2010, 21, 2561e2601.
2. For books, see: (a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis-from
Biomimetic Concepts to Powerful Methods for Asymmetric Synthesis; Wiley-
VCH: Weinheim, 2005; (b) Dalko, P. I. Enantioselective Organocatalysis Reactions
and Experimental Procedure; Wiley-VCH: Weinheim, 2007.
3. For selected reviews, see: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471e5569; (b) Enders, D.; Grondal, C.; Huttl, M. R. M.
Angew. Chem., Int. Ed. 2007, 46, 1570e1581; (c) Barbas, C. F., III. Angew. Chem.,
Int. Ed. 2008, 47, 42e47; (d) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008,
11. He, T.; Wu, X.-Y. Synth. Commun. 2011, 42, 667e677.
12. (a) Tsandi, E.; Kokotos, C. G.; Kousidou, S.; Ragoussis, V.; Kokotos, G. Tetrahedron
2009, 65, 1444e1449; (b) Kokotos, C. G.; Limnios, D.; Triggidou, D.; Trifonidou,
M.; Kokotos, G. Org. Biomol. Chem. 2011, 9, 3386e3395; (c) Fotaras, S.; Kokotos,
C. G.; Tsandi, E.; Kokotos, G. Eur. J. Org. Chem. 2011, 1310e1317; (d) Trifonidou,
M.; Kokotos, C. G. Eur. J. Org. Chem. 2012, 1563e1568; (e) Kokotos, C. G. J. Org.
Chem. 2012, 77, 1131e1135.