Enantioselective LaIII-pyBOX-catalyzed nitro-michael addition to (E)-2-azachalcones

Article abstract of DOI:10.1002/ejoc.201201579

A [La(OTf)₃] complex with a new pyBOX ligand bearing a bulky 1-naphthylmethyl substituent at the 4′-position of the oxazoline ring catalyzes the conjugate addition of nitroalkanes to a broad range of (E)-2-azachalcones, providing the expected nitro-Michael products with good yields and enantiomeric excesses up to 87 %. The optical purity of the products can be increased by a single crystallization. A plausible stereochemical model to account for the observed stereochemistry has been proposed. Conjugate addition of nitroalkanes to (E)-2-azachalcones is catalyzed by La ^III-pyBOX complexes to give nitro-Michael products with good yields and enantiomeric excesses up to 87 %. Some products can be obtained almost enantiopure by a single crystallization. The scope of the reaction is shown with 24 examples involving substituted 2-azachalcones and nitroalkanes. Copyright

Full text of DOI:10.1002/ejoc.201201579

FULL PAPER
DOI: 10.1002/ejoc.201201579
Enantioselective LaIII-pyBOX-Catalyzed Nitro-Michael Addition to
(E)-2-Azachalcones
Gonzalo Blay,*[a] Celia Incerti,[a] M. Carmen Muñoz,[b] and José R. Pedro*[a]
Keywords: Asymmetric catalysis / C–C coupling / Michael addition / Lanthanum / Enones
A [La(OTf)3] complex with a new pyBOX ligand bearing a
bulky 1-naphthylmethyl substituent at the 4Ј-position of the
oxazoline ring catalyzes the conjugate addition of nitro-
alkanes to a broad range of (E)-2-azachalcones, providing the
expected nitro-Michael products with good yields and enan-
tiomeric excesses up to 87%. The optical purity of the prod-
ucts can be increased by a single crystallization. A plausible
stereochemical model to account for the observed stereo-
chemistry has been proposed.
enantioselectivities have been obtained even with the less
reactive chalcones.[9a,9b,9k,11a,11b,11k,11l,12e] However, to the
best of our knowledge, a catalytic asymmetric nitro-
Michael reaction with 2-azachalcones has not been re-
ported.[14] Such a reaction would give useful intermediates
for the synthesis of heteroaryl-substituted chiral pyridines,
pyrimidines, natural products, and several pharmaceutically
active compounds.[15] Furthermore, the 2-acylpyridine[16]
and related 2-acylpyridine N-oxide[17] moieties have been
shown to be very useful templates for highly enantioselec-
tive catalytic reactions. Herein, we describe the first cata-
lytic enantioselective nitro-Michael reaction with (E)-2-aza-
chalcones using LaIII-pyBOX complexes as catalysts.
Introduction
The conjugate addition of stabilized carbanions to acti-
vated unsaturated systems has become a fundamental
bond-forming reaction in organic synthesis.[1] The broad
spectrum of potential donors and acceptors make this reac-
tion exceptionally versatile. In particular, the conjugate ad-
dition of nitroalkanes to α,β-unsaturated ketones (nitro-
Michael reaction) has attracted enormous attention because
subsequent manipulation of the nitro group[2] allows con-
version of the conjugate addition products into a variety of
valuable structures such as pyrrolidines,[3] lactones,[4]
carbocycles,[5] and amino acids.[6] Because of this interesting
synthetic versatility, the development of catalytic asymmet-
ric versions of the nitro-Michael reaction has been the focus
of considerable effort.[7]
So far, most of the activity in this area has focused on
organocatalytic procedures involving iminium activation,[8]
phase-transfer conditions,[9] chiral base,[10] and hydrogen-
bonding activation.[11] Furthermore, a small number of
metal-catalyzed procedures have been reported for the ni-
tro-Michael reaction with α,β-unsaturated ketones[12] and
with other electrophilic double bonds.[13] Thus, despite
some limitations concerning reaction efficiency, selectivity
and substrate scope, highly enantioselective nitro-Michael
additions have been accomplished with enones, enals, nitro-
alkenes, and α,β-unsaturated amides and esters.[8–13] Good
Results and Discussion
For initial exploration we chose the reaction of nitro-
methane with azachalcone 1a in the presence of a standard
set of Lewis acids with BOX and pyBOX ligands
(Scheme 1) and molecular sieves (MS, 4 Å) in dichloro-
methane.[12d] The most significant results are summarized
in Table 1.
An initial screening of divalent metals combined with
BOX-1 and pyBOX-1, as well as of trivalent metals com-
bined with pyBOX-1 indicated the superior performance of
lanthanum triflate with respect to other metal triflates in
terms of both yield and enantioselectivity (Table 1, entry 8).
We then screened pyBOX ligands in combination with
lanthanum triflate (Table 2). First we tested the reaction
with commercially available ligands pyBOX-2–4 in di-
chloromethane. Because pyBOX-4, bearing a phenylethyl
moiety linked to the oxazoline ring, afforded the best
enantioselectivity, we checked the effect of the solvent with
this ligand. Toluene performed better than alternative sol-
vents, allowing a significant increase in the enantio-
selectivity (entry 7). The effect of the amount of molecular
[a] Departament de Química Orgànica, Facultat de Química,
Universitat de València,
c/ Dr. Moliner, 50, 46100 Burjassot, Valènci, Spain
Fax: +34-963544328
E-mail: gonzalo.blay@uv.es
jose.r.pedro@uv.es
Homepage: www.uv.es
[b] Departament de Física Aplicada, Universitat Politècnica de
València,
Camí de Vera s/n, 46022 València, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201579.
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1696–1705

Nitro-Michael Addition to 2-Azachalcones
Table 2. Nitro-Michael reaction with azachalcone 1a catalyzed by
[La(OTf)3] complexes. Screening of ligands and solvents.[a]
Entry
L
Solvent
t [h]
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
pyBOX-1
pyBOX-2
pyBOX-3
pyBOX-4
pyBOX-4
pyBOX-4
pyBOX-4
pyBOX-4
pyBOX-4
pyBOX-4
pyBOX-4
pyBOX-4
pyBOX-5
pyBOX-5
pyBOX-6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
THF
toluene
hexane
EtOH
toluene
toluene
toluene
toluene
toluene
toluene
144
144
96
72
168
24
72
24
24
72
72
24
72
240
72
83
81
65
61
61
62
65
71
93
68
75
94
74
54
65
23
30
–43[d]
56
51
55
69
25
40
59
63
0
9
10[e]
11[f]
12[g]
13
14[h]
15
79
75
62
[a] Reaction conditions: L (10 mol-%), [La(OTf)3] (10 mol-%),
CH3NO2 (52 equiv.), 4 Å MS (1.0 g/mmol 1a), room temp., solvent.
[b] Yield of isolated 2a. [c] Determined by HPLC analysis with chi-
ral stationary phase. [d] The opposite enantiomer to that observed
in entry 1 was obtained. [e] 4 Å MS (0.5 g/mmol 1a) was used.
[f] 4 Å MS (2.0 g/mmol 1a) was used. [g] Basic alumina (1.0 g/mmol
1a) was used. [h] Reaction carried out at 0 °C.
Scheme 1. Nitro-Michael reaction with azachalcone 1a and ligands
tested in this study.
Table 1. Nitro-Michael reaction with azachalcone 1a according to
Scheme 1. Screening of metal ions.[a]
Entry
L
M
t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
BOX-1
Cu(OTf)2
Zn(OTf)2
Mg(OTf)2
Cu(OTf)2
Zn(OTf)2
Sc(OTf)3
In(OTf)3
La(OTf)3
Yb(OTf)3
96
72
38
44
24
22
55
15
35
83
20
11
11
–15[d]
0
BOX-1
BOX-1
144
144
144
144
144
144
144
pyBOX-1
pyBOX-1
pyBOX-1
pyBOX-1
pyBOX-1
pyBOX-1
0
11
14
23
0
[a] Reaction conditions: L (10 mol-%), M (10 mol-%), CH3NO2
(52 equiv.), 4 Å MS (1.0 g/mmol 1a), room temp., CH2Cl2. [b] Yield
of isolated 2a. [c] Determined by HPLC analysis with chiral sta-
tionary phase. [d] The opposite enantiomer to that observed in en-
try 1 was obtained.
Scheme 2. Synthesis of pyBOX-5 and pyBOX-6. Reagents and con-
ditions: (i) BH3·Me2S, THF, 60 °C, 4a (54%), 4b (60%); (ii) 2,6-
sieves was also tested; an increase or decrease in the load
of molecular sieves above or below 1 g/mmol 1a was delete- pyridinedicarbonyl dichloride, Et3N, CH2Cl2, 0 °C, 5a (57%), 5b
rious in both cases (entries 10 and 11 vs. entry 7). Finally,
the use of basic alumina as an additive provided the racemic
(53%); (iii) a. DAST, CH2Cl2, –78 °C; b. K2CO3, –78 °C to room
temp. pyBOX-5 (47%), pyBOX-6 (46%).
product 1a, although in very high yield, which constitutes
a practical alternative for the preparation of these products
in racemic form (entry 12).
With the optimal conditions established (Table 2, en-
Because the presence of the bulky, conformationally flex- try 13), we studied the applicability of the reaction with
ible phenylethyl substituent in ligand pyBOX-4 seemed to other azachalcones bearing different groups at the β-posi-
favor higher enantioselectivities with respect to pyBOX-1–3 tion; the results are gathered in Table 3.
ligands, we decided to prepare two new ligands pyBOX-5
The substituent on the β-carbon of the double bond was
and py-BOX-6, which were synthesized by standard meth- amenable to variation. Azachalcones bearing aromatic rings
odologies from l-3-(1-naphthyl)alanine and l-3-(2-naphth- substituted in different positions with either electron-with-
yl)alanine, respectively (Scheme 2). Both new ligands were drawing or electron-donating groups could be used as sub-
tested and pyBOX-5 gave the best results, allowing com- strates in this reaction, providing the expected products
pound 2a to be obtained in 74% yield and 79% ee (en- with good enantioselectivities (Table 3, entries 1–8), regard-
try 13). Attempts to increase the enantioselectivity by low- less of the electronic features or position of the substituent.
ering the reaction temperature to 0 °C, brought about a de- A bulky 1-naphthyl group as well as electron-rich heterocy-
crease of both yield and enantioselectivity.
clic groups were also tolerated, giving the expected nitro-
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G. Blay, C. Incerti, M. C. Muñoz, J. R. Pedro
FULL PAPER
Table 3. Addition of nitromethane to azachalcones 1 catalyzed by
[La(OTf)3-pyBOX-5] complex.[a]
Table 4. Addition of nitroalkanes to azachalcones 1 catalyzed by
[La(OTf)3-pyBOX-5] complex.[a]
Entry
1
R1
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Ph
74 (77)[d]
79 (98)[e]
2-ClC6H4
3-ClC6H4
3-BrC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-NO2C6H4
1-naphthyl
2-thienyl
3-thienyl
2-furanyl
CH3
69
73
58 (80)[d]
82 (95)[e]
68
78
73
77
74 (75)[d]
79 (97)[e]
65 (82)[d]
78 (99)[e]
Entry
1
R1
t [h] R2 6/7 Yield [%][b] anti/syn ee [%][c]
70
68
72
69
68
65
72
74
77
81
81
79
87
81
9
1
2
3
4
5
6
7
8
9
10
1a Ph
1a Ph
1f 4-BrC6H5
1f 4-BrC6H5
1g 4-CH3OC6H5
72 Me 6a
72 Et 7a
72 Me 6f
72 Et 7f
72 Me 6g
68
50
67
53
60
50
66
54
66
51
73:27
64:36
76:24
65:35
69:31
56:44
72:28
65:35
62:38
73:27
81:71
80:72
57:55
51:54
77:71
64:61
81:79
83:57
81:70
75:71
10
11
12
13
14
tBu
1g 4-CH3OC6H5 192 Et 7g
[a] Reaction conditions: pyBOX-5 (10 mol-%), [La(OTf)3] (10 mol-
%), CH3NO2 (52 equiv.), 4 Å MS (1.0 g/mmol 1a), toluene, room
temp., 72 h. [b] Yield of isolated 2. [c] Determined by HPLC analy-
sis with chiral stationary phase. [d] Yield for the crystallization pro-
cess. [e] ee after crystallization.
1h 4-NO2C6H5
1h 4-NO2C6H5
1k 3-thienyl
72 Me 6h
168 Et 7h
72 Me 6k
72 Et 7k
1k 3-thienyl
[a] Reaction conditions: pyBOX-5 (10 mol-%), [La(OTf)3] (10 mol-
%), R2CH2NO2 (52 equiv.), 4 Å MS (1.0 g/mmol 1a), toluene, room
temp., 72 h. [b] Yield of isolated 6 and 7. [c] Determined by HPLC
analysis with chiral stationary phase.
Michael products with good enantioselectivities (entries 9–
12). Finally, the reaction was tested with azachalcones bear-
ing an aliphatic group at the β-position. Compound 1m,
having a methyl group, as well as compound 1n, substituted
with a bulky tert-butyl group, both reacted to give the cor-
responding products with good enantioselectivities (en-
tries 13 and 14). It should be mentioned that solid com-
pounds 2 can be obtained in almost enantiopure form by a
single crystallization from hexane/EtOAc (Table 3, entries
1, 3, 6 and 7).
We then explored the use of larger nitroalkanes such as
nitroethane and nitropropane with some azachalcones 1.
These nitroalkanes are often very demanding reactants in
enantioselective reactions, and their use in nitro-Michael re-
actions has been little studied compared with nitrometh-
ane.[8b,8e,8g,8h,9j,11c,11d,11l,13b–13d] The results of these ad-
ditions are shown in Table 4. The addition of nitroethane
or nitropropane to azachalcones 1 lead to the formation of
two anti/syn diastereomers with moderate diastereoselectivi-
ties ranging from 56:44 to 76:24, favoring the anti dia-
stereomer[18] for both nitroalkanes. Good enantioselectivit-
ies, similar to those obtained with nitromethane, were found
for the addition of nitroethane and nitropropane to aza-
chalcones 1a, 1g, 1h and 1k, whereas slightly lower enantio-
meric excesses were found for the addition products to aza-
chalcone 1f.
X-ray crystallographic analysis of a monocrystal ob-
tained from enantiomerically enriched 2f allowed the abso-
lute stereochemistry of the stereogenic center to be deter-
mined as S configuration (Figure 1).[19] For compounds 2,
6 and 7, the absolute stereochemistry was assigned on the
assumption of a common stereochemical pathway.[20] These
results indicate the preference of the nitronate to attack
from the Si face of the double bond of the azachalcone.
Taking into account previous studies on [LaIII-pyBOX]-cat-
Figure 1. ORTEP plot for the X-ray structure of compound 2f with
ellipsoids draw at 50% probability level. Flack parameter 0.010 (2).
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Eur. J. Org. Chem. 2013, 1696–1705

Nitro-Michael Addition to 2-Azachalcones
alyzed reactions,[21] we propose a plausible stereochemical
model that accounts for the observed stereochemistry (Fig-
ure 2). According to these studies and to our experimental
observations, we assume that LaIII coordinates three nitro-
gen atoms from the pyBOX ligand, one oxygen and one
nitrogen atom from azachalcone 1, and two triflate ions in
the apical positions of the cation coordination sphere.[22]
The shielding effect exerted by the bulky 1-naphthylmethyl
substituent at the 4Ј-position of pyBOX-5 would determine
the preferential attack from the Si-face of the double bond
β-carbon.
using residual nondeuterated solvent (CHCl3) as internal standard
(δ = 7.26 and 77.0 ppm, respectively). Chemical shifts are given
in ppm. High-resolution mass spectra (ESI) were recorded with a
Q-TOF spectrometer equipped with an electrospray source with a
capillary voltage of 3.3 kV. Specific optical rotations were measured
using sodium light (D line 589 nm). Chiral HPLC analyses were
performed in a chromatograph equipped with a UV diode-array
detector using chiral stationary columns from Daicel. Retention
times are given in min.
(S)-2-Amino-3-(naphthalen-1-yl)propan-1-ol (4a):[24] To a solution
of l-3-(naphthalen-1-yl)alanine (3a, 1.5 g, 7.0 mmol) in anhydrous
THF (15 mL) was added dropwise BH3·Me2S (2 m in THF, 8.7 mL,
17.4 mmol) under nitrogen. The reaction mixture was then intro-
duced in a bath at 60 °C and stirred overnight. The excess of borane
was destroyed by careful addition of MeOH until no gas evolution
was observed. The solvents were removed under reduced pressure
and the residue was suspended in 2M aqueous NaOH (20 mL) and
extracted with CH2Cl2 (4ϫ 20 mL). The organic layers were
washed with brine (20 mL) and dried with Na2SO4. Crystallization
of the crude product from toluene gave 4a (0.90 g, 64%) as a white
solid (m.p. 142–144 °C). [α]2D0 = –58.0 (c = 0.21, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 8.03 (d, J = 9.0 Hz, 1 H), 7.86 (dd, J =
9.6, 2.4 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.47 (m, 2 H), 7.39 (m,
2 H), 3.70 (dd, J = 10.5, 3.6 Hz, 1 H), 3.49 (dd, J = 10.8, 6.6 Hz,
1 H), 3.31 (m, 2 H), 2.96 (dd, J = 15.0, 9.9 Hz, 1 H), 2.13 (br. s, 3
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 134.7 (s), 134.0 (s),
132.0 (s), 128.8 (d), 127.4 (d), 127.3 (d), 126.0 (d), 125.7 (d), 125.4
(d), 123.7 (d), 66.4 (t), 53.3 (d), 37.8 (t) ppm. HRMS (ESI): m/z
calcd. for C13H15NO [M + H] 202.1232; found 202.1237.
Figure 2. Proposed stereochemical model for the [La(OTf)3-py-
BOX-5]-catalyzed enantioselective nitro-Michael reaction of aza-
chalcones 2 with nitroalkanes.
Conclusions
N2,N6-Bis[(S)-1-hydroxy-3-(naphthalen-1-yl)propan-2-yl]pyridine-
2,6-dicarboxamide (5a): Compound 4a (365 mg, 8.0 mmol) was
vigorously stirred with CH2Cl2 (10 mL) under nitrogen until com-
pletely dissolved. The solution was cooled to 0 °C and Et3N
(0.45 mL, 3.24 mmol) was added followed by 2,6-pyridinedicarb-
onyl dichloride (185 mg, 0.91 mmol) dissolved in CH2Cl2 (2 mL).
After 6 h, the reaction mixture was diluted with EtOAc (100 mL),
washed with saturated aqueous NaHCO3 (2ϫ 30 mL) and dried
with MgSO4. After removal of the solvent under reduced pressure,
column chromatography on silica gel (EtOAc/MeOH/Et3N,
40:60:10) gave 5a (554 mg, 57%) as a white solid (m.p. 160–163 °C).
We have described the first catalytic asymmetric nitro-
Michael reaction with (E)-2-azachalcones. The reaction is
catalyzed by a [La(OTf)3] complex with a new pyBOX li-
gand bearing a bulky 1-naphthylmethyl substituent at the
4Ј-position of the oxazoline rings. The reaction can be car-
ried out with a broad range of azachalcones bearing substi-
tuted aromatic rings, heterocyclic and alkyl groups at the β-
position, providing the expected products with good yields
and enantiomeric excesses near to 80%, which can be en-
hanced by a single crystallization. Larger nitroalkanes also
react under the catalytic conditions to give products with
moderate diastereoselectivity and similar enantioselectivity.
The absolute stereochemistry of the nitro-Michael products
has been determined by X-ray analysis and we have pro-
posed a plausible stereochemical model to account for the
observed stereochemistry.
1
[α]2D0 = –218.9 (c = 0.27, CHCl3). H NMR (300 MHz, CDCl3): δ
= 8.35 (t, J = 8.1 Hz, 2 H), 8.29 (d, J = 7.8 Hz, 2 H), 7.97 (t, J =
7.7 Hz, 1 H), 7.82 (d, J = 7.8 Hz), 7.71 (dd, J = 6.6, 3.3 Hz), 7.55
(td, J = 7.0, 1.2 Hz), 7.46 (t, J = 7.2 Hz, 2 H), 7.32 (m, 4 H), 4.50
(m, 2 H), 3.75 (d, J = 3.9 Hz, 4 H), 3.58 (dd, J = 13.8, 5.7 Hz, 2
H), 3.34 (dd, J = 13.8, 5.7 Hz) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 163.7 (s), 148.6 (s), 139.0 (d), 133.93 (s), 133.89 (s), 132.1 (d),
128.7 (d), 127.5 (d), 126.4 (d), 125.8 (d), 125.3 (d), 124.9 (d), 124.0
(d), 63.0 (t), 52.1 (d), 34.2 (t) ppm. HRMS (ESI): m/z calcd. for
C33H31N3NaO4 [M + Na] 556.2207; found 556.2204.
Experimental Section
2,6-Bis{(S)-4,5-dihydro-4-[(naphthalen-1-yl)methyl]oxazol-2-
yl}pyridine (pyBOX-5): Diethylaminosulfur trifluoride (DAST,
0.37 mL, 2.8 mmol) was added dropwise to a solution of 5a
(385 mg, 0.72 mmol) in CH2Cl2 (7 mL) at –78 °C under nitrogen.
After 4 h, K2CO3 (540 mg, 3.89 mmol) was added and the mixture
was stirred overnight at room temperature.[25] Water (5 mL) was
added and the mixture was extracted with CH2Cl2 (3ϫ 10 mL).
The organic layer was washed with brine (5 mL) and dried with
Na2SO4. Column chromatography (hexane/EtOAc, 10:90) gave py-
General: Glassware for anhydrous reactions was oven-dried over-
night at 120 °C. Commercial reagents were used as purchased. Aza-
chalcones 1 were prepared according to literature procedures.[23]
Toluene and dichloromethane were dried and distilled from CaH2.
THF was distilled from sodium-benzophenone. Powdered molecu-
lar sieves (4 Å) was stored in an oven at 120 °C. Reactions were
monitored by TLC analysis using Merck Silica Gel 60 F-254 thin-
layer plates. Flash column chromatography was performed on
Merck silica gel 60, 0.040–0.063 mm.
BOX-5 (171 mg, 47%) as a white solid (m.p. 155–160 °C). [α]2D0
–65.4 (c = 0.33, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.24 (d,
=
Melting points were determined in capillary tubes. NMR spectra
were recorded at 300 MHz for 1H and at 75 MHz for 13C nuclei J = 7.8 Hz, 2 H), 8.17 (d, J = 8.1 Hz, 2 H), 7.92 (t, J = 7.5 Hz, 1
Eur. J. Org. Chem. 2013, 1696–1705
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G. Blay, C. Incerti, M. C. Muñoz, J. R. Pedro
FULL PAPER
H), 7.87 (dd, J = 8.4, 1.5 Hz, 2 H), 7.78 (d, J = 8.1 Hz, 2 H), 7.6–
7.3 (m, 8 H), 4.85 (m, 2 H), 4.38 (m, 4 H), 3.84 (dd, J = 14.1,
mixture was heated until the solid dissolved, then hexane (2 mL)
was added. The flask was stoppered with aluminum foil containing
4.8 Hz, 2 H), 3.06 (dd, J = 14.1, 9.9 Hz, 2 H) ppm. 13C NMR two small holes made with a needle. The flask was left overnight
(75.5 MHz, CDCl3): δ = 162.7 (s), 146.8 (s), 137.4 (d), 133.9 (s),
133.6 (s), 128.8 (d), 127.5 (d), 127.0 (d), 126.2 (d), 125.8 (d), 125.7
(d), 125.4 (d), 123.7 (d), 72.8 (d), 67.1 (t), 39.0 (t) ppm. HRMS
(ESI): m/z calcd. for C33H27N3NaO2 [M + Na] 520.2001; found
520.2007.
so most of diethyl ether evaporated slowly. The mother liquors were
removed with a pipette and the solid was washed twice with hexane
(1 mL) containing 3–4 drops of diethyl ether. After drying, com-
pound 2a (89.9 mg, 77%, 98% ee) was obtained.
Typical Procedure for the Preparation of Racemic Compounds: To
the azachalcone (0.25 mmol) and the nitroalkane (13.0 mmol) in
toluene (2 mL) were added a catalytic amount of [La(OTf)3] and
basic alumina (250 mg), and the mixture was stirred until comple-
tion. The products were isolated after filtration and column
chromatography.
(S)-2-Amino-3-(naphthalen-2-yl)propan-1-ol (4b):[24] Following the
same procedure used for the synthesis of 4a, starting from l-3-
(naphthalene-2-yl)alanine (3b, 1.5 g, 7.0 mmol), compound 4b
(0.84 g, 60%) was obtained as a white solid (m.p. 95–98 °C). [α]2D0
1
= –6.5 (c = 0.40, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.82–
7.76 (m, 6 H), 7.64 (s, 2 H), 7.48–7.35 (m, 4 H), 7.31 (dd, J = 8.4,
1.8 Hz, 2 H), 3.68 (dd, J = 10.8, 3.6 Hz, 2 H), 3.44 (dd, J = 10.8,
7.2 Hz, 1 H), 3.23 (m, 1 H), 2.96 (dd, J = 13.5, 5.6 Hz, 1 H), 2.69
(dd, J = 13.5, 8.7 Hz, 1 H), 2.51 (s, 3 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 136.1 (s), 133.5 (s), 132.2 (s), 128.2 (d),
127.62 (d), 127.61 (d), 127.5 (d), 127.4 (d), 125.5 (d), 66.4 (t), 54.0
(t), 41.0 (d) ppm. HRMS (ESI): m/z calcd. for C13H15NO [M + H]
202.1232; found 202.1237.
(S)-(–)-4-Nitro-3-phenyl-1-(pyridin-2-yl)butan-1-one (2a): Purified
by column chromatography (hexane/EtOAc, 70:30). Enantiomeric
excess (79 %, 98 % after crystallization) determined by HPLC
analysis (Chiralpak AD-H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
17.1 (major enantiomer), 17.9 (minor enantiomer) min; white solid;
1
m.p. 65–67 °C. [α]2D0 = –29.5 (c = 0.43, CHCl3, ee 98%). H NMR
(300 MHz, CDCl3): δ = 8.61 (dq, J = 4.8, 0.9 Hz, 1 H), 7.93 (dt, J
= 7.8, 0.9 Hz, 1 H), 7.78 (td, J = 7.8, 1.2 Hz, 1 H), 7.43 (ddd, J =
7.8, 4.8, 1.2 Hz, 1 H), 7.23 (m, 5 H), 4.75 (dd, J = 12.3, 6.6 Hz, 1
H), 4.63 (dd, J = 12.3, 8.1 Hz, 1 H), 4.20 (m, 1 H), 3.79 (dd, J =
18.3, 7.2 Hz, 1 H), 3.58 (dd, J = 18.3, 7.2 Hz, 1 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 198.5 (s), 152.6 (s), 148.9 (d), 139.2 (s),
132.0 (d), 128.9 (d), 127.7 (d), 127.5 (d), 127.5 (d), 121.9 (d), 79.8
(t), 40.7 (t), 39.2 (d) ppm. HRMS (ESI): m/z calcd. for C15H15N2O3
[M + H] 271.1083; found 271.1083.
N2,N6-Bis[(S)-1-hydroxy-3-(naphthalen-2-yl)propan-2-yl]pyridine-
2,6-dicarboxamide (5b): Following the same procedure used for the
synthesis of 5a, starting from amino alcohol 4b (890 mg,
4.4 mmol), compound 5b (623 mg, 53%) was obtained as a white
solid (m.p. 142–145 °C). [α]2D0 = –105 (c = 0.26, CHCl3). H NMR
1
(300 MHz, CDCl3): δ = 8.21 (d, J = 7.8 Hz, 2 H), 8.14 (d, J =
8.4 Hz, 2 H), 7.86 (t, J = 7.8 Hz, 1 H), 7.85–7.30 (m, 12 H), 4.36
(br. m, 2 H), 3.70 (m, 2 H), 3.07 (m, 2 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 163.7 (s), 148.5 (s), 138.9 (d), 135.2 (s),
133.4 (s), 132.1 (s), 128.2 (d), 127.8 (d), 127.6 (d), 127.5 (d), 126.2
(d), 125.6 (d), 124.9 (d), 63.2 (t), 52.9 (d), 37.0 (t) ppm. HRMS
(ESI): m/z calcd. for C33H31N3NaO4 [M + Na] 556.2207; found
556.2206.
(S)-(–)-3-(2-Chlorophenyl)-4-nitro-1-(pyridin-2-yl)butan-1-one (2b):
Purified by column chromatography (hexane/EtOAc, 70:30). Enan-
tiomeric excess (73 %) determined by HPLC (Chiralpak AD-H;
hexane/iPrOH, 90:10; 1 mL/min): tR = 14.9 (major enantiomer),
15.7 (minor enantiomer) min; Oil. [α]2D0 = –22.7 (c = 0.26, CHCl3,
ee 73 %). 1H NMR (300 MHz, CDCl3): δ = 8.67 (dq, J = 4.8,
0.9 Hz, 1 H), 8.00 (dt, J = 7.8, 0.9 Hz, 1 H), 7.83 (td, J = 7.8,
1.2 Hz, 1 H), 7.48 (ddd, J = 7.8, 4.8, 1.2 Hz, 1 H), 7.42 (m, 1 H),
7.34 (m, 1 H), 7.23 (m, 2 H), 4.83 (s, 2 H), 4.73 (m, 1 H), 3.89 (dd,
2,6-Bis{(S)-4,5-dihydro-4-[(naphthalen-2-yl)methyl]oxazol-2-
yl}pyridine (pyBOX-6): Following the same procedure used for the
synthesis of pyBOX-5, starting from compound 5b (350 mg,
0.66 mmol), pyBOX-6 (150 mg, 46%) was obtained as a white solid J = 18.6, 6.6 Hz, 1 H), 3.78 (dd, J = 18.6, 7.5 Hz, 1 H) ppm. 13C
(m.p. 163–165 °C). [α]2D0 = –34.5 (c = 0.11, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 8.23 (d, J = 8.1 Hz, 2 H), 7.90 (t, J =
7.8 Hz, 1 H), 7.82–7.80 (m, 6 H), 7.68 (s, 2 H), 7.5–7.3 (m, 6 H),
4.76 (m, 2 H), 4.47 (t, J = 8.7 Hz, 2 H), 4.31 (dd, J = 8.7, 7.8 Hz,
2 H), 3.44 (dd, J = 13.5, 5.1 Hz, 2 H), 2.90 (dd, J = 13.5, 8.7 Hz,
2 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 162.8 (s), 146.8 (s),
137.3 (d), 135.2 (s), 133.5 (s), 132.2 (s), 128.3 (d), 127.6 (d), 127.5
(d), 126.1 (d), 125.8 (d), 125.5 (d), 72.6 (t), 68.0 (d), 41.8 (t) ppm.
HRMS (ESI): m/z calcd. for C33H27N3NaO2 [M + Na] 520.2001;
found 520.2008.
NMR (75.5 MHz, CDCl3): δ = 198.4 (s), 152.6 (s), 148.9 (d), 137.1
(d), 136.4 (s), 133.9 (s), 130.3 (d), 128.8 (d), 128.4 (d), 127.6 (d),
127.3 (d), 121.9 (d), 77.8 (t), 39.4 (t), 35.9 (d) ppm. HRMS (ESI):
m/z calcd. for C15H14ClN2O3 [M + H] 305.0693; found 305.0687.
(S)-(–)-3-(3-Chlorophenyl)-4-nitro-1-(pyridin-2-yl)butan-1-one (2c):
Purified by column chromatography (hexane/EtOAc, 70:30). Enan-
tiomeric excess (82 %, 95 % after crystallization) determined by
HPLC (Chiralpak AD-H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
17.0 (major enantiomer), 16.1 (minor enantiomer) min; white solid;
m.p. 76–77 °C. [α]2D0 = –24.4 (c = 0.32, CHCl3, ee 95%). H NMR
1
General Procedure for the Nitro-Michael Reaction Catalyzed by
(300 MHz, CDCl3): δ = 8.66 (dq, J = 4.8, 0.9 Hz, 1 H), 7.90 (dt, J
[LaIII-pyBOX-5]: [La(OTf)3] (14.6 mg, 0.025 mmol) contained in a = 7.8, 0.9 Hz, 1 H), 7.84 (td, J = 7.8, 1.8 Hz, 1 H), 7.48 (ddd, J =
Schlenk tube was dried under vacuum. pyBOX-5 (12.4 mg,
0.025 mmol) and 4 Å MS (250 mg) were introduced, the tube was
filled with nitrogen and the nitroalkane (13 mmol) was injected.
After 1 h, azachalcone 1 (0.25 mmol) in toluene (2 mL) was added
and the mixture was stirred until the reaction was complete (TLC).
The reaction mixture was filtered through a short pad of Celite and
purified by chromatography on silica gel (hexane/EtOAc). Com-
pounds 2a, 2c, 2f and 2g obtained after column chromatography
were recrystallized to give enantiomerically enriched compounds.
7.8, 4.8, 1.8 Hz, 1 H), 7.32 (m, 4 H), 4.78 (dd, J = 12.6, 6.6 Hz, 1
H), 4.66 (dd, J = 12.6, 8.4 Hz, 1 H), 4.22 (m, 1 H), 3.81 (dd, J =
18.3, 7.2 Hz, 1 H), 3.61 (dd, J = 18.3, 7.2 Hz, 1 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 198.2 (s), 152.5 (s), 149.0 (d), 141.3 (s),
137.0 (d), 134.7 (s), 130.2 (d), 128.0 (d), 127.8 (d), 127.7 (d), 125.9
(d), 121.9 (d), 79.4 (t), 40.5 (t), 38.9 (d) ppm. HRMS (ESI): m/z
calcd. for C15H14ClN2O3 [M + H] 305.0693; found 305.0697.
(S)-(–)-3-(3-Bromophenyl)-4-nitro-1-(pyridin-2-yl)butan-1-one (2d):
Purified by column chromatography (hexane/EtOAc, 70:30). Enan-
tiomeric excess (78 %) determined by HPLC (Chiralpak AD-H;
hexane/iPrOH, 90:10; 1 mL/min): tR = 18.8 (major enantiomer),
17.6 (minor enantiomer) min; oil. [α]2D0 = –19.1 (c = 0.46, CHCl3,
Typical Procedure for the Recrystallization of Compound 2a: To
compound 2a (108 mg, 79% ee) contained in a 25 mL round-bot-
tom flask was added hexane (4 mL) and diethyl ether (5 mL). The
1700
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1696–1705

Nitro-Michael Addition to 2-Azachalcones
ee 78 %). 1H NMR (300 MHz, CDCl3): δ = 8.65 (dq, J = 4.8,
0.9 Hz, 1 H), 7.99 (dt, J = 7.8, 0.9 Hz, 1 H), 7.85 (td, J = 7.8,
1.8 Hz, 1 H), 7.42 (m, 2 H), 7.31 (m, 1 H), 7.18 (m, 2 H), 4.78 (dd,
7.85 (td, J = 7.8, 1.2 Hz, 1 H), 7.52 (m, 2 H), 4.85 (dd, J = 12.9,
6.3 Hz, 1 H), 4.72 (dd, J = 12.9, 8.7 Hz, 1 H), 4.37 (m, 1 H), 3.88
(dd, J = 18.3, 7.5 Hz, 1 H), 3.66 (dd, J = 18.3, 6.6 Hz, 1 H) ppm.
J = 12.6, 6.6 Hz, 1 H), 4.66 (dd, J = 12.9, 8.4 Hz, 1 H), 4.22 (m, 1 13C NMR (75.5 MHz, CDCl3): δ = 197.7 (s), 152.2 (s), 148.9 (d),
H), 3.80 (dd, J = 18.0, 6.9 Hz, 1 H), 3.61 (dd, J = 18.3, 7.2 Hz, 1
147.8 (s), 146.6 (s), 137.3 (d), 128.7 (d), 127.9 (d), 124.1 (d), 122.0
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 198.1 (s), 152.5 (s), (d), 79.0 (t), 40.4 (t), 39.0 (d) ppm. HRMS (ESI): m/z calcd. for
149.0 (d), 141.6 (s), 137.1 (d), 130.9 (d), 130.5 (d), 127.7 (d), 126.4
(d), 122.9 (s), 122.0 (d), 79.4 (t), 40.6 (t), 38.9 (d) ppm. HRMS
(ESI): m/z calcd. for C15H14BrN2O3 [M + H] 349.0188; found
349.0190.
C15H14N3O5 [M + H] 316.0933; found 316.0937.
(S)-(–)-3-(Naphthalen-1-yl)-4-nitro-1-(pyridin-2-yl)butan-1-one (2i):
Purified by column chromatography (hexane/EtOAc, 70:30). Enan-
tiomeric excess (77%) determined by HPLC (Chiralpak AY-H; hex-
(S)-(–)-3-(4-Chlorophenyl)-4-nitro-1-(pyridin-2-yl)butan-1-one (2e): ane/iPrOH, 80:20; 1 mL/min): tR = 45.2 (major enantiomer), 42.3
Purified by column chromatography (hexane/EtOAc, 70:30). Enan-
tiomeric excess (77 %) determined by HPLC (Chiralpak AD-H;
hexane/iPrOH, 90:10; 1 mL/min): tR = 19.6 (major enantiomer),
22.1 (minor enantiomer) min. [α]2D0 = –25.7 (c = 0.35, CHCl3, ee
77%). H NMR (300 MHz, CDCl3): δ = 8.64 (dq, J = 4.8, 0.9 Hz,
1 H), 7.96 (dt, J = 7.8, 0.9 Hz, 1 H), 1.82 (td, J = 7.8, 1.8 Hz, 1
(minor enantiomer) min; white solid; m.p. 81–87 °C. [α]2D0 = –29.7
(c = 0.35, CHCl3, ee 77%). H NMR (300 MHz, CDCl3): δ = 8.67
(dq, J = 4.8, 0.9 Hz, 1 H), 7.83 (dt, J = 7.8, 0.9 Hz, 1 H), 7.79 (m,
5 H), 7.46 (m, 4 H), 4.87 (dd, J = 12.3, 6.9 Hz, 1 H), 4.78 (dd, J =
12.6, 8.1 Hz, 1 H), 4.43 (m, 1 H), 3.96 (dd, J = 18.3, 7.2 Hz, 1 H),
3.77 (dd, J = 18.3, 7.2 Hz, 1 H) ppm. 13C NMR (75.5 MHz,
1
1
H), 7.48 (ddd, J = 7.8, 4.8, 1.8 Hz, 1 H), 7.25 (m, 4 H), 4.75 (dd, CDCl3): δ = 198.4 (s), 152.5 (s), 148.9 (d), 137.1 (d), 136.5 (s), 133.3
J = 12.6, 6.6 Hz), 4.63 (dd, J = 12.3, 8.7 Hz, 1 H), 4.21 (m, 1 H),
3.77 (dd, J = 18.3, 7.2 Hz, 1 H), 3.57 (dd, J = 18.3, 6.9 Hz, 1
(s), 132.7 (s), 128.8 (d), 127.8 (d), 127.6 (d), 127.5 (d), 126.7 (d),
126.3 (d), 126.0 (d), 125.3 (d), 122.0 (d), 79.0 (t), 40.8 (t), 39.4
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 198.3 (s), 152.5 (s), (d) ppm. HRMS (ESI): m/z calcd. for C19H17N2O3 [M + H]
149.0 (d), 137.7 (s), 137.1 (d), 133.6 (s), 129.1 (d), 129.0 (d), 127.6
(d), 121.9 (d), 79.6 (t), 40.6 (t), 38.7 (d) ppm. HRMS (ESI): m/z
calcd. for C15H14ClN2O3 [M + H] 305.0693; found 305.0693.
321.1239; found 321.1236.
(S)-(–)-4-Nitro-1-(pyridin-2-yl)-3-(thien-2-yl)-butan-1-one (2j): Puri-
fied by column chromatography (hexane/EtOAc, 70:30). Enantio-
(S)-(–)-3-(4-Bromophenyl)-4-nitro-1-(pyridin-2-yl)butan-1-one (2f): meric excess (81%) determined by HPLC (Chiralpak AD-H; hex-
Purified by column chromatography (hexane/EtOAc, 70:30). Enan-
tiomeric excess (79 %, 97 % after crystallization) determined by
ane/iPrOH, 90:10; 1 mL/min): tR = 18.4 (major enantiomer), 19.6
(minor enantiomer) min; oil. [α]2D0 = –41.3 (c = 0.38, CHCl3, ee
1
HPLC (Chiralpak AD-H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
81%). H NMR (300 MHz, CDCl3): δ = 8.67 (dq, J = 4.8, 0.9 Hz,
21.3 (major enantiomer), 24.2 (minor enantiomer); white solid;
1 H), 8.02 (dt, J = 7.8, 0.9 Hz, 1 H), 7.85 (td, J = 7.8, 1.8 Hz, 1
H), 7.51 (ddd, J = 7.8, 4.8, 1.8 Hz, 1 H), 7.18 (m, 2 H), 6.98 (m, 2
m.p. 67–69 °C. [α]2D0 = –38.4 (c = 0.53, CHCl3, ee 97%). H NMR
1
(300 MHz, CDCl3): δ = 8.66 (dq, J = 4.8, 0.9 Hz, 1 H), 7.98 (dt, J H), 4.81 (dd, J = 12.6, 6.6 Hz, 1 H), 4.70 (dd, J = 12.6, 7.8 Hz, 1
= 7.8, 0.9 Hz, 1 H), 7.84 (td, J = 7.8, 1.2 Hz, 1 H), 7.49 (ddd, J =
7.8, 4.8, 1.2 Hz, 1 H), 7.27 (m, 2 H), 7.19 (m, 2 H), 4.77 (dd, J =
12.3, 6.3 Hz, 1 H), 4.65 (dd, J = 12.6, 8.4 Hz, 1 H), 4.21 (m, 1 H),
3.81 (dd, J = 18.3, 7.2 Hz, 1 H), 3.59 (dd, J = 18.3, 6.9 Hz, 1
H), 4.57 (m, 1 H), 3.88 (dd, J = 18.3, 6.6 Hz, 1 H), 3.68 (dd, J =
18.3, 6.9 Hz, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 198.1
(s), 152.0 (s), 148.9 (d), 142.0 (s), 137.1 (d), 127.6 (d), 127.0 (d),
125.5 (d), 124.6 (d), 122.0 (d), 80.1 (t), 41.7 (t), 34.7 (d) ppm.
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 198.2 (s), 152.5 (s), HRMS (ESI): m/z calcd. for C13H13N2O3S [M + H] 277.0647;
148.9 (d), 138.2 (s), 137.1 (d), 132.0 (d), 129.3 (d), 127.6 (d), 121.9
(d), 121.7 (s), 79.5 (t), 40.6 (t), 38.8 (d) ppm. HRMS (ESI): m/z
calcd. for C15H14BrN2O3 [M + H] 349.0188; found 349.0186.
found 277.0645.
(S)-(–)-4-Nitro-1-(pyridin-2-yl)-3-(thien-3-yl)-butan-1-one (2k):
Purified by column chromatography (hexane/EtOAc, 70:30). Enan-
tiomeric excess (81 %) determined by HPLC (Chiralpak AD-H;
hexane/iPrOH, 90:10; 1 mL/min): tR = 20.0 (major enantiomer),
(S)-(–)-3-(4-Methoxyphenyl)-4-nitro-1-(pyridin-2-yl)butan-1-one
(2g): Purified by column chromatography (hexane/EtOAc, 70:30).
Enantiomeric excess (78%, 99% after crystallization) determined
by HPLC (Chiralpak AD-H; hexane/iPrOH, 90:10; 1 mL/min): tR
= 26.5 (major enantiomer), 28.3 (minor enantiomer) min; white so-
lid; m.p. 66–69 °C. [α]2D0 = –41.5 (c = 0.27, CHCl3, ee 99%). 1H
NMR (300 MHz, CDCl3): δ = 8.64 (dq, J = 4.8, 0.9 Hz, 1 H), 7.95
(dt, J = 7.8, 0.9 Hz, 1 H), 7.80 (td, J = 7.8, 1.2 Hz, 1 H), 7.47 (ddd,
J = 7.8, 4.8, 1.2 Hz, 1 H), 7.20 (m, 2 H), 6.80 (m, 2 H), 4.73 (dd,
21.7 (minor enantiomer) min; white solid; m.p. 55–58 °C. [α]2D0
=
1
–30.2 (c = 0.46, CHCl3, ee 81%). H NMR (300 MHz, CDCl3): δ
= 8.67 (dq, J = 4.8, 0.9 Hz, 1 H), 8.00 (dt, J = 7.8, 0.9 Hz, 1 H),
7.85 (td, J = 7.8, 1.2 Hz, 1 H), 7.51 (ddd, J = 7.8, 4.8, 1.2 Hz, 1
H), 7.27 (m, 1 H), 7.15 (m, 1 H), 7.04 (m, 1 H), 4.77 (dd, J = 12.3,
6.6 Hz, 1 H), 4.66 (dd, J = 12.3, 7.8 Hz, 1 H), 4.39 (m, 1 H), 3.83
(dd, J = 18.3, 7.2 Hz, 1 H), 3.62 (dd, J = 18.3, 7.2 Hz, 1 H) ppm.
J = 12.3, 6.6 Hz, 1 H), 4.60 (dd, J = 12.3, 8.1 Hz, 1 H), 4.17 (m, 1 13C NMR (75.5 MHz, CDCl3): δ = 198.4 (s), 152.5 (s), 148.9 (d),
H), 3.78 (dd, J = 18.3, 7.2 Hz, 1 H), 3.73 (s, 3 H), 3.57 (dd, J = 139.7 (s), 137.2 (d), 127.6 (d), 126.5 (d), 122.1 (d), 122.0 (d), 79.6
18.0, 7.2 Hz, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 198.5
(t), 40.6 (t), 34.7 (d) ppm. HRMS (ESI): m/z calcd. for
(s), 159.0 (s), 152.6 (s), 148.8 (d), 137.1 (d), 131.1 (s), 128.6 (d), C13H13N2O3S [M + H] 277.0647; found 277.0649.
127.5 (d), 121.9 (d), 114.3 (d), 110.7 (d), 80.1 (t), 55.2 (q), 40.9 (t),
(S)-(–)-3-(Furan-2-yl)-4-nitro-1-(pyridin-2-yl)butan-1-one (2l): Puri-
38.6 (d) ppm. HRMS (ESI): m/z calcd. for C16H17N2O4 [M + H]
fied by column chromatography (hexane/EtOAc, 70:30). Enantio-
301.1188; found 301.1190.
meric excess (79%) determined by HPLC (Chiralpak AS-H; hex-
(S)-(–)-4-Nitro-3-(4-nitrophenyl)-1-(pyridin-2-yl)butan-1-one (2h): ane/iPrOH, 80:20; 1 mL/min): tR = 14.2 (major enantiomer), 15.1
Purified by column chromatography (hexane/EtOAc, 70:30). Enan-
tiomeric excess (74 %) determined by HPLC (Chiralpak AD-H;
hexane/iPrOH, 70:30; 1 mL/min): tR = 17.9 (major enantiomer),
23.9 (minor enantiomer) min; yellow oil. [α]2D0 = –25.3 (c = 0.34,
CHCl3, ee 74%). H NMR (300 MHz, CDCl3): δ = 8.64 (dq, J =
4.8, 0.9 Hz, 1 H), 8.19 (m, 2 H), 8.00 (dt, J = 7.8, 0.9 Hz, 1 H),
(minor enantiomer) min; oil. [α]2D0 = –18.5 (c = 0.32, CHCl3, ee
79%). H NMR (300 MHz, CDCl3): δ = 8.67 (dq, J = 4.8, 0.9 Hz,
1 H), 8.02 (dt, J = 7.8, 0.9 Hz, 1 H), 7.86 (td, J = 7.8, 1.8 Hz, 1
H), 7.50 (ddd, J = 7.8, 4.8, 1.8 Hz, 1 H), 7.32 (dd, J = 1.8, 0.9 Hz,
1 H), 6.27 (dd, J = 3.3, 1.8 Hz, 1 H), 6.18 (dd, J = 3.3, 0.9 Hz, 1
H), 4.76 (d, J = 6.9 Hz, 2 H), 4.34 (quint., J = 6.9 Hz, 1 H), 3.84
1
1
Eur. J. Org. Chem. 2013, 1696–1705
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1701

G. Blay, C. Incerti, M. C. Muñoz, J. R. Pedro
(dd, J = 18.3, 6.6 Hz, 1 H), 3.64 (dd, J = 18.6, 7.2 Hz, 1 H) ppm. Major Diastereomer: Enantiomeric excess (57 %) determined by
FULL PAPER
13C NMR (75.5 MHz, CDCl3): δ = 198.2 (s), 152.5 (s), 152.1 (s), HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
=
149.0 (d), 142.2 (d), 137.1 (d), 127.6 (d), 121.9 (d), 110.4 (d), 107.1
13.7 (major enantiomer), 17.0 (minor enantiomer) min; oil. [α]2D0
1
(d), 77.4 (t), 38.5 (t), 33.1 (d) ppm. HRMS (ESI): m/z calcd. for –23.6 (c = 0.33, CHCl3, ee 57%). H NMR (300 MHz, CDCl3): δ
C13H13N2O4 [M + H] 261.0875; found 261.0876.
= 8.64 (dq, J = 4.8, 0.9 Hz, 1 H), 7.89 (dt, J = 7.8, 0.9 Hz, 1 H),
7.79 (td, J = 7.8, 1.8 Hz, 1 H), 7.43 (m, 3 H), 7.15 (m, 2 H), 4.86
(m, 1 H), 4.02 (m, 2 H), 3.41 (m, 1 H), 1.37 (d, J = 6.6 Hz,
3 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 198.1 (s), 152.6 (s),
148.9 (d), 137.5 (s), 137.0 (d), 132.0 (d), 130.1 (d), 127.5 (d), 121.9
(d), 121.6 (s), 86.8 (d), 44.7 (d), 40.3 (t), 17.5 (q) ppm. HRMS
(ESI): m/z calcd. for C16H16BrN2O3 [M + H] 363.0344; found
363.0338.
(R)-(+)-3-Methyl-4-nitro-1-(pyridin-2-yl)butan-1-one (2m): Purified
by column chromatography (hexane/EtOAc, 70:30). Enantiomeric
excess (87 %) determined by HPLC (Chiralpak AS-H; hexane/
iPrOH, 80:20; 1 mL/min): tR = 10.5 (major enantiomer), 11.5
(minor enantiomer) min; oil. [α]2D0 = +5.2 (c = 0.30, CHCl3, ee
1
87%). H NMR (300 MHz, CDCl3): δ = 8.66 (dq, J = 4.8, 0.9 Hz,
1 H), 8.04 (dt, J = 7.8, 0.9 Hz, 1 H), 7.85 (td, J = 7.8, 1.8 Hz, 1
H), 7.46 (ddd, J = 7.8, 4.8, 1.8 Hz, 1 H), 4.54 (dd, J = 11.7, 5.7 Hz,
1 H), 4.38 (dd, J = 11.7, 7.2 Hz, 1 H), 3.33 (dd, J = 7.2, 1.2 Hz, 2
H), 3.02 (m, 1 H), 1.15 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 199.4 (s), 152.9 (s), 148.9 (d), 137.0 (d),
127.4 (d), 121.8 (d), 80.6 (t), 41.0 (t), 28.6 (d), 17.6 (q) ppm. HRMS
(ESI): m/z calcd. for C10H13N2O3 [M + H] 209.0926; found
209.0925.
Minor Diastereomer: Enantiomeric excess (55 %) determined by
HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
16.3 (major enantiomer), 19.4 (minor enantiomer) min; white solid;
1
m.p. 81–85 °C. [α]2D0 = –29.4 (c = 0.24, CHCl3, ee 55%). H NMR
(300 MHz, CDCl3): δ = 8.67 (dq, J = 4.8, 0.9 Hz, 1 H), 7.94 (dt, J
= 7.8, 0.9 Hz, 1 H), 7.82 (td, J = 7.8, 1.2 Hz, 1 H), 7.48 (ddd, J =
7.8, 4.8, 1.2 Hz, 1 H), 7.40 (m, 2 H), 7.13 (m, 2 H), 4.93 (m, 1 H),
3.97 (m, 1 H), 3.87 (dd, J = 17.7, 8.7 Hz, 1 H), 3.66 (dd, J = 17.7,
5.1 Hz, 1 H), 1.61 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 198.3 (s), 152.9 (s), 148.9 (d), 137.7 (s), 137.1 (d), 131.8
(d), 130.0 (d), 127.6 (d), 122.0 (d), 121.7 (s), 86.8 (d), 44.3 (d), 38.9
(t), 17.1 (q) ppm. HRMS (ESI): m/z calcd. for C16H16BrN2O3 [M
+ H] 363.0344; found 363.0338.
(S)-(–)-4,4-Dimethyl-3-(nitromethyl)-1-(pyridin-2-yl)pentan-1-one
(2n): Purified by column chromatography (hexane/EtOAc, 70:30).
Enantiomeric excess (81%) determined by HPLC (Chiralpak AS-
H; hexane/iPrOH, 80:20; 1 mL/min): tR = 7.2 (major enantiomer),
8.4 (minor enantiomer) min; oil. [α]2D0 = –8.6 (c = 0.48, CHCl3, ee
1
81%). H NMR (300 MHz, CDCl3): δ = 8.67 (dq, J = 4.8, 0.9 Hz,
1 H), 8.03 (dt, J = 7.8, 0.9 Hz, 1 H), 7.85 (td, J = 7.8, 1.2 Hz, 1
H), 7.48 (ddd, J = 7.8, 4.8, 1.2 Hz, 1 H), 4.60 (dd, J = 12.6, 4.8 Hz,
1 H), 4.34 (dd, J = 12.6, 8.1 Hz, 1 H), 3.59 (dd, J = 18.3, 4.5 Hz,
1 H), 3.24 (dd, J = 18.3, 7.5 Hz, 1 H), 2.98 (m, 1 H), 0.99 (s, 9
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 199.7 (s), 148.8 (d),
137.1 (d), 127.4 (d), 122.1 (d), 77.6 (t), 42.1 (d), 36.8 (t), 33.3 (s),
28.7 (d), 27.3 (q) ppm. HRMS (ESI): m/z calcd. for C13H19N2O3
[M + H] 251.1396; found 251.1397.
3-(4-Methoxyphenyl)-4-nitro-1-(pyridin-2-yl)pentan-1-one (6g):
Purified by column chromatography (hexane/EtOAc, 80:20).
Major Diastereomer: Enantiomeric excess (77 %) determined by
HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
=
17.4 (major enantiomer), 20.2 (minor enantiomer) min; oil. [α]2D0
1
–28.8 (c = 0.24, CHCl3, ee 77%). H NMR (300 MHz, CDCl3): δ
= 8.64 (dq, J = 4.8, 0.9 Hz, 1 H), 7.88 (dt, J = 7.8, 0.9 Hz, 1 H),
7.77 (td, J = 7.8, 1.8 Hz, 1 H), 7.45 (ddd, J = 7.8, 4.8, 1.2 Hz, 1
H), 7.16 (m, 2 H), 6.80 (m, 2 H), 4.83 (m, 1 H), 3.95 (m, 2 H), 3.74
(s, 3 H), 3.39 (m, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
198.3 (s), 158.8 (s), 152.7 (s), 148.7 (d), 136.9 (d), 130.3 (s), 129.4
(d), 127.3 (d), 121.8 (d), 114.1 (d), 87.3 (d), 55.1 (q), 44.4 (d), 40.5
(t), 17.5 (q) ppm. HRMS (ESI): m/z calcd. for C17H19N2O4 [M +
H] 315.1345; found 315.1345.
4-Nitro-3-phenyl-1-(pyridin-2-yl)pentan-1-one (6a): Purified by col-
umn chromatography (hexane/EtOAc, 80:20).
Major Diastereomer: Enantiomeric excess (81 %) determined by
HPLC (Chiralpak AD-H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
13.7 (major enantiomer), 17.0 (minor enantiomer) min; white solid;
1
m.p. 61–67 °C. [α]2D0 = –29.9 (c = 0.31, CHCl3, ee 81%). H NMR
(300 MHz, CDCl3): δ = 8.65 (dq, J = 4.8, 0.9 Hz, 1 H), 7.89 (dt, J
= 7.8, 0.9 Hz, 1 H), 7.78 (td, J = 7.8, 1.8 Hz, 1 H), 7.44 (ddd, J =
7.8, 4.8, 1.8 Hz, 1 H), 7.25 (m, 5 H), 4.89 (m, 1 H), 3.99 (m, 2 H),
3.46 (m, 1 H), 1.36 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 198.2 (s), 152.6 (s), 148.8 (d), 138.5 (s), 136.9 (d), 128.8
(d), 128.4 (d), 127.6 (d), 127.3 (d), 121.8 (d), 87.2 (d), 45.1 (d), 40.5
(t), 17.6 (q) ppm. HRMS (ESI): m/z calcd. for C16H17N2O3 [M +
H] 285.1239; found 285.1240.
Minor Diastereomer: Enantiomeric excess (71 %) determined by
HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
21.1 (major enantiomer), 24.2 (minor enantiomer) min; white solid;
1
m.p. 63–67 °C. [α]2D0 = –35.9 (c = 0.17, CHCl3, ee 71%). H NMR
(300 MHz, CDCl3): δ = 8.67 (dq, J = 4.8, 0.9 Hz, 1 H), 7.93 (dt, J
= 7.8, 0.9 Hz, 1 H), 7.82 (td, J = 7.8, 1.8 Hz, 1 H), 7.49 (ddd, J =
7.8, 4.8, 1.8 Hz, 1 H), 7.15 (m, 2 H), 6.78 (m, 2 H), 4.92 (quint., J
= 6.6 Hz, 1 H), 3.95 (m, 1 H), 3.84 (dd, J = 17.7, 8.7 Hz, 1 H),
3.74 (s, 3 H), 3.65 (dd, J = 17.7, 5.1 Hz, 1 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 198.6 (s), 158.8 (s), 152.6 (s), 148.7 (d),
137.2 (d), 130.5 (s), 129.2 (d), 127.4 (d), 122.0 (d), 114.0 (d), 87.2
(d), 55.1 (q), 44.1 (d), 39.1 (t), 16.9 (q) ppm. HRMS (ESI): m/z
calcd. for C17H19N2O4 [M + H] 315.1345; found 315.1345.
Minor Diastereomer: Enantiomeric excess (71 %) determined by
HPLC (Chiralpak AD-H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
13.7 (major enantiomer), 17.0 (minor enantiomer) min; white solid;
1
m.p. 78–83 °C. [α]2D0 = –54.4 (c = 0.27, CHCl3, ee 71%). H NMR
(300 MHz, CDCl3): δ = 8.60 (dq, J = 4.8, 0.9 Hz, 1 H), 7.88 (dt, J
= 7.8, 0.9 Hz, 1 H), 7.74 (td, J = 7.8, 1.8 Hz, 1 H), 7.40 (ddd, J =
7.8, 4.8, 1.8 Hz, 1 H), 7.18 (m, 5 H), 4.89 (quint., J = 6.6 Hz, 1 H),
3.95 (m, 1 H), 3.79 (dd, J = 18, 8.7 Hz, 1 H), 3.63 (dd, J = 18,
5.7 Hz, 1 H), 1.53 (d, J = 6.6 Hz, 1 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 198.5 (s), 152.4 (s), 148.8 (d), 138.6 (s), 137.1 (d), 128.6
(d), 128.2 (d), 127.6 (d), 127.5 (d), 122.0 (d), 87.1 (d), 44.7 (d), 38.9
(t), 16.9 (q) ppm. HRMS (ESI): m/z calcd. for C16H17N2O3 [M +
H] 285.1239; found 285.1240.
4-Nitro-3-(4-nitrophenyl)-1-(pyridin-2-yl)pentan-1-one (6h): Purified
by column chromatography (hexane/EtOAc, 80:20).
Major Diastereomer: Enantiomeric excess (81 %) determined by
HPLC (Chiralpak AD–H; hexane/iPrOH, 70:30; 1 mL/min): tR
=
13.0 (major enantiomer), 17.9 (minor enantiomer) min; yellow so-
lid; m.p. 98–100 °C. [α]2D0 = –48.2 (c = 0.31, CHCl3, ee 81%). 1H
NMR (300 MHz, CDCl3): δ = 8.64 (dq, J = 4.8, 0.9 Hz, 1 H), 8.16
(m, 2 H), 7.87 (dt, J = 7.8, 0.9 Hz, 1 H), 7.80 (td, J = 7.8, 1.8 Hz,
1 H), 7.45 (m, 3 H), 4.92 (m, 1 H), 4.13 (m, 2 H), 3.47 (dt, J = 17.4,
3-(4-Bromophenyl)-4-nitro-1-(pyridin-2-yl)pentan-1-one (6f): Puri-
fied by column chromatography (hexane/EtOAc, 80:20).
1702
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1696–1705

Nitro-Michael Addition to 2-Azachalcones
0.6 Hz, 1 H), 1.40 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 197.7 (s), 152.3 (s), 148.9 (d), 147.4 (s), 146.0 (s), 137.0
(d), 129.4 (d), 127.7 (d), 124.0 (d), 121.8 (d), 86.3 (d), 44.8 (d), 40.1
(t), 17.4 (q) ppm. HRMS (ESI): m/z calcd. for C16H16N3O5 [M +
H] 330.1090; found 330.1091.
10.3 (q) ppm. HRMS (ESI): m/z calcd. for C17H19N2O3 [M + H]
299.1396; found 299.1396.
Minor Diastereomer: Enantiomeric excess (72 %) determined by
HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
13.7 (major enantiomer), 12.0 (minor enantiomer) min; white solid;
m.p. 80–85 °C. [α]2D0 = –23.2 (c = 0.41, CHCl3, ee 72%). H NMR
1
Minor Diastereomer: Enantiomeric excess (79 %) determined by
(300 MHz, CDCl3): δ = 8.69 (dq, J = 4.8, 0.9 Hz, 1 H), 7.95 (dt, J
= 7.8, 0.9 Hz, 1 H), 7.83 (td, J = 7.8, 1.8 Hz, 1 H), 7.49 (ddd, J =
7.8, 4.8, 1.8 Hz, 1 H), 7.25 (m, 5 H), 4.81 (m, 1 H), 3.99 (m, 1 H),
3.82 (dd, J = 18.0, 6.8 Hz, 1 H), 3.73 (dd, J = 18.0, 6.0 Hz, 1 H),
2.06 (m, 1 H), 1.98 (m, 1 H), 1.01 (t, J = 7.5 Hz, 3 H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 198.5 (s), 152.6 (s), 148.7 (d), 138.8
(s), 137.1 (d), 128.5 (d), 128.2 (d), 127.6 (d), 127.4 (d), 122.0 (d),
94.2 (d), 43.9 (d), 39.6 (t), 24.6 (t), 10.4 (q) ppm. HRMS (ESI): m/z
calcd. for C17H19N2O3 [M + H] 299.1396; found 299.1396.
HPLC (Chiralpak AD–H; hexane/iPrOH, 70:30; 1 mL/min): tR
=
14.1 (major enantiomer), 23.3 (minor enantiomer) min; yellow so-
1
lid; m.p. 119–123 °C. [α]2D0 = –51.2 (c = 0.17, CHCl3, ee 79%). H
NMR (300 MHz, CDCl3): δ = 8.66 (dq, J = 4.8, 0.9 Hz, 1 H), 8.13
(m, 2 H), 7.92 (dt, J = 7.8, 0.9 Hz, 1 H), 7.81 (td, J = 7.8, 1.2 Hz,
1 H), 7.50 (ddd, J = 7.8, 4.8, 1.2 Hz, 1 H), 7.45 (m, 2 H), 4.98 (m,
1 H), 4.13 (m, 1 H), 3.92 (dd, J = 18, 9 Hz, 1 H), 3.68 (dd, J = 18,
5.1 Hz, 1 H), 1.66 (d, J = 6.6 Hz, 1 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 197.9 (s), 152.4 (s), 149.0 (d), 146.3 (s), 137.1 (d), 129.2
(d), 127.8 (d), 123.8 (d), 122.0 (d), 86.7 (d), 44.7 (d), 38.9 (t), 17.3
(q) ppm. HRMS (ESI): m/z calcd. for C16H16N3O5 [M + H]
330.1090; found 330.1091.
3-(4-Bromophenyl)-4-nitro-1-(pyridin-2-yl)hexan-1-one (7f): Purified
by column chromatography (hexane/EtOAc, 80:20).
Major Diastereomer: Enantiomeric excess (51 %) determined by
4-Nitro-1-(pyridin-2-yl)-3-(thien-3-yl)pentan-1-one (6k): Purified by
column chromatography (hexane/EtOAc, 80:20).
HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
12.8 (major enantiomer), 15.4 (minor enantiomer) min; white solid;
1
m.p. 80–88 °C. [α]2D0 = –13.6 (c = 0.34, CHCl3, ee 51%). H NMR
Major Diastereomer: Enantiomeric excess (81 %) determined by
(300 MHz, CDCl3): δ = 8.63 (dq, J = 4.8, 0.9 Hz, 1 H), 7.87 (dt, J
= 7.8, 0.9 Hz,1 H), 7.77 (td, J = 7.8, 1.8 Hz, 1 H), 7.43 (m, 3 H),
7.15 (m, 2 H), 4.67 (td, J = 9.6 Hz, 1 H), 3.99 (m, 2 H), 3.33 (m,
1 H), 1.84 (m, 1 H), 1.53 (m, 1 H), 0.88 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 198.1 (s), 152.3 (s), 148.8 (d),
137.9 (s), 136.9 (d), 132.0 (d), 130.1 (d), 127.4 (d), 121.8 (d), 121.5
(s), 94.0 (d), 44.0 (d), 40.4 (t), 25.4 (t), 10.2 (q) ppm. HRMS (ESI):
m/z calcd. for C17H18BrN2O3 [M + H] 377.0501; found 377.0506.
HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
13.2 (major enantiomer), 15.6 (minor enantiomer) min; white solid;
m.p. 67–69 °C. [α]2D0 = –36.9 (c = 0.16, CHCl3, ee 81%). H NMR
1
(300 MHz, CDCl3): δ = 8.66 (dq, J = 4.8, 0.9 Hz, 1 H), 7.94 (dt, J
= 7.8, 0.9 Hz, 1 H), 7.80 (td, J = 7.8, 1.8 Hz, 1 H), 7.47 (ddd, J =
7.8, 4.8, 1.8 Hz, 1 H), 7.27 (dd, J = 3, 1.5 Hz, 1 H), 7.15 (m, 1 H),
7.00 (dd, J = 4.8, 1.4 Hz, 1 H), 4.89 (m, 1 H), 4.23 (m, 1 H), 3.95
(dd, J = 17.7, 9.3 Hz, 1 H), 3.42 (dd, J = 17.7, 4.5 Hz, 1 H), 1.42
(d, J = 6.9 Hz,1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 198.3
(s), 152.7 (s), 148.9 (d), 138.7 (s), 137.0 (d), 127.4 (d), 126.3 (d),
122.9 (d), 121.8 (d), 86.6 (d), 40.4 (d), 40.3 (t), 17.1 (q) ppm. HRMS
(ESI): m/z calcd. for C14H15N2O3S [M + H] 291.0803; found
291.0807.
Minor Diastereomer: Enantiomeric excess (54 %) determined by
HPLC (Chiralpak IC; hexane/iPrOH, 90:10; 1 mL/min): tR = 9.0
(major enantiomer), 7.9 (minor enantiomer) min; oil. [α]2D0 = –20.9
1
(c = 0.57, CHCl3, ee 54%). H NMR (300 MHz, CDCl3): δ = 8.66
(dq, J = 4.8, 0.9 Hz, 1 H), 7.93 (dt, J = 7.8, 0.9 Hz, 1 H), 7.81 (td,
J = 7.8, 1.2 Hz, 1 H), 7.48 (ddd, J = 7.8, 4.8, 1.2 Hz, 1 H), 7.37
(m, 2 H), 7.12 (m, 2 H), 4.75 (m, 1 H), 3.94 (m, 1 H), 3.81 (dd, J
= 17.7, 8.4 Hz, 1 H), 3.68 (dd, J = 18, 5.7 Hz, 1 H), 1.99 (m, 2 H),
1.00 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
198.2 (s), 152.5 (s), 148.8 (d), 137.8 (s), 137.1 (d), 131.7 (d), 129.9
(d), 127.6 (d), 122.0 (d), 121.6 (s), 93.9 (d), 43.5 (d), 39.5 (t), 24.8
(t), 10.3 (q) ppm. HRMS (ESI): m/z calcd. for C17H18BrN2O3 [M
+ H] 377.0501; found 377.0506.
Minor Diastereomer: Enantiomeric excess (70 %) determined by
HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
15.0 (major enantiomer), 17.2 (minor enantiomer) min; white solid;
m.p. 97–99 °C. [α]2D0 = –36.2 (c = 0.32, CHCl3, ee 70%). H NMR
1
(300 MHz, CDCl3): δ = 8.67 (dq, J = 4.8, 0.9 Hz, 1 H), 7.96 (dt, J
= 7.8, 0.9 Hz, 1 H), 7.82 (td, J = 7.8, 1.8 Hz, 1 H), 7.51 (ddd, J =
7.8, 4.8, 1.8 Hz, 1 H), 7.23 (dd, J = 4.8, 2.7 Hz, 1 H), 7.11 (m, 1
H), 7.00 (dd, J = 5.1, 1.5 Hz, 1 H), 4.99 (quint., J = 6.6 Hz, 1 H),
4.17 (m, 1 H), 3.85 (dd, J = 18, 8.1 Hz, 1 H), 3.66 (dd, J = 18,
5.7 Hz, 1 H), 1.58 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 198.5 (s), 152.6 (s), 148.8 (s), 139.1 (d), 137.2 (d), 127.5
(d), 126.9 (d), 126.0 (d), 122.7 (d), 122.0 (d), 86.4 (d), 40.2 (d), 39.0
(t), 16.7 (q) ppm. HRMS (ESI): m/z calcd. for C14H15N2O3S [M +
H] 291.0803; found 291.0807.
3-(4-Methoxyphenyl)-4-nitro-1-(pyridin-2-yl)hexan-1-one (7g): Puri-
fied by column chromatography (hexane/EtOAc, 80:20).
Major Diastereomer: Enantiomeric excess (64 %) determined by
HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
17.5 (major enantiomer), 19.1 (minor enantiomer) min; white solid;
1
m.p. 77–80 °C. [α]2D0 = –14.6 (c = 0.30, CHCl3, ee 64%). H NMR
4-Nitro-3-phenyl-1-(pyridin-2-yl)hexan-1-one (7a): Purified by col-
umn chromatography (hexane/EtOAc, 80:20).
(300 MHz, CDCl3): δ = 8.64 (dq, J = 4.8, 0.9 Hz, 1 H), 7.87 (dt, J
= 7.8, 0.9 Hz, 1 H), 7.75 (td, J = 7.8, 1.5 Hz, 1 H), 7.17 (m, 2 H),
6.80 (m, 2 H), 4.67 (m, 1 H), 3.95 (m, 2 H), 3.74 (s, 3 H), 3.32 (dd,
J = 17.1, 3 Hz, 1 H), 1.85 (m, 1 H), 1.55 (m, 1 H), 0.86 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 198.4 (s),
158.8 (s), 152.7 (s), 148.8 (d), 136.8 (d), 130.8 (s), 129.3 (d), 127.2
(d), 121.8 (d), 114.2 (d), 94.6 (d), 55.1 (d), 43.8 (q), 40.7 (t), 25.4
(t), 10.3 (q) ppm. HRMS (ESI): m/z calcd. for C18H21N2O4 [M +
H] 329.1501; found 329.1501.
Major Diastereomer: Enantiomeric excess (80 %) determined by
HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
=
11.7 (major enantiomer), 13.5 (minor enantiomer) min; oil. [α]2D0
1
–21.2 (c = 0.24, CHCl3, ee 80%). H NMR (300 MHz, CDCl3): δ
= 8.63 (dq, J = 4.8, 0.9 Hz, 1 H), 7.86 (dt, J = 7.8, 0.9 Hz, 1 H),
7.73 (td, J = 7.8, 1.2 Hz, 1 H), 7.41 (ddd, J = 7.8, 4.8, 1.2 Hz, 1
H), 7.25 (m, 5 H), 4.68 (td, J = 10.8, 3.3 Hz, 1 H), 3.98 (m, 2 H),
3.35 (dt, J = 17.4, 1.2 Hz, 1 H), 1.86 (m, 1 H), 1.53 (m, 1 H), 0.86 Minor Diastereomer: Enantiomeric excess (61 %) determined by
(t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 198.2
(s), 152.7 (s), 148.8 (d), 138.9 (s), 136.8 (d), 128.8 (d), 128.4 (d),
127.5 (d), 127.3 (d), 121.8 (d), 94.5 (d), 44.5 (d), 40.7 (t), 25.5 (t),
HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR =
22.0 (major enantiomer), 20.7 (minor enantiomer) min; white solid;
m.p. 115–120 °C. [α]2D0 = –18.4 (c = 0.83, CHCl3, ee 61%). 1H NMR
Eur. J. Org. Chem. 2013, 1696–1705
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1703

G. Blay, C. Incerti, M. C. Muñoz, J. R. Pedro
FULL PAPER
(300 MHz, CDCl3): δ = 8.67 (dq, J = 4.8, 0.9 Hz, 1 H), 7.93 (dt, J 3.79 (dd, J = 18.0, 8.1 Hz, 1 H), 3.67 (dd, J = 18.0, 6.0 Hz, 1 H),
= 7.8, 0.9 Hz, 1 H), 7.80 (td, J = 7.8, 1.8 Hz, 1 H), 7.47 (ddd, J =
7.8, 4.8, 1.8 Hz, 1 H), 7.15 (m, 2 H), 6.77 (m, 2 H), 4.75 (m, 1 H),
3.94 (m, 1 H), 3.79 (dd, J = 17.7, 8.1 Hz, 1 H), 3.74 (s, 3 H), 3.68
2.02 (m, 1 H), 1.88 (m, 1 H), 0.99 (t, J = 7.1 Hz, 3 H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 198.5 (s), 152.6 (s), 148.8 (d), 139.2
(s), 137.1 (d), 127.5 (d), 127.0 (d), 125.8 (d), 122.7 (d), 122.0 (d),
(dd, J = 17.7, 6 Hz, 1 H), 2.02 (m, 2 H), 0.98 (t, J = 7.5 Hz, 3 93.6 (d), 39.5 (d), 39.4 (t), 24.5 (t), 10.4 (q) ppm. HRMS (ESI): m/z
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 198.6 (s), 158.8 (s), calcd. for C15H17N2O3S [M + H] 305.0960; found 305.0963.
152.7 (s), 148.7 (d), 137.1 (d), 130.7 (s), 129.2 (d), 127.4 (d), 121.9
(d), 113.9 (d), 94.4 (d), 55.1 (d), 43.3 (q), 39.7 (t), 24.7 (t), 10.4
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of compounds 2 and
(q) ppm. HRMS (ESI): m/z calcd. for C18H21N2O4 [M + H]
4–7.
329.1501; found 329.1501.
4-Nitro-3-(4-nitrophenyl)-1-(pyridin-2-yl)hexan-1-one (7h): Purified
by column chromatography (hexane/EtOAc, 80:20).
Acknowledgments
Major Diastereomer: Enantiomeric excess (83 %) determined by
Financial support from the Ministerio de Ciencia e Innovación
HPLC (Chiralpak AD–H; hexane/iPrOH, 70:30; 1 mL/min): tR
=
(MICINN) and Fundo Europeu de Desenvolvimento Regional
(FEDER) (grant number CTQ2009-13083) and from Generalitat
Valenciana (grant numbers ACOMP/2012/212 and ISIC 2012/001)
is acknowledged.
13.8 (major enantiomer), 18.5 (minor enantiomer) min; yellow so-
lid; m.p. 124–125 °C. [α]2D0 = –41.7 (c = 0.12, CHCl3, ee 83%). H
1
NMR (300 MHz, CDCl3): δ = 8.64 (dq, J = 4.8, 0.9 Hz, 1 H), 8.17
(m, 2 H), 7.87 (dt, J = 7.8, 0.9 Hz, 1 H), 7.79 (td, J = 7.8, 1.8 Hz,
1 H), 7.47 (m, 3 H), 4.73 (m, 1 H), 4.10 (m, 2 H), 3.39 (m, 1 H),
1.88 (m, 1 H), 1.52 (m, 1 H), 0.91 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 197.7 (s), 152.3 (s), 148.9 (d), 147.5
(s), 146.4 (s), 137.0 (d), 129.4 (d), 127.6 (d), 124.0 (d), 121.8 (d),
93.5 (d), 44.2 (d), 40.2 (t), 25.4 (t), 10.2 (q) ppm. HRMS (ESI): m/z
calcd. for C17H18N3O5 [M + H] 344.1246; found 344.1255.
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Minor Diastereomer: Enantiomeric excess (57 %) determined by
HPLC (Chiralpak AD–H; hexane/iPrOH, 70:30; 1 mL/min): tR
=
14.2 (major enantiomer), 15.8 (minor enantiomer) min; yellow so-
lid; m.p. 155–160 °C. [α]2D0 = –30.1 (c = 0.80, CHCl3, ee 57%). H
1
NMR (300 MHz, CDCl3): δ = 8.66 (dq, J = 4.8, 0.9 Hz, 1 H), 8.12
(m, 2 H), 7.92 (dt, J = 7.8, 0.9 Hz, 1 H), 7.80 (td, J = 7.8, 1.5 Hz,
1 H), 7.48 (ddd, J = 7.8, 4.8, 1.5 Hz, 1 H), 7.43 (m, 2 H), 4.82 (m,
1 H), 4.08 (m, 1 H), 3.88 (dd, J = 18.3, 9.0 Hz, 1 H), 3.69 (dd, J =
18.3, 5.4 Hz, 1 H), 2.01 (m, 1 H), 1.00 (t, J = 7.5 Hz, 3 H) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 197.8 (s), 152.3 (s), 148.9 (d),
147.3 (s), 146.5 (s), 137.1 (d), 129.3 (d), 127.8 (d), 123.7 (d), 121.9
(d), 93.7 (d), 43.8 (d), 39.5 (t), 25.0 (t), 10.3 (q) ppm. HRMS (ESI):
m/z calcd. for C17H18N3O5 [M + H] 344.1246; found 344.1255.
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HPLC (Chiralpak AD–H; hexane/iPrOH, 90:10; 1 mL/min): tR
=
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12.3 (major enantiomer), 14.3 (minor enantiomer) min; white solid;
m.p. 80–85 °C. [α]2D0 = –9.3 (c = 0.42, CHCl3, ee 75%). H NMR
1
(300 MHz, CDCl3): δ = 8.64 (dq, J = 4.8, 0.9 Hz, 1 H), 7.90 (dt, J
= 7.8, 0.9 Hz, 1 H), 7.78 (td, J = 7.8, 1.8 Hz, 1 H), 7.44 (ddd, J =
7.8, 4.8, 1.8 Hz, 1 H), 7.24 (m, 1 H), 7.13 (m, 1 H), 6.98 (dd, J =
5.1, 1.5 Hz, 1 H), 4.69 (m, 1 H), 4.13 (td, J = 9.9, 3.6 Hz, 1 H),
3.97 (dd, J = 17.4, 10.2 Hz, 1 H), 3.32 (dd, J = 17.4, 3.6 Hz, 1 H),
1.86 (m, 1 H), 1.60 (m, 1 H), 0.88 (t, J = 7.5 Hz, 3 H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 198.3 (s), 152.7 (s), 148.8 (d), 139.2
(s), 136.9 (d), 127.3 (d), 126.7 (d), 126.3 (d), 122.8 (d), 121.8 (d),
94.0 (d), 40.4 (d), 39.8 (t), 25.3 (t), 10.3 (q) ppm. HRMS (ESI): m/z
calcd. for C15H17N2O3S [M + H] 305.0960; found 305.0963.
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=
15.1 (major enantiomer), 14.3 (minor enantiomer) min; white solid;
m.p. 108–116 °C. [α]2D0 = –20.3 (c = 0.46, CHCl3, ee 71%). 1H NMR
(300 MHz, CDCl3): δ = 8.67 (dq, J = 4.8, 0.9 Hz, 1 H), 7.96 (dt, J
= 7.8, 0.9 Hz, 1 H), 7.83 (td, J = 7.8, 1.8 Hz, 1 H), 7.49 (ddd, J =
7.8, 4.8, 1.8 Hz, 1 H), 7.22 (dd, J = 5.1, 3.0 Hz, 1 H), 7.09 (m, 1
H), 6.98 (dd, J = 5.1, 1.2 Hz, 1 H), 4.78 (m, 1 H), 4.14 (m, 1 H),
1704
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Eur. J. Org. Chem. 2013, 1696–1705

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Received: November 23, 2012
Published Online: February 6, 2013
Eur. J. Org. Chem. 2013, 1696–1705
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1705