Enantioselective organocatalytic michael additions of oxyacetaldehydes to nitroolefins

Article abstract of DOI:10.1002/ejoc.201001032

Alkyl and aryloxyacetaldehydes add enantioselectively to various nitroalkenes. Addition products were isolated in good yield and high enantiomeric purity (up to 96 ee) but only mediocre syn/anti ratios were achieved. The course of the reaction was investi

Full text of DOI:10.1002/ejoc.201001032

FULL PAPER
DOI: 10.1002/ejoc.201001032
Enantioselective Organocatalytic Michael Additions of Oxyacetaldehydes to
Nitroolefins
[a]
[a]
[b]
[b][†]
ˇ
ˇ
ˇ
Martin Hutka, Viera Polácková, Jozef Marák, Dusan Kaniansky,
[a]
[a]
ˇ
ˇ
Radovan Sebesta,* and Stefan Toma
Keywords: Aldehydes / Michael addition / Enantioselectivity / Organocatalysis / Density functional calculations
Alkyl and aryloxyacetaldehydes add enantioselectively to
various nitroalkenes. Addition products were isolated in
good yield and high enantiomeric purity (up to 96%ee) but
only mediocre syn/anti ratios were achieved. The course of
the reaction was investigated by mass spectrometry and by
DFT calculations.
The first report on the enantioselective addition of simple
aldehydes to nitroalkene was published by Barbas and later
extended with good results also to α,α-disubstituted alde-
hydes.[7] Alexakis used a diamine catalyst that provided the
addition product with high enantio- and diastereoselectiv-
ity.[8] Hayashi showed that diphenylprolinol silyl ethers cat-
alyzed the addition of simple aldehydes to nitroalkenes with
high diastereo- and enantioselectivities.[9] Lu and Chan
achieved excellent results in this reaction with a modified
diphenylperhydroindol silyl ether catalyst.[10] Replacement
of the phenyl groups with 1-methylimidazole in prolinol sil-
yl ether enabled the reaction to be performed in water.[11]
Palomo used 4-hydroxyprolylamides as catalysts and ob-
tained addition products with high diastereo- and enantio-
selectivities.[12] Other organocatalysts such as bimorpholine
derivatives, tripeptides, and spirocyclic diamines have cata-
lyzed this reaction as well.[13] Chiral thioureas were also
shown to be viable catalysts for the addition of simple alde-
hydes to nitroalkenes.[14] Enantioselective addition of alde-
hydes to β-nitroacrolein dimethyl acetal was published by
Vicario.[15] The best results (up to 88%ee) were achieved
with simple prolinol as the catalyst. The addition of benzyl-
oxyacetaldehyde wasalso mentioned in this work, although
for this particular example, the enantioselectivity was not
reported because of HPLC detection problems. Later, Vic-
ario and Badia expanded this methodology by applying
enantioselective addition of aldehydes to nitroacrolein di-
methylacetal in the construction of substituted pyrrolid-
ines.[16] Alexakis described nitrodienes as acceptors in the
addition of aldehydes and only 1,4-addition products have
been obtained in high yields and with high enantioselectivi-
ties.[17]
Introduction
Michael addition is one of the most important C–C
bond-forming reactions. A broad variety of stabilized as
well as nonstabilized nucleophiles can add to numerous
Michael acceptors, thus producing countless possibilities
for the construction of interesting structures or building
blocks suitable for further synthetic elaboration. Apart
from a range of metal-based catalysts, a diverse array of
small molecular weight organocatalysts has been investi-
gated for Michael additions.[1] Both major concepts devel-
oped in organocatalysis and enamine[2] and iminium acti-
vation[3] can operate in conjugate addition. Carbonyl com-
pounds can be rendered nucleophilic through enamine for-
mation, and α,β-unsaturated carbonyl compounds can be
activated through iminium formation. Furthermore, enan-
tioselective 1,4-addition is not restricted to α,β-unsaturated
carbonyl compounds. Nitroalkenes, alkenylphosphonates,
and sulfones are also useful Michael acceptors.[4] In particu-
lar, nitroalkenes attract a lot of attention. After the seminal
paper by List,[5] a number of organocatalyzed conjugate ad-
ditions of simple ketones[6] and aldehydes to nitroolefins
have been described.
Conjugate addition of aldehydes is more challenging due
to the greater reactivity of the aldehyde functionality, which
results in the undesired auto-aldol reaction. Several re-
search groups successfully overcame this problem, and 1,4-
additions of aldehydes have also been described recently.
[a] Department of Organic Chemistry, Faculty of Natural Sciences,
Comenius University,
Mlynska dolina CH-2, 84215 Bratislava, Slovakia, Slovak
Republic
Fax: +421-2-60296337
E-mail: sebesta@fns.uniba.sk
Michael addition of acetaldehyde, as the most reactive
enolizable aldehyde, constitutes a special challenge. List
solved this issue by slow addition of acetaldehyde to the
nitroolefin and thus obtained good yields and enantio-
selectivities.[18] On the other hand, functionalized acetalde-
[b] Department of Analytical Chemistry, Faculty of Natural
Sciences, Comenius University,
Mlynska dolina CH-2, 84215 Bratislava, Slovakia, Slovak
Republic
[†] Deceased
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Organocatalytic Michael Additions of Oxyacetaldehydes to Nitroolefins
hydes are rather unreactive and their use as donors in or-
ganocatalyzed additions is rare. However, they represent
valuable building blocks for target-oriented synthesis. Mac-
Millan described the auto-aldol reaction of oxyaldehydes
for the synthesis of carbohydrates.[19] Cordova used benzyl-
oxyacetaldehyde in the Mannich reaction for the synthesis
of the side chain of Paclitaxel.[20] Recently, Hayashi success-
fully utilized conjugate addition of 3-pentyloxyacetaldehyde
to nitroacrylate en route to Oseltamivir.[21] These examples
show the usefulness of oxyacetaldehydes in synthesis.
Therefore, we decided to study the Michael addition of sub-
stituted oxyacetaldehydes. In this paper, we report the de-
velopment of the enantioselective addition of oxyacetal-
dehydes to nitroalkenes.
Figure 1. Structures of organocatalysts used in the screening reac-
tion.
Table 1. Catalyst screening in the addition of benzyloxyacetal-
dehyde (2) to β-nitrostyrene (1).
Results and Discussion
Catalyst
Yield [%]
syn/anti[b]
ee (syn/anti)[c]
C1
C2
86
0
54:46
–
95:93
–
Initial testing was performed with β-nitrostyrene (1) and
benzyloxyacetaldehyde (2). However, no product was de-
tected with the Jørgensen–Hayashi catalyst (C1)[9,22] in tolu-
ene (Scheme 1). The reactivity did not improve with use of
an excess amount of aldehyde. On the other hand, if
5 equiv. of β-nitrostyrene was used, product 3 was isolated
in good yield (86%), although as an inseparable mixture of
syn and anti isomers. The diastereoselectivity of the reaction
C3
24
67
69
25
36
50
Ն10
44
0
56:44
50:50
50:50
57:43
52:48
52:48
50:50
83:17
–
95:84
91:90
74:40
60:–
95:57
51:41
–
61:–
–
–
C4
C5
C6
C7
C8
C9
C9[a]
C10
C11
1
was determined by analysis of the H NMR spectrum of
0
–
the crude reaction mixture. To facilitate determination of
the enantiomeric purity of product 3 by HPLC analysis,
we reduced the aldehyde to the corresponding alcohol with
NaBH4.
[a] DMF was used as the solvent. [b] Determined by 1H NMR
spectroscopy. [c] Determined by HPLC on a Chiralpak AD-H col-
umn (3 reduced to corresponding alcohol with NaBH4).
Having determined the most active catalyst, we contin-
ued in our investigation with organocatalyst C1. During op-
timization of the reaction conditions, we found that the sol-
vent has a profound effect on the reaction. In solvents other
than toluene, some or all reaction parameters were inferior.
In more polar solvents, such as iPrOH, DMF, or CH3CN,
the syn/anti ratio improved; however, the yield and enantio-
selectivity decreased. The results of solvent screening are
collected in Table 2.
Scheme 1.
Table 2. Addition of 2 to β-nitrostyrene catalyzed by C1 in various
solvents.
To improve the addition of aldehyde 2 to β-nitrostyrene
(1), we screened a series of common organocatalysts cap-
able of enamine formation and thus benzyloxyacetaldehyde
activation (Figure 1). This testing revealed that the
Jørgensen–Hayashi catalyst (C1) was the most active one,
and it afforded product 3 with the highest chemical yield
(86%) and enantioselectivities (95 and 93%ee). With all or-
ganocatalysts except proline (C9), compound 3 was isolated
with ca. 1:1dr. (S)-Proline provided product 3 with better
diastereoselectivity (syn/anti, 83:17), but the chemical yield
and enantioselectivity were lower. The results of the catalyst
screening are given in Table 1.
Solvent
Yield [%]
syn/anti[a]
ee (syn/anti)[b]
Toluene
Hexane
CH2Cl2
iPrOH
CF3CH2OH
DMF
CH3CN
tBuOMe
86
56
78
65
25
37
55
Ն10
54:46
50:50
50:50
71:29
58:42
67:33
62:38
50:50
95:93
92:91
89:87
90:70
90:67
95:76
95:83
–
[a] Determined by 1H NMR spectroscopy. [b] Determined by
HPLC on a Chiralpak AD-H column (3 reduced to corresponding
alcohol with NaBH4).
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The reaction is not restricted to benzyloxyacetaldehyde Table 4. Nitroalkenes 14–19 in the reaction with aldehyde 2.
(2). Oxyacetaldehydes with various O-protecting groups
were investigated. Aryl- and alkyl-substituted aldehydes 4–
6 and silyl ether 9 were successfully added to 1 (Scheme 2).
Resulting addition products 10–13 were isolated in medium
to good yields. Aldehyde 7 with a benzoyl group and com-
pound 8 with a sterically hindered trityl group did not af-
ford the expected addition products. Additions of substi-
tuted oxyacetaldehydes to β-nitrostyrene are summarized in
Table 3.
Nitroalkene
R
Yield
[%]
syn/anti[a]
ee
(syn/anti)[b]
14
15
16
17
18
19
4-CF3C6H4
4-ClC6H4
thiophen-2-yl
COOEt
iPr
ferrocenyl
51
95
88
88
30
14
63:37
54:46
60:40
71:29
79:21
56:44
96:93
96:95
93:91
95:93
82:93[c]
–
[a] Determined by 1H NMR spectroscopy. [b] Determined by
HPLC on a Chiralpak AD-H or OD-H column as the correspond-
ing α,β-unsaturated ethyl ester after derivatization with ethyl(tri-
phenylphosphoranylidene)acetate. [c] Determined by HPLC on a
Chiralpak IC column as the corresponding alcohol.
lyzed by LC–HRMS. Iminium cation Int-1 (m/z = 458.252)
and the adduct of enamine to β-nitrostyrene (Int-2, m/z =
607.302) were observed. Figure 2 shows the mass spectrum
and structures of the observed intermediates; the peak at
m/z = 326.195 is catalyst C1 and the peak at m/z = 236.144
is from the cation formed from catalyst C1 after cleavage of
the silyloxy group.
Scheme 2.
Table 3. Addition of substituted oxyacetaldehydes to β-nitrostyrene
catalyzed by C1.
R
Yield [%]
syn/anti[a]
ee (syn/anti)[b]
Ph
4-MeOC6H4
CF3CH2
PhCO
58
73
55
0
61:39
54:46
56:44
–
96:96
94:94
94:94
–
Ph3C
0
–
–
SiMe2tBu
43
59:41
84:84
[a] Determined by 1H NMR spectroscopy. [b] Determined by
HPLC on a Chiralpak AD-H or OD-H column as the correspond-
ing α,β-unsaturated ethyl ester after derivatization with ethyl(tri-
phenylphosphoranylidene)acetate.
Benzyloxyaldehyde (2) also added well to other aromatic
and heteroaromatic nitroalkenes 14–16 (Scheme 3). Ethyl 3-
nitroacrylate (17) afforded product 23 in good yield (88%)
and with high enantioselectivity (syn 95%ee, anti 93%ee;
Scheme 3). In the same reaction under Hayashi’s condi-
tions,[20] the product was isolated in 85% yield with 92%ee
(both diastereomers). The addition proceeded also with ali-
phatic nitroalkene 18 and ferrocenyl derivative 19, but in
these cases, products 24 and 25 were isolated only in low
yields. Table 4 summarizes the screening of nitroolefins.
Figure 2. High-resolution mass spectrum of the reaction of β-nitro-
styrene with aldehyde 2 and catalyst 4 after 4 h.
The low diastereoselectivity for the addition of aldehyde
2 to β-nitrostyrene can be explained by formation of both
(E)- and (Z)-enamine from the aldehyde and the catalyst.
DFT calculations support this notion, as there is only a
small energy difference (2.9 kJ/mol) between these en-
amines. All calculations were performed in the Spartan 08
program.[23] A conformational search was performed by
molecular mechanics; three lowest-energy conformers were
Scheme 3.
We also studied the reaction of β-nitrostyrene (1) with further refined by the semiempirical AM1 method and fi-
benzyloxyacetaldehyde (2) in the presence of catalyst C1 by nally geometrical optimization was performed by DFT by
mass spectrometry. Aliquot samples were taken and ana- using the B3LYP functional and the 6-31G* basis set.[24]
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Eur. J. Org. Chem. 2010, 6430–6435

Organocatalytic Michael Additions of Oxyacetaldehydes to Nitroolefins
Single-point energy calculation on the lowest-energy con- ing enamine. The nitroolefin will then approach it from the
former was then performed by using the 6-311+G** basis Re face. The (E)- and (Z)-enamine will then give rise to
set. Figure 3 shows the DFT-optimized structures of the (E) (R,S)- and (S,S)-3.
and (Z)-enamine intermediates formed from catalyst C1
and aldehyde 2.
Conclusions
We have developed methodology for the enantioselective
addition of oxyacetaldehydes to nitroalkenes. Although the
resulting products were isolated as diastereomeric mixtures,
chemical yields were good as were the enantioselectivities
(up 96%ee).
Experimental Section
General: Solvents were dried and purified by standard methods be-
fore use. NMR spectra were recorded with a Varian NMR System
300 instrument (300 MHz for 1H, 75 MHz for 13C). Chemical shifts
(δ) are given in ppm relative to tetramethylsilane. Flash chromatog-
raphy was performed on Merck silica gel 60. Thin-layer chromatog-
Figure 3. Optimized structures of the (E)- and (Z)-enamines from
catalyst C1 and aldehyde 2.
raphy was performed on Merck TLC-plates silica gel 60, F-254.
Enantiomeric excesses were determined by HPLC on a Chiralpak
AD-H, AS-H, or IC column or on a Chiralcel OD-H (Daicel
Chemical Industries) column by using hexane/iPrOH as the mobile
phase and UV detection. HRMS analyses were performed with a
LC-IT-TOF MS (Shimadzu, Kyoto, Japan) by using an Ascentis
C18 column with gradient H2O/acetonitrile elution over 33 min.
Racemic mixtures of all the products were prepared according to
the general procedure by using morpholine as the catalyst.
Another at least partial reason for the deterioration of
the diastereoselectivity is probably epimerization of the
product by the catalyst. To verify this idea, compound 3
(syn/anti, 67:33) was stirred in toluene in the presence of
catalyst C1 (10 mol-%) for 72 h. Subsequent 1H NMR spec-
troscopic analysis of diastereomers of 3 showed an syn/anti
ratio of 53:47. We believe that both the small energy differ-
ence between the enamines and product epimerization con-
tribute to the low diastereoselectivity of the reaction.
Typical Procedure: Benzyloxyacetaldehyde (2; 100 mg, 0.666 mmol)
was added to a solution of β-nitrostyrene (1; 496 mg, 3.32 mmol)
On the basis of Seebach’s earlier work on the Michael
addition of achiral enamines to nitroolefins,[25] we propose
an open-transition-state model to explain the course of the
reaction of benzyloxyacetaldehyde (2) with β-nitrostyrene
(1, Figure 4). On the basis of our calculations we suppose
that the enamine formed from aldehyde 2 and catalyst C1
adopts a more favorable anti arrangement with respect to
the large trimethylsilyloxy(diphenyl)methyl group. See-
bach’s recent X-ray studies on the reaction of phenylacetal-
dehyde enamine with C1 also support this supposition.[26]
Chiral catalyst (S)-C1 shields the Si face of the correspond-
and
(S)-2-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine
(C1;
21.5 mg, 0.066 mmol) in toluene (1 mL) at room temperature. The
reaction mixture was stirred for 96 h at room temperature. The
solution was diluted with CH2Cl2 (10 mL) and washed with water.
The aqueous phase was extracted with CH2Cl2 (3ϫ4 mL). The
combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. Flash chromatography
(SiO2, EtOAc/hexane, 1:7 to 1:5) provided Michael adduct 3 as a
pale-orange oil.
HPLC Analyses: Enantiomeric purities of the products of the
Michael addition of oxyacetaldehydes to nitroolefins are difficult
to analyze by HPLC. Therefore, these compounds were derivatized
before analysis. Products 3, 10, and 24 were reduced to the corre-
sponding alcohol with NaBH4 (4 equiv.) in MeOH (8 mL) at 0 °C
for 1.5 h. The reaction was quenched with 5% HCl. The aqueous
layer was extracted with Et2O (3ϫ8 mL). The combined organic
extracts were washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. Flash chromatography (SiO2, EtOAc/n-
hexane, 1:5 to 1:3) afforded the product as a pale-orange–yellow
oil. Products 11–13 and 20–23 were derivatized with ethyl(tri-
phenylphosphoranylidene)acetate (1.5 equiv.) to the corresponding
α,β-unsaturated ethyl esters at room temperature in benzene (2 mL)
for 4 h. The crude reaction mixture was concentrated under re-
duced pressure. Flash chromatography (SiO2, EtOAc/n-hexane, 1:5)
afforded the product as a colorless oil.
2-(Benzyloxy)-4-nitro-3-phenylbutanal (3): 1H NMR (300 MHz,
CDCl3): δ = 9.51, 9.41 (d, J = 1.5 Hz, 1 H, CHO), 7.21–7.39 (m,
10 H, 2 Ph), 4.85 (m, 1 H, CH2NO2), 4.77 (dd, J = 7.0, 18.7 Hz, 1
H, PhCH2O), 4.65 (dd, J = 12.0, 17.3 Hz, 1 H, PhCH2O), 4.52 (dd,
J = 11.5, 14.0 Hz, 1 H, CH2NO2), 4.09 (dd, J = 1.6, 4.3 Hz, 1 H,
Figure 4. Proposed transition-state model.
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FULL PAPER
OCHCHO), 3.99 (m, 1 H, PhCH) ppm. 13C NMR (75 MHz, CH2NO2), 4.78 (m, 1 H, PhCH2), 4.66 (m, 1 H, PhCH2), 4.58 (m,
CDCl3): δ = 202.7 (CHO), 200.3 (CHO), 136.6 (CAr), 136.4 (CAr),
135.3 (CAr), 134.2 (CAr), 128.5 (CAr), 84.1, 82.6 (CHCHO), 76.3,
1 H, CH2NO2), 4.53 (m, 1 H, CHCHO), 4.06 (m, 1 H, ArCH)
ppm. 13C NMR (300 MHz, CDCl3): δ = 202.0, 200.2 (CHO), 138.2
76.2 (CH2NO2), 74.0, 73.5 (PhCH2O), 45.3, 44.8 (PhCH) ppm. (CAr), 136.0 (CAr), 129.6 (CAr), 128.7 (CAr), 128.6 (CAr), 128.4
HRMS: calcd. for C17H16NO4 [M – H]– 298.108; found 298.079.
HPLC (AD-H, iPrOH/n-hexane = 5:95, 1 mL/min, λ = 217 nm): tR
= 71.2 (syn-minor), 60.8 (syn-major), 46.7 (anti-major), 43.6 (anti-
minor) min.
(CAr), 125.9 (CF3), 83.7, 82.2 (CHCHO), 76.0, 75.2 (CH2NO2),
74.0, 73.7 (CH2O), 44.8, 44.3 (ArCH) ppm. HRMS: calcd. for
C18H15F3NO4 [M – H]– 366.095; found 366.095. HPLC (Chiralpak
AD-H, iPrOH/n-hexane = 5:95, 0.8 mL/min, λ = 217 nm): tR
=
64.8 (syn-minor), 51.8 (anti-minor), 33.2 (anti-major), 24.5 (syn-
major) min.
4-Nitro-3-phenyl-2-(phenyloxy)butanal (10): 1H NMR (300 MHz,
CDCl3): δ = 9.61, 9.40 (d, J = 1.8 Hz, 1 H, CHO), 7.34 (m, 8 H,
Ph), 6.88 (m, 2 H, Ph), 5.00, 4.98 (dd, J = 8.1, 13.5 Hz, 1 H,
CH2NO2), 4.83–4.87 (m, 1 H, CHCHO), 4.79 (dd, J = 7.1, 13.4 Hz,
1 H, CH2NO2), 4.15–4.20 (m, 1 H, PhCH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 201.8, 199.7 (CHO), 129.4 (CAr), 122.8
(CAr), 115.4 (CAr), 82.5, 81.0 (CHCHO), 75.8 (CH2NO2), 45.2, 44.8
(PhCH) ppm. HRMS: calcd. for C16H14NO4 [M – H]– 284.092;
found 284.065. HPLC (Chiralpak AD-H, iPrOH/n-hexane = 5:95,
1 mL/min, λ = 217 nm): tR = 41.9 (syn-minor), 39.0 (anti-minor),
36.1 (syn-major), 33.6 (anti-major) min.
2-(4-Methoxybenzyloxy)-4-nitro-3-phenylbutanal (11): 1H NMR
(300 MHz, CDCl3): δ = 9.48, 9.37 (d, J = 1.6 Hz, 1 H, CHO), 7.28
(m, 5 H, Ph), 6.89 (m, 4 H, MeOPh), 4.82 (dd, J = 8.4, 13.1 Hz, 1
H, CH2NO2), 4.68 (dd, J = 5.2, 12.7 Hz, 1 H, PhCH2O), 4.61 (dd,
J = 4.0, 9.0 Hz, 1 H, PhCH2O), 4.46 (dd, J = 11.3, 17.0 Hz, 1 H,
CH2NO2), 4.06 (dd, J = 1.5, 4.3 Hz, 1 H, CHCHO), 3.96 (m, 1 H,
PhCH), 3.81 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 202.7, 200.2 (CHO), 159.8 (CH3OCAr), 135.2 (CAr), 134.0 (CAr),
129.2 (CAr), 114.1 (CAr), 83.5, 82.1 (CHCHO), 76.3, 76.2
(CH2NO2), 73.5, 73.0 (CH2O), 55.3 (OCH3), 45.1, 44.7 (PhCH)
ppm. HRMS: calcd. for C18H18NO5 [M – H]– 328.119; found
2-(Benzyloxy)-3-(4-chlorophenyl)-4-nitrobutanal (21): 1H NMR
(300 MHz, CDCl3, 23 °C): δ = 9.55, 9.44 (d, J = 1.9 Hz, 1 H,
CHO), 7.25 (m, 9 H, HAr), 4.88 (dd, J = 4.7, 8.5 Hz, 1 H,
CH2NO2), 4.76 (dd, J = 1.5, 3.9 Hz, 1 H, PhCH2O), 4.69 (m, 1 H,
PhCH2), 4.52 (dd, J = 11.5, 15.8 Hz, 1 H, CH2NO2), 4.07 (dd, J =
1.4, 4.15 Hz, 1 H, CHCHO), 3.99 (m, 1 H, PhCH) ppm. 13C NMR
(300 MHz, CDCl3): δ = 202.2, 200.2 (CHO), 132.5 (ClCAr), 128.4–
129.5 (CAr), 83.8, 82.2 (CHCHO), 76.1, 75.6 (CH2NO2), 73.9, 73.6
(CH2O), 44.5, 43.9 (PhCH) ppm. HRMS: calcd. for C17H15ClNO4
[M – H]– 332.069; found 332.069. HPLC (Chiralpak AD-H, iP-
rOH/n-hexane = 5:95, 0.8 mL/min, λ = 217 nm): tR = 71.5 (syn-
minor), 54.4 (anti-minor), 36.6 (anti-major), 32.9 (syn-major) min.
2-(Benzyloxy)-4-nitro-3-(thiophen-2-yl)butanal (22): 1H NMR
(300 MHz, CDCl3): δ = 9.57, 9.48 (d, J = 1.9 Hz, 1 H, CHO), 7.37
(m, 5 H, Ph), 7.25 (m, 1 H, Hthio), 6.97 (m, 1 H, Hthio), 6.93 (m, 1
H, Hthio), 4.56–4.86 (m, 4 H, CH2NO2, PhCH2), 4.35 (m, 1 H,
CHCHO), 4.05 (m, 1 H, CH) ppm. 13C NMR (300 MHz, CDCl3,
23 °C): δ = 202.7, 199.8 (CHO), 137.2, 136.3 (Cthio), 134.9 (CAr),
128.7 (CAr), 128.5 (CAr), 128.2 (CAr), 127.14 (Cthio), 126.8 (Cthio),
126.6 (Cthio), 83.9, 81.7 (CHCHO), 76.8, 76.7 (CH2NO2), 73.9, 73.7
(CH2O), 40.9, 40.2 (CHthio) ppm. HRMS: calcd. for C15H14NO4S
[M – H]– 304.064; found 304.064. HPLC (Chiralpak AS-H, iPrOH/
n-hexane = 3:97, 0.8 mL/min, λ = 217 nm): tR = 72.2 (anti-minor),
65.8 (anti-major), 58.5 (syn-major), 50.9 (syn-minor) min.
328.086. HPLC (Chiralpak AD-H, iPrOH/n-hexane
= 5:95,
0.75 mL/min, λ = 217 nm): tR = 32.6 (anti-minor), 28.5 (syn-
minor), 21.8 (anti-major), 20.2 (syn-major) min.
4-Nitro-3-phenyl-2-(2,2,2-trifluoroethoxy)butanal (12): 1H NMR
(300 MHz, CDCl3): δ = 9.51 (d, J = 1.2 Hz, 1 H, CHO), 9.46 (s, 1
H, CHO), 7.21–7.38 (m, 5 H, Ph), 4.96 (dd, J = 8.8, 13.4 Hz, 1 H,
CH2NO2), 4.85 (dd, J = 6.0, 13.5 Hz, 1 H, CF3CH2O), 4.77 (dd, J
= 8.4, 13.5 Hz, 1 H, CF3CH2O), 4.68 (dd, J = 6.5, 13.4 Hz, 1 H,
CH2NO2), 4.05–4.12 (m, 1 H, CHCHO), 3.82–3.88 (m, 1 H, PhCH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 199.3 (CHO), 198.1 (CHO),
134.5 (CAr), 133.2 (CAr), 128.9 (CAr), 128.0 (CF3), 86.1, 84.8
(CHCHO), 75.7, 75.5 (CH2NO2), 68.6 (CF3CH2), 44.6, 44.5
(PhCH) ppm. HRMS: calcd. for C12H11F3NO4 [M – H]– 290.064;
found 290.036. HPLC (Chiralpak AD-H, iPrOH/n-hexane = 4:96,
0.45 mL/min, λ = 217 nm): tR = 95.6 (syn-minor), 87.3 (anti-
minor), 70.9 (syn-major), 66.3 (anti-major) min.
2-(tert-Butyldimethylsilyloxy)-4-nitro-3-phenylbutanal (13): 1H
NMR (300 MHz, CDCl3): δ = 9.56, 9.35 (d, J = 1.44 Hz, 1 H,
CHO), 7.29 (m, 5 H, Ph), 4.87 (dd, J = 8.3, 13.4 Hz, 1 H,
CH2NO2), 4.78 (m, 2 H, CHCHO), 4.68 (dd, J = 6.9, 13.4 Hz, 1
H, CH2NO2), 3.97 (m, 1 H, PhCH), 0.95, 0.92 [s, 9 H, C(CH3)3],
0.064, 0.057 (s, 3 H, 2 CH3) ppm. 13C NMR (300 MHz, CDCl3,
23 °C): δ = 202.5, 201.2 (CHO), 135.8, 134.2 (CAr), 129.0 (CAr),
128.4 (CAr), 128.0 (CAr), 79.5, 77.3 (CHCHO), 75.9, 75.0
(CH2NO2), 46.0 (PhCH), 25.7 [(CH3)3C], 25.6 [(CH3)3C], 18.1
(CH3) ppm. HRMS: calcd. for C16H24NO4Si [M – H]– 322.148;
found 322.148. HPLC (Chiralpak IC, iPrOH/n-hexane = 5:95,
0.5 mL/min, λ = 217 nm): tR = 44.8 (anti-minor), 22.9 (syn-major),
20.4 (anti-major), 16.9 (syn-minor) min.
1
Ethyl 3-(Benzyloxy)-2-(nitromethyl)-4-oxobutanoate (23): H NMR
(300 MHz, CDCl3): δ = 9.70 (s, 1 H, CHO), 9.66 (d, J = 0.8 Hz, 1
H, CHO), 7.30–7.42 (m, 5 H, Ph), 4.86 (dd, J = 7.4, 14.6 Hz, 1 H,
CH2NO2), 4.79 (d, J = 11.8 Hz, 1 H, PhCH2O), 4.63 (d, J =
11.8 Hz, 1 H, PhCH2O), 4.40 (dd, J = 6.0, 14.6 Hz, 1 H, CH2NO2),
4.20 (m, 2 H, CH2CH3), 4.06 (d, J = 3.5 Hz, 1 H, CHCHO), 3.85,
3.71 (ddd, J = 3.5, 6.0, 7.5 Hz, 1 H, EtO2CCH), 1.25, 1.23 (t, J =
7.2 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 200.3
(CHO), 199.2 (CHO), 169.1 (COOEt), 167.9 (COOEt), 135.0 (CAr),
135.9 (CAr), 128.8 (CAr), 80.1, 80.2 (CHCHO), 73.7 (PhCH2), 71.8,
70.9 (CH2NO2), 62.3 (OCH2CH3), 44.8, 43.7 (EtOOCCH), 13.9
(CH2CH3) ppm. HRMS: [M]+ calcd. for C17H17NO4 not visible.
HRMS: calcd. for C16H16NO3 [M – CO]– 299.113; found 299.993.
HPLC (Chiralcel OD-H, iPrOH/n-hexane = 10:90, 0.9 mL/min, λ
= 217 nm): tR = 43.2 (syn-minor), 29.2 (anti-minor), 24.7 (syn-
major), 19.8 (anti-major) min.
2-(Benzyloxy)-3-ethyl-4-methylpentanal (24): 1H NMR (300 MHz,
CDCl3): δ = 9.55, 9.44 (d, J = 1.2 Hz, 1 H, CHO), 7.35 (m, 9 H,
HAr), 4.74 (d, J = 11.6 Hz, 1 H, CH2NO2), 4.54 (d, J = 11.5 Hz, 1
H, CH2NO2), 4.48 (m, 2 H, PhCH2), 3.90, 3.87 (dd, J = 1.2, 4.2 Hz,
1 H,CHCHO), 2.69 (m, 1 H, iPrCH), 1.92 (m, 1 H, Me2CH), 0.97,
0.93 (d, J = 6.8 Hz, 2 CH3) ppm. 13C NMR (300 MHz, CDCl3): δ
= 202.8, 202.0 (CHO), 136.7 (CAr), 128.6 (CAr), 128.4 (CAr), 128.1
(CAr), 83.0, 82.2 (CHCHO), 73.8, 73.7 (CH2NO2), 73.3, 72.9
2-(Benzyloxy)-4-nitro-3-(4-trifluoromethylphenyl)butanal (20): 1H (CH2O), 45.2, 43.8 (iPrCH), 28.3, 27.1 (Me2CH), 19.9, 19.4 (2
NMR (300 MHz, CDCl3): δ = 9.59, 9.43 (d, J = 1.8 Hz, 1 H, CH3) ppm. HRMS: calcd. for C14H18NO4 [M – H]– 264.124; found
CHO), 7.58 (m, 2 H, HAr), 7.38 (m, 7 H, HAr), 4.83 (m, 1 H,
6434
264.124. HPLC (Chiralpak IC, iPrOH/n-hexane = 8:92, 0.5 mL/
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6430–6435

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(300 MHz, CDCl3): δ = 9.47, 9.58 (d, J = 1.8 Hz, 1 H, CHO), 7.27–
7.39 (m, 5 H), 4.97–4.75 (m, 2 H, PhCH2O), 4.67 (dd, J = 8.1,
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68.33 (CH), 68.30 (CH), 68.0 (CH), 67.9 (CH), 66.9 (CH), 66.8
(CH) ppm. HRMS: calcd. for C21H21FeNO4 [M – H]– 406.075;
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Received: July 21, 2010
Published Online: October 5, 2010
Eur. J. Org. Chem. 2010, 6430–6435
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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