A new imidazole-containing imidazolidinone catalyst for organocatalyzed asymmetric conjugate addition of nitroalkanes to aldehydes

Article abstract of DOI:10.1002/adsc.200600316

Herein we report a new organocatalyst for the asymmetric Michael addition of nitroalkanes to α,β-unsaturated aldehydes. This catalyst incorporates a basic imidazole group in addition to the secondary amine responsible for activation of the α,β-unsaturated carbonyl compounds via iminium ion formation. The new organocatalyst is capable of catalyzing the enantioselective carbon-carbon bond formation with a high degree of enantiocontrol providing products in enantiomeric excesses of up to 92% and yields of up to to 91 %. These results constitute the best results so far reported for organocatalyzed Michael additions of nitroalkanes to α,β-unsaturated aldehydes, and provide proof of principle that organocatalysts incorporating two internal basic moieties may find broad application in organocatalyzed Michael additions.

Full text of DOI:10.1002/adsc.200600316

FULL PAPERS
DOI: 10.1002/adsc.200600316
A New Imidazole-Containing Imidazolidinone Catalyst for
Organocatalyzed Asymmetric Conjugate Addition of Nitroal-
kanes to Aldehydes
Leila Hojabri,a,d Antti Hartikka,a Firouz Matloubi Moghaddam,b
and Per I. Arvidssona,c,*
a
Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden
Fax : (+46)-18-471-3818; Phone: (+46)-18-471-3787; e-mail: Per.Arvidsson@biorg.uu.se
Department of Chemistry, Sharif University of Technology, PO Box 11365-9516, Tehran, Iran
Discovery CNS & Pain Control, AstraZeneca R&D Sçdertälje, SE-151 85 Sçdertälje, Sweden
b
c
Fax : (+46)-8-553-28892; Phone: (+46)-8-553-25923; e-mail: Per.Arvidsson@astrazeneca.se
Visiting PhD student at UU 2005/2006 from Sharif University of Technology, Tehran, Iran
d
Received: June 29, 2006
Abstract: Herein we report a new organocatalyst for best results so far reported for organocatalyzed Mi-
the asymmetric Michael addition of nitroalkanes to chael additions of nitroalkanes to a,b-unsaturated al-
a,b-unsaturated aldehydes. This catalyst incorporates dehydes, and provide proof of principle that organo-
a basic imidazole groupin addition to the secondary
catalysts incorporating two internal basic moieties
amine responsible for activation of the a,b-unsatu- may find broad application in organocatalyzed Mi-
rated carbonyl compounds via iminium ion forma- chael additions.
tion. The new organocatalyst is capable of catalyzing
the enantioselective carbon-carbon bond formation
with a high degree of enantiocontrol providing prod- Keywords: asymmetric catalysis; C C coupling; imi-
ucts in enantiomeric excesses of upto 92% and
yields of upto to 91%. These results constitute the
À
nium ion activation; Michael addition; organocataly-
sis; a,b-unsaturated aldehydes
Introduction
which dramatically increases the reactivity towards
nucleophiles due to lowered energy of the LUMO
The Michael addition to a,b-unsaturated systems is (lowest unoccupied molecular orbital) making bond-
one of the fundamental bond-forming processes in or- ing energetically more favorable.[7] Several organoca-
ganic chemistry and offers an extremely powerful tool talytic systems (Figure 1) have been developed for
for the synthesis of functionalized organic mole- conjugate additions of nitroalkanes to enones:
cules.[1] Among the many nucleophiles that can be
l-Proline rubidium salt,[8a,b] l-proline 1 in the pres-
employed in this reaction nitroalkanes stand out as ence of 2,5-dimethylpiperazine,[9] imidazoline catalyst
especially useful, as the resulting products can be con- 2,[10] chiral diamine-dipeptide catalyst,[11] tetrazole-
verted to ketones, reduced to an amines, or modified containing imidazoline catalyst 3,[12] and the l-proline-
by radical substitution with hydrogen.[2] With such a derived tetrazole catalysts 4 and the homologous ana-
plethora of possibilities, it is not surprising that asym- logue 5 in the presence of 2,5-dimethylpiperazine.[13,14]
metric implementations of this Michael addition have
Despite these impressive developments of organo-
attracted much attention in the past decade. Various catalytic systems enabling addition of nitroalkanes to
catalyst have been utilized for the asymmetric 1,4-ad- a,b-unsaturated ketones, the protocol for achieving
dition of nitroalkanes to chalcones,[3] including a re- the same type of reactions with the corresponding
cently developed Al-salen complex[4] and a system a,b-unsaturated aldehydes is far more embryonic. The
based on nanocrystalline MgO.[5]
major reason for the absence of representative exam-
Asymmetric conjugate addition to enones has been ples relates to the fact that enals readily undergo 1,2-
developed to also include organocatalytic methodolo- addition instead of the desired selective 1,4-addition.
gies.[6] Organocatalytic methodologies often take ad- To the best of our knowledge, there are only a few ex-
vantage of the possibility for temporary covalent amples of the catalytic asymmetric addition of nitroal-
bonding of the catalyst to form an iminium cation kanes to an a,b-unsaturated aldehydes. The most suc-
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Adv. Synth. Catal. 2007, 349, 740 – 748

Asymmetric Conjugate Addition of Nitroalkanes to Aldehydes
FULL PAPERS
Table 1. Initial investigation of various organocatalysts for
the 1,4-addition of nitroethane to trans-cinnamaldehyde (10)
to yield 4-nitro-3-phenylpentanal (11).[a]
Entry Catalyst Time [h] Yield [%][b] syn:anti[c] ee [%][d]
1
2
3
4
5
4
5
6
7
8
150
48
72
100
15
60
82
0
0
91
1:1.2
1:1
-
33:30
66:73
-
-
-
1:1.2
49:5
[a]
[b]
[c]
[d]
10 (0.5 mmol), catalyst (20 mol%), nitoethane (2 mmol).
Isolated yield after column chromatography.
1
Determined by H NMR.
Figure 1. Organocatalysts discussed in the text.
Determined by GC-MS using a chiral column [Astec
Chiradex C-TA].
cessful, in terms of yield and selectivity, is based on a
chiral phase-transfer catalyst for the addition of silyl
nitronates to aldehyde,[16] while two other papers with the neutral form of the catalyst, i.e., 7 (Table 1,
report on the organocatalyzed conjugate addition of entries 3 and 4). Finally, catalyst 8 was tested; this cat-
nitroalkanes to enals although only with limited suc- alyst was found to be the most reactive, giving 91%
cess, 46% ee for addition to crotonaldehyde[13,14] and conversion in only 15 h, but with moderate enantiose-
29% ee for addition to hexenal.[8b] In this paper, we lectivity for the syn diastereomer and a poor enantio-
give a full account of our progress in the organocata- selectivity for the anti adduct (Table 1, entry 5).
lyzed enantioselective conjugate addition of nitroal-
Based on these results, and on those reported in
kanes to enals utilizing a novel type of catalyst (9) the literature for ketone substrates, we reasoned that
closely resembling MacMillanꢁs well known imidazoli- it would be advantageous to build in a basic unit
dinone catalyst (6). Structural modifications enabled a within the catalyst. The most straightforward catalyst,
modulation of the reactivity, for example, allowing in- in terms of synthetic efficiency, we could think of was
corporation of enals as a reactive partner but at the the novel imidazole containing the MacMillan type of
same time retaining important features such as con- catalyst 9 Although the imidazole ring of catalyst 9 is
trol of iminium ion geometry and existence of direct- too weak a base (pKa of conjugate acid approx. 7) to
ing steric bulk.
promote extensive deprotonation of the substrate
(pKa ꢀ9) in water, the pKa difference in an organic
solvent like DMSO is on the other hand in favor of
the catalyst deprotonating the substrate (pKa of nitro-
alkanes approx. 17, pKa of imidazole approx. 19).[15]
The new catalyst 9 was synthesized from l-histidine
Results and Discussion
Initially, the efficiency, e.g., reactivity and selectivity
of the various organocatalysts previously described in according to a procedure similar to that reported for
the literature, for the Michael addition of nitroethane synthesis of catalyst 6.[7] The synthesis commenced
to trans-cinnamaldehyde 10 to yield 4-nitro-3-phenyl- with the preparation of the methyl ester of l-histidine
pentanal (11) (Table 1) was investigated. The tetra- which then was transformed into the corresponding
zole analogue of proline 4 which has proven to readily methylamide·2 HCl salt. After filtration of the highly
facilitate the reactions between a,b-unsaturated ke- hydroscopic amide dihydrochloric salt under an inert
tones and nitroalkanes in the presence of 2,5-dime- atmosphere, it was directly cyclized to the corre-
thylpiperazine,[13,14] turned out to be a less suitable sponding imidazolidinone 9 through acid-catalyzed
catalyst for the addition to a,b-unsaturated aldehydes, condensation with acetone generating a transient
proceeding only in moderate yield and with low enan- imine which upon protonation undergoes the desired
tioselectivity (Table 1, entry 1). Homologous tetrazole cyclization (Scheme 1).
5 provided the product in good yield and enantiose-
Catalyst 9 was evaluated under the same conditions
lectivity (Table 1, entry 2), even in the absence of as used for the other catalysts in Table 1. As seen in
added base. No conversion was observed with the hy- Table 2, this catalyst did indeed provide the product
drochloric salt of the MacMillan organocatalyst 6, or in high yield and enantioselectivity (Table 2, entry 1).
Adv. Synth. Catal. 2007, 349, 740 – 748
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741

Leila Hojabri et al.
FULL PAPERS
lectivity was kept at acceptable levels. Addition of
water was found to increase the rate of the reaction
but concurrently decreasing enantioselectivity when
dichloromethane was used as solvent (Table 2, en-
tries 5 and 6). Poor conversion and moderate to ac-
ceptable enantioselectivities were obtained in THF,
CH3CN, and methanol (Table 2, entries 2, 7 and 8).
Consequently, neat reaction condition appeared to
offer the best compromise between reactivity and
enantioselectivity. It should be noted that the initial
reaction between trans-cinnamaldehyde (10) and ni-
troethane catalyzed by catalyst (9) indicated that no
1,2-addition was observed (vide infra).
After these initial experiments, the possibility of
elaborating the nitroalkane structure was investigated.
Nitromethane and 2-nitropropane were examined, es-
pecially since the bulkier 2-nitropropane was expect-
ed to yield an increased enantioselectivity in the prod-
uct. Unfortunately, the results obtained employing ni-
tromethane as donor displayed a non-selective reac-
tion, propably due to a second consecutive nucleo-
philic attack by the 1,4-product towards the accessible
a,b-unsaturated aldehyde, accompanied by low enan-
tiocontrol (Table 3, entry 1). Reaction employing 2-ni-
tropropane was sluggish only furnishing 65% isolated
yield and 48% ee after a reaction time of 170 h
(Table 3, entry 2)
Next, we investigated the scope for the aldehyde
substrate. Surprisingly, when a-methyl-trans-cinnamal-
dehyde was utilized as a Michael acceptor, the sepa-
rated product was not in accord with that expected.
The NMR spectrum showed that significant 1,2-addi-
tion had taken place (Table 3, entry 3). Utilization of
other organocatalysts to achieve the 1,4-Michael addi-
tion for this substrate was also unprofitable (data not
shown). Most likely, the a-methyl groupprevents the
catalyst from forming the desired iminium ion thereby
seriously reducing the reactivity; also catalysts 4 and
5, which have a monosubstituted pyrrolidine ring,
gave sluggish reactions rendering mostly 1,2-addition
adduct.
Scheme 1. Synthesis of (5S)-5-[(1H-imidazol-5-yl)methyl]-
2,2,3-trimethylimidazolidin-4-one (9).
Table 2. Evaluation of the new imidazole based catalyst 9
(20 mol%) for the archetypical reaction between nitro-
ethane and trans-cinnamaldehyde (10) (see Table 1) under
various reaction conditions. No 1,2-addition was observed.
Entry Solvent Time
[h]
Conversion
[%][a]
syn:anti[a] ee
[%][b]
1[c]
2[d]
3[d]
4[e]
5[f]
-
47
48
48
70
93
22
39
79
14
35
22
44
1:1
1:1.2
1:1
82:80
72:68
92:90
90:86
90:85
81:76
50:46
65:60
THF
DMF
DMF
CH2Cl2 64
CH2Cl2 64
CH3CN 48
CH3OH 48
1:1
1:1.4
1:1.2
1:1
6[f,g]
7[d]
8[d]
1:1.2
[a]
1
Determined by H NMR.
[b]
Determined by GC-MS using a chiral column [Astec
Chiradex C-TA].
10 (0.5 mmol), EtNO2 (2 mmol).
10 (0.1 mmol), EtNO2 (0.4 mmol), solvent (0.2 mL).
10 (0.1 mmol), EtNO2 (0.4 mmol), solvent (0.1 mL).
10 (0.25 mmol), EtNO2 (1 mmol), solvent (1 mL).
0.25 equivs. H2O added
[c]
[d]
[e]
[f]
[g]
Significant 1,2-addition was also observed with the
Although the reaction is not as fast as that with cata- electron-withdrawing nitro groupon the phenyl ring
lyst 8 (Table 1, entry 5), the new catalyst produced in cinnamaldehyde; both the ortho- and para-nitrocin-
the product in the same yield, and with the best selec- namaldehydes yielded 1,2-addition products (Table 3,
tivity of the catalysts evaluated. The effect of solvent entries 4 and 5). The lack of solubility of the starting
was also investigated by performing the archetypical materials prohibited neat reaction conditions to be
reaction between trans-cinnamaldehyde and nitro- employed, thus making the use of solvent inevitable.
ethane in various solvents with 20 mol-percent of cat- Based on our results in Table 2, we considered DMF
alyst (Table 2, entries 2–8).
as the solvent of choice. It was predicted that the re-
It is evident that the rate of reaction is reduced in actions involving nitrocinnamaldehyde would display
the presence of additional solvent. Excellent enantio- an acceptable rate even in the presence of DMF as
selectivity was obtained in DMF, but unfortunately solvent. Our experiments showed formation of both
the reaction was too slow to be practically useful unwanted 1,2-addition product and desired 1,4-addi-
(Table 2, entry 3). Increasing the concentration of re- tion product for both nitroethane and nitropropane,
actants, while prolonging the reaction time resulted in thus yielding a plurality of regioisomeric and diaste-
higher conversion (Table 2, entry 4) while enantiose- reomeric products that were difficult to separate.
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Asymmetric Conjugate Addition of Nitroalkanes to Aldehydes
FULL PAPERS
Table 3. Addition of nitroalkanes to a,b-unsaturated aldehydes catalyzed by 9.
Entry
R1
R2
R3
R4
Solvent
Time
Yield [%][a]
1,2-:1,4-addition[b]
syn:anti[b]
ee[c] [%]
1[d]
2[d]
3[d]
4[e]
5[e]
6[d]
Ph
Ph
Ph
H
H
Me
H
H
H
H
Me
H
H
H
-
-
-
72 h
170 h
4 d
2 d
2 d
36 [g]
65 [g]
20 [h]
62[i]
0:1
0:1
1:0
1:1.1
1.3:1
0:1
-
-
-
47
48
-
-
Me
Me
Et
Et
Me
[f]
p-NO2C6H4
o-NO2C6H4
n-Pr
DMF
DMF
-
1.2:1
1.2:1
1:1
48[i]
-
H
H
40 h
74 [g]
16:9
[a]
Isolated yield after column chromatography.
Determined by H NMR.
Determined by GC-MS using a chiral column [Astec Chiradex C-TA].
Aldehyde (0.5 mmol), nitroalkane (2 mmol).
Aldehyde (0.5 mmol), nitroalkane (2 mmol), solvent (0.2 mL).
Predominantly trans-
Yield is related to 1,4-adduct.
Yield is related to 1,2-adduct.
Yield is related to the total of 1,2 and 1,4- adduct.
[b]
[c]
[d]
[e]
[f]
1
[g]
[h]
[i]
One aliphatic aldehyde was also investigated under effect of o-OMe is counterbalanced on changing the
neat reaction conditions (Table 3, entry 6). The reac- substitution pattern to p-OMe as seen in Table 4 (en-
tion yielded exclusively the 1,4-adduct in fair yield tries 7 and 8); however the diastereoselectivities and
but the enantioselectivity was poor only (16:9). Like- enantioselectivities obtained were still fair.
wise, the ability of catalyst 9 to effect the 1,4-addition
of nitroalkanes to ketones was investigated by em-
ployed 2-cyclohexenone as a substrate in neat nitro- Conclusions
methane. Despite prolonged reaction time, no product
was observed in this case, probably due to steric re- In conclusion, we have disclosed an organocatalytic,
pulsion of two methyl groups on the imidazolidinone enantioselective Michael addition of nitroalkanes to
ring on catalyst 9. Overall, these results (Table 3, en- a,b-unsaturated aldehydes using a new imidazole-
tries 1–6) suggest that aliphatic aldehydes and a,b-un- based catalyst. The catalyst readily facilitates reac-
saturated ketones are not good substrates under the tions between straight-chain nitroalkanes and non-a-
present reaction conditions. A non-substituted ana- substituted aromatic a,b-unsaturated aldehydes pro-
logue of this catalyst is thus expected to be required viding access to b,g-functionalized saturated alde-
in order to provide good conversions for ketone sub- hydes in isolated yields of upto 91% and enantiose-
strates.
lectivities of upto 92%. Although the results indicate
A series of different enals was employed as Michael a limited substrate scope, in terms of permitted nitro-
acceptors for two different straight-chain nitroalkanes alkanes and a,b-unsaturated aldehydes, they are still
as shown in Table 4. Due to the lower reactivity of ni- the best obtained for the organocatalyzed Michael ad-
tropropane, a longer reaction time was needed for re- dition of nitroalkanes to enal substrates, and provide
action compared to nitroethane (cf. entries 1 and 2). proof of principle that organocatalysts with an inter-
Although both the reaction rate and enantioselectivi- nal basic moiety are indeed advantageous for this re-
ty were decreased when the smaller and more electro- action.
philic furyl group was used instead of a phenyl group
(cf. entries 1 and 3), both acceptable relative and spe-
cific stereochemistry could be obtained (Table 4 en-
Experimental Section
tries 3 and 4). An electron-donating methoxy groupin
the ortho-position on the phenyl ring increased the re-
action rate and both diastereoselectivty and enantio-
selectivty (entries 5 and 6). As seen in Table 4 entry 6,
this substrate yieled an excellent stereoselectivity (up
General Remarks
Chemicals and solvents were either purchased puris p.A.
from commercial suppliers or purified by standard tech-
to 90%) for the nitropropane adduct. The positive niques. For thin layer chromatography (TLC), precoated
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Leila Hojabri et al.
FULL PAPERS
Table 4. Catalytic asymmetric organocatalyzed Michael addition of nitroethane and nitropropane to a,b-unsaturated alde-
hydes employing organocatalyst 9.[a]
Entry
R1
R2
Time [h]
Yield [%][b]
syn:anti[c]
ee[d] [%]
1
2
3
4
5
6
7
8
Ph
Ph
Me
Et
Me
Et
Me
Et
Me
Et
47
68
68
48
45
49
65
62
91
75
61
49
91
81
60
43
1:1
1:1
82:80
74:63
68:66
77:67
68:71
90:79
77:56
68:53
2-Furyl
2-Furyl
o-MeO-C6H4[e]
o-MeO-C6H4
p-MeO-C6H4
p-MeO-C6H4
1:1.1
1:1
1:2.3
1:2.6
1:1.3
1:1.3
[e]
[a]
Unsaturated aldehyde (0.5 mmol), nitroalkane (2 mmol).
Isolated product after column chromatography.
Determined by H NMR.
Determined by GC-MS using a chiral column [Astec Chiradex C-TA] or HPLC using a Daicel Chiralcel AS-H column.
Predominantly trans.
[b]
[c]
[d]
[e]
1
0.25 mm silica plates (Macherey–Nagel 60 Alugramꢂ Sil G/
UV254) were used and spots were visualized either with UV
light or by heating after soaking the TLC plate in a solution
consisting of 0.5% 2,4-dinitrophenylhydrazine in 2M HCl.
Column chromatography was performed on silica gel
(Matrexꢃ 60 A, 37–70 mm) and basic alumina oxide supplied
ing mobile phase compositions and column types are pre-
sented below individually for each compound. GC-MS de-
termination of enantiomeric excesses was done using a
Varian CP-8410 auto injector and a Varian Saturn 2100T
GC-MS system equipped with a column (30 m”0.25 mm),
consisting of fused silica capillary tubing coated with a
chiral stationary phase (film thickness 0.125 mm) supplied by
Astec with helium gas at 10 psi as carrier gas. Details con-
cerning the columns and temperature programs used are
given specifically for each compound below.
1
by ICN EcoCHROM. H NMR (500 and 300 MHz) spectra
were recorded on Varian Unity 500 MHz and Varian Mercu-
ry plus 300 MHz spectrometer, respectively, and 13C NMR
(75 MHz) spectra were recorded on a Varian Mercury plus
300 MHz spectrometer. All spectra were acquired at ambi-
ent temperature. Chemical shifts (d) in ppm are reported
using residual chloroform or methanol as internal reference
(1H d=7.26, 13C=d 77.0) or (1H d=3.30, 13C d=49.0) and
coupling constants (J) are given in Hz. Infrared spectra was
recorded on a Perkin–Elmer Spectrum 100 FT/IR spectrom-
eter. Melting point determination was done using a SMP3
melting point apparatus supplied by Stuart Scientific and
are uncorrelated. Purity of catalyst was confirmed by ele-
mental analysis performed by Mikro Kemi Uppsala and by
means of a high pressure liquid chromatography (HPLC)
system coupled to an MS detector and an evaporative light-
scattering detector (ELSD); the system consisted of a
Gilson 322 pump, Gilson 233 XL autosampler and a Gilson
UV/VIS 152 detector, coupled in series with a Finnigan
AQA mass spectrometer and an ELSD (Sedex 85 CC) from
Sedere. The reverse phase HPLC analysis was done using a
Phenomenex Gemini C18 (3 m, 3.0”150 mm) column em-
ploying acetonitrile-water (both containing 0.1% formic
acid) as mobile phase (gradient: 5–95% acetonitrile in
6 min+6 min at 95%, flow 1.0 mLminÀ1). Enantiomeric ex-
cesses were determined using a high pressure liquid chroma-
tography (HPLC) system equipped with a column consisting
of a chiral stationary phase (4 mm, 0.46”250 mm) supplied
by Daicel Chemical Industries, Ltd. The HPLC system con-
sisted of a Gilson 322 pump, Gilson 233 XL autosampler,
and an Agilent 1100 diode-array detector. Details concern-
Methyl (2S)-2-Amino-3-(1H-imidazol-4-yl)propanoate
Dihydrochloride (13)
To a stirred solution of l-histidine (3.87 g, 24 mmol) in dry
methanol (50 mL) kept at 08C was added thionyl chloride
(2.72 mL, 37.5 mmol). After 15 min at 08C, the reaction
mixture was allowed to warm to room temperature, and
then refluxed for 48 h. The solution was concentrated under
vacuum and l-histidine methyl ester dichloride crystallized
from methanol to give white crystals; yield: 4.7 g (81%).
1H NMR and 13C NMR are identical with commercially
available material.
(2S)-2-Amino-3-(1H-imidazol-4-yl)-N-methylpropan-
amide (12)
To a solution of ethanolic MeNH2 (8M, 6 mL) was added l-
histidine methyl ester dihydrochloride 13 (2.41 g, 10 mmol).
The solution was stirred at room temperature for 24 h. The
solvent was removed under reduced pressure and CH2Cl2
(20 mL), Na2CO3 (7 g) and H2O (2 mL) were added and the
resulting mixture was stirred for 1 hour before filtration of
the resulting precipitate. Boiling i-PrOH was added to the
solid under a stream of N2 before the solid was filtered
under an inert atmosphere. The i-PrOH was removed under
reduced pressure to give a white powder; yield: 2.14 g
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Asymmetric Conjugate Addition of Nitroalkanes to Aldehydes
FULL PAPERS
1
(89%). H NMR (500 MHz, CD3OD): d=2.6 (s, 3H), 2.9–
(pentane:ethyl acetate) (9:1) or (pentane:diethyl ether)
(80:20).
3.10 (dd, J=14, 4.9 Hz, 2H), 3.9 (dd, J=8.3, 4.9 Hz, 1H),
6.9 (s, 1H), 7.6 (s,1H); 13C NMR (75 MHz, CD3OD): d=28,
34, 52, 120, 132, 137, 172.
4-Nitro-3-phenylpentanal (Table 1)
1
Syn: Colorless oil, H NMR (300 MHz, CDCl3): d=1.35 (d,
(5S)-5-[(1H-Imidazol-5-yl)methyl]-2,2,3-trimethyl-
imidazolidin-4-one (9)
J=6.9 Hz, 3H), 2.71–3.02 (m, 2H, CH2C=O), 3.71–3.79 (dt,
J=9.9, 4.5 Hz, 1H), 4.73–4.83 (m, 1H), 7.20 (m, 2H), 7.29–
7.39 (m, 3H), 9.56 (dd, J=2.1, 1.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=17.7, 44.2, 46.4, 87.1, 128.1, 128.2,
129,2, 137.5, 198.6. The enantiomeric excess was determined
by means of GC-MS using an Astec Chiradex C-TA
column, 1508C isothermal, tr =19.3 min (major) and
22.5 min (minor). MS (EI): m/z (rel. intensity)=160 (1), 143
(50), 131 (25), 117 (50), 105 (55), 91 (100),
Anti: The enantiomer of this compound has been charac-
terized previously.[16] The enantiomeric excess was deter-
mined using an Astec Chiradex C-TA column, 1508C iso-
thermal, tr =21.5 min (minor) and 23.9 min (major). MS
(EI): m/z (rel. intensity)=160 (100), 143 (25), 131 (30), 117
(50), 105 (40), 91 (80), 65 (27).
To
(2S)-2-amino-3-(1H-imidazol-4-yl)-N-methylpropan-
amide (3.64 g, 15.2 mmol) was added 30 mL dry MeOH,
acetone (5.8 mL, 4.59 g; 79 mmol) and a catalytic amount of
p-toluenesulfonic acid (30 mg, 0.16 mmol). The resulting so-
lution was refluxed for 24 h and stirred at room temperature
for 2 h. The mixture was subsequently concentrated under
reduced pressure giving the crude product as a yellow oil.
The crude product was purified by means of column chro-
matography using basic alumina oxide and CH2Cl2:MeOH
(9:1; Rf =0.54) to give a slightly red colored oil; yield: 2.46 g
(78%). 1H NMR (500 MHz, CD3OD): d=1.28 (d, J=
2.1 Hz, 6H), 2.75 (d, J=0.74 Hz, 3H), 2.85–2.95 (ddd, J=
15, 7.3, 0.75 Hz, 1H), 3.0–3.10 (ddd, J=15, 4.3, 0.85 Hz,
1H), 3.76–3.8 (ddd, J=7.3, 4.3, 0.73 Hz, 1H) 6.9 (s, 1H),
7.59 (d, J=1.23 Hz, 1H); 13C NMR (75 MHz, CD3OD): d=
24.9, 25.5, 27.0, 29.6, 59.7, 77.5, 118.7, 136.2, 175.3.
4-Methyl-4-nitro-3-phenylpentanal (Table 3, entry 2)
1
Colorless oil, H NMR (300 MHz, CDCl3): d=1.48 (s, 3H),
In order to provide a crystalline material, 2.46 g of the
free base were dissolved in approximately 30 mL dry metha-
nol. To the mixture was then added hydrogen chloride in
ether. Under vigorous stirring was added dry diethyl ether
until formation of a precipitate was visible. The precipitate
was filtered under N2 and recrystallized from a mixture of 2-
propanol and methanol to furnish 9·2HCl salt as white
flakes; yield: 2.52 g (76%); mp225–227 8C. 1H NMR
(500 MHz, CD3OD): d=1.65 (s, 3H), 1.81 (s, 3H), 2.91 (d,
J=0.6 Hz, 3H), 3.40–3.46 (ddd, J=15.83, 8.53, 0.8 Hz, 1H),
3.49–3.55 (ddd, J=15.85, 5.97, 0.97 Hz, 1H), 4.62–4.66 (ddd,
J=8.53 5.97 0.80 Hz, 1H), 7.6 (s, 1H), 8.9 (d, J=1.39 Hz,
1H); 13CNMR (75 MHz, CD3OD): d=23.6, 25.6, 25.9, 26.6,
57.4, 80.2, 120.4, 130.1, 136.4, 168; IR (neat): n=3119, 2571,
2326, 1718, 1573, 1384, 1065, 783, 676 cmÀ1; HPLC-MS: Rt =
0.9 min; MS (ESI): m/z=211 [M+3H]+; [a]D25: À368 (c 1.00,
MeOH) measured on crystalline 9·2HCl; anal. calcd. for
C10H18Cl2N4O: C 42.7, H 6.45, N 19.9; found: C 42.4, H 6.4,
N 19.6.
1.57 (s, 3H), 2.67–3.11 (m, 2H), 3.99 (dd, J=11.2, 3.7 Hz,
1H), 7.18–7.22 (m, 2H), 7.28–7.33 (m, 3H), 9.52 (dd, J=2.4,
0.6 Hz, 1H); 13CNMR (75 MHz, CDCl3): d=22.2, 25.5, 43.9,
47.6, 91.0, 128.1, 128.7, 129.2, 136.8, 199.0. The enantiomeric
excess was determined using an Astec Chiradex C-TA
column, 1408C isothermal, tr =40.7 min (minor) and
42.1 min (major). MS (EI): m/z (rel. intensity)=220 (M+,
10), 191 (25), 174 (30), 157 (30), 145 (60), 131 (100), 117
(30), 91 (25).
4-Nitro-3-(4-nitrophenyl)hexanal (Table 3, entry 4)
Syn: Slightly yellow oil, 1H NMR (300 MHz, CDCl3): d=
0.88 (t, J=7.5 Hz, 3H), 1.40–1.54 (m, 1H), 1.78–1.93 (m,
1H), 2.82–3.11 (m, 2H, CH2C=O), 3.85–3.93 (dt, J=9.9,
3.6 Hz, 1H), 4.60–4.68 (dt, J=10.3, 3.3 Hz, 1H), 7.42 (d, J=
9 Hz, 2H), 8.22 (d, J=9 Hz, 2H), 9.59 (d, J=0.9 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=10.2, 25.5, 42.8, 46.2, 93.1,
124.4, 129.2, 145.6, 147.6, 197.4
1
Anti: Slightly yellow oil, H NMR (300 MHz, CDCl3): d=
0.99 (t, J=7.2 Hz, 3H), 1.78–2.04 (m, 2H), 2.92–3.14 (m,
2H, CH2C=O), 3.88–3.95 (m, 1H), 4.70–4.78 (ddd, J=10.3,
7.8, 3.9 Hz, 1H), 7.37 (d, J=9 Hz, 2H), 8.18 (d, J=9 Hz,
2H), 9.70 (s, 1H); 13C NMR (75 MHz, CDCl3): d=10.3,
24.8, 42.2, 45.4, 92.7, 124.0, 129.2, 145.2, 147.6, 197.7.
General Procedure for the Catalytic Asymetric
Michael Addition of Nitroalkane to a,b-Unsaturated
Aldehydes
To 0.1 mmol of the catalyst in a flask equipped with a mag-
netic stirring bar was added 0.5 mmol of the a,b-unsaturated
aldehyde and 2 mmol of the nitroalkane (and in those cases
indicated a solvent). The reaction mixture was stirred at
room temperature using N2 as protecting atmosphere, indi-
vidual reaction times are given in the respective tables. Re-
action progress was monitored by thin layer chromatogra-
phy and spots were visualized using UV light or by heating
after soaking the TLC plates in a solution of 0.5% 2,4-dini-
trophenylhydrazine in 2M HCl. The crude reaction mixture
was concentrated under reduced pressure in order to
remove nitroalkane after which the residue was purified by
means of column chromatography using silica gel and either
4-Nitro-3-(2-nitrophenyl)hexanal (Table 3, entry 5)
Syn: Slightly yellow oil, 1H NMR (300 MHz, CDCl3): d=
0.94 (t, J=7.5 Hz, 3H), 1.56–1.68 (m, 1H), 2.00–2.15 (m,
1H), 2.94–3.12 (m, 2H, CH2C=O), 4.37–4.44 (ddd, J=9.3,
8.1, 4.5 Hz, 1H), 4.79–4.87 (ddd, J=10.8, 8.1, 3.6 Hz, 1H),
7.29 (dd, J=7.7, 1.2, Hz, 1H), 7.45 (dt, J=8.1, 1.2 Hz, 1H),
7.59 (dt, J=7.7, 1.2 Hz, 1H), 7.89 (dd, J=8.1, 1.2 Hz, 1H),
9.58 (d, J=0.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=
10.4, 25.5, 36.8, 45.3, 93.4, 125.2, 128.5, 128.8, 133.0, 133.3,
150.1, 197.8.
Adv. Synth. Catal. 2007, 349, 740 – 748
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
745

Leila Hojabri et al.
FULL PAPERS
1
Anti: Slightly yellow oil, H NMR (300 MHz, CDCl3): d=
0.98 (t, J=7.5 Hz, 3H), 1.86–1.97 (m, 2H), 2.90–3.19 (m,
2H, CH2C=O), 4.44–4.52 (m, 1H), 4.94–5.02 (dt, J=9,
4.5 Hz, 1H), 7.41–7.46 (m, 2H), 7.58 (dt, J=7.8, 1.2 Hz,
1H), 7.85 (dd, J=8.2, 1.2 Hz, 1H), 9.58 (t, J=1.2 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=10.2, 24.8, 37.3, 45.5, 92.1,
125.2, 129.0, 129.4, 132.5, 133.2, 150.1, 198.3.
4.63–4.71 (dt, J=7.7, 3.6 Hz, 1H), 6.22 (dd, J=3.3, 0.3 Hz,
1H), 6.31 (dd, J=3.3, 1.8 Hz, 1H), 7.36 (dd, J=1.8, 0.9 Hz,
1H), 9.62 (dd, J=1.6, 1.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=10.1, 25.3, 36.8, 43.9, 91.9, 108.9, 110.6, 142.6,
150.5, 198.2. The enantiomeric excess was determined using
an Astec Chiradex C-TA column, 1508C isothermal, tr =
8.9 min (major) and 9.6 min (minor). MS (EI): m/z (rel. in-
tensity)=181 (10), 164 (80), 150 (100), 122 (80), 107 (50), 95
(45), 79 (60), 67 (50), 55 (50), 41 (20).
3-(1-Nitroethyl)hexanal (Table 3, entry 6).
Anti: White crystals, 1H NMR (CDCl3): d=0.97 (t, J=
7.5 Hz, 3H), 1.72–1.86 (m, 1H), 1.93–2.09 (m, 1H), 2.94–
2.98 (m, 2H, CH2C=O), 3.94 (m, 1H), 4.67–4.74 (ddd, J=
10.2, 6.2, 3.9 Hz, 1H), 6.15 (td, J=3.3, 0.6 Hz, 1H), 6.30 (dd,
J=3.3, 1.8 Hz, 1H), 7.35 (dd, J=1.8, 0.9 Hz, 1H), 9.72 (t,
J=1.2 Hz, 1H);13C NMR (75 MHz, CDCl3): d=10.4, 23.9,
36.3, 43.0, 91.3, 108.3, 110.5, 142.6, 150.8, 198.6. The enantio-
meric excess was determined using an Astec Chiradex C-TA
column, 1508C isothermal, tr =10.1 min (minor) and
11.7 min (major). MS (EI): m/z (rel. intensity)=181 (5), 164
(75), 149 (30), 121 (100), 108 (75), 95 (70), 77 (75), 67 (80),
55 (60), 41 (45).
The enantiomer of this compound has been characterized
previously.[16] Both syn and anti: MS (EI): m/z (rel. intensi-
ty)=174 (2), 144 (5), 127 (8), 109 (20), 83 (60), 67 (20), 55
(100), 41 (30).
4-Nitro-3-phenylhexanal (Table 4, entry 2)
1
Syn: White crystals, H NMR (300 MHz, CDCl3): d=0.85 (t,
J=7.5 Hz, 3H), 1.43–1.56 (m, 1H), 1.75–1.91 (m, 1H), 2.66–
3.01 (m, 2H, CH2C=O), 3.69–3.77 (dt, J=10.3, 3.9 Hz, 1H),
4.56–4.64 (dt, J=10.5, 3.3 Hz, 1H), 7.19–7.22 (m, 2H), 7.28–
7.35 (m, 3H), 9.54 (dd, J=2.1, 0.9 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=10.2, 25.4, 43.5, 46.5, 94.2, 128.1,
128.1, 129.3, 137.9, 198.6. The enantiomeric excess was de-
termined using an Astec Chiradex C-TA column, 1608C iso-
thermal, tr =12.8 min (major) and 13.6 min (minor).
Anti: The enantiomer of this compound has been charac-
terized previously.[16] The enantiomeric excess was deter-
mined using an Astec Chiradex C-TA column, 1608C iso-
thermal, tr =14.2 min (minor) and 14.9 min (major). MS
(EI): m/z (rel. intensity)=191 (5), 174 (80), 145 (20), 131
(100), 105 (75), 91 (80), 77 (30), 51 (25).
3-(2-Methoxyphenyl)-4-nitropentanal (Table 4,
entry 5)
1
Syn: Slightly yellow oil, H NMR (CDCl3): d=1.33 (d, J=
6.9 Hz, 3H), 2.65–2.72 (m, 1H, CH2C=O), 3.02–3.12 (m, 1H,
CH2C=O), 3.86 (s, 3H), 3.96–4.04 (dt, J=9.9, 4.2 Hz, 1H),
5.02–5.12 (m, 1H), 6.87–6.96 (m, 2H), 7.17 (dd, J=7.5,
1.8 Hz, 1H), 7.25 (ddd, J=8.1, 7.5, 1.8 Hz, 1H), 9.54 (dd,
J=2.1, 1.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=18.3,
40.7, 44.9, 55.3, 85.9, 111.1, 121.1, 125.5, 129.3, 130.4, 157.1,
199.6. The enantiomeric excess was determined using HPLC
with a Daicel Chiralpak AS-H column, 5:95 i-PrOH/hexane,
1 mLminÀ1 flow rate, tr =26.8 min (minor) and 28.5 min
(major).
3-(Furan-2-yl)-4-nitropentanal (Table 4, entry 3)
Syn: White crystals, 1H NMR (300 MHz, CDCl3): d=1.42
(d, J=6.9 Hz, 3H), 2.67–3.04 (m, 2H, CH2C=O), 3.94–4.02
(dt, J=9.6, 4.5 Hz, 1H), 4.76–4.87 (m, 1H), 6.22 (d, J=
3 Hz, 1H), 6.32 (dd, J=3, 1.8 Hz, 1H), 7.36 (d, J=1.8 Hz,
1H), 9.65 (dd, J=1.8, 0.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=17.1, 37.5, 43.8, 84.9, 109.0, 110.6, 142.7, 150.2,
198.2. The enantiomeric excess was determined using an
Astec Chiradex C-TA column, 1508C isothermal, tr =8.5
Anti: Slightly yellow oil, 1H NMR (CDCl3): d=1.50 (d,
J=6.6 Hz, 3H), 2.84–3.04 (m, 2H, CH2C=O), 3.86 (s, 3H),
4.13–4.20 (m, 1H), 5.03–5.13 (m, 1H), 6.87–6–92 (m, 2H),
7.06 (dd, J=7.7, 1.2 Hz, 1H), 7.26 (m, 1H), 9.63 (dd, J=2.2,
1.3 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=16.5, 39.0,
43.4, 55.4, 84.6, 111.1, 120.9, 125.4, 129.2, 129.5 157.1, 199.9.
The enantiomeric excess was determined using HPLC with
a Daicel Chiralpak AS-H column, 5:95 i-PrOH/hexane,
1 mLminÀ1 flow rate, tr =40.3 min (major) and 43.7 min
(minor).
(major) min and 9.4 minACHTRE(UNG minor). MS (EI): m/z (rel. intensi-
ty)=167 (8), 150 (100), 122 (80), 107 (50), 95 (40), 79 (50),
67 (30), 55 (20).
1
Anti: White crystals, H NMR (300 MHz, CDCl3): d=1.52
(d, J=6.6 Hz, 3H), 2.95 (dd, J=7.2, 1.2 Hz, 2H, CH2C=O),
3.97–4.03 (m, 1H), 4.85–4.94 (m, 1H), 6.16 (d, J=3.3 Hz,
1H), 6.31 (dd, J=3.3, 1.8 Hz, 1H), 7.35 (d, J=1.8 Hz, 1H),
9.73 (t, J=1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=15.9,
37.0, 42.5, 84.1, 108.3, 110.5, 142.6, 150.7, 198.6. The enantio-
meric excess was determined using an Astec Chiradex C-TA
column, 1508C isothermal, tr =9.9 min (minor) and 11.1 min-
ACHTREUNG(major). MS (EI): m/z (rel. intensity)=198 (8), 167 (5), 150
(100), 122 (80), 107 (50), 95 (45), 79 (60), 67 (50), 55 (50), 41
(20).
3-(2-Methoxyphenyl)-4-nitrohexanal (Table 4,
entry 6)
1
Syn: Slightly yellow oil, H NMR (CDCl3): d=0.85 (t, J=
7.5 Hz, 3H), 1.42–1.54 (m, 1H), 1.74–1.90 (m, 1H), 2.60–
3.11 (m, 2H, CH2C=O), 3.86 (s, 3H), 3.99–4.07 (dt, J=10.2,
4.2 Hz, 1H), 4.85–4.93 (dt, J=10.2, 3.3 Hz, 1H), 6.87–6.95
(m, 2H), 7.16 (dd, J=7.5, 1.8 Hz, 1H), 7.27 (ddd, J=8.1,
7.5, 1.8 Hz, 1H), 9.54 (dd, J=2.2, 1.1 Hz, 1H); 13C NMR
(75 MHz; CDCl3): d=10.2, 25.6, 39.6, 44.9, 55.4, 92.8, 111.2,
121.1, 125.6, 129.3, 130.2, 157.1, 199.6. The enantiomeric
excess was determined using HPLC with a Daicel Chiralpak
AS-H column, 5:95 i-PrOH/hexane, 1 mLminÀ1 flow rate,
tr =19.9 min (minor) and 24.2 min (major).
3-(Furan-2-yl)-4-nitrohexanal (Table 4, entry 4)
Syn: White crystals, 1H NMR (CDCl3): d=0.91 (t, J=
7.5 Hz, 3H), 1.54–1.66 (m, 1H), 1.80–1.96 (m, 1H), 2.62–
3.03 (m, 2H, CH2C=O), 3.87–3.95 (dt, J=9.6, 3.9 Hz, 1H),
746
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 740 – 748

Asymmetric Conjugate Addition of Nitroalkanes to Aldehydes
FULL PAPERS
1
Anti: Slightly yellow oil, H NMR (CDCl3): d=0.96 (t, J=
Acknowledgements
7.5 Hz, 3H), 1.75–2.02 (m, 2H), 2.86–3.03 (m, 2H, CH2C=
O), 3.86 (s, 3H), 4.08 (m, 1H), 4.88–4.95 (ddd, J=10.6, 8.2,
3.9 Hz, 1H), 6.86–6.91 (m, 2H), 7.06 (dd, J=7.8, 1.2 Hz,
1H), 7.25 (dt, J=7.8, 1.5 Hz, 1H), 9.56 (t, J=1.5 Hz, 1H);
13C NMR (75 MHz; CDCl3): d=10.5, 24.4, 38.8, 44.1, 55.4,
91.9, 111.1, 120.9, 125.6, 129.2, 129.8, 157.1, 199.9. The enan-
tiomeric excess was determined using HPLC with a Daicel
Chiralpak AS-H column, 5:95 i-PrOH/hexane, 1 mLminÀ1
flow rate, tr =27.4 min (major) and 33.2 min (minor).
We are grateful to Vetenskapsrådet (The Swedish Research
Council) for financial support, and to the Swedish Institute
(SI) for a scholarship to LH.
References
[1] P. Perlmutter, Conjugate addition reactions in organic
synthesis, Pergamon Press, Oxford, 1992.
[2] R. Billini, G. Bosica, D. Fiorini, A. Palmieri, M. Petrini,
3-(4-Methoxyphenyl)-4-nitropentanal (Table 4,
entry 7)
Chem. Rev. 2005, 105, 933–972.
1
[3] a) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033–
8061; b) N. Krause, A. Haffmann-Roder, Synthesis
2001, 171–196; c) P. Bako, T. Kiss, L. Toke, Tetrahe-
dron Lett. 1997, 38, 7259–7262; d) P. Bako, A. Szoello-
esy, P. Bombicz and L. Toeke, Synlett 1997, 291–292;
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Trans. 1 1999, 3651–3655; f) P. Bako, T. Novak, K. Lu-
danyi, B. Pete, L. Toke, G. Keglevich, Tetrahedron:
Asymmetry 1999, 10, 2373–2380; g) T. Bako, P. Bako,
A. Szollosy, M. Czugler, G. Keglevich, L. Toke, Tetra-
hedron: Asymmetry 2002, 13, 203–209; h) T. Bako, P.
Bako, G. Keglevich, N. Bathori, M. Czugler, J. Tatai, T.
Novak, G. Parlagh, L. Toke, Tetrahedron: Asymmetry
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Kanai, T. Arai, H. Sasai, M. Shibasaki, Tetrahedron
Lett. 1998, 39, 7557–7558; j) S. Colonna, H. Hiemstra,
H. Wynberg, J. Chem. Soc., Chem. Commun. 1978,
238–239; k) S. Colonna, A. Re, H. Wynberg, J. Chem.
Soc., Perkin Trans. 1 1981, 547–552; l) E. J. Corey, F. Y.
Zhang, Org. Lett. 2000, 2, 4257–4259; m) C. Botteghi,
S. Paganelli, A. Schionato, C. Boga, A. Fava, J. Mol.
Catal. 1991, 66, 7–21.
[4] M. S. Taylor, D. N. Zalatan, D. N. Lerchner, E. N. Ja-
cobsen, J. Am. Chem. Soc. 2005, 127, 1313–1317.
[5] B. M. Choudary, K. V. S. Ranganath, U. Pal, M. L.
Kantam, B. Sreedhar, J. Am. Chem. Soc. 2005, 127,
13167–13171.
[6] For a collection of reviews on organocatalysis see:
a) Asymmetric Organocalysis, (Eds.: A. Berkessel, H.
Grçger), Wiley-VCH, Weinheim, 2005; b) Comprehen-
sive Asymmetric Catalysis, (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999;
c) B. List, Chem. Commun. 2006, 819–824; d) P. I.
Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001, 40,
3726–3748; e) J. Seayad, B. List, Org. Biomol. Chem.
2005, 3, 719–724; f) K. N. Houk, B. List, Acc. Chem.
Res. 2004, 37, 487–487.
Syn: Slightly yellow oil, H NMR (CDCl3): d=1.34 (d, J=
6.6 Hz, 3H), 2.68–2.97 (m, 2H, CH2C=O), 3.67–3.75 (dt, J=
9.9, 4.5 Hz, 1H), 3.79 (s, 3H), 4.68–4.77 (m, 1H), 6.87 (d,
J=8.7 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H), 9.56 (dd, J=1.9,
1.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=17.6, 43.5,
46.4, 55.3, 87.2, 114.6, 129.2, 129.2, 159.3, 198.8. The enantio-
meric excess was determined using HPLC with a Daicel
Chiralpak AS-H column, 20:80 i-PrOH/hexane, 1 mLminÀ1
flow rate, tr =20.3 min (minor) and 27.3 min (major).
Anti: Slightly yellow oil, 1H NMR (CDCl3): d=1.51 (d,
J=6.6 Hz, 3H), 2.84–3.02 (m, 2H, CH2C=O), 3.72–3.79 (m,
1H), 3.77 (s, 3H), 4.77–4.86 (m, 1H), 6.84 (d, J=8.7 Hz,
2H), 7.09 (d, J=8.7 Hz, 2H), 9.66 (t, J=1.3 Hz, 1H);
13CNMR (75 MHz, CDCl3): d=16.6, 42.9, 44.9, 55.2, 86.5,
114.3, 129.1, 129.2, 159.3, 199.3. The enantiomeric excess
was determined using HPLC with a Daicel Chiralpak AS-H
column, 15:85 i-PrOH/hexane, 1 mLminÀ1 flow rate, tr =
35.8 min (minor) and 39.5 min (major).
3-(4-Methoxyphenyl)-4-nitrohexanal (Table 4,
entry 8)
1
Syn: Slightly yellow oil, H NMR (CDCl3): d=0.85 (t, J=
7.5 Hz, 3H), 1.43–1.58 (m, 1H), 1.73–1.87 (m, 1H), 2.63–
2.96 (m, 2H, CH2C=O), 3.64–3.72 (dt, J=10.2, 3.9 Hz, 1H),
3.79 (s, 3H), 4.50–4.59 (dt, J=10.5, 3.3 Hz, 1H), 6.87 (d, J=
8.7 Hz, 2H), 7.12 (d, J=8.7 Hz, 2H), 9.53 (dd, J=2.1,
0.9 Hz, 1H); 13C NMR (75 MHz; CDCl3): d=10.2, 25.4,
42.8, 46.5, 55.3, 94.4, 114.7, 129.1, 129.6, 159.3, 198.9. The en-
antiomeric excess was determined using HPLC with a
Daicel Chiralpak AS-H column, 5:95 i-PrOH/hexane,
1 mLminÀ1 flow rate, tr =36.7 min (minor) and 45.0 min
(major).
1
Anti: Slightly yellow oil, H NMR (CDCl3): d=0.97 (t, J=
7.5 Hz, 3H), 1.73–1.87 (m, 1H), 1.87–2.00 (m, 1H), 2.81–
3.02 (m, 2H, CH2C=O), 3.69–3.82 (m, 1H), 3.77 (s, 3H),
4.61–4.68 (ddd, J=10.5, 7.2, 3.3 Hz, 1H), 6.83 (d, J=8.7 Hz,
2H), 7.08 (d, J=8.7 Hz, 2H), 9.64 (t, J=1.2 Hz, 1H);
13C NMR (75 MHz; CDCl3): d=10.4, 24.5, 42.1, 45.5, 55.2,
93.7, 114.3, 129.1, 129.5, 159.3, 199.3. The enantiomeric
excess was determined using HPLC with a Daicel Chiralpak
AS-H column, 5:95 i-PrOH/hexane, 1 mLminÀ1 flow rate,
tr =46.7 (minor) min and 49.2 min (major).
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
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FULL PAPERS
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748
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 740 – 748