Nitroalkenes as electrophiles in the asymmetric Michael reaction involving chiral imines/enamino esters

Article abstract of DOI:10.1016/S0957-4166(99)00180-9

Addition of 2-nitropropene to the chiral imine derived from 2- methylcyclopentanone and (S)-1-phenylethylamine furnished the expected Michael adduct. The latter compound was then efficiently converted into (R)- pentalenone through a Nef reaction. Condensa

Full text of DOI:10.1016/S0957-4166(99)00180-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2015–2021
Nitroalkenes as electrophiles in the asymmetric Michael reaction
involving chiral imines/enamino esters
Cyrille Thominiaux,a Sébastien Roussé,a Didier Desmaële,a,∗ Jean d’Angelo a,∗,† and
Claude Riche b
aUnité de Chimie Organique associée au CNRS, Centre d’Etudes Pharmaceutiques, Université Paris-Sud, 5 rue J.-B. Clément,
92296 Châtenay-Malabry, France
bI.C.S.N., CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette, France
Received 30 April 1999; accepted 11 May 1999
Abstract
Addition of 2-nitropropene to the chiral imine derived from 2-methylcyclopentanone and (S)-1-
phenylethylamine furnished the expected Michael adduct. The latter compound was then efficiently
converted into (R)-pentalenone through a Nef reaction. Condensation of the enamino ester derived from 2-
carbethoxycyclopentanone and (S)-1-phenylethylamine with 1-nitropropene gave with excellent diastereo- and
enantioselectivity the corresponding Michael adduct. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The use of nitroalkenes as Michael acceptors has received much resurgent attention, due to the
continuous discovery of efficient methods for converting aliphatic nitro groups into amines, carbonyl
groups, etc.1 Among the asymmetric versions of this reaction, condensation of chiral enamines with
nitroalkenes was proved to be of great value.2 As part of systematic studies devoted to the asymmetric
Michael reaction, we recently disclosed that the conjugate addition of enamino ester (S)-1 to nitroethylene
2 furnished, after hydrolytic work up, adduct (S)-3 with an 80% yield and an excellent stereoselectivity
(90% ee)3 (Scheme 1). In this paper, we wish to report further investigation of this methodology, hence
extending its pratical utility in asymmetric C–C bond construction.
∗
†
Corresponding authors.
E-mail: jean.dangelo@cep.u-psud.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00180-9

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Scheme 1.
2. Results and discussion
Addition of nitroethylene 24 to imine (S)-4, prepared from racemic 2-methylcyclopentanone and (S)-1-
phenylethylamine (96% ee), was examined first. This condensation (THF, 1 h at 0°C, then 20% aqueous
AcOH) gave with 80% yield a nearly equimolar mixture of regioisomers 5 and 6, as revealed by 1H NMR
spectroscopy. However, all attempts at chromatographic separation of the reaction mixture over silica gel
failed (Scheme 2).
Scheme 2.
In sharp contrast, addition of imine (S)-4 to the three-carbon acetonyl equivalent 2-nitropropene 74
(THF, 2 h at 0°C, then 20% aqueous AcOH) was highly regioselective, furnishing with a 77% yield a
mixture of diastereomeric adducts (1S,10R)-8 and (1R,10R)-9, in a product ratio of about 9:1. The R-
configuration at C-10 in both isomers was determined by chemical correlation with known derivative
13. The S-configuration at C-1 in major diastereomer 8, although not definitely established, rests on the
proposed transition-state model for this Michael reaction (vide infra 17)5 (Scheme 3).
Scheme 3.
Conversion of nitro ketones 8 and 9 into corresponding diketone 11 through the Nef reaction was
then studied. While treatment of the mixture of 8 and 9 with TiCl3 (24 h at 20°C in H2O) gave only
oxime (R)-10 in 70% yield,6 sequential exposure of 8 and 9 to 1N NaOH in EtOH (1 h at 0°C) and 3N
1
HCl furnished diketone (R)-11 with a 68% yield.7 The ee of 11 (=95%) was determined by H NMR

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spectroscopy, after addition of Eu(hfc)3 as chiral shift reagent. The absolute configuration of compound
(R)-11 was unequivocally assigned by correlation with the known bicyclic ketone (1R,5S)-13.8 For that
purpose, 11 was first cyclized into enone (R)-12 (t-BuOK in t-BuOH, 2 h at 20°C, 75% yield) which was
then reduced to (1R,5S)-13 (1 bar of H2, Pd–C, EtOH, 95%) (Scheme 4).9
Scheme 4.
(E)-1-Nitropropene 14,4 a 1-formylethyl synthon equivalent, also constitutes a particularly attractive
electrophile in the Michael reaction. While condensation of 14 with imine (S)-4 afforded a complex
mixture of regio- and diastereomeric adducts, addition of this nitroalkene to enamino ester (S)-1 (THF,
24 h at 20°C then 20% aqueous AcOH) gave Michael adduct (10S,2S)-15 in 80% yield and with an
excellent stereoselectivity (de and ee=95%). The structural assignment for compound 15 was verified by
an X-ray diffraction analysis (Scheme 5), with the exception of the absolute configuration, founded on
the proposed transition-state model 17.
Scheme 5.
The stereochemical outcome observed in the previous experiments can be rationalized by invoking
that the reaction proceeds through the cyclic ‘aza-ene-synthesis-like’ transition state 16, which involves
as nucleophilic partner enamino ester 1 (R=COOEt), or the more substituted secondary enamine in
tautomeric equilibrium with imine 4 (R=Me).5 In accordance with this mechanism, the proton borne by
the nitrogen atom of the enamino ester (enamine) is transferred to the α-carbon atom of the nitroalkene,
concertedly with the creation of the C–C bond. This requires a synclinal arrangement of the two reactants,

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as shown in the corresponding compact approach 17. According to such a model, the alkylation takes
place anti to the bulky phenyl ring of the chiral amine moiety portrayed in its energetically preferred
conformation minimizing the A1,3-type strain (C–H bond more or less eclipsing the cyclopentene ring).
This accounts for the absolute configuration in adducts 8, 9 and 15. On the other hand, to rationalize
the stereochemical relationship of the two stereogenic centers in adducts 8 and 15, nitroalkenes 7 and
14 need to be arranged as depicted in model 17, namely the nitro group facing the nitrogen atom of the
enamine partner (Scheme 6).
Scheme 6.
In conclusion, we have established that additions of chiral imine 4 to 2-nitropropene, and chiral
enamino ester 1 to 1-nitropropene proceed smoothly, delivering the expected adducts 8 and 9, and 15,
respectively, with a high degree of regio- and stereoselectivity. The stereochemical outcomes have been
rationalized on the basis of a cyclic ‘aza-ene-synthesis-like’ transition state. Studies on the application of
these adducts as chiral synthons for the asymmetric synthesis are underway.
3. Experimental
3.1. General
Infrared (IR) spectra were obtained on a Perkin–Elmer 841 spectrometer as neat films between
1
NaCl plates or KBr pellets. Only the most significant absorptions are listed. The H and 13C NMR
1
spectra were recorded on Bruker AC 200 P (200 MHz and 50 MHz, for H and 13C, respectively), or
Bruker ARX 400 (400 MHz and 100 MHz, for 1H and 13C, respectively) spectrometers. Recognition of
methyl, methylene, methine, and quaternary carbon nuclei in 13C NMR spectra rests on the J-modulated
spin–echo sequence. Optical rotations were measured at 20°C on a Perkin–Elmer 241 MC polarimeter
in a 1 dm cell. Analytical thin-layer chromatography was performed on Merck silica gel 60F254 glass
precoated plates (0.25 mm layer). Column chromatography was performed using Merck silica gel 60
(230–400 mesh ASTM). Tetrahydrofuran (THF) was distilled from sodium–benzophenone ketyl. CH2Cl2
was distilled from calcium hydride. All reactions involving air- or water-sensitive compounds were
routinely conducted in glassware which was flame-dried under a positive pressure of nitrogen. Organic
layers were dried over anhydrous MgSO4. Chemicals obtained from commercial suppliers were used
without further purification. All elemental analyses were performed by the Service de microanalyse,
Centre d’Etudes Pharmaceutiques, Châtenay-Malabry, France, with a Perkin–Elmer 2400 analyzer.

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3.2. (S)-α-Methyl-N-(2-methylcyclopentylidene)benzenemethanamide 4
(S)-(−)-1-Phenylethylamine of 96% ee (8.9 g, 74 mmol) was added to a solution of 2-
methylcyclopentanone (7.3 g, 74 mmol) and p-toluenesulfonic acid (0.1 g, 0.6 mmol) in toluene
(60 mL). The reaction mixture was refluxed for 18 h with azeotropic removal of water. The reaction
mixture was concentrated and distilled under reduced pressure to give imine 4 as a pale yellow oil
(11.7 g, 79%); bp 95–98°C (0.1 torr); IR (neat, cm−1) ν=1680, 1604, 1493; 1H NMR (C6D6, 200 MHz)
δ=1.05 and 1.20 (2 d, J=6.7 Hz, 3H), 1.30 and 1.40 (2 d, J=6.6 Hz, 3H), 1.40–2.15 (m, 7H), 4.20 (q,
J=6.6 Hz, 1H), 6.90–7.40 (m, 5H); 13C NMR (C6D6, 50 MHz) δ=16.8 and 16.9 (CH3), 22.5 and 22.6
(CH2), 25.4 and 25.5 (CH3), 28.1 (CH2), 32.9 and 33.0 (CH2), 41.3 and 41.6 (CH), 61.6 and 61.9 (CH),
126.3–127.7 (5 CH), 146.7 and 147.0 (C), 178.6.
3.3. (1S,10R)-2-Methyl-2-(2-nitropropyl)cyclopentanone 8 and (1S,10S)-2-methyl-2-(2-nitropropyl)-
cyclopentanone 9
To an ice-cooled solution of freshly distilled imine 4 (2.93 g, 14.6 mmol) in THF (6 mL) was
added dropwise 2-nitropropene 7 (1.27 g, 14.6 mmol). The reaction mixture was stirred at 0°C for 2
h and 20% aqueous acetic acid (10 mL) in methanol (6 mL) was added. After being stirred at 20°C
for 2 h, the reaction mixture was concentrated in vacuo and the residue extracted with diethyl ether.
The combined organic layers were washed with brine, dried and concentrated under reduced pressure.
Chromatographic purification on silica gel (cyclohexane:ethyl acetate, 4:1) afforded 2.08 g (77%) of a
mixture of nitroketone 8 and 9 in a 9:1 ratio, as a colorless oil; IR (neat, cm−1) ν=1738, 1550, 1459; 1H
NMR (CDCl3, 200 MHz, only the major isomer is described) δ=0.89 (s, 3H), 1.41 (d, J=6.7 Hz, 3H),
1.60 (dd, J=15.8, 4.0 Hz, 1H), 1.65–1.90 (m, 5H), 2.05–2.24 (m, 1H), 2.30 (dd, J=15.8, 8.4 Hz, 1H), 4.49
(ddq, J=8.4, 4.0, 6.7 Hz, 1H); 13C NMR (CDCl3, 50 MHz, only the major isomer is described) δ=18.2
(CH2), 21.5 (CH3), 21.8 (CH3), 35.3 (CH2), 36.8 (CH2), 40.7 (CH2), 47.3 (C), 80.4 (CH), 221.0 (CO).
3.4. (R)-2-Methyl-2-(oxopropyl)cyclopentanone 11
To an ice-cooled solution of sodium hydroxide (650 mg, 16.2 mmol) in absolute ethanol (13 mL) was
added 1.0 g of nitro ketones 8 and 9 (5.4 mmol). The reaction mixture was stirred at 0°C for 30 min and
poured into chilled 3N HCl (30 mL). The reaction mixture was stirred at 20°C for 12 h and concentrated
under reduced pressure. The oily residue was extracted with diethyl ether and the combined organic layers
were successively washed with aqueous sodium bicarbonate and brine. The organic phase was dried
and concentrated under reduced pressure. Chromatographic purification on silica gel (cyclohexane:ethyl
acetate, 2:1) gave 566 mg (68%) of diketone 11 as a colorless oil; [α]D20=−15.8 (c 3.6, EtOH); IR (neat,
1
cm−1) ν=1740, 1716; H NMR (CDCl3, 200 MHz) δ=0.98 (s, 3H), 1.60–2.10 (m, 4H), 2.07 (s, 3H),
2.15–2.60 (m, 2H), 2.67 (d, J=18.2 Hz, 1H), 2.83 (d, J=18.2 Hz, 1H); 13C NMR (CDCl3, 50 MHz)
δ=18.7, 22.7, 30.1, 34.6, 37.0, 45.6, 51.0, 206.4, 221.0.
3.5. (R)-5-Methyl-bicyclo[3,3,0]octen-3-one 12
To a solution of potassium tert-butoxide (262 mg, 2.1 mmol) in tert-butanol (10 mL) was added
dropwise a solution of diketone 11 (294 mg, 1.9 mmol) in tert-butanol (3 mL). After being stirred at
20°C for 2 h, a saturated aqueous solution of NH4Cl was added. The mixture was extracted with CH2Cl2;
the organic phase was dried and concentrated under reduced pressure. Chromatographic purification over

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silica gel (cyclohexane:ethyl acetate, 2:1) gave 195 mg of enone 12 (75%) as a colorless oil; bp 80°C (1
torr); [α]D20=+72.1 (c 6.3, EtOH); IR (neat, cm−1) ν=1713, 1629; 1H NMR (CDCl3, 200 MHz) δ=1.24
(s, 3H), 1.45 (t, J=10.9 Hz, 1H), 1.80–2.20 (m, 3H), 2.25 (d, J=17.0 Hz, 1H), 2.47 (d, J=17.0 Hz, 1H),
2.40–2.70 (m, 2H), 5.75 (s, 1H); 13C NMR (CDCl3, 50 MHz) δ=23.1 (CH2), 24.7 (CH2), 25.1 (CH3),
36.4 (CH2), 50.2 (C), 51.0 (CH2), 123.4 (CH), 194.7 (C), 210.7 (CO).
3.6. (1R,5S)-5-Methyl-bicyclo[3,3,0]octan-3-one 13
A mixture of enone 12 (175 mg, 1.3 mmol) and 10% palladium on carbon (50 mg) in ethanol (5 mL)
was stirred under hydrogen (4 bars) for 12 h. The mixture was filtered off and concentrated in vacuo.
Distillation of the residue left enone 13 (165 mg, 95%) as a colorless oil; bp 100°C (20 torr); [α]D=−22.4
1
(c 0.6, CHCl3); IR (neat, cm−1) ν=1731, 1451; H NMR (CDCl3, 200 MHz) δ=1.16 (s, 3H), 1.42 (m,
1H), 1.36–1.80 (m, 5H), 1.92–2.30 (m, 4H), 2.53 (ddd, J=18.0, 8.5, 2.3 Hz, 1H); 13C NMR (CDCl3, 50
MHz) δ=24.4 (CH3), 27.5 (CH2), 32.9 (CH2), 40.0 (CH2), 45.0 (CH2), 46.9 (CH), 47.0 (C), 51.7 (CH2),
220.3 (CO).
3.7. (1S,20S)-1-[(1-Methyl-2-nitro)ethyl]-2-oxo-cyclopentanecarboxylic acid ethyl ester 15
(E)-1-Nitropropene (0.9 g, 12 mmol) was added dropwise to a solution of enamino ester 1 (1.0 g, 3.9
mmol) in THF (10 mL). The reaction mixture was stirred for 16 h at 20°C, and an additional portion
of nitropropene (0.30 g, 3 mmol) was added and the stirring continued for 5 h. A solution of 20%
aqueous acetic acid (20 mL) in methanol (10 mL) was added. After being stirred at 20°C for 12 h, the
reaction mixture was concentrated in vacuo and the residue extracted with diethyl ether. The combined
organic layers were washed with brine, dried and concentrated under reduced pressure. Chromatographic
purification on silica gel (cyclohexane:ethyl acetate, 4:1) gave nitro ester 15 (750 mg, 80%) as colorless
1
crystals; mp 53–54°C (i-PrOH); [α]D20=+21.4 (c 2.9, EtOH); IR (neat, cm−1) ν=1755, 1729, 1553; H
NMR (CDCl3, 200 MHz) δ=1.04 (d, J=6.9 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.85–2.60 (m, 6H), 2.98
(m, 1H), 4.18 (q, J=7.1 Hz, 2H), 4.26 (dd, J=12.8, 9.8 Hz, 1H), 4.86 (dd, J=12.8, 3.7 Hz, 1H); 13C
NMR (CDCl3, 50 MHz) δ=13.7 (CH3), 13.8 (CH3), 19.3 (CH2), 30.5 (CH2), 35.5 (CH), 38.0 (CH2),
61.8 (CH2), 67.9 (C), 78.0 (CH), 168.2 (CO), 212.0 (CO); anal. calcd: C, 54.30; H, 7.05; N, 5.76;
found: C, 54.25; H, 7.07; N, 5.73. Crystal data: C11H17NO5; MW=243.26, crystal of 0.50×0.35×0.25
mm, monoclinic, space group P 21, Z=2, a=6.407 (2), b=10.707 (4), c=9.930 (2) Å, β=106.94 (3)°,
V=651.6 (3) Å3, dcalc=1.24 g cm−3, F(000)=260, λ=0.71070 Å (Mo Kα) Å, µ=0.098 mm−1. Nonius
CAD4 diffractometer, theta range: 2.14–27.94, 3462 collected reflexions, 3119 unique (Rint=0.094), 2469
observed (I=2σ(I)). The structure was refined by full-matrix least-squares with SHELX93, R=0.0437 for
2469 observed reflexions and wR2=0.1273 for 3119 unique reflexions, goodness of fit=1.046. Residual
electron density between −0.123 and 0.167 e Å−3.
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