α-Thiosubstituted chiral imines/secondary enamines: Their use in the asymmetric Michael reaction

Article abstract of DOI:10.1016/S0957-4166(00)00021-5

The asymmetric Michael reaction between 2-thiosubstituted chiral imines/secondary enamines derived from (S)-1-phenylethylamine and electrophilic alkenes (methyl acrylate, MVK) was investigated. 2-Phenylthio derivatives furnished the expected Michael adducts with excellent ee. By contrast, an in situ elimination of p-toluenesulfenic acid took place when using the p-toluenesulfinyl analogs. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00021-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 995–1002
α-Thiosubstituted chiral imines/secondary enamines: their use in
the asymmetric Michael reaction
Mohammed Nour,a Kimny Tan,a Christian Cavé,a,∗ David Villeneuve,b Didier Desmaële,b
Jean d’Angelo b and Claude Riche c
aUnité de Molécules d’Intérêt Biologique, UFR Pharmacie, B.P. 87900, 21079 Dijon Cedex, France
bUnité de Chimie Organique associée au CNRS, Centre d’Etudes Pharmaceutiques, Université Paris-Sud,
5, rue J.-B. Clément, 92296 Châtenay-Malabry, France
cICSN, CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette, France
Received 16 December 1999; accepted 10 January 2000
Abstract
The asymmetric Michael reaction between 2-thiosubstituted chiral imines/secondary enamines derived from (S)-
1-phenylethylamine and electrophilic alkenes (methyl acrylate, MVK) was investigated. 2-Phenylthio derivatives
furnished the expected Michael adducts with excellent ee. By contrast, an in situ elimination of p-toluenesulfenic
acid took place when using the p-toluenesulfinyl analogs. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Since our first report in 1985, considerable attention has been given to the use of chiral imines in the
asymmetric Michael reaction under neutral conditions.1 This reaction indeed provides one of the most
efficient tools for the enantioselective elaboration of quaternary carbon centers, frequently encountered
in architecturally complex natural compounds (terpenes, steroids, alkaloids, etc).
Basically, addition of chiral imines 3, derived from racemic 2-alkylcyclanones 1 and optically active
1-phenylethylamine 2, to electrophilic alkenes 4 furnished Michael adducts 5 with an excellent yield and
a high degree of regio- and stereoselectivity (Scheme 1).
It is worthy of note that the presence of an α-alkoxy substituent in starting cyclanone 1 (R=OMe,
OBn) does not significantly alter the two remarkable features of this reaction, namely the high degree
of regio- and stereochemical control.2 The aim of this paper was to extend this Michael reaction to
the α-thiosubstituted analogs 1 (R=SPh, S(O)Ph), because the expected Michael adducts 5 would offer
∗
Corresponding author. E-mail: christian.cave@u-bourgogne.fr
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00021-5
tetasy 3244

996
M. Nour et al. / Tetrahedron: Asymmetry 11 (2000) 995–1002
Scheme 1.
attractive opportunities of ‘transfer of chirality’, e.g. via sigmatropic rearrangements involving the sulfur
atom.3
2. Results and discussion
Condensation of 2-phenylthiocyclohexanone 64 with (S)-1-phenylethylamine 2 gave compound (S)-7,
as the unique α-sulfenylenamine form.5 Addition of this crude enamine to methyl acrylate (THF, 24 h
at 20°C) furnished, after hydrolytic work-up, Michael adduct (S)-8 with a 68% yield. The ee of 8 (93%)
was determined by 1H NMR spectroscopy, after addition of Eu(hfc)3 as chiral shift reagent. The depicted
absolute configuration of 8 was deduced from mechanistic considerations (vide infra) (Scheme 2).
Scheme 2.
Addition of enamine (S)-7 to methyl vinyl ketone (THF, 12 h at 0°C) afforded Michael adduct (S)-9
in 60% yield and a 95% ee, accompanied by ca. 10% of octalone (S)-10. The structural assignment for
compound 9 was verified by X-ray diffraction analysis, including the absolute configuration, based on
the anomalous diffusion of the sulfur atom (Bijvoet method) (Scheme 3).
When 2-phenylthiocyclopentanone 114 was condensed with amine (S)-2, a mixture of enamine 12
and tautomeric imine 13 was obtained in the respective ratio of 4:1. Addition of this crude mixture to
methyl acrylate (THF, 24 h at 20°C) gave the expected Michael adduct (S)-14 (ee=92%), albeit in low
yield (25%). Only polymeric material was obtained when methyl acrylate was replaced by methyl vinyl
ketone in this reaction (Scheme 4).

M. Nour et al. / Tetrahedron: Asymmetry 11 (2000) 995–1002
997
Scheme 3.
Scheme 4.
It is of particular interest to note that the stereochemical outcome observed in the previous Michael
reactions using α-phenylthioenamines 7 and 12 follow the general mechanistic rule we have established
in this series.6 In accordance with this mechanism, the reaction proceeds through the ‘aza-ene-synthesis-
like’ transition state 15, in which the proton borne by the nitrogen atom of thioenamine is transferred
to the α-carbon atom of the electrophilic alkene, concertedly with the creation of the C–C bond. This
requires a synclinal arrangement of the two reactants, as shown in the corresponding compact approach
16. According to such a model, the alkylation takes place predominantly 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 enamine ring). This accounts for the absolute configuration
in adducts 8, 9 and 14 (Scheme 5).

998
M. Nour et al. / Tetrahedron: Asymmetry 11 (2000) 995–1002
Scheme 5.
A nearly equimolar mixture of tautomeric sulfinylimine/sulfinylenamine forms 18 was obtained in the
condensation between 2-p-toluenesulfinylcyclohexanone 177 and amine (S)-2. Surprisingly, addition of
18 to methyl acrylate (THF, 40 h at 45°C) and to methyl vinyl ketone (THF, 48 h at 20°C) furnished
cyclohexenones 198 (83% yield) and 20 (40% yield), respectively. Thus, an in situ, unusually facile
elimination of p-toluenesulfenic acid took place in these reactions, presumably at the level of the
intermediary sulfinylimines 21 (Scheme 6).
Scheme 6.
Another unexpected result was obtained when the above sequence of reactions was applied to the five-
membered series. Thus, employing 2-p-toluenesulfinylcyclopentanone 227 as starting cyclanone and an
excess of methyl acrylate as electrophilic alkene, a norbornane derivative was isolated with a 60% yield,
as a mixture of three diastereomers in the ratio 3:1:1, established by gas chromatography. Stereochemistry
of the major isomer was tentatively assigned as 23, on the basis of NMR spectroscopy including COSY,
HMQC, HMBC and NOESY experiments. However, this compound exhibited a very low ee (ca. 10%)
(Scheme 7).
Formation of compound 23 and diastereomeric congeners can be interpreted as follows. Addition
of sulfinylimine/sulfinylenamine resulting from the condensation between 22 and 2 to methyl acrylate
would give primarily Michael adduct 24. This probably underwent elimination of p-toluenesulfenic acid,
furnishing α-ethylenic imine 25, in tautomeric equilibrium with the very reactive aminocyclopentadiene

M. Nour et al. / Tetrahedron: Asymmetry 11 (2000) 995–1002
999
Scheme 7.
26. Diels–Alder cycloaddition of 26 with methyl acrylate then afforded norbornene 27, subsequently
hydrolyzed into norbornanone 23 (Scheme 8).
Scheme 8.
3. Experimental
3.1. General
Infrared (IR) spectra were obtained on a Perkin–Elmer 881 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 a Bruker AC 200 P (200 and 50 MHz, for H and 13C, respectively), or
1
a Bruker ARX 400 (400 and 100 MHz, for H and 13C, respectively) spectrometer. 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 Polax L 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

1000
M. Nour et al. / Tetrahedron: Asymmetry 11 (2000) 995–1002
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.
3.2. (S)-(1-Phenylethyl)-(2-phenylsulfenylcyclohex-1-enyl)amine 7
A solution of 2-phenylthiocyclohexanone 6 (0.93 g, 4.5 mmol), (S)-1-phenylethylamine 2 (0.55 g, 4.5
mmol) and p-toluenesulfonic acid (10 mg) in anhydrous toluene (80 mL) was refluxed for 12 h with
azeotropic removal of water. The solution was cooled to 20°C and the solvent was removed in vacuo to
1
afford the crude enamine 7 as a yellow oil; IR (film, cm−1) 3300, 1618, 1581; H NMR (CDCl3, 200
MHz) δ: 7.45–6.85 (m, 10H), 5.5 (d, J=7.0 Hz, 1H), 4.2 (quint., J=7.0 Hz, 1H), 2.35–1.60 (m, 4H),
1.40–1.20 (m, 4H), 1.05 (d, J=7.0 Hz, 3H).
3.3. (S)-3-(2-Oxo-1-phenylsulfenylcyclohexyl)propionic acid methyl ester 8
To the enamine 7 (0.31 g, 1.0 mmol) were added freshly distilled methyl acrylate (1.0 g, 12 mmol),
hydroquinone (5 mg) and THF (20 mL). The stirred mixture was heated at 20°C for 24 h and 5 mL of
20% aqueous acetic acid were added. The mixture was stirred for 3 h. The solvents were removed under
reduced pressure and 1N hydrochloric acid (10 mL) was added. The mixture was extracted with ether
and the combined organic phases were washed with brine, dried and concentrated. Chromatographic
purification over silica gel (1:1 hexane:dichloromethane) gave keto ester 8 (199 mg, 68%) as a colorless
1
oil; [α]D20=−195 (c 1.0, MeOH); IR (film, cm−1) 1735, 1705, 1438; H NMR (CDCl3, 200 MHz) δ:
7.30–7.10 (m, 5H), 3.56 (s, 3H), 3.25 (ddd, J=14.5, 13.2, 6.2 Hz, 1H), 2.55–2.15 (m, 3H), 2.05–1.50 (m,
8H); 13C NMR (CDCl3, 50 MHz) δ: 206.9 (C), 173.8 (C), 136.2 (2 CH), 129.8 (C), 129.5 (CH), 129.0
(2 CH), 60.9 (C), 51.6 (CH3), 37.8 (CH2), 36.4 (CH2), 29.8 (CH2), 28.8 (CH2), 26.9 (CH2), 21.2 (CH2);
anal. calcd: C, 65.72: H, 6.89; found: C, 64.98: H, 6.75.
3.4. (S)-2-(3-Oxobutyl)-2-phenylsulfenylcyclohexanone 9
To the enamine 7 (0.155 g, 0.5 mmol) were added at 0°C freshly distilled methyl vinyl ketone (1.0
g, 15 mmol), hydroquinone (3 mg) and THF (10 mL). The stirred mixture was kept at 0°C for 12
h and 5 mL of 10% aqueous acetic acid were added. The mixture was stirred for 1 h. The solvents
were removed under reduced pressure and 1N hydrochloric acid (10 mL) was added. The mixture was
extracted with dichloromethane and the combined organic phases were washed with brine, dried and
concentrated. Chromatographic purification over silica gel (1:1 hexane:dichloromethane) gave adduct
9 (83 mg, 60%) as colorless crystals; mp 62–63°C (hexane); [α]D20=−187 (c 2.0, MeOH); IR (film,
1
cm−1) 1717, 1700, 1438; H NMR (CDCl3, 200 MHz) δ: 7.30–7.10 (m, 5H), 3.35 (ddd, J=14.0, 13.3,
6.1 Hz, 1H), 2.60–2.30 (m, 3H), 2.05 (s, 3H), 2.00–1.50 (m, 8H); 13C NMR (CDCl3, 50 MHz) δ: 207.8
(C), 207.0 (C), 136.0 (2 CH), 129.8 (C), 129.3 (CH), 128.8 (2 CH), 61.0 (C), 38.1 (CH2), 37.8 (CH2),
36.6 (CH2), 29.8 (CH2), 28.4 (CH2), 26.7 (CH2), 21.1 (CH3); anal. calcd: C, 69.53; H, 7.29; found: C,
69.48; H, 7.42. Crystal data: C16H20O2S, Mw=276.38, crystal of 0.40×0.10×0.02 mm, orthorhombic,
space group P 21 21 21, Z=8, a=6.927(3), b=12.778(6), c=35.064(8) Å, V=3103.6(21) Å3, dcalc=1.183
g cm−3, F(000)=1184, λ=1.54180 Å (CuKα), µ=1.812 mm−1, Nonius CAD4 diffractometer, theta
range: 2.52–67.87°, 3484 collected reflections, 3051 unique (Rint=0.0446), 1328 observed ( I>2σ(I)),
full-matrix least-squares (SHELXL93), R=0.0529 for 1328 observed reflections, wR2=0.1304 for 3051
unique reflections, goodness of fit=0.944, residual electron density between −0.233 and 0.207 eA−3
,

M. Nour et al. / Tetrahedron: Asymmetry 11 (2000) 995–1002
1001
absolute configuration was established by comparison of selected Bijvoet pairs of reflections; for the 28
largest calculated differences (Fcalc(+++)–Fcalc(−−−)) only one observed difference was wrong, the two
molecules of the asymmetric unit adopt a similar conformation.
3.5. (S)-3-(2-Oxo-1-phenylsulfenylcyclopentyl)propionic acid methyl ester 14
A solution of 2-phenylthiocyclopentanone 11 (0.29 g, 1.5 mmol), (S)-1-phenylethylamine 2 (0.18 g,
1.5 mmol) and p-toluenesulfonic acid (10 mg) in anhydrous toluene (20 mL) was refluxed for 12 h with
azeotropic removal of water. The solution was cooled to 20°C and the solvent was removed in vacuo
to afford a crude mixture of enamine 12 and imine 13 as a brown oil. To this crude was added freshly
distilled methyl acrylate (2.0 g, 23 mmol), hydroquinone (5 mg) and THF (20 mL). The stirred mixture
was heated at 20°C for 24 h and 5 mL of 20% aqueous acetic acid were added. The mixture was stirred
for 3 h. The solvents were removed under reduced pressure and 1N hydrochloric acid (10 mL) was added.
The mixture was extracted with ether and the combined organic phases were washed with brine, dried
and concentrated. Chromatographic purification over silica gel (1:1 hexane:dichloromethane) gave keto
ester 14 (104 mg, 25%) as a colorless oil; [α]D20=−79.4 (c 0.38, MeOH); IR (film, cm−1) 1735, 1700,
1
1438; H NMR (CDCl3, 200 MHz) δ: 7.40–7.10 (m, 5H), 3.56 (s, 3H), 2.70–2.50 (m, 2H), 2.40–1.80
(m, 6H), 1.70–1.50 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ: 201.7 (C), 173.3 (C), 136.9 (2 CH), 129.5
(CH), 129.4 (C), 128.7 (2 CH), 60.1 (C), 51.5 (CH3), 35.4 (CH2), 34.2 (CH2), 29.4 (CH2), 27.9 (CH2),
17.8 (CH2); anal. calcd: C, 64.72; H, 6.52; found: C, 64.52; H, 6.70.
3.6. 3-(6-Oxo-cyclohex-1-enyl)propionic acid methyl ester 19
A mixture of 4.40 g of 5 Å molecular sieves, 0.40 g of silica and 0.80 g of basic alumina was activated
by heating for a few minutes at 0.05 torr with a free flame. After cooling, a solution of 1-phenylethylamine
2 (0.57 g, 4.7 mmol) in 5 mL of THF was added, followed by ceto-sulfoxide 17 (1.30 g, 4.0 mmol)
in 3 mL of THF. The suspension was vigorously stirred at 20°C for 18 h. The reaction mixture was
then filtered and the solid residue was repeatedly washed with anhydrous THF. The organic filtrate was
concentrated under reduced pressure (0.05 torr, 40°C) to leave a yellow oil (1.28 g) which was used
directly in the next step. To the crude imine 18 (0.50 g, 1.47 mmol) were added freshly distilled methyl
acrylate (2.60 g, 30 mmol) and hydroquinone (5 mg). The stirred mixture was heated at 45°C for 40 h.
After cooling to 20°C, 20% aqueous acetic acid (5 mL) and THF (20 mL) were added, and the mixture
was stirred for 3 h. The solvents were removed under reduced pressure and 1N hydrochloric acid (10 mL)
was added. The mixture was extracted with ether and the combined organic phases were washed with
brine, dried and concentrated. Chromatographic purification over silica gel (20:10 hexane:ethyl acetate)
1
gave enone ester 19 (220 mg, 83%) as a colorless oil. IR (film, cm−1) 1739, 1674, 1436; H NMR
(CDCl3, 200 MHz) δ: 6.72 (t, J=1.4 Hz, 1H), 3.58 (s, 3H), 2.50–2.25 (m, 8H), 2.05–1.95 (m, 2H); 13
C
NMR (CDCl3, 50 MHz) δ: 199.1 (C), 173.0 (C), 146.3 (CH), 138.0 (C), 51.5 (CH3), 38.4 (CH2), 33.1
(CH2), 26.1 (CH2), 25.5 (CH2), 23.0 (CH2).
3.7. 2-(3-Oxobutyl)cyclohexen-2-one 20
To the crude imine 18 (0.38 g, 1.12 mmol) obtained as described above were added freshly distilled
methyl vinyl ketone (1.0 g, 14.3 mol) and hydroquinone (5 mg), and the reaction mixture was stirred at
20°C for 48 h. Aqueous acetic acid (5 mL, 20%) and THF (20 mL) were then added, and the mixture was
stirred for 3 h. The solvents were removed under reduced pressure and 1N hydrochloric acid (10 mL)

1002
M. Nour et al. / Tetrahedron: Asymmetry 11 (2000) 995–1002
was added. The mixture was extracted with ether and the combined organic phases were washed with
brine, dried and concentrated. Chromatographic purification over silica gel (20:10 hexane:ethyl acetate)
gave enone 20 (75 mg, 40%) as a colorless oil. IR (film, cm−1) 1715, 1669; 1H NMR (CDCl3, 200 MHz)
δ: 6.79 (t, J=1.5 Hz, 1H), 2.50–2.20 (m, 8H), 2.12 (s, 3H), 2.00–1.80 (m, 2H); 13C NMR (CDCl3, 50
MHz) δ: 208.4 (C), 199.5 (C), 146.7 (CH), 138.3 (C), 42.5 (CH2), 38.5 (CH2), 29.9 (CH3), 26.0 (CH2),
24.5 (CH2), 23.0 (CH2).
3.8. 6-(2-Methoxycarbonylethyl)-5-oxo-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester 23
A solution of 1-phenylethylamine 2 (0.72 g, 5.9 mmol) in 2 mL of THF and ceto-sulfoxide 22 (1.1
g, 5.0 mmol) in 2 mL of THF were added to 2 g of catalyst prepared as above. The suspension was
vigorously stirred at 20°C for 18 h. The reaction mixture was then filtered and the solid residue was
repeatedly washed with anhydrous THF. The organic filtrate was concentrated under reduced pressure
(0.05 torr, 40°C) to leave a colorless oil (1.28 g) which crystallized on standing. To this crude were
added freshly distilled methyl acrylate (5 mL) and hydroquinone (5 mg). The stirred mixture was heated
at 45°C for 40 h. After cooling to 20°C, 20% aqueous acetic acid (5 mL) and THF (20 mL) were
added, and the mixture was stirred for 3 h. The solvents were removed under reduced pressure and
1N hydrochloric acid (10 mL) was added. The mixture was extracted with ether and the collected organic
phases were concentrated. Chromatographic purification over silica gel (20:10 hexane:ethyl acetate) gave
a colorless oil (0.77 g, 60%). GC analysis revealed the presence of three isomers in a 3:1:1 ratio. Careful
chromatography provided an analytical sample of major isomer 23 as a colorless oil: IR (film, cm−1
)
1743, 1738; 1H NMR (CDCl3, 400 MHz) δ: 3.68 (s, 3H), 3.65 (s, 3H), 3.04 (ddd, J=11.4, 5.7, 1.2 Hz,
1H), 2.69 (m, 1H), 2.59 (dd, J=4.9, 1.1 Hz, 1H) 2.43 (m, 2H), 2.05 (ddd, J=13.8, 11.4, 4.9 Hz, 1H),
1.98–1.80 (m, 4H), 1.68–1.55 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ: 216.2 (C), 173.2 (C), 172.8
(C), 51.5 (CH3), 51.1 (CH3), 49.6 (CH), 47.3 (CH), 44.1 (CH), 42.7 (CH), 35.5 (CH2), 31.8 (CH2), 26.6
(CH2), 23.8 (CH2).
References
1. For a recent report in this field, see: Thominiaux, C.; Roussé, S.; Desmaële, D.; d’Angelo, J.; Riche, C. Tetrahedron:
Asymmetry 1999, 10, 2015–2021, and references cited therein.
2. Desmaële, D.; d’Angelo, J. Tetrahedron Lett. 1989, 30, 345–348. See also: Desmaële, D.; d’Angelo, J.; Bois, C. Tetrahedron:
Asymmetry 1990, 1, 759–762; Desmaële, D.; Pain, G.; d’Angelo, J. Ibid. 1990, 3, 863–866.
3. For an example, see: Hill, R. K. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando, 1984; Vol. 3, pp.
503–572.
4. Seebach, D.; Tescher, M. Tetrahedron Lett. 1973, 51, 5113–5116.
5. In sharp contrast, a unique α-sulfenylimine form was reported for a closely related compound (3d in this reference): Youn,
J.-H.; Herrmann, R.; Ugi, I. Synthesis 1987, 159–161.
6. Tran Huu Dau, M. E.; Riche, C.; Dumas, F.; d’Angelo, J. Tetrahedron: Asymmetry 1998, 9, 1059–1064.
7. Coates, R. M.; Pigott, H. D. Synthesis 1975, 319–320.
8. Barillier, D.; Benhida, R.; Vazeux, M. Phosphorus, Sulfur, and Silicon 1993, 78, 83–95.