Michael reactions of unsubstituted aromatic chiral imines with substituted unsaturated acid esters

Article abstract of DOI:10.1016/S0957-4166(03)00527-5

The Michael reaction of chiral imines 1-3, derived from aromatic ketones' with substituted electrophilic olefins generated asymmetric tertiary carbon centers. Nevertheless, asymmetric inductions were weaker than those usually observed with cycloalkanone imines.

Full text of DOI:10.1016/S0957-4166(03)00527-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2747–2753
Michael reactions of unsubstituted aromatic chiral imines with
substituted unsaturated acid esters
Nicolas Monnier-Benoit,a Ivan Jabin,a,* Mohamed Selkti,b Alain Tomasb and Gilbert Revialc,*
aURCOM, Universite´ du Havre, Faculte´ des Sciences et Techniques, BP 540, F 76058 Le Havre Cedex, France
bLaboratoire de Cristallographie et RMN Biologiques, UMR 8515, Universite´ de Paris V, 4 Avenue de l’observatoire,
F 75270 Paris Cedex 06, France
cLaboratoire de Chimie Organique, UMR 7084, ESPCI, 10 rue Vauquelin, F 75231 Paris Cedex 05, France
Received 20 June 2003; accepted 1 July 2003
Abstract—The Michael reaction of chiral imines 1–3, derived from aromatic ketones’ with substituted electrophilic olefins
generated asymmetric tertiary carbon centers. Nevertheless, asymmetric inductions were weaker than those usually observed with
cycloalkanone imines.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
sion of the imine method was possible, this reaction
could allow access to 3,4-dihydropyridin-2-ones which
could be useful for the preparation of pipecolic acid
derivatives, key intermediates in the synthesis of many
biologically active compounds.3 For this purpose and
avoiding any alkylation in the a%-position, a-tetralone
or an alkylarylketone could be used, and the adduct
could be cyclised into a lactam.
The enantioselective Michael reaction of chiral imines
with unsubstituted electrophilic olefins is limited to the
creation of quaternary asymmetric carbon centers, i.e.
those non-epimerisable by imine–enamine tautomerism.
However, with a- or b-substituted olefins, this same
reaction allows the simultaneous generation of a second
tertiary asymmetric carbon in the b- or g-position rela-
tive to the imine function, which in turn are not
epimerisable.1 It occurred to us that it could be possible
to use these substituted olefins to create a compound
having an asymmetric tertiary carbon center in the b
and/or g-position while the a-position would be a CH2
group or a sp2 carbon atom.2 In the present study, only
the latter situation is studied. Indeed, if such an exten-
In the model suggested to account for the observed
stereoselectivity of the Michael reaction with a-substi-
tuted chiral cycloalkanone imines, the reactive confor-
mation of the secondary enamine is that in which the
chiral moiety is on the opposite side of the double
bond. This preference induces the usual diastereofacial
selectivity as shown in Figure 1.4
Figure 1.
* Corresponding authors. E-mail: gilbert.revial@espci.fr
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00527-5

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N. Monnier-Benoit et al. / Tetrahedron: Asymmetry 14 (2003) 2747–2753
Figure 2.
In the present instance dealing with a sterically hin-
dered tetralone or alkylarylketone, the reactive confor-
mation should be that in which the chiral moiety is on
the same side of the double bond, thus inducing the
opposite diastereofacial selectivity compared with the
general case above (Fig. 2).
ketones was not observed. These experimental details
reveal the low reactivity of these conjugated aromatic
ketones with bulky amines. Since they are thermally
unstable and cannot be purified by distillation, the
crude imines were used in the Michael reactions.
Normally, the Michael reaction of the imines with
substituted electrophilic olefins is slow and difficult.1
Drastic conditions and long reaction times without
solvent are required. In the present instance, the
Michael reaction is followed by an aza-cyclization lead-
ing to a g,d-ethylenic-d-lactam thus, as expected, avoid-
ing any asymmetric center in the a-position (Scheme 1
and Table 1).
2. Results
The reactions of the chiral imines of a-tetralone, ace-
tophenone and propiophenone were studied with three
substituted olefins, i.e. phenyl crotonate 4, diphenyl
ethylidenemalonate 5 and phenyl methacrylate 6. The
imines 1–3 were prepared from the corresponding
ketones and chiral (S)- or (R)-a-methylbenzylamine by
azeotropic removal of water with toluene. Even in the
presence of an acid catalyst (pTSA or TFA) the
observed reaction times (48 h to 3 days) are rather long,
and in some cases total conversion of the starting
Conversions as well as diastereoselectivities of the reac-
tions were evaluated by GC–MS analysis of the crude
mixture. In two cases (entries
6
and 9) the
diastereomers could not be separated by GC–MS and
diastereomeric excesses were measured by 1H NMR.
Scheme 1.

N. Monnier-Benoit et al. / Tetrahedron: Asymmetry 14 (2003) 2747–2753
Table 1. Michael reactions of aromatic imines
2749
Entry
Imines
Olefins
Reaction times at 100°C
Michael adducts
Diastereoselectivity
Overall yieldb
1
2
3
4
5
6
7
8
9
1
1
1
2
2
2
3
3
3
4
5
6
4
5
6
4
5
6
5 days
15 ha
15 h
7a/7b
7a/7b
8a/8b
9a/9b
63:37
60:40
63:37
–
52:48
64:36
70:30
57:43
77:23
42
36
33
–
33
19
81
80
70
72 h
24 ha
48 h
9a/9b
10a/10b
11a/11b
11a/11b
12a/12b
10 days
18 ha
10 days
a Followed by: (i) NaOH/MeOH, 60°C, 17 h; (ii) toluene, 110°C, 4 h.
b Calculated from the corresponding starting ketones.
The diastereoselectivities observed in the reactions with
the bicyclic imine 1 (entries 1, 2 and 3) are weak with
the three olefins 4,
5
and
6
(20–26%). The
diastereomeric lactams 7a, 7b, 8a, and 8b were isolated
by flash chromatography (FC). The observed
diastereoselectivity of the reaction with diphenyl ethyl-
idenemalonate 5 (entry 2) is slightly lower than that
obtained with the phenyl crotonate 4 (entry 1). This
fact is in agreement with the results already observed
with this type of diactivated olefin.5 Careful monitoring
by GC–MS showed that the Michael reaction is rela-
tively fast but that the aza-cyclization which follows is
definitely slower (see Section 3). As long reaction times
are necessary, partial degradation of the reagents takes
place, thus lowering the yields.
With imine 2 (entries 5 and 6) the expected lactams 9
and 10 were obtained with olefins 5 and 6 but the
observed yield was even lower with olefin 6 than in the
case of imine 1. These low yields are due to competition
with self-aldolization of imine 2. With the phenyl croto-
nate 4, this last reaction was in fact the only one
observed (entry 4). The diastereoselectivities are poor
(entry 6) to non-existent (entry 5).
Figure 3. X-Ray structure of the major adduct 7a.
Finally, with imine 3 the diastereoselectivities and the
yields are higher than those obtained with imines 1 and
2. In this case self-aldolization was not observed. With
phenyl methacrylate 6 (entry 9) the reaction leads to
lactam with a diastereoisomeric excess higher than 50%
and a 70% yield. The two diastereoisomers 12a and 12b
were not separable by FC.
The stereochemistry of the new stereogenic center in the
major adduct 7a is of the opposite configuration com-
pared to the one observed with the cycloalkanone-
imines in reaction with substituted olefins. This case
thus represents the first example of inversion of
diastereoselectivity. It can be explained if, as supposed
(vide supra) the chiral moiety is located on the opposite
side compared with the usual case. The observed
weaker asymmetric induction, than in the normal cases,
can be rationalized by the existence, in the chair transi-
tion state, of a destabilizing interaction between the
methyl group of the chiral moiety and the vinyl hydro-
gen of the olefin. Conversely the boat transition state,
while higher in energy,4 does not present this type of
interaction and can thus be in competition with the
chair transition state (Fig. 4). Participation of the disfa-
voured structure shown in Fig. 2, can also account for
the lowering of the usual diastereoselectivity.
3. Discussion
As opposed to the diastereomers obtained from imines
2 and 3, the two diastereomers 7a and 7b (entries 1 and
2) were separable by FC, and could be purified by
recrystallization. The relative configuration of the
major diastereomer 7a was determined by single-crystal
X-ray diffraction (Fig. 3).

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N. Monnier-Benoit et al. / Tetrahedron: Asymmetry 14 (2003) 2747–2753
Figure 4. Possible transition states of the Michael reaction.
Finally, concerning the difficult aza-cyclization of the
Michael adduct obtained from imine 1, a similar result
has already been observed for closely related com-
pounds.6 It may be due to the existence of a steric
interaction between the chiral moiety and the aromatic
ring in the ester function approach to the nitrogen atom
(Fig. 5).
flash chromatography separations (FC) were carried
out with silica gel (200–450 mesh), using EtOAc/cyclo-
hexane as eluents (% EtOAc given). GLC–MS were
performed with a HP 6890 GC apparatus (equipped
with a 12 m×0.20 mm dimethylpolysiloxane capillary
column) linked to a HP 5973 EIMS. [h]D values are
1
given in 10−1 deg cm2 g−1. H and 13C NMR spectra of
CDCl3 solutions were recorded at 200 and 50 MHz,
respectively. Chemical shifts are expressed in ppm using
TMS as internal standard and coupling constants (J)
are given in Hz. All reactions were performed under an
argon atmosphere. Unless indicated otherwise, organic
phases were washed with a saturated NaCl aqueous
solution, dried over MgSO4, filtered, and evaporated
under reduced pressure.
5.2. (3,4-Dihydro-2H-naphthalen-1-ylidene)-[1-(R)-
phenyl-ethyl])-amine 1
Figure 5.
A solution of a-tetralone (3.00 g, 20.5 mmol) and
(R)-(+)-a-methylbenzylamine (99.9% ee, 2.64 mL, 20.5
mmol, 1 equiv.) with a trace of TFA in toluene (50 mL)
was heated under reflux in a Dean–Stark apparatus for
48 h. After removal of the solvent under reduced
pressure, crude imine 1 (5.67 g) was isolated and used
for the next steps without purification. A GLC–MS
analysis showed two signals at 4.97 min (a-tetralone,
30%) and 10.91 min (imine 1, 70%); 1H NMR l 1.44 (d,
J=7.0, 3H), 1.7–1.9 (m, 2H), 2.3–2.8 (m, 4H), 4.76 (q,
J=7.0, 1H), 6.9–7.5 (m, 8H), 8.25–8.3 (m, 1H); EIMS
(m/z): 249 (M+, 33%), 248 (34), 234 (41), 105 (100), 77
(27).
4. Conclusion
The Michael reaction of aromatic imines with substi-
tuted olefins has allowed the generation only of asym-
metric tertiary carbon centers in the cyclized adducts.
However, the asymmetrical inductions were weaker
than those usually observed with a-substituted
cycloalkanones imines. Studies are in hand in our labo-
ratory to make this process more efficient for applica-
tions in organic synthesis.
5. Experimental
5.1. General
5.3. 4-Methyl-1-(1-(R)-phenyl-ethyl)-3,4,5,6-tetrahydro-
1H-benzo[h]quinolin-2-one 7a and 7b
Method A: from phenyl crotonate. Crude imine 1 (1.00
g, 4.01 mmol), phenyl crotonate 4 (0.72 mL, 4.42 mmol,
Thin layer chromatography (TLC) was performed with
glass plates (0.25 mm) precoated with silica gel and

N. Monnier-Benoit et al. / Tetrahedron: Asymmetry 14 (2003) 2747–2753
2751
1.1 equiv.) with a trace of hydroquinone were heated at
100°C for 5 days. A GLC-MS analysis of the crude
mixture showed two signals at 13.32 min (37%) and
13.56 min (63%). At rt, ether (60 mL) and 2.5 M
aqueous NaOH (25 mL) were then added to the crude
mixture which was stirred for 20 min. After ether
extraction, washing with water to neutral pH and FC
(15%), the lactams 7a and 7b (479 mg, 42% overall yield
from a-tetralone) were isolated as a mixture of two
diastereomers. Method B: from diphenyl 2-ethylidene-
malonate. Crude imine 1 (0.50 g, 2.00 mmol), diphenyl
2-ethylidenemalonate 5 (622 mg, 2.20 mmol, 1.1 equiv.)
with a trace of hydroquinone were heated at 100°C for
15 h. MeOH (20 mL) and 2.5 M aqueous NaOH (10
mL) were then added to the crude mixture which was
heated at 60°C for 17 h. After evaporation of the
MeOH under reduced pressure, 10% aqueous HCl was
slowly added to acid pH. Ether extraction followed by
usual work-up gave crude material which was dissolved
in toluene (10 mL) and heated at 100°C for 3 h. A
GLC–MS analysis of the crude mixture showed two
signals at 13.37 (40%) and 13.63 min (60%). After
toluene evaporation under reduced pression, extraction
with ether and washing with 2.5 M NaOH (10 mL),
usual work-up followed by FC (15%) gave the lactams
7a and 7b as a mixture of two diastereomers (204 mg,
36% overall yield from a-tetralone). Analytical samples
of the two diastereomers were then obtained through
recrystallization to give pure lactam 7a and pure lactam
were then added to the crude mixture which was stirred
for 20 min. After ether extraction and washing with
water to neutral pH, usual work-up followed by FC
(15%) gave the lactams 8a and 8b (378 mg, 33% overall
yield from a-tetralone) as a diastereomeric mixture.
Analytical samples of the two diastereomers were
obtained by careful FC separations followed by distilla-
tion; major diastereomer 8a: [h]2D0 +8.4, [h]52708=+8.8,
[h]52406=+10.5, [h]42306=+24.6 (c 3.07, CHCl3); IR (thin
1
film) 1671 cm−1; H NMR: l 1.10 (d, J=7.0, 3H), 1.79
(d, J=7.0, 3H), 2.0–2.8 (m, 7H), 4.81 (q, J=7.0, 1H),
7.1–7.5 (m, 9H), 13C NMR: l 14.69 (CH3), 18.16 (CH3),
28.40 (CH2), 28.48 (CH2), 33.13 (CH2), 36.95 (CH),
57.52 (CH), 121.9 (CH), 125.5 (Cq), 126.2 (CH), 126.3
(3CH), 126.6 (CH), 127.7 (CH), 128.0 (2CH), 131.1
(Cq), 135.7 (Cq), 136.6 (Cq), 142.0 (Cq), 175.5 (Cq),
EIMS (m/z): 317 (M+, 6%), 213 (100), 198 (27), 105
(92), 77 (46); minor diastereomer 8b: [h]2D0=−79.4,
[h]25078=−82.6, [h]52406=−93.4, [h]420316=−158.4 (c 1.36,
CHCl3); IR (thin film) 1672 cm−1; H NMR: l 1.05 (d,
J=6.3, 3H), 2.08 (d, J=7.0, 3H), 2.0–2.8 (m, 5H), 4.86
(q, J=7.0, 1H), 6.7–7.5 (m, 9H); 13C NMR: l 14.46
(CH3), 18.27 (CH3), 28.11 (CH2), 28.53 (CH2), 33.02
(CH2), 36.68 (CH), 57.14 (CH), 122.1 (CH), 126.0 (Cq)
126.3 (CH), 126.6 (CH), 126.7 (CH), 127.8 (CH), 127.9
(CH), 128.0 (CH), 131.2 (Cq), 136.4 (Cq), 136.7 (Cq),
142.2 (Cq), 175.6 (Cq); EIMS (m/z): 317 (M+, 5%), 213
(98), 198 (28), 105 (100), 77 (53).
7b; major diastereomer 7a: mp 130°C (AcOEt, cyclohex-
5.5. [1-(S)-Phenyl-ethyl)-(1-phenyl-ethylidene]-amine 2
ane); [h]2D0=+54.8, [h]52708=+57.7, [h]25406=+68.0, [h]
=
20
436
+147.5 (c 0.95, CHCl3); IR (CHCl3) 1670 cm−1; 1H
NMR: l 1.12 (d, J=6.3, 3H), 1.84 (d, J=7.0, 3H),
2.21–2.77 (m, 7H), 4.81 (q, J=7.0, 1H), 7.10–7.40 (m,
9H). 13C NMR: l 17.17 (CH3), 17.80 (CH3), 26.09
(CH2), 28.74 (CH2), 30.47 (CH), 40.90 (CH2), 57.54
(CH), 122.2 (CH), 126.3 (3CH), 126.6 (CH), 127.6
(CH), 128.0 (2CH), 130.8 (Cq), 131.0 (Cq), 136.5 (2Cq),
142.0 (Cq), 172.0 (Cq), EIMS (m/z): 317 (M+, 3%), 213
A solution of acetophenone (3.00 mL, 25.6 mmol) and
(S)-(−)-a-methylbenzylamine (99.9% ee, 3.30 mL, 25.6
mmol, 1 equiv.) with a trace of pTSA in toluene (50
mL) was heated under reflux in a Dean-Stark apparatus
for 3 days. After removal of the solvent under reduced
pressure, crude imine 2 (6.40 g) was obtained and used
for the next steps without purification. A GLC–MS
analysis of this crude imine showed three signals at
1.51, 1.63 min (starting materials) and 8.69 min (imine
(28), 198 (100), 105 (45), 77 (22); minor diastereomer 7b:
20
578
1
mp 102°C (AcOEt, cyclohexane), [h]2D0=−66.4, [h]
=
2, 77% conversion); H NMR l 1.60 (d, J=7.0, 3H),
−69.2, [h]25406=−79.2, [h]42306=−145.5 (c 0.47, CHCl3), IR
2.30 (s, 3H), 4.90 (q, J=7.0, 1H), 7.1–7.6 (m, 9H), 7.9
(m, 1H); EIMS (m/z): 223 (M+, 28%), 222 (37), 208
(21), 105 (100), 77 (34).
(CHCl3) 1662 cm−1, H NMR: l 0.55 (d, J=7.0, 3H),
1
2.08 (d, J=7.0, 3H), 2.05–2.30 (m, 4H), 2.55 (q, J=6.3,
1H), 2.70–2.80 (m, 2H), 4.77 (q, J=7.0, 1H), 6.95–7.40
(m, 9H). 13C NMR: l 16.69 (CH3), 17.77 (CH3), 26.69
(CH2), 28.88 (CH2), 30.83 (CH), 40.53 (CH2), 57.88
(CH), 122.3 (CH), 126.4 (CH), 126.7 (CH), 127.1 (CH),
127.6 (2CH), 127.7 (CH), 128.2 (CH) 131.1 (Cq), 131.3
(Cq), 135.1 (Cq), 136.6 (Cq) 140.3 (Cq), 172.7 (Cq);
EIMS (m/z): 317 (M+, 4%), 213 (25), 198 (100), 105
(55), 77 (28); X-ray structure determination of major
diastereomer 7a: vide infra.
5.6. 4-Methyl-6-phenyl-1-(1-(S)-phenyl-ethyl)-3,4-dihy-
dro-1H-pyridin-2-one 9a and 9b
Crude imine 2 (253 mg, 1.13 mmol), diphenyl 2-ethyl-
idenemalonate 5 (346 mg, 1.22 mmol, 1.1 equiv.) with a
trace of hydroquinone were heated at 100°C for 24 h.
MeOH (20 mL) and 2.5 M aqueous NaOH (10 mL)
were then added to the crude mixture which was heated
at 60°C for 17 h. After evaporation of the MeOH under
reduced pressure, 10% aqueous HCl was slowly added
to acid pH. Ether extraction followed by usual work-up
gave crude material which was dissolved in toluene (10
mL) and heated at 100°C for 3 h. A GLC–MS analysis
of the crude mixture showed two signals at 27.51 (48%)
and 27.68 min (52%). After toluene evaporation under
reduced pressure, extraction with ether and washing
with 2.5 M aqueous NaOH (10 mL), usual work-up
followed by FC (15%) gave the lactams as a mixture of
5.4. 3-Methyl-1-(1-(R)-phenyl-ethyl)-3,4,5,6-tetrahydro-
1H-benzo[h]quinolin-2-one 8a and 8b
Crude imine 1 (1.00 g, 4.01 mmol), phenyl methacrylate
6 (0.72 mL, 4.42 mmol, 1.1 equiv.) with a trace of
hydroquinone were heated at 100°C for 15 h. A GLC–
MS analysis of the crude mixture showed two signals at
40.92 (37%) and 41.03 min (63%). At room tempera-
ture, ether (60 mL) and 2.5 M aqueous NaOH (25 mL)

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N. Monnier-Benoit et al. / Tetrahedron: Asymmetry 14 (2003) 2747–2753
two diastereomers 9a and 9b (98 mg, 33% overall yield
from acetophenone); IR (thin film) 1644 cm−1; 1H
NMR (two diastereomers mixture): l 0.90 and 1.05 (d,
J=7.0, 3H), 1.64 and 1.71 (d, J=7.0, 3H), 2.2–2.7 (m,
6H), 4.70 and 4.95 (q, J=7.0, 1H), 5.18 and 5.22 (d,
J=4, 1H) 7.0–7.4 (m, 10H). 13C NMR (two
diastereomers mixture): l 17.04 (CH3), 17.27 (CH3),
18.98 (CH3), 19.51 (CH3), 26.19 (CH), 26.27 (CH),
40.86 (CH2), 41.41 (CH2), 54.82 (CH), 55.14 (CH),
118.0 (2CH), 122.4 (2CH), 126.4 (CH), 126.5 (2CH),
126.9 (2CH), 127.7 (3CH), 127.9 (2CH), 128.0, 128.1
(2CH), 128.2 (CH), 128.4 (2CH), 136.7 (Cq), 136.8 (Cq),
141.0 (Cq), 141.9 (Cq), 142.7 (Cq), 143.3 (Cq), 171.8
(Cq), 172.0 (Cq); EIMS (m/z): 291 (M+, 14%), 187 (38),
172 (100), 105 (40), 77 (17).
5.9. 4,5-Dimethyl-6-phenyl-1-(1-(S)-phenyl-ethyl)-3,4-
dihydro-1H-pyridin-2-one 11a and 11b
Method A: from phenyl crotonate. Crude imine 3 (1.50
g, 6.23 mmol), phenyl crotonate 4 (1.23 mL, 7.56 mmol,
1.2 equiv.) with a trace of hydroquinone were heated at
100°C for 10 days. A GLC–MS analysis of the crude
mixture showed two signals at 25.37 (70%) and 25.51
min (30%). At room temperature, ether (60 mL) and 2.5
M aqueous NaOH (25 mL) were added to the crude
mixture which was stirred for 20 min. After ether
extraction, washing with water to neutral pH, usual
work-up followed by FC (15%) gave the lactams 11a
and 11b (1.57 g, 81% overall yield from
propiophenone).
Method B: from diphenyl 2-ethylidenemalonate. Crude
imine 3 (531 mg, 2.24 mmol), diphenyl 2-ethylidene-
malonate 5 (642 mg, 2.27 mmol, 1 equiv.) with a trace
of hydroquinone were heated at 100°C for 18 h. MeOH
(30 mL) and 2.5 M aqueous NaOH (20 mL) were then
added to the crude mixture which was heated at 60°C
for 17 h. After evaporation of the MeOH under
reduced pressure, 10% aqueous HCl was slowly added
to the mixture at 0°C until acid pH. Ether extraction
followed by usual work-up gave crude material which
was dissolved in toluene (10 mL) and heated at 100°C
for 3 h. A GLC–MS analysis of the crude mixture
showed two signals at 25.19 (57%) and 25.34 min
(43%). After toluene evaporation under reduced pres-
sion, extraction with ether and washing with 2.5 M
aqueous NaOH, usual work-up followed by FC (15%)
gave the lactams 11a and 11b as a mixture of two
diastereomers (545 mg, 80% overall yield from propio-
phenone); IR (thin film) 1650 cm−1; 1H NMR (two
diastereomeric mixture): l 0.95 and 1.15 (d, J=7.0,
3H), 1.55 and 1.63 (s, 3H), 1.58 and 1.64 (d, J=7.0,
3H), 2.2–2.4 (m, 2H), 2.6–2.8 (m, 1H), 4.68 and 4.80 (q,
J=7.0, 1H), 7.1–7.5 (m, 10H); 13C NMR: l 16.42
(CH3), 16.84 (2CH3), 17.01 (CH3), 17.61 (CH3), 18.08
(CH3), 31.90 (CH), 32.43 (CH), 39.73 (CH2), 40.14
(CH2), 53.97 (CH), 54.33 (CH), 121.5 (Cq), 121.6 (Cq),
126.2 (CH), 126.4 (2CH), 127.1 (CH), 127.6 (CH),
127.7 (CH), 127.8 (2CH), 128.1 (2CH), 128.3 (2CH),
135.2 (Cq), 135.4 (Cq), 135.6 (2Cq), 141.8 (Cq), 141.9
(Cq), 169.7 (Cq), 169.9 (Cq); EIMS (m/z): 305 (M+,
17%), 201 (40), 186 (100), 105 (27), 77 (18).
5.7. 3-Methyl-6-phenyl-1-(1-(S)-phenyl-ethyl)-3,4-dihy-
dro-1H-pyridin-2-one 10a and 10b
Crude imine 2 (1.02 g, 4.57 mmol), phenyl methacrylate
6 (0.85 mL, 5.24 mmol, 1.14 equiv.) with a trace of
hydroquinone were heated at 100°C for 48 h. A GLC–
MS analysis of the crude mixture showed one signal at
27.41 min. At room temperature, THF (15 mL), ether
(35 mL) and 2.5 M aqueous NaOH (25 mL) were then
added to the crude mixture which was stirred for 30
min. After ether extraction and washing with water to
neutral pH, usual work-up followed by FC (15%) gave
the lactams 10a and 10b (226 mg, 19% overall yield
from acetophenone) as a diastereomeric mixture; IR
(thin film) 1680 cm−1; 1H NMR (64:36 two
diastereomers mixture): l 1.18 and 1.30 (d, J=7.0, 3H),
1.67 and 1.79 (d, J=7.0, 3H), 2.0–2.8 (m, 3H), 4.81 and
5.00 (q, J=7.0, 1H), 5.25 and 5.40 (dd, J=5.5 and 6.3,
4.7 and 3.1, 1H), 7.0–7.7 (m, 10H), 13C NMR: l 14.96
(CH3), 15.30 (CH3), 17.21 (CH3), 17.48 (CH3), 27.63
(CH2), 27.67 (CH2), 36.58 (CH), 36.79 (CH), 54.59
(CH), 55.0 (CH), 110.3 (CH), 110.6 (CH), 121.4 (CH),
125.8 (CH), 126.3 (2CH), 126.4 (CH), 126.9 (CH),
127.3 (CH), 127.6 (CH), 127.8 (2CH), 127.9 (2CH),
128.0 (2CH), 128.1 (2CH), 128.3 (CH), 128.6 (CH),
129.4 (CH), 133.1 (CH), 137.1 (Cq), 137.2 (Cq), 141.6
(Cq), 142.3 (Cq), 143.4 (Cq), 144.4 (Cq), 174.4 (2Cq);
EIMS (m/z): 291 (M+, 26%), 187 (100), 172 (61), 159
(23), 105 (74), 77 (27).
5.8. (1-(S)-Phenyl-ethyl)-(1-phenyl-propylidene)-amine 3
5.10. 3,5-Dimethyl-6-phenyl-1-(1-(S)-phenyl-ethyl)-3,4-
dihydro-1H-pyridin-2-one 12a and 12b
A solution of propiophenone (6.80 mL, 48.2 mmol) and
(S)-(−)-a-methylbenzylamine (99.9% ee, 6.20 mL, 48.2
mmol, 1 equiv.) with a trace of pTSA in toluene (50
mL) was heated under reflux in a Dean–Stark appara-
tus for 96 h. After removal of the toluene under
reduced pressure, crude imine 3 (11.5 g) was obtained
and used for the next steps without purification. A
GLC–MS analysis of this crude imine showed two
signals at 2.66 (12.5%, propiophenone) and 8.49 min
Crude imine 3 (1.50 g, 6.23 mmol), phenyl methacrylate
6 (1.23 mL, 7.56 mmol, 1.2 equiv.) with a trace of
hydroquinone were heated at 100°C for 10 days. A
GLC–MS analysis of the crude mixture showed one
signal at 12.96 min. At room temperature, ether (40
mL) and 2.5 M aqueous NaOH (25 mL) were then
added to the crude mixture which was stirred for 20
min. After ether extraction and washing with water to
neutral pH, usual work-up followed by FC (15%) gave
the lactams 12a and 12b (1.35 g, 70% overall yield from
propiophenone) as a diastereomeric mixture; IR (thin
1
(imine 3, 87.5% conversion); H NMR (Z and E iso-
mers mixture) l 1.02 and 1.07 (t, J=7.8, 3H), 1.34 and
1.51 (d, J=6.3 and 7.0, 3H), 2.53 and 2.70 (q, J=7.8,
2H), 4.36 and 4.86 (q, J=7.0 and 6.3, 1H), 7.1–8.0 (m,
10H); EIMS (m/z): 237 (M+, 21%), 105 (100), 77 (27).
1
film) 1650 cm−1; H NMR (77:23 diastereomeric mix-

N. Monnier-Benoit et al. / Tetrahedron: Asymmetry 14 (2003) 2747–2753
2753
ture): l 1.20 and 1.25 (d, J=6.3, 3H), 1.53 and 1.63
Acknowledgements
(d, J=7.0, 3H), 1.58 and 1.65 (s, 3H), 2.1–2.5 (m,
2H), 2.5–2.8 (m, 1H), 4.80 and 5.0 (q, J=7.0, 1H),
6.8–7.4 (m, 10H), 13C NMR (77:23 diastereomeric
mixture): l 14.87 (CH3), 15.05 (CH3), 16.82 (CH3),
17.05 (CH3), 19.45 (CH3), 19.53 (CH3), 34.58 (CH2),
34.67 (CH2), 36.02 (CH), 36.21 (CH), 53.63 (CH),
54.13 (CH), 115.3 (CH), 116.5 (Cq), 116.7 (Cq), 119.4
(CH), 126.1 (2CH), 126.2 (CH), 126.4 (CH), 127.7
(2CH), 127.8 (CH), 127.9 (2CH), 128.1 (CH), 129.2
(CH), 130.0 (2CH), 135.4 (Cq), 135.5 (2Cq), 136.3
(Cq), 141.8 (Cq), 142.5 (Cq), 173.4 (Cq), 173.5 (Cq);
EIMS (m/z): 305 (M+, 26%), 201 (100), 186 (70), 172
(32), 105 (51), 77 (29).
We thank Dr. Michel Pfau for stimulating discus-
sions.
References
1. (a) Pfau, M.; Tomas, A.; Lim, S.; Revial, G. J. Org. Chem.
1995, 60, 1143–1147; (b) Jabin, I.; Revial, G.; Tomas, A.;
Lemoine, P.; Pfau, M. Tetrahedron: Asymmetry 1995, 6,
1795–1812; (c) Jabin, I.; Revial, G.; Pfau, M.; Decroix, B.;
Netchita¨ılo, P. Org. Lett. 1999, 1, 1901–1904; (d) Revial,
G.; Jabin, I.; Pfau, M. Tetrahedron: Asymmetry 2000, 11,
4975–4983; (e) Jabin, I.; Redolfi, M.; Pfau, M. Tetra-
hedron: Asymmetry 2001, 12, 1683–1688.
2. One example of this concept with chiral enaminoesters was
already described: Revial, G.; Lim, S.; Viossat, B.;
Lemoine, P.; Tomas, A.; Duprat, A. F.; Pfau, M. J. Org.
Chem. 2000, 65, 4593–4600.
3. (a) Agami, C.; Bihan, D.; Morgentin, R.; Puchot-Kadouri,
C. Synlett 1997, 799–800; (b) Agami, C.; Comesse, S.;
Kadouri-Puchot, C. J. Org. Chem. 2000, 65, 4435–4439;
(c) Maldaner, A.; Pilli, R. Tetrahedron 1999, 55, 13321–
13332.
4. (a) Sevin, A.; Tortajada, J.; Pfau, M. J. Org. Chem. 1986,
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Benoit, N. Ph.D. Thesis, Le Havre University, Jan. 31,
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5.11. X-Ray structure determination of lactame 7a
Formula: C22H23NO, MW=317.43, monoclinic, space
,
group P21; a=9.132(1), b=14.702(1), c=13.501(1) A,
3
,
i=102.83(1), V=1767.8(3) A , Z=4; M=317.4 g;
D
calcd=1.193 g cm−3; F(000)=680. The structure was
solved by direct methods using SHELXS97.7 Refine-
ment, based on F,8 was carried out by full matrix
least squares with SHELXL97 software. An ORTEP9
diagram is given in Figure 3. Non hydrogen atoms
were refined anisotropically. The hydrogen atoms
were positioned geometrically and refined riding on
their carrier atom with isotropic thermal displacement
parameters fixed at 1.2 times those of their parent
atoms. Convergence was reached at R1=0.033 for
5768 reflections (I>2|(I)), wR2=0.077 for all data
and S=1.023 for 437 parameters. The residual elec-
tron density in the final difference Fourrier does not
−3
7. Sheldrick, G. M. SHELXS97. Program for solution of
crystal structures. University of Go¨ttingen, Germany,
1990.
,
show any feature above 0.139 e A
−0.198 e A .
and below
−3
,
8. Sheldrick, G. M.; Schneider, T. R. SHELXL97: high
resolution refinement, Methods in Enzymology, 277,
Carter, C. W., Jr.; Sweet, L. M., Eds.; Academic Press:
San Diego, pp. 319–343.
9. Johnson, C. K. ORTEP. A thermal Ellipsoid Plotting
Program; Oak Ridge National, Laboratories: Oak Ridge,
TN, 1976.
Crystallographic data (excluding structure factors)
have been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publication no.
CCDC 205637. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [fax: +44 (0) 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].