Stereoselective synthesis of new classes of atropisomeric compounds through a tandem Michael reaction-azacyclization process. Part 2

Article abstract of DOI:10.1016/j.tetasy.2003.10.025

Three new classes of atropisomeric compounds, that is, 6-aryl-dihydro- pyridin-2-ones, 6-aryl-pyridin-2-ones and 2-aryl-pyrroles, have been prepared from chiral imines through an efficient stereoselective tandem Michael-azacyclization process. In all cases, a study has shown that the barrier to rotation of the chiral axis is remarkably high.

Full text of DOI:10.1016/j.tetasy.2003.10.025

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 139–145
Stereoselective synthesis of new classes of atropisomeric compounds
through a tandem Michael reaction–azacyclization process. Part 2
a
a
a
ꢀ
Stephane Le Gac, Nicolas Monnier-Benoit, Lionel Doumampouom Metoul,
Samuel Petitb and Ivan Jabina,*
aFaculteꢀ des Sciences et Techniques, URCOM, Universiteꢀ du Havre, 25 rue Philippe Lebon, BP 540, 76058 Le Havre Cedex, France
bSciences et Meꢀthodes Seꢀparatives (SMS), UPRES EA 2659, IRCOF-Universiteꢀ de Rouen, F-76821 Mont Saint-Aignan Cedex,
France
Received 17 September 2003; accepted 27 October 2003
Abstract—Three new classes of atropisomeric compounds, that is, 6-aryl-dihydro-pyridin-2-ones, 6-aryl-pyridin-2-ones and 2-aryl-
pyrroles, have been prepared from chiral imines through an efficient stereoselective tandem Michael–azacyclization process. In all
cases, a study has shown that the barrier to rotation of the chiral axis is remarkably high.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
New classes
of atropisomeric
compounds
R*
R*
HN
O
N
O
Enantiomerically pure atropisomers of axially chiral
biaryls or non-biaryls compounds (i.e., chiral anilides,
1-naphthamides and benzamides) have been widely
studied for their applications as chiral ligands or aux-
iliaries.1 However, enantioselective syntheses of enan-
tiomerically pure atropisomers are still rare and they are
generally obtained by resolution.2 We recently reported
an efficient method for the stereoselective synthesis of
non-biaryl atropisomeric compounds from chiral imines
through a tandem process consisting of a Michael
reaction followed by an azacyclization.3 Thus, 5,6-
disubstituted-3,4-dihydro-1H-pyridin-2-ones, bearing a
6-exo bulky cyclopropyl moiety, which generates the
atropisomerism, were obtained in a two step sequence
with good diastereoselectivities (Scheme 1, left side).
The presence of the chiral auxiliary on the product
permitted an easy separation of the atropisomers and an
NMR study revealed that they possessed a remarkably
high barrier to interconversion. However, this pre-
liminary work also showed that the fragile cyclopropyl
moiety led to degradation compounds, thus limiting
the synthetic usefulness of this class of atropisomeric
compounds.
X
R*
X
N
R1
X = Et, OMe
R* = (S)-HC(Me)Ph
COOPh
Tandem
process
R
R2
O
R*
O
N
O
+
Chiral ligands or
organocatalysts
O
N
X
X
R*
de 60 - 64 %
Scheme 1.
Thus, we focused our interest on the stereoselective
preparation, through the tandem Michael reaction–
azacyclization process, of new classes of atropisomeric
compounds consisting in five- or six-membered aza-
heterocycles bearing an aryl substituent. The atrop-
isomerism should result a priori from restricted rotation
around the single bond connecting the aryl moiety to the
heterocycle. Our final aim was to produce atropisomeric
compounds that would be useful as either chiral ligands
or organocatalysts (Scheme 1, right side).
Herein, we report a straightforward stereoselective route
to the first members of these new atropisomer families,
that is, 6-aryl-3,4-dihydro-1H-pyridin-2-ones, 6-aryl-
1H-pyridin-2-ones and 2-aryl-pyrroles.4
* Corresponding author. Tel.: +33-232-74-43-94; fax: +33-232-74-43-
91; e-mail: ivan.jabin@univ-lehavre.fr
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.025

140
S. Le Gac et al. / Tetrahedron: Asymmetry 15 (2004) 139–145
2. Results and discussion
bonding between the nitrogen atom and the phenolic
group. The atropisomerism of aryl imines has been
already described in the 1970ꢀs9 but, to our knowledge,
no further developments have been reported.
The synthesis and resolution of atropisomeric pyridyl
phenols has already been achieved by Chan et al.5
These biaryl compounds have previously been used as
ligands in catalytic asymmetric reactions and as starting
material for the preparation of efficient P,N6 or 2,20-
bipyridine7 ligands. In our case, we thought that if
phenol and naphthol groups were used as the aryl
groups, the obtained atropisomeric compounds would
possess structures close to those reported by Chan and
thus would be good candidates for the preparation of
chiral ligands. The required starting chiral imines 3 and
6 were prepared in two steps, respectively, from 3,5-di-
methyl phenol 1 and naphthalen-2-ol 4 through a Fries
rearrangement8 and a subsequent condensation with
(S)-1-phenylethylamine under classical conditions (i.e.,
azeotropic removal of water in a Dean–Stark apparatus)
(Scheme 2).
The Michael reaction of chiral imines followed by an
azacyclization step has been studied by others and
ourselves. The azacyclization can take place only if the
starting electrophilic olefin possesses a leaving group.
For this purpose, the use of three electrophilic olefin
types has been reported: Unsaturated acid derivatives
(phenyl esters,10 acyl chlorides and anhydrides11) which
can lead to 3,4-dihydro-1H-pyridin-2-ones while nitro-
olefins12 and chloroacrylonitrile13 afford pyrrole deriva-
tives through different mechanisms. We decided to
investigate the possibility of using these three types of
electrophilic olefins with imine 3 for the production of
new classes of atropisomeric compounds. Thus, the
reaction of imine 3 with chloroacrylonitrile in the pres-
ence of a base (collidine) led to the expected 2-aryl-
pyrrole 7 in excellent yield (Scheme 3; Table 1, entry 1).
The role of the base was to trap HCl and HCN formed
during the reaction. The GC–MS and 1H NMR analyses
of crude 7 were consistent with the presence of two
diastereomers in close proportions (de 14%), which were
separated by flash chromatography (FC) on silica gel
and thus fully characterized. In order to improve the low
diastereoselectivity observed, we studied the influence of
a Lewis acid. When the reaction was conducted in the
presence of ZnCl2 (1equiv) the diastereomeric excess
rose to 44%14 (Table 1, entry 2). Several Lewis acids
were compared in the course of this study and it was
observed that ZnCl2 and Mg(ClO4)2 gave similar results
while TiCl4 and Cu(OTf)2 led to complex mixtures of
unidentified compounds.15 With trans-b-nitrostyrene as
the electrophilic olefin, imine 3 led, through the tandem
process and with a poor stereoselectivity, to the pyrrole
8 as a mixture of separable atropisomers (Scheme 3;
R*
OH
O
OH
N
OH
(EtCO) O
2
AlCl
R*NH , TFA
2
3
Toluene, reflux
85%
Cl(CH
reflux
79%
) Cl
2
2
1
2
3
~
R* =
Ph
R*
H
OH
Me
O
OH
N
OH
(EtCO)
O
2
R*NH , TFA
2
AlCl
3
Toluene, reflux
73%
Cl(CH
reflux
) Cl
2
2
95%
4
5
6
Scheme 2.
1
It is noteworthy that the H NMR spectra of imines 3
and 6 revealed the presence of three diastereomers in
proportions of ca. 1:1:1 and ca. 12:1:1, respectively. A
1
variable temperature H NMR study showed that the
R*
R*
signals of the three diastereomers of 3 did not coalesce
up to 330 K. In order to rationalize these unexpected
results, we suggested that, in addition to the E–Z
isomerism, two distinct nonplanar atropisomers with a
high barrier to rotation around the aryl-imino bond are
possible for the Z-isomer (Fig. 1, example given for
imine 3).
N
OR1
N
R
R
See Table 1
OH
+
R1O
R*
N
With major
diastereomer:
EtI, K CO
7 (two diast.): R = H, R1= H
8 (two diast.): R = Ph, R1 = H
9: R = Ph, R1 = Et
2
3
Acetone, reflux, 4d.
With major
O
O
3
diastereomer:
R*
R*
R*
Pd(OAc) (0.05 eq.)
R*
N
OH
N
OH
N
R*
2
N
OH
Cu(OAc) (2.5 eq.)
2
N
OH
MeCN, MeOH
50°C, 4h
See Table 1
83%
HO
Major diast.
E-3
Z-aR-3
Z-aS-3
10 (two diast.)
11
O
Figure 1. Restricted rotation of the aryl-imino bond of the Z-isomer
leading to three diastereomers.
O
R*
R*
N
N
OH
OH
R*
N
See Table 1
The different isomeric proportions observed for the
imines 3 and 6 can be explained by the bulkiest naph-
thol group, which favoured the formation of the
less hindered E-diastereomer. Moreover, this latter
can be also stabilized by intramolecular hydrogen
+
HO
12 (two diast.)
6
Scheme 3.

S. Le Gac et al. / Tetrahedron: Asymmetry 15 (2004) 139–145
Table 1. Conditions and results of the reactions depicted in Scheme 3
141
Entry
Imine
Electrophilic olefin
Conditions
Producta
Deb
1
Overall yield (%)c
4 92
Cl
(2 eq.)
1
3
THF, collidine, reflux, 1h
7
CN
Cl
ZnCl2, THF, collidine, rt, 3 days
7
44
72
(2 eq.)
2
3
CN
NO2
d
19
56
3
4
3
3
(1.5 eq.)
Toluene, collidine, molecular sieves, 90 ꢁC, 4 h
8
1
9
49
Ph
COCl
COCl
(i) THF, collidine, reflux, 16 h
(ii) NaOH (1M), MeOH, 55 ꢁC, 1h
10
60
(2.2 eq)
(i) ZnCl2, THF, collidine, 0 ꢁC, 3 h
(ii) NaOH (1M), MeOH, 55 ꢁC, 1h
5
3
10
12
77
28
(2.2 eq)
(2.2 eq)
COCl
(i) ZnCl2, THF, collidine, 0 ꢁC, 3 h
(ii) NaOH (1M), MeOH, 55 ꢁC, 1h
6
6
39
a In all cases, the products consisted of a mixture of two separable diastereomers.
b The diastereomeric excess was determined by GC–MS and 1H NMR analyses of the crude product.
c For the two diastereomers, calculated after flash chromatography on silica gel.
d
1H NMR estimation (see text).
Table 1, entry 3). For purification and characterization
purposes,16 the major diastereomer of 8 was alkylated by
iodoethane leading to the less polar derivative 9.
Attempts to enhance the stereoselectivity in presence of
a Lewis acid failed, since in this case the reaction pro-
ceeded only by heating in toluene.
by single-crystal X-ray diffraction (Fig. 2, left side). Its
stereochemistry can be tentatively rationalized (Fig. 2,
right side) if we consider that during the azacyclization
step:
(i) The chiral auxiliary moiety has to be placed on the
opposite side of the approaching acyl chain.
(ii) The Lewis acid chelates the hydroxy and the car-
bonyl groups.
(iii) The ring closing occurs on the opposite side of the
bulky phenyl group borne by the chiral auxiliary.
Concerning the preparation of the desired 3,4-dihydro-
1H-pyridin-2-ones, we first attempted the Michael
reactions of imines 3 and 6 with phenyl acrylate but only
traces of the products (i.e., 10 and 12) were obtained
even under drastic conditions (neat, high temperature,
long reaction time, catalysis by a Lewis acid), with
hydrolysis of the starting imine taking place preferen-
tially. When phenyl acrylate was replaced by the more
reactive acryloyl chloride, imine 3 led, under heating
conditions, to the desired 6-aryl-3,4-dihydro-1H-pyri-
din-2-one 10 in low yield (Table 1, entry 4). However, to
our delight, a Lewis acid catalysis by ZnCl2 proved to be
extremely efficient since a good 56% yield and a high
diastereoselectivity (de 77%) were obtained14 (Scheme 3;
Table 1, entry 5). Under the same conditions, 6-naph-
thyl compound 12 was obtained as a mixture of atrop-
isomers from imine 6 (Scheme 3; Table 1, entry 6).
Surprisingly, in this case the reaction proceeded with
moderate diastereoselectivity (de 28%). In both cases
(i.e., imines 3 and 6), the reactions were conducted in the
presence of at least 2 equiv of acryloyl chloride since
when they were performed with only 1equiv of elec-
trophilic olefin, phenol esterification was observed to a
small extent. Consequently, a subsequent saponification
step (NaOH, MeOH) was needed in order to obtain the
final products 10 and 12.
Figure 2. Left side: X-ray structure of the major diastereomer of 10.
Right side: proposed low energy conformation during the azacycliza-
tion step.
After all the diastereomers of compounds 7, 8, 10 and 12
were obtained as enantiomerically pure samples, we
studied the barrier to rotation around their chiral axis
by 1H NMR. Thus all diastereomers (majors and
minors) of 7, 8, 10 and 12 were heated separately in
refluxing toluene for 4 h. In all cases, no traces of the
other atropisomeric diastereomer was detected by
1H NMR. These results clearly show that these com-
pounds possess a remarkably high rotation barrier,
Atropisomers of 10 and 12 were separated by FC on
silica gel and fully characterized. The relative configu-
ration of the major diastereomer of 10 was determined

142
S. Le Gac et al. / Tetrahedron: Asymmetry 15 (2004) 139–145
which prevents their interconversion into their atrop-
isomer even at elevated temperature (ca. 110 ꢁC). This
NMR study also suggested that the observed stereose-
lectivities arose from asymmetric induction of the chiral
auxiliary during the azacyclization step and not from
slow equilibration of the final atropisomeric diastereo-
mers.
umn) (GC method: 70 ꢁC for 2 min then 15 ꢁC/min until
20
1
280 ꢁC). ½aŠ values are given in 10À1 deg cm2 gÀ1. H
D
and 13C NMR spectra were recorded, respectively, at
200 and 50 MHz. Chemical shifts are expressed in ppm
using TMS as the internal standard. Unless indicated
otherwise, all reactions were performed under an argon
atmosphere. Anhydrous THF and toluene were ob-
tained by distillation over sodium/benzophenone and
P2O5, respectively. For the preparation of compounds 2
and 5, see Ref. 8. Elemental analyses were performed at
the Laboratoire de Microanalyse Organique, IRCOF,
France.
Finally, with an efficient preparation of the enantio-
merically pure major diastereomer of 10 in hand, we
tested the feasibility of converting this compound into
its oxidized pyridin-2-one counterpart 11. In fact, the
pyridin-2-one cycle possessed a more planar and resis-
tant (to oxidation and ring opening reactions) structure
that was more suitable for the further development
of chiral ligands and organocatalysts. Preliminary
attempts, under reported conditions (t-BuOK–DMSO)
with closely related compounds,17 only led to moderate
yields since dihydro-1H-pyridin-2-one ring opening was
competitive. However, the oxidation of the major dia-
stereomer of 10 was successfully performed under mild
reaction conditions by Pd(II) catalysis [0.05 equiv of
Pd(OAc)2 and 2.5 equiv of Cu(OAc)2] (Scheme 3). To
our knowledge, this reaction constitutes the first exam-
ple of such an oxidation catalyzed by Pd(II). The
enantiomerically pure pyridin-2-one 11 was heated 4 h in
refluxing toluene without any detection of its atrop-
4.2. 3,5-Dimethyl-2-[1-(1-(S)-phenyl-ethylimino)-propyl]-
phenol 3
A solution of ketone 2 (11.85 g, 66.4 mmol) and (S)-1-
phenylethylamine (99.9% ee, 8.56 mL, 66.4 mmol) with a
trace of TFA in toluene (200 mL) was heated under
reflux in a Dean–Stark apparatus for 18 h. After cooling
the reaction mixture to 0 ꢁC, the resulting precipitate
was isolated by suction filtration and recrystallized in
toluene, giving 15.88 g (85%) of imine 3 as a mixture of
three diastereomers in the proportions of ca. 1:1:1. Beige
solid. EIMS m=z (rel int) 281(M þ, 57), 266 (47), 162
(35), 148 (24), 105 (base), 77 (24). IR (CHCl3): 3544–
1
isomer by H NMR analyses. This result shows that, as
in compounds 7, 8, 10 and 12, compound 11 possesses
an important barrier to rotation around its chiral axis.
3189, 1629 cmÀ1 1H NMR (200 MHz, CDCl3/C6D6,
.
20:1) d: spectrum of the three diastereomers: 1.00 (t,
J ¼ 7.0 Hz, 3H), 1.10 (t, J ¼ 7.0 Hz, 3H), 1.12 (t, J ¼
7.0 Hz, 3H), 1.42 (d, J ¼ 7.0 Hz, 3H), 1.51 (d, J ¼ 7.0 Hz,
3H), 1.60 (d, J ¼ 7.0 Hz, 3H), 1.68 (s, 3H), 2.18 (s, 3H),
2.22 (s, 3H), 2.26 (s, 6H), 2.36 (s, 3H), 2.45–2.81
(m, 6H), 4.32 (q, J ¼ 7.0 Hz, 1H), 4.40 (q, J ¼ 7.0 Hz,
1H), 4.97 (q, J ¼ 6.3 Hz, 1H), 6.40–6.65 (m, 6H), 7.10–
7.45 (m, 15H).
3. Conclusion
In conclusion, new classes of atropisomeric compounds,
that is, 6-aryl-dihydro-1H-pyridin-2-ones, 6-aryl-1H-
pyridin-2-ones and 2-aryl-pyrroles, have been prepared
from chiral imines with stereoselectivities up to 77%.
The key step of their synthesis consists of an efficient
tandem Michael reaction–azacyclization process. In all
cases, the diastereomeric atropisomers have been sepa-
rated and obtained enantiomerically pure. A study has
shown that the barrier to rotation around their chiral
axis was remarkably high. Work towards the use of
these new classes of atropisomeric compounds for the
preparation of chiral ligand or organocatalysts, in par-
ticular after the removal of the chiral auxiliary moiety
(i.e., R*) are under progress in our laboratory.
4.3. 1-[1-(1-(S)-Phenyl-ethylimino)-propyl]-naphthalen-
2-ol 6
A solution of ketone 5 (5.54 g, 27.7 mmol) and (S)-1-
phenylethylamine (99.9% ee, 3.57 mL, 27.7 mmol) with a
trace of TFA in toluene (100 mL) was heated under
reflux in a Dean–Stark apparatus for 18 h. After cooling
the reaction mixture to 0 ꢁC, the resulting precipitate
was isolated by suction filtration and recrystallized in
toluene, yielding 6.17 g (73%) of imine 6 as a mixture of
three diastereomers in the proportions of ca. 12:1:1.
Brown solid. EIMS m=z (rel int) 303 (Mþ, 11), 198 (52),
105 (base), 79 (30), 77 (34). 1H NMR (200 MHz, CDCl3)
d: spectrum of the major diastereomer: 1.40 (t,
J ¼ 7.0 Hz, 3H), 1.72 (d, J ¼ 6.3 Hz, 3H), 2.62–3.10 (m,
2H), 5.08 (q, J ¼ 6.3 Hz, 1H), 6.93–7.80 (m, 11H).
4. Experimental
4.1. General
Thin layer chromatography (TLC) was performed with
glass plates (0.25 mm) precoated with silica gel. Reaction
components were then visualized under UV light and
dipped in a Dragendorff solution. Flash chromatogra-
phy separations (FC) were carried out with silica gel
(230–400 mesh). GC–MS analyses were performed with
a Thermofinnigan Automass Multi GC–MS apparatus
(equipped with a 15 m · 0.20 mm PDMS capillary col-
4.4. 3,5-Dimethyl-2-[3-methyl-1-(1-(S)-phenyl-ethyl)-
1H-pyrrol-2-yl]-phenol 7
Method A: without Lewis acid catalysis: To a solution of
imine 3 (0.20 g, 0.71mmol) in anhydrous THF (0.4 mL)
were added collidine (0.375 mL, 2.84 mmol) and chloro-
acrylonitrile (0.114 mL, 1.42 mmol). After refluxing for

S. Le Gac et al. / Tetrahedron: Asymmetry 15 (2004) 139–145
143
1h, the THF was removed under reduced pressure and
the resulting residue dissolved in ethyl acetate, washed
with water and dried over MgSO4. After removal of the
solvent under reduced pressure, a GC–MS analysis of
the crude residue showed two signals corresponding to
the two diastereomers of 7 (de 14%). A FC (cyclohex-
ane/ethyl acetate, 95:5) gave product 7 (200 mg, 92%) as
a mixture of two diastereomers.
tion under reduced pressure, a GC–MS analysis of the
crude residue showed two signals corresponding to the
two diastereomers of 8 (de 19%). A FC (cyclohexane/
ethyl acetate, 96:4) yielded product 8 (748 mg, 49%) as a
mixture of two diastereomers.
Major diastereomer: This compound was fully charac-
terized through its derivative 9, see Ref. 16. EIMS m=z
(rel int) 381(M þ, 37), 277 (54), 276 (45), 105 (base), 79
(36), 77 (38). 1H NMR (200 MHz, CDCl3) d 1.65 (s, 3H),
1.70 (d, J ¼ 7.0 Hz, 3H), 1.99 (s, 3H), 2.32 (s, 3H), 4.89
(q, J ¼ 7.0 Hz, 1H), 5.07 (s, 1H), 6.58 (s, 1H), 6.70 (s,
1H), 7.10 (s, 1H), 7.14–7.59 (m, 10H).
Method B: with Lewis acid catalysis: To a solution of
ZnCl2 (72 mg, 0.53 mmol) in anhydrous THF (0.2 mL)
were successively added imine 3 (150 mg, 0.53 mmol)
in anhydrous THF (1.8 mL), collidine (0.28 mL,
2.12 mmol)
and
chloroacrylonitrile
(0.085 mL,
20
Minor diastereomer: Beige solid, mp ¼ 39–40 ꢁC, ½aŠ +9
1.06 mmol). The mixture was stirred for 3 days at room
temperature and then the THF removed under reduced
pressure. The crude mixture was dissolved in dichloro-
methane and washed with an aqueous solution of HCl
(0.1M). After evaporation of the solvent under reduced
pressure, a GC–MS analysis of the crude residue showed
two signals corresponding to the two diastereomers of
7 (de 44%). A FC (cyclohexane/ethyl acetate, 95:5)
afforded product 7 (116 mg, 72%) as a mixture of two
diastereomers. Analytical samples of the two diastereo-
mers of 7 were obtained by careful FC separations.
D
(c 0.90, CHCl3). EIMS m=z (rel int) 381(M þ, 58), 277
(57), 276 (45), 105 (base), 79 (31), 77 (33). IR (CHCl3):
1
3495, 1627, 1602 cmÀ1. H NMR (200 MHz, CDCl3) d
1.76 (d, J ¼ 7.0 Hz, 3H), 1.97 (s, 3H), 2.07 (s, 3H), 2.31
(s, 3H), 4.80 (s, 1H), 4.86 (q, J ¼ 7.0 Hz, 1H), 6.57 (s,
1H), 6.70 (s, 1H), 6.95–7.02 (m, 2H), 7.14–7.53 (m, 9H).
13C NMR (50 MHz, CDCl3) d 11.18, 20.19, 21.77, 22.09,
55.59, 113.2, 115.6, 117.4, 117.6, 122.8, 124.0, 124.8,
125.7, 126.2 (2C), 127.5 (2C), 127.8, 128.8 (2C), 128.9
(2C), 136.7, 140.0, 140.4, 143.0, 155.4. Anal. Calcd for
C27H27NOÆ0.3H2O: C, 83.81; H, 7.19; N, 3.62. Found:
C, 83.86; H, 7.21; N, 3.63.
Major diastereomer: Beige solid, mp ¼ 70 ꢁC, ½aŠ20 )111.5
D
(c 0.81, CHCl3). EIMS m=z (rel int) 305 (Mþ, 52), 201
(base), 200 (92), 186 (51), 105 (99), 79 (61), 77 (69). IR
(CHCl3): 3498, 1627, 1571 cmÀ1. H NMR (200 MHz,
1
4.6. 2-(2-Ethoxy-4,6-dimethyl-phenyl)-3-methyl-4-
phenyl-1-(1-(S)-phenyl-ethyl)-1H-pyrrole 9
CDCl3) d 1.6 (s, 3H), 1.67 (d, J ¼ 7.0 Hz, 3H), 1.87 (s,
3H), 2.32 (s, 3H), 4.85 (q, J ¼ 7.0 Hz, 1H), 5.02 (s, 1H),
6.18 (d, J ¼ 2.4 Hz, 1H), 6.56 (s, 1H), 6.68 (s, 1H), 6.92
(d, J ¼ 3.1 Hz, 1H), 6.94–7.02 (m, 2H), 7.16–7.28 (m,
3H). 13C NMR (50 MHz, CDCl3) d 11.63, 19.69, 21.78,
22.82, 55.71, 109.9, 112.8, 115.7, 119.1, 119.8, 122.8,
123.0, 126.6 (2C), 127.5, 128.7 (2C), 140.2, 141.0, 143.1,
155.1.
K2CO3 (0.66 g, 4.80 mmol) and iodoethane (0.19 mL,
2.40 mmol) were successively added to the major dia-
stereomer of 8 (305 mg, 0.80 mmol) in 25 mL of acetone.
After refluxing for 4 days, the reaction mixture was fil-
tered in order to remove inorganic salts. After concen-
tration under reduced pressure, the resulting residue was
dissolved in dichloromethane and washed with an
aqueous solution of NaOH (1M). After solvent evapo-
20
Minor diastereomer: Colourless oil, ½aŠ )141.8 (c 0.60,
D
EtOH). EIMS m=z (rel int) 305 (Mþ, 35), 201(97), 200
(81), 186 (33), 105 (base), 79 (40), 77 (47). IR (film): 3620
ration, a FC (cyclohexane/ethyl acetate, 97:3) afforded
20
D
9 (247 mg, 76%). Red oil, ½aŠ +16.2 (c 1.05, EtOH).
(m OH), 1626 cmÀ1. H NMR (200 MHz, CDCl3) d 1.73
1
EIMS m=z (rel int) 410 (23), 409 (Mþ, 61), 207 (25), 105
(d, J ¼ 7.0 Hz, 3H), 1.86 (s, 3H), 2.04 (s, 3H), 2.31 (s,
3H), 4.77 (s, 1H), 4.83 (q, J ¼ 7.0 Hz, 1H), 6.18 (d,
J ¼ 3.1 Hz, 1H), 6.55 (s, 1H), 6.68 (s, 1H), 6.88–7.0 (m,
1He, 2H), 7.15–7.3 (m, 3H). 13C NMR (50 MHz,
CDCl3) d 11.53, 20.09, 21.76, 22.10, 55.51, 110.0, 113.1,
115.6, 119.0, 119.8, 122.6, 122.7, 126.1 (2C), 127.7, 128.9
(2C), 140.0, 140.2, 143.3, 155.4. Anal. Calcd for
C21H23NO: C, 82.59; H, 7.59; N, 4.59. Found: C, 82.43;
H, 7.75; N, 4.62.
1
(base), 79 (25). IR (CHCl3): 1602, 1571 cmÀ1. H NMR
(200 MHz, CDCl3) d 1.27 (t, J ¼ 7.0 Hz, 3H), 1.70 (s,
3H), 1.77 (d, J ¼ 7.0 Hz, 3H), 1.96 (sl, 3H), 2.33 (s, 3H),
3.86–4.11 (m, 2H), 4.97 (q, J ¼ 7.0 Hz, 1H), 6.61 (s, 1H),
6.63 (s, 3H), 6.86–6.96 (m, 2H), 7.07 (s, 1H), 7.11–7.26
(m, 4H), 7.34 (t, J ¼ 7.4 Hz, 2H), 7.54 (d, J ¼ 7.4 Hz,
2H). 13C NMR (50 MHz, CDCl3) d 11.79, 15.26, 19.83,
22.01, 22.23, 55.39, 64.37, 111.3, 114.7, 114.9, 119.2,
123.6, 125.0, 126.5 (2C), 127.1, 127.3 (2C), 127.90, 128.5
(2C), 128.6 (2C), 137.8, 139.1, 141.6, 144.0, 158.1. Anal.
Calcd for C29H31NO: C, 85.04; H, 7.63; N, 3.42. Found:
C, 85.08; H, 7.53; N, 3.43.
4.5. 3,5-Dimethyl-2-[3-methyl-4-phenyl-1-(1-(S)-
phenyl-ethyl)-1H-pyrrol-2-yl]-phenol 8
To a solution of imine 3 (1.00 g, 3.56 mmol) in anhy-
drous toluene (10 mL) were successively added trans-b-
nitrostyrene (0.795 g, 5.33 mmol), collidine (0.47 mL,
3.90 mmol) and molecular sieves (3 A). The reaction
mixture was heated at 90 ꢁC for 4 h and then filtered in
order to remove the molecular sieves. After concentra-
4.7. 6-(2-Hydroxy-4,6-dimethyl-phenyl)-5-methyl-
1-(1-(S)-phenyl-ethyl)-3,4-dihydro-1H-pyridin-2-one 10
ꢁ
To a solution of imine 3 (0.50 g, 1.78 mmol) in anhy-
drous THF (10 mL) were added ZnCl2 (243 mg,

144
S. Le Gac et al. / Tetrahedron: Asymmetry 15 (2004) 139–145
1.78 mmol) in anhydrous THF (2 mL) and collidine
(0.518 mL, 3.92 mmol). Then, acryloyl chloride
(0.318 mL, 3.92 mmol) was added at 0 ꢁC and the reac-
tion mixture stirred for 3 h at this temperature. Metha-
nol (10 mL) and an aqueous NaOH solution (1 M,
10 mL) were then added to the crude mixture, which was
heated at 55 ꢁC for 1h. At 0 ꢁC, an aqueous HCl solu-
tion (0.1M) was slowly added until acidic pH after
which the solvents were removed under reduced pres-
sure. After dichloromethane extraction and concentra-
tion under reduced pressure, a GC–MS analysis of the
crude mixture showed two signals corresponding to the
two diastereomers of 10 (de 77%). A FC (dichlorome-
thane/ethyl acetate, 85:15) gave the expected product 10
(337 mg, 56%) as a mixture of two diastereomers. Ana-
lytical samples of the two diastereomers of 10 were ob-
tained by careful FC separations.
)155.6 (c 0.99, CHCl3). EIMS m=z (rel int) 333 (Mþ, 17),
229 (41), 214 (base), 105 (55), 104 (57), 103 (43), 77 (41).
1
IR (CHCl3): 1648 cmÀ1. H NMR (200 MHz, CDCl3) d
1.76 (s, 3H), 1.89 (d, J ¼ 7.0 Hz, 3H), 2.00 (s, 3H), 2.18
(s, 3H), 5.21(q, J ¼ 7.0 Hz, 1H), 6.47 (d, J ¼ 9.4 Hz,
1H), 6.47 (s, 1H), 6.53 (s, 1H), 7.10–7.25 (m, 5H), 7.29
(d, J ¼ 9.4 Hz, 1H). 13C NMR (50 MHz, CDCl3) d 17.84,
18.09, 19.97, 21.61, 59.61, 114.7, 116.8, 118.7, 120.9,
122.6, 126.4 (2C), 126.6, 128.3 (2C), 137.4, 140.8, 141.6,
143.0, 144.7, 155.0, 163.8. Anal. Calcd for
C22H25NO2ÆH2O: C, 75.19; H, 7.17; N, 3.99. Found: C,
75.25; H, 6.92; N, 4.16.
4.9. 6-(2-Hydroxy-naphthalen-1-yl)-5-methyl-1-(1-(S)-
phenyl-ethyl)-3,4-dihydro-1H-pyridin-2-one 12
20
D
Major diastereomer: White solid, mp ¼ 191 ꢁC, ½aŠ
To a solution of imine 6 (0.50 g, 1.65 mmol) in anhy-
drous THF (9 mL) were added ZnCl2 (225 mg,
1.65 mmol) in anhydrous THF (2 mL) and collidine
(0.444 mL, 3.63 mmol). Acryloyl chloride (0.295 mL,
3.63 mmol) was then added at 0 ꢁC, and the reaction
mixture stirred for 3 h at this temperature. Methanol
(10 mL) and an aqueous NaOH solution (1 M, 10 mL)
were then added to the reaction mixture, which was then
heated at 55 ꢁC for 1h. At 0 ꢁC, an aqueous HCl solu-
tion (0.1M) was slowly added until acidic pH after
which the solvents were removed under reduced pres-
sure. After dichloromethane extraction and evaporation
of the solvent under reduced pressure, a 1H NMR
analysis of the crude mixture allowed us to calculate the
relative proportions of the two diastereomers of 12 (de
28%). A FC (dichloromethane/ethyl acetate, 85:15) led
to product 12 (230 mg, 39%) as a mixture of two dia-
stereomers. Analytical samples of the two diastereomers
of 12 were obtained by careful FC separations.
)121.8 (c 1.02, EtOH). EIMS m=z (rel int) 335 (Mþ, 12),
231 (82), 216 (76), 105 (base), 77 (31). IR (CHCl3):
1649 cmÀ1 1H NMR (200 MHz, CDCl3) d 1.46 (d,
.
J ¼ 7.0 Hz, 3H), 1.50 (s, 3H), 2.07 (s, 3H), 2.18–2.64 (m,
4H), 2.24 (s, 3H), 4.35 (s, 1H), 5.10 (q, J ¼ 7.0 Hz, 1H),
6.43 (s, 1H), 6.54 (s, 1H), 7.04–7.12 (m, 2H), 7.15–7.30
(m, 3H). 13C NMR (50 MHz, CDCl3) d 17.20, 19.13,
19.89, 21.62, 26.79, 33.34, 53.82, 113.8, 118.6, 122.5,
123.2, 127.0 (2C), 127.2, 128.6 (2C), 130.1, 138.9, 140.3,
141.7, 154.1, 171.5. Anal. Calcd for C22H25NO2: C,
78.77; H, 7.51; N, 4.18. Found: C, 78.66; H, 7.82; N,
4.16. X-ray structure determination of this major dia-
stereomer: vide infra.
20
D
Minor diastereomer: White solid, mp ¼ 241 ꢁC, ½aŠ
)93.4 (c 0.99, EtOH). EIMS m=z (rel int) 335 (Mþ, 17),
231 (91), 216 (83), 105 (base), 103 (34), 77 (44). IR
(CHCl3): 1651 cmÀ1. 1H NMR (200 MHz, CDCl3) d 1.56
(s, 3H), 1.58 (d, J ¼ 7.8 Hz, 3H), 2.05–2.20 (m, 1H), 2.11
(s, 3H), 2.25 (s, 3H), 2.34–2.58 (m, 3H), 4.47 (q,
J ¼ 7.0 Hz, 1H), 5.50 (s, 1H), 6.55, (s, 1H), 6.59 (s, 1H),
7.05–7.35 (m, 5H). 13C NMR (50 MHz, CDCl3) d 17.16,
19.21, 19.56, 21.62, 26.45, 33.15, 55.44, 113.8, 118.5,
120.0, 123.3, 126.7, 127.1 (2C), 128.1 (2C), 131.3, 138.2,
140.1, 142.5, 154.3, 171.1. Anal. Calcd for C22H25NO2:
C, 78.77; H, 7.51; N, 4.18. Found: C, 78.87; H, 7.66; N,
4.15.
20
Major diastereomer: Amorphous solid. ½aŠ )173.1 (c
D
1.1, EtOH). EIMS m=z (rel int) 357 (Mþ, 19), 253 (base),
252 (73), 238 (48), 105 (76), 104 (33), 77 (39). IR
(CHCl3): 3272, 1638 cmÀ1. 1H NMR (200 MHz, CDCl3)
d 1.12 (d, J ¼ 7.0 Hz, 3H), 1.49 (s, 3H), 2.28–2.45 (m,
1H), 2.51–2.86 (m, 3H), 4.62 (s, 1H), 5.25 (q, J ¼ 7.0 Hz,
1H), 6.92–7.03 (m, 2H), 7.14–7.25 (m, 4H), 7.26–7.48
(m, 2H), 7.63 (d, J ¼ 7.8 Hz, 1H), 7.70–7.78 (m, 2H) 13C
NMR (50 MHz, CDCl3) d 17.07, 19.19, 26.84, 33.15,
53.33, 113.8, 117.7, 123.7, 124.1, 126.8 (2C), 126.9,
127.2, 128.3 (2C), 128.4, 128.7, 128.8, 131.0, 133.5,
141.4, 152.4, 171.3.
4.8. 6-(2-Hydroxy-4,6-dimethyl-phenyl)-5-methyl-1-(1-(S)-
phenyl-ethyl)-1H-pyridin-2-one 11
20
D
Under an air atmosphere, acetonitrile (30 mL), metha-
nol (10 mL), Pd(OAc)2 (17 mg, 0.0746 mmol) and
Cu(OAc)2, H2O (744 mg, 3.725 mmol) were successively
added to the major diastereomer of 10 (0.50 g,
1.49 mmol). After 4 h at 50 ꢁC, the solvents were
removed under reduced pressure. The crude mixture was
then dissolved in dichloromethane and washed with an
aqueous HCl solution (0.1M). The aqueous layer was
extracted with dichloromethane and the combined or-
ganic layers concentrated under reduced pressure. A FC
Minor diastereomer: White solid, mp ¼ 213 ꢁC (dec), ½aŠ
)141.8 (c 0.36, EtOH). EIMS m=z (rel int) 357 (Mþ, 18),
253 (99), 252 (73), 238 (51), 105 (base), 104 (58), 77 (55).
IR (CHCl3): 3437, 1613 cmÀ1 1H NMR (200 MHz,
.
CDCl3) d 1.40 (d, J ¼ 7.0 Hz, 3H), 1.59 (s, 3H), 2.24–
2.38 (m, 1H), 2.49–2.90 (m, 3H), 4.35 (q, J ¼ 7.0 Hz,
1H), 5.61 (s, 1H), 7.08–7.27 (m, 6H), 7.29–7.48 (m, 2H),
7.62 (d, J ¼ 8.6 Hz, 1H), 7.74–7.82 (m, 2H). 13C NMR
(50 MHz, CDCl3) d 17.65, 19.62, 26.93, 33.52, 56.11,
113.9, 117.6, 122.1, 124.2 (2C), 126.9, 127.1 (2C), 127.5,
128.3 (2C), 128.7, 129.3, 129.9, 131.4, 132.8, 142.1,
151.9, 170.7.
(dichloromethane/ethyl acetate, 40:60) yielded product
11 (411 mg, 83%). Yellow solid, mp ¼ 270 ꢁC (dec), ½aŠ
20
D

S. Le Gac et al. / Tetrahedron: Asymmetry 15 (2004) 139–145
145
4. Only atropisomeric 1- and 3-aryl-pyrroles have been
reported yet. For 1-aryl-pyrroles, see: Fogassy, K.; Har-
mat, V.; Bocskei, Z.; Tarkanyi, G.; Toke, L.; Faigl, F.
Tetrahedron: Asymmetry 2000, 11, 4771–4780; For
4.10. X-ray structure determination of the major
diastereomer of 10
Formula: C22H25NO2, MW ¼ 335.43, monoclinic, space
ꢀ
3-aryl-pyrroles, see: Alazard, J. P.; Boye, O.; Gillet, B.;
Guenard, D.; Beloeil, J. C.; Thal, C. Bull. Soc. Chim. Fr.
ꢁ
group C2; a ¼ 14:951ð2Þ, b ¼ 7:610ð1Þ, c ¼ 16:453ð2Þ A,
ꢀ
3
b ¼ 92:439ð1Þꢁ, V ¼ 1870ð3Þ A , Z ¼ 4, Z0 ¼ 1;
ꢁ
1993, 130, 779–787; Furusho, Y.; Aida, T.; Inoue, S. J.
Chem. Soc., Chem. Commun. 1994, 653–655; Boiadjiev, S.
E.; Lightner, D. A. Tetrahedron 2002, 58, 7411–7421.
5. Zhang, H.; Xue, F.; Mak, T. C. W.; Chan, K. S. J. Org.
Chem. 1996, 61, 8002–8003; Zhang, H.; Kwong, F. Y.;
Tian, Y.; Chan, K. S. J. Org. Chem. 1998, 63, 6886–6890.
6. Kwong, F. Y.; Chan, A. S. C.; Chan, K. S. Tetrahedron
2000, 56, 8893–8899; Kwong, F. Y.; Yang, Q.; Mak, T. C.
W.; Chan, A. S. C.; Chan, K. S. J. Org. Chem. 2002, 67,
2769–2777.
Dc ¼ 1:191 g cmÀ3; T ¼ 296ð2Þ K, crystal habit ¼ pris-
matic, crystal colour ¼ colourless, approximate crystal
size ¼ 0.10 · 0.46 · 0.60 mm, F ð000Þ ¼ 720, l(MoKa) ¼
0.076 mmÀ1. Structure solution and refinement: The
program package SHELXTL (V6.10) was used for space
group determination, structure solution and refinement.
The space group C2 was reliably determined from sys-
tematic extinctions and the relative F02 of equivalent
reflections (XPREP). The structure was solved by direct
methods (SHELXS). An ORTEP view of the title
compound is presented in Figure 2 and provides a rep-
resentation of the stereochemistry of this compound.
The absolute configuration of the stereogenic centre of
the methylbenzylamine moiety is (S). Anisotropic dis-
placement parameters were refined for nonhydrogen
atoms. Some hydrogen atoms could not be located from
subsequent difference Fourier synthesis and refined.
Ideal positions were calculated for each one (SHELXL).
The final cycle of full-matrix least-square refinement on
F 2 was based on 3763 observed reflections and 296
7. Wong, H. L.; Tian, Y.; Chan, K. S. Tetrahedron Lett.
2000, 41, 7723–7726.
8. Compounds 2 and 5 have already been reported. For 2,
see: Martin, R.; Demerseman, P. Synthesis 1989, 1, 25–28;
€
For 5, see: Buu-Hoı, N. P.; Seailles, J., Jr. J. Org. Chem.
ꢀ
1955, 20, 606–609.
9. Boyd, D. R.; Al-Showiman, S.; Jennings, W. B. J. Org.
Chem. 1978, 43, 3335–3339.
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Tetrahedron: Asymmetry 1995, 6, 1795–1812; Jabin, I.;
€
Revial, G.; Pfau, M.; Decroix, B.; Netchitaılo, P. Org.
Lett. 1999, 1, 1901–1904; Revial, G.; Jabin, I.; Pfau, M.
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variable parameters and converged with unweighted and
€
Revial, G.; Monnier-Benoit, N.; Netchitaılo, P. J. Org.
Chem. 2001, 66, 256–261; Jabin, I.; Netchitaılo, P.
P
weighted agreement factors of R1 ¼ ðkF0j À jFCkÞ=
€
P
jF0j ¼ 0:0390 [0.0352 for 3445 F0 > 4:0rðF0Þ],
Tetrahedron Lett. 2001, 42, 7823–7827; Revial, G.; Jabin,
I.; Redolfi, M.; Pfau, M. Tetrahedron: Asymmetry 2001,
12, 1683–1688; Camara, C.; Joseph, D.; Dumas, F.;
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P
P
2
2
1=2
wR2 ¼ f ½wðF02 À FC2Þ Š= ½wðF02Þ Šg ¼ 0:1001. Crys-
tallographic data (excluding structure factors) has been
deposited with the Cambridge Crystallographic Data
Center as supplementary publication no. CCDC 218213.
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].
€
1445–1448; Jabin, I.; Revial, G.; Pfau, M.; Netchitaılo, P.
Tetrahedron: Asymmetry 2002, 13, 563–567; Jabin, I.;
€
Monnier-Benoit, N.; Le Gac, S.; Netchitaılo, P. Tetrahe-
dron Lett. 2003, 44, 611–614; Monnier-Benoit, N.; Jabin,
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metry 2003, 14, 2747–2753.
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ꢀ
5328; Cave, C.; Gassama, A.; Mahuteau, J.; dꢀAngelo, J.;
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J.; Guingant, A.; Riche, C.; Chiaroni, A. Tetrahedron Lett.
1988, 29, 2667–2670.
Supplementary material
Detailed crystal structure determination of major dia-
stereomer of 10 is available free of charge from the au-
thor.
12. Lim, S.; Jabin, I.; Revial, G. Tetrahedron Lett. 1999, 40,
4177–4180.
ꢀ
ꢀ
13. dꢀAngelo, J.; Cave, C.; Desmaele, D. Isr. J. Chem. 1997,
37, 81–85.
14. In both cases (i.e., under heating conditions or with a
Lewis acid catalysis), the obtained major diastereomer was
identical.
References and Notes
15. The comparison between the different Lewis acids was
made on the reaction of imine 3 with acryloyl chloride.
16. We were unable to obtain an analytical sample of the
major diastereomer of 8 since this compound was insep-
arable, by FC on silica gel, from traces of ketone 2 formed
during the reaction. Thus, the 49% yield, given for the
1. Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994; Clayden, J. Angew. Chem., Int.
Ed. Engl. 1997, 9, 949–951.
2. See Ref. 1: Chen, Y.; Smith, M. D.; Shimizu, K. D.
Tetrahedron Lett. 2001, 42, 7185–7187; Clayden, J.;
McCarthy, C.; Cumming, J. G. Tetrahedron Lett. 2000, 41,
3279–3283.
1
mixture of diastereomers of 8, was determined by an H
NMR purity estimation of major diastereomer of 8.
17. Massiot, G.; Sousa Oliveira, F.; Levy, J. Tetrahedron Lett.
1982, 23, 177–180.
€
3. Jabin, I.; Monnier-Benoit, N.; Le Gac, S.; Netchitaılo, P.
Tetrahedron Lett. 2003, 44, 611–614.