Diastereoselective cycloadditions of chiral non-racemic azomethine imines

Article abstract of DOI:10.1055/s-2000-6311

(5R)-5-Phenyl[1,3,4]oxadiazinan-2-one (6) is an easily available building block and acts as a chiral non-racemic precursor for azomethine imines. The ylid can be formed regioselectively with various aldehydes and reacts in an efficient manner with a wide range of dipolarophiles. The regio- and diastereoselectivity of the cycloadditions have been fully investigated and can lead, in the best cases, to the creation of three contiguous asymmetric centers in a single step, with complete control of relative and absolute configurations.

Full text of DOI:10.1055/s-2000-6311

1170
FEATURE ARTICLE
Diastereoselective Cycloadditions of Chiral Non-racemic Azomethine Imines
Fanny Roussi, Ariane Chauveau, Martine Bonin, Laurent Micouin, Henri-Philippe Husson*
Laboratoire de Chimie Thérapeutique Associé au CNRS (UMR 8638) et à l'Université René Descartes, Faculté des Sciences Pharmaceu-
tiques et Biologiques, 4 Av. de l'Observatoire, 75270 Paris Cedex 06, France
Fax +33(01)43291403, E-mail; Husson@pharmacie.univ-paris5.fr
Received 3 April 2000
We report herein our full results in this field, using com-
Abstract: (5R)-5-Phenyl[1,3,4]oxadiazinan-2-one (6) is an easily
pound 6 (Scheme 1) as achiral non-racemic template.9
available building block and acts as a chiral non-racemic precursor
Phenylglycinol, commercially available in both enantio-
merically pure forms, was chosen as the source of nitro-
for azomethine imines. The ylid can be formed regioselectively
with various aldehydes and reacts in an efficient manner with a wide
range of dipolarophiles. The regio- and diastereoselectivity of the gen and chirality.
cycloadditions have been fully investigated and can lead, in the best
cases, to the creation of three contiguous asymmetric centers in a
single step, with complete control of relative and absolute configu-
Preparation of Chiral Template 6
rations.
Key words: azomethine imines, cycloadditions, phenylglycinol,
asymmetric synthesis, cyclic hydrazines
Cyclic carbazate 6 possesses several structural elements
required for an efficient and versatile building block:
(a) Electronically different substituents on both nitrogens
should allow a regioselective formation of ylid.
Concerted cycloaddition reactions are powerful methods
for the straightforward elaboration of complex structures.1
They usually provide access to polyfunctional molecules
with excellent stereocontrol of the relative configuration
of several consecutive asymmetric centres, and are per-
formed under relatively simple and scalable experimental
procedures. It is also important to note that the regioselec-
tivity of such reactions can now be easily predicted thanks
to the powerful tool of Frontier Molecular Orbitals(FMO)
theory.2
Although asymmetric hetero Diels-Alder3 or 1,3-dipolar
cycloadditions with azomethine ylids4 are now well
known methods for the synthesis of piperidine or pyrroli-
dine derivatives, very little work is known on the azome-
thine imine series. Since the pioneering works of Dorn5
and Oppolzer in this field,6 it was known that azomethine
imines could react with several dipolarophiles, leading to
polysubstituted pyrazolidines.7 Some recent important re-
sults were also reported by Stanovnik and co-workers,8
showing that in the racemic series, good control of relative
configurations could be obtained with this reaction. The
design of a chiral non-racemic precursor for such ylids
should therefore not only permit the preparation of enan-
tiopure polysubstituted pyrazolidines, but also provide a
versatile and efficient route toward 1-3 diamines, after re-
ductive cleavage of the N-N bond (Figure 1).
(b) An electron-withdrawing group on one nitrogen
should enhance the stability of the transient ylid.
(c) Cyclic carbazate structure should lead to an almost
planar ylid, with the phenyl ring pushed out of this plane
by A(1,3) strain, allowing good facial selectivity.
(d) Both nitrogens can be selectively deprotected after cy-
cloaddition.
This stable, crystalline, enantiopure compound can be ob-
tained in five steps from (R)-(-)-phenylglycinol (1) on a
multigram scale, without any chromatographic purifica-
tion steps10 (Scheme 1).
Ph
Ph
Ph
Ph
OH
NH2
OH
NO
OH
a
OH
b
c
N
N
NH2
NH
1
2
3
4
Ph
Ph
Ph
d
H
N
Ph
Ph
O
NH
e
N
5
N
H
O
O
O
6
Ph
Reagents and conditions :
a) PhCHO, NaBH4, MeOH, 90%;
b) NaNO2, H2O/HCl, 70 °C, 86%; c) LiAlH4, Et2O, -78 °C to -10 °C,
84%; d) Im2CO, CH2Cl2, r.t., 92%; e) H2, Pd(OH)2, MeOH, 10 bars,
97%.
Scheme 1
*
R
NH2 NH2
*
R
R1CHO
R2
R3
N
N
*
*
R3
*
R3
N
H
*
R1
N
*
*
Phenyl Substituted Azomethine Imine
H
R1
R2
R2
Our study started with azomethine imine 7 generated from
carbazate 6 and benzaldehyde.
Figure 1
Synthesis 2000, No. 8, 1170–1179 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Diastereoselective Cycloadditions of Chiral Non-racemic Azomethine Imines
1171
Facial stereoselectivity was first evaluated with diethyl % yield. The modest yield of the reaction was due not only
acetylene dicarboxylate as a dipolarophile. Mixing all to the once more competitive 1,4-addition but also to the
three components together only led to a large amount of low stability of 8. Indeed, as an oil, it rapidly oxidised to
1,4-addition of carbazate 6 on the good Michael accep- 9 in the presence of air, but could be stored for weeks after
tor.11 Best results were obtained when the ylid was first crystallization (Scheme 2).
generated with benzaldehyde dimethyl acetal, followed
by addition of the dipolarophile. Using this procedure,
compound 8 was obtained as a single diastereomer in 35
Biographical Sketches
From left to right:
Dr. M. Bonin,
Prof. H.-P. Husson,
Dr. L. Micouin,
A. Chauveau,
F. Roussi
Dr. M. Bonin was born in 1957. She trained as a pharmacist in the University of Bordeaux (1979), and obtained her
PhD in Chemistry at the University of Orsay (1986) on the total synthesis of piperidine alkaloids. Enlisted as researcher
in CNRS in Prof. Husson’s group (1983), she began a collaboration with Dr. J.-C. Quirion on aminonitrile and oxazo-
lidine synthons and followed that with a one year postdoc in Orsay (Drs G. Balavoine and F. Guibe, organometallic and
radical chemistry, 1992). Her main research interests are the development of new diastereoselective routes towards bi-
ological active compounds.
Prof. H.-P. Husson was born in 1939. He received his Pharmacy degree in 1961 from Paris University and his PhD in
Chemistry from the same University. He was a postdoctoral fellow with Professor E. Wenkert at Indiana University,
Bloomington. He spent the first part of his career in the Institut de Chimie des Substances Naturelles (CNRS) at Gif-
sur-Yvette in Professor Potier’s Group as a Director of Research. In 1987 he was appointed Full Professor and Chairman
of the Department of Medicinal Chemistry of the Faculty of Pharmacy in Paris (Université René Descartes). The main
research interests of Professor Husson are the chemistry of natural products and the development of new chemical meth-
ods for enantioselective synthesis of biologically active molecules.
Dr. L. Micouin was born in 1968. He received his Engineer Diploma from the Ecole Nationale Supérieure de Chimie
de Paris in 1990. He obtained his PhD in 1995 in the laboratory of Prof. H.-P. Husson under the guidance of Dr. J.-C.
Quirion. After a one year postdoctoral stay in Prof. P. Knochel's laboratory at Marburg (Germany), he went back to
Prof. Husson's group in 1996 as Chargé de Recherche (CNRS). His main research interest is concerned with the use of
organometallic chemistry in the asymmetric synthesis of nitrogen containing compounds.
A. Chauveau was born in 1977. She was trained as a chemist in Ecole Nationale Supérieure de Chimie de Paris and
received her engineer diploma in 1999. She is currently working as a D.E.A student on the use of diastereoselective
cycloadditions of azomethine imines for the preparation of enantiopure 1-3 diamines.
F. Roussi was born in 1971. She received her Pharmacy degree in 1996 from Paris University (Université René Des-
cartes). She performed her PhD work on the use of chiral non racemic cyclic hydrazines for the asymmetric synthesis
of nitrogen containing compounds, under the guidance of Dr. M. Bonin and Dr. L. Micouin. She obtained her PhD in
1999 and is currently on a postdoctoral stay in Prof. J. Baldwin's group at Oxford.
Synthesis 2000, No. 8, 1170–1179 ISSN 0039-7881 © Thieme Stuttgart · New York

1172
F. Roussi et al.
FEATURE ARTICLE
Ph
Ph
H
Ph
N
OH
O
N
Ph
N
Ph
H
N
Ph
N
N
O
b
a
6
O
O
EtO2C
CO2Et
EtO2C
CO2Et
7
8
9
Reagents and conditions : a) PhCH(OMe)2, PTSA, toluene, 70 °C, M.
Sieves; ii diethyl acetylene dicarboxylate, 35 %, d.e. > 97 %. b) air.
Scheme 2
Figure 3
Absolute configuration of 8 was determined by X-ray
analysis. It is in agreement with an approach of the dipo-
larophile from the less sterically hindered face of the S-
shape ylid 7 (Figure 2). Small amount of non reacted ylid
7 could be isolated and its configuration was confirmed by
NOE between the two benzylic protons.
In contrast dimethyl fumarate afforded a mixture of dia-
stereomers. After chromatographic separation, the rela-
tive configuration of the major diastereomer 11 was estab-
lished by NMR NOE experiments.
Regioselectivity was then studied. All electron-deficient
dipolarophiles led again to a single regioisomer 12 and 13,
with preferentially an endo selectivity (established by
NMR experiments).
CO2Me
CO2Me
Ph
Ph
Ph
N
Ph
N
Ph
N
N
b
a
6
O
O
O
O
13
12
Reagents and conditions : a) PhCHO (5 eq.), methyl acrylate (5 eq.),
H2O (1 eq.), CHCl3, D, 48 h, 74 %, d.e. = 97 % b) PhCHO (5 eq.), me-
thyl cinnamate (5 eq.), DCE, D, 48 h, 40 %, d.e. = 92 %.
Figure 2
Scheme 4
endo/exo-Selectivity was then investigated with symmet-
rical dipolarophiles dimethyl maleate and fumarate. These
reagents proved to be less prone to 1,4-addition, and reac-
tion could be conducted by simply refluxing all compo-
nents together. Chloroform appeared as the proper solvent
for this cycloaddition (Scheme 3).
On the contrary, cycloaddition with styrene led to 14 with
an opposite regioselectivity and mainly an exo approach.
With this dipolarophile, reaction had to be performed in
1,2-dichloroethane since no cycloaddition occurred in
chloroform (Scheme 5).
Surprisingly, ylid 7 was reactive enough to give 15 with
CO2Me
CO2Me
oct-1-ene in a single regio and diastereomeric form.
Ph
Ph
Ph
N
Ph
N
CO2Me
CO2Me
N
N
b
a
6
Ph
Ph
O
O
O
O
Ph
N
Ph
N
C6H13
Ph
11
10
N
N
b
a
6
O
O
O
O
Reagents and conditions : a) PhCHO (5 eq.), dimethyl maleate (5 eq.),
H2O (1 eq.), CHCl3, D, 48 h, 63 %, d.e. > 97 % b) PhCHO (5 eq.), di-
methyl fumarate (4 eq.), H2O (1 eq.), CHCl3, D, 48 h, 82 %, d.e. = 45
%.
15
14
Reagents and conditions : a) PhCHO (5 eq.), styrene (5 eq.), DCE, D,
24 h, 48 %, d.e. = 72 %. b) PhCHO (5 eq.), octene (5 eq.), DCE, D,
120 h, 50 %, d.e. > 97 %.
Scheme 3
Scheme 5
Compound 10 was obtained in good yield and as a single
diastereomer. The exclusive endo approach of this dipo-
larophile was established according to X-ray analysis of
compound 10 (Figure 3).
Although the absolute configuration of the newly created
centre could not be determined by X-ray analysis or NMR
Synthesis 2000, No. 8, 1170–1179 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Diastereoselective Cycloadditions of Chiral Non-racemic Azomethine Imines
1173
studies, we believe cycloaddition occurred in an endo
way, as in the styrene case.
6
overall yield : 69 %
d.r. = 21/14/65
Since we established that ylid 7 presents an interesting re-
activity spectrum with a broad range of various dipolaro-
philes, we then decided to study the influence of aldehyde
on this reactivity.
CO2Me
N
CO2Me
CO2Me
N
N
Ph
N
Ph
N
Ph
CO2Me
N
CO2Me
N
N
N
CO2Me
We first investigated the use of heteroaromatic aldehydes
as ylid precursors. Pyridine aldehydes were chosen as a
model.
O
20 b
O
O
20 a
O
O
20 c
O
Reagents and conditions : 2-PyCHO (2 eq.) methyl fumarate (2 eq.),
DCE, D, 8 h.
Heteroaromatic Substituted Azomethine Imine
Scheme 7
Azomethine imine prepared by condensation of 6 and py-
ridine 3-carboxaldehyde proved to be more reactive than
ylid 7. In 1,2-dichloroethane, completion of the reaction
was observed within less than 8 hours reflux, with only 2
equivalents of aldehyde. Similar regio- and diastereose-
lectivity were observed, as depicted in Scheme 6. Relative
configurations of 16–20 were assigned by NMR spectra
analogies with the benzaldehyde series.
N
CO2Me
Ph
N
O
CO2Me
N
6
O
21
Reagents and conditions : 2-PyCHO (1.7 eq.), dimethyl maleate (3.5
eq.), DCE, D, 9 h, 30%, d.e. > 97 %.
N
N
Scheme 8
CO2Me
CO2Me
Ph
N
O
Ph
N
N
CO2Me
CO2Me
N
N
3-pyridine series were observed (2 compounds, 66 %, d.e.
= 66 %).
b
a
O
O
17
O
16
N
CO2Me
6
The striking difference of reactivities between ylids gen-
erated with 2 ,3 and 4-substituted pyridine can be ex-
plained in two ways:
d
c
Ph
N
Ph
N
Ph
N
N
(a) There is no interconversion between W and S-shaped
ylids, and the ratio is different in the three series.
O
19
O
O
18
O
(b) Ylids isomerization is fast and their reactivity is differ-
ent in the three series.
Reagents and conditions : a) 3-PyCHO (2 eq.), dimethyl maleate (4
eq.), DCE, D, 8 h, 69 %, d.e. > 97 %. b) 3-PyCHO (1.3 eq.), dimethyl
fumarate (1.3 eq.), DCE, D, 8 h, 80 %, d.e. = 70 %. c) 3-PyCHO (2
eq.), methyl acrylate (4 eq.), DCE, D, 8 h, 78 %, d.e. > 97%. d) 3-Py-
CHO (2 eq.), styrene (4 eq.), DCE, D, 8 h, 78 %, d.e.= 71 %.
We decided to check this hypothesis with the following
experiment: compound 22 was obtained by condensation
of 6 with two moles of 2-pyridinecarboxaldehyde as a di-
astereomeric mixture.12
Scheme 6
N
Different results were obtained when performing cycload-
ditions with pyridine 2-carboxaldehyde: for the first time
a poor facial selectivity was observed with dimethyl fu-
marate (Scheme 7).
N
O
O
N
N
Ph
N
O
Ph
N
O
N
a
N
b
6
Formation of compound 20a can be explained by the re-
action of a W-shaped ylid with the dipolarophile. This loss
of facial selectivity was not observed with methyl maleate
(Scheme 8). However, the lower yield observed could be
due to the same reaction of W-shaped ylid with dipolaro-
phile leading to an unstable "all cis" adduct, which de-
composes in the reaction mixture.
O
O
22
22
c
20 a + 20 b + 20 c
cycloreversion
d.r. = 15/17/68
Reagents and conditions: a) 2-PyCHO (4 eq.), toluene, D, 7h. b) chro-
matographic purification, 40 % from 6. c) dimethyl fumarate, toluene,
D, 7 h.
When performing cycloaddition with 4-pyridinecarboxal-
dehyde and dimethyl fumarate, the same results as in the
Scheme 9
Synthesis 2000, No. 8, 1170–1179 ISSN 0039-7881 © Thieme Stuttgart · New York

1174
F. Roussi et al.
FEATURE ARTICLE
The major diastereomer could be isolated by column chro-
matography and its relative configuration assessed by
NOE experiments. When heated in the presence of dime-
thyl fumarate, this diastereomerically pure oxadiazolidine
led to a mixture of compounds 20a, 20b and 20c in the
same ratio as with direct cycloadditions (Scheme 9).
O
O
N
N
N
Ph
Ph
N
O
Ph
N
O
N
6
O
O
28
O
27
O
O
N
Since cycloreversions are known to be concerted reac-
tions,13 this experiment clearly shows that under cycload-
dition conditions, an initially configurationally pure S-
shaped ylid is in equilibrium with a W-shaped ylid, and
the reaction obeys the Curtin-Hammett principle (We
also checked that no interconversions among final com-
pounds occurred).
O
N
N
Ph
N
O
Ph
Ph
N
O
Ph
N
O
NH
N
O
30
29
Scheme 11
These results in the heteroaromatic series clearly showed
that electronic effects can have a dramatic influence on
the relative reactivity of the two ylids isomers, leading to
a great modification of facial selectivity in such cycload-
ditions.
of free ylid in the reaction mixture, and avoid this trouble-
some side reaction dimerization. In some cases, this tan-
dem cycloreversion-cycloaddition sequence led to a
dramatic improvement of chemical yield, without any loss
of diastereoselectivity. (Scheme 12).14
Alkyl Substituted Azomethine Imine
25
We then investigated the reactivity of an ylid generated by
condensation of 6 and butyraldehyde.
a
c
CO2Me
CO2Me
b
After optimization, toluene proved to be the solvent of
choice with this substrate. As in the aromatic series, sev-
eral cycloadducts were obtained, albeit in lower yields
(Scheme 10).
Ph
N
Ph
N
CO2Me
Ph
CO2Me
N
N
O
O
O
O
N
O
23
24
CO2Me
N
CO2Me
CO2Me
O
31
Ph
N
O
Ph
N
O
CO2Me
Reagents and conditions : a) dimethyl maleate (4 eq.), toluene, D, 96
h, 71 %, d.e. > 95 %. b) dimethyl fumarate (4 eq.), toluene, 144 h, 54
%, d.e. = 91 % c) methyl acrylate (4 eq.), toluene, 80 °C, 72 h, 38 %,
d.e. = 30%.
N
N
b
a
O
O
24
23
6
O
N
c
d
Scheme 12
Ph
N
O
Ph
26
N
Ph
N
25
O
O
O
Conclusion
Reagents and conditions : a) PrCHO (2.5 eq.) dimethyl maleate (4
eq.), toluene, 70 °C, 48 h, 27 %, d.e. > 95 %. b) PrCHO (1.1 eq.) me-
thyl acrylate (4 eq.), toluene, 70 °C, 16 h, 62 %, d.e. = 30%. c) PrCHO
(4 eq.), toluene, 60 °C, 16 h, 98 %, d.e. > 95 %. d) PrCHO (2.5 eq.),
styrene (4 eq.), toluene, 70 °C, 16 h, 11 %, d.e. = 30%.
As a summary, we have shown the potential interest of
carbazate 6 as azomethine imine precursor in asymmetric
1,3 dipolar cycloadditions. This chiral non-racemic build-
ing block is easily available in a simple and scalable pro-
cedure. The ylid is formed regioselectively with various
aldehydes and reacts with a wide range of dipolarophiles.
In the best cases, three contiguous asymmetric centers
could be created in a single step with complete control of
relative and absolute configurations, with simple and eas-
ily scalable experimental procedures. The extension of
these cycloadditions to the synthesis of optically pure
polysubstituted 1,3-diamines is currently in progress in
our laboratory.
Scheme 10
Facial selectivity was once again excellent, and relative
configurations of cycloadducts were attributed by analogy
to NMR spectra with aromatic series. Decrease of yields
can be explained by competitive formation of dioxazoli-
dine 25 and, in some cases, by a head-to-tail dimerization
of the transient ylid, followed by a non-concerted ring
opening and intramolecular prototropy (Scheme 11).
We therefore investigated the generation of ylid by cyclo-
reversion. This procedure should lower the concentration
The solvents were distilled according to standard procedures (P2O5
for CH2Cl2, Na/benzophenone for THF). NMR spectra were ob-
Synthesis 2000, No. 8, 1170–1179 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Diastereoselective Cycloadditions of Chiral Non-racemic Azomethine Imines
1175
tained at 300 MHz (1H field value); chemical shifts are reported in
ppm. IR spectra were recorded as thin film unless otherwise stated.
Optical rotation measurements were performed using a 1 dm path
length cell. Elemental analyses were obtained from the Service de
microanalyse of the Institut de Chimie des Substances Naturelles,
Gif-sur-Yvette, France.
for 24 h at r.t., concentrated and dissolved in CH2Cl2 (50 mL). The
organic phase was washed with aq 1M HCl (148 mL), with sat. aq
Na2CO3 (2 x 80 mL) and evaporated to give 5 as a yellow oil (12.2
g, 92 %); [a]D20 -83 (CHCl3, c = 1.01).
IR (cm-1): n = 3054, 2987, 1654.
1H NMR (CDCl3, 300 MHz): d = 3.75 (d, J = 12.9 Hz, 1H), 3.98 (d,
J = 12.9 Hz, 1H), 4.08 (t, J = 5.1 Hz, 1H), 4.60 (d, J = 5.1 Hz, 2H),
6.9 (s, 1H), 7.0-7.4 (m, 10 H).
13C NMR (CDCl3, 75.43 MHz): d = 59.5, 60.9, 67.3, 127.6, 129.2,
134.9, 135.4, 151.7.
MS (CI, NH3) : 269 (MH+).
(2R)-2-Benzylamino-2-phenylethanol (2)
To a solution of R-(-)-phenylglycinol 1 (1g, 7.3 mmol) in MeOH (8
mL) was added benzaldehyde (740 mL, 7.3 mmol) and the mixture
was stirred for 30 min. The solution was then cooled to -10 °C and
NaBH4 (414 mg, 10.95 mmol) was added over 1 h. The mixture was
stirred for 22 h. Water (10 mL) was added, the aqueous layer was
extracted with CH2Cl2 (2 x 30 mL) and organic phases were dried
(MgSO4) and evaporated to give 1.49 g of 2 (90%) (amorphous);
[a]D20 -62 (CHCl3, c = 1.1); mp = 72-74 °C.
calcd. HRMS for C16H16N2O2 : 269.1290. Found : 269.1299.
(5R)-5-Phenyl[1,3,4]oxadiazinan-2-one (6)
Compound 5 (11.52 g, 43.0 mmol) was stirred 48 h in anhyd MeOH
(300 mL) under 10 bars hydrogen atmosphere in presence of a small
amount of 20% palladium hydroxide on carbon. The mixture was
then filtered, concentrated and recrystallized from THF to give 7.42
g of compound 6 as white crystals (97 %); [a]D20 -10.5 (MeOH, c =
0.85); mp = 170-172 °C.
IR (cm-1): n = 3250, 1675.
1H NMR (CD3OD, 300 MHz): d = 3.40 (s, 2H), 4.20 (dd, J = 9.0,
3.8 Hz, 1H), 4.50 (dd, J = 11.0, 9.0 Hz, 1H), 4.6 (dd, J = 11.0, 3.8
Hz, 1H), 7.2 (m, 5H).
IR (cm-1): n = 3248, 1486, 1452.
1H NMR (CDCl3, 300 MHz): d = 2.30-2.50 (br. s, 2H), 3.55 (dd, J
= 10.9, 8.7 Hz, 1H), 3.58 (d, J = 13.0 Hz, 1H), 3.69 (dd, J = 10.9,
4.3 Hz, 1H), 3.74 (d, J = 13.0 Hz, 1H), 3.81 (dd, J = 8.7, 4.3 Hz, 1H)
7.2-7.4 (m, 10H).
13C NMR (CDCl3, 75.43 MHz): d = 50.9, 62.9, 66.3, 125.2, 129.2,
139.0, 139.5.
MS (CI, NH3): 288 (MH+).
(2R)-2-(N-Benzylnitrosoamino)-2-phenylethanol (3)
An aqueous solution of NaNO2 (3.68g, 53.3 mmol in 15 mL H2O)
was added dropwise over 1 h at 70 °C to a solution of 2 hydrochlo-
ride (7.22g, 26.65 mmol) in H2O (20 mL). The mixture was stirred
at 70 °C for 1.5 h, cooled and extracted with Et2O (100 mL). The
organic phase was washed with H2O (10 mL), dried (MgSO4) and
evaporated to give 3 as an oil (6.27g, 86 %); [a]D20 +119 (CHCl3, c
= 1.26);
13C NMR (CDCl3, 75.43 MHz): d = 55.6, 73.7, 126.6, 130.2, 136.6,
155.1.
MS (CI, NH3): 179 (MH+).
Anal. Calcd. for C9H11N2O2 : C 60.66, H 5.66, N 15.72. Found : C
60.74, H 5.71, N 15.61.
Typical Procedures for Cycloadditions
Method A
IR (cm-1): n = 3421, 3090, 3066, 3033.
Compound 6 (100 mg, 0.56 mmol) and benzaldehyde dimethyl ac-
etal (140 mL, 1.35 mmol) were stirred at 70 °C for 3 h in the pres-
ence of 4Å molecular sieves and PTSA (10 mg). Ethyl acetylene
dicarboxylate (360 mL, 2.25) was added and the mixture was stirred
for 16 h at 70 °C, cooled to r.t., washed with sat. aq brine (5 mL), aq
Na2S2O4 (5 mL), dried (MgSO4) and concentrated. Crude product
was purified by column chromatography if necessary.
1H NMR (CDCl3, 300 MHz): d = 3.88 (d, J = 14.7 Hz, 1H), 4.10 (dd,
J = 12.4, 4.7 Hz, 1H), 4.48 (dd, J = 12.4, 8.5 Hz, 1H), 5.09 (dd, J =
8.5, 4.7 Hz, 1H), 5.47 (d, J = 14.7 Hz, 1H), 6.6-7.3 (m, 10H).
13C NMR (CDCl3, 75.43 MHz): d = 47.0, 64.0, 68.5, 127.3, 128.9,
133.7, 135.6.
MS (CI, NH3): 257 (MH+).
Method B
(2R)-2-(N-Benzylhydrazino)-2-phenylethanol (4)
Compound 6, aldehyde and dipolarophile were stirred in the appro-
priate solvent (see theoretical part) under heating until total conver-
sion of 6 was noticed by thin layer chromatography. Solvent was
then evaporated and the crude mixture was purified by column
chromatography if necessary.
LiAlH4 (11.2 g, 29.5 mmol) was slowly added under N2 to a cooled
solution of 3 (11.2 g, 43.9 mmol) in anhyd Et2O (300 mL) keeping
the temperature under -10 °C. The mixture was stirred two addi-
tional hours at this temperature, cooled to -78 °C, quenched with
H2O (11.2 mL), 15% aq NaOH (11.2 mL) and H2O (33.6 mL), fil-
tered and evaporated to give white crystals of 4 (8.9 g, 84 %); [a]D
-10 (CHCl3, c = 1.1); mp = 78-80 °C.
IR (cm-1): n = 3345, 3055, 2937.
1H NMR (CDCl3, 300 MHz): d = 3.19 (d, J = 13.4 Hz, 1H), 3.62 (dd,
J = 11.4, 2.6 Hz, 1H), 3.75 (dd, J = 8.9, 2.6 Hz, 1H), 3.81 (d, J =
13.4 Hz, 1H), 4.11 (dd, J = 11.4, 8.9 Hz, 1H), 6.9-7.5 (m, 10H).
13C NMR (CDCl3, 75.43 MHz): d = 65.0, 67.9, 71.7, 125.4, 128.8,
137.1, 138.6.
Ylid 7 (byproduct of method A).
20
[a]D20 -46 (CHCl3, c = 1.15); mp = 206-208 °C.
IR (cm-1): n = 3421, 3054, 2986, 1775.
1H NMR (CDCl3, 300 MHz): d = 4.21 (dd, J = 8.8, 5.7 Hz, 1H), 4.80
(t, J = 8.8 Hz, 1H) 5.31 (dd, J = 8.8, 5.7 Hz, 1H), 7.1-7.6 (m, 10H),
7.88 (s, 1H).
13C NMR (CDCl3, 75.43 MHz): d = 59.3, 69.6, 125.9, 130.3, 133.7,
136.9, 147.2, 165.3.
MS (CI, NH3): 267 (MH+).
MS (CI, NH3): 243 (MH+).
Anal. Calcd. for C15H18N2O : C 74.35, H 7.49, N 11.56. Found : C
74.49, H 7.69, N 11.27.
(4R,6S)-1-Oxo-4,6-diphenyl-3,4-dihydro-6H-pyrazolo[1,2-
c][1,3,4]oxadiazine-7,8-dicarboxylic Acid Diethyl Ester (8)
(Method A, Silica gel, cyclohexane/EtOAc 9:1).
(5R)-4-Benzyl-5-phenyl[1,3,4]oxadiazinan-2-one (5)
Carbonyldiimidazole (10.4 g, 64.3 mmol) was added to a solution
of 4 (11.9 g, 49.5 mmol) in THF (50 mL). The mixture was stirred
[a]D20 244 (CH2Cl2, c = 1.1); mp = (EtOAc, cyclohexane).
IR (cm-1): n = 3416, 3058, 2984, 1706, 1644.
Synthesis 2000, No. 8, 1170–1179 ISSN 0039-7881 © Thieme Stuttgart · New York

1176
F. Roussi et al.
FEATURE ARTICLE
1H NMR (CDCl3, 300 MHz): d = 1.02 (t, J = 7.1 Hz, 3H), 1.43 (t, J
= 7.1 Hz, 3H), 3.90 (m, 2H), 4.03 (m, 2H), 4.32 (dt, J = 12.7, 3.3
Hz, 2H), 4.46 (m, 1H), 5.19 (s, 1H), 7.10 (m, 10 H).
13C NMR (CDCl3, 75.43 MHz): d = 13.6, 13.8, 60.6, 62.9, 65.1,
72.6, 73.3, 110.9, 127.0, 131.2, 138.1, 140.1, 161.8, 172.0.
1H), 4.05 (d, J = 8.1 Hz, 1H), 4.42 (dd, J = 11.2, 6.6 Hz, 1H), 7.0
(m, 10H).
13C NMR (CDCl3, 75.43 MHz): d = 47.2, 50.5, 52.4, 65.3, 71.1,
73.1, 128.1, 133.1, 136.2, 149.7, 171.3.
MS (CI, NH3): 353 (MH+).
MS (CI, NH3): 437 (MH+).
calcd. HRMS for C20H21N2O4 : 353.1501. Found : 353.1510.
(2R)-1-(2-Hydroxy-1-phenylethyl)-5-phenyl-1H-pyrazole-3,4-
dicarboxylic Acid Diethyl Ester (9)
9 was obtained quantitatively by air oxidation of compound 8.
[a]D20 1.5 (CH2Cl2, c = 1.1).
(4R,6R,7S,8S)-1-Oxo-4,6,8-triphenyltetrahydropyrazolo[1,2-
c][1,3,4]oxadiazine-7-carboxylic Acid Methyl Ester (13) (Meth-
od B, Silica gel, cyclohexane)
[a]D20 +34 (CH2Cl2, c = 0.96).
IR (cm-1): n = 3424, 1728, 1714.
IR (cm-1): n = 1736, 1700.
1H NMR (CDCl3, 300 MHz): d = 1.06 (t, J = 6.9 Hz, 3H), 1.41 (t, J
= 6.9 Hz, 3H), 3.98 (dd, J = 12.2, 4.1 Hz, 1H), 4.10 (dd, J = 7.4, 6.9
Hz, 2H), 4.44 (dd, J = 7.4, 6.9 Hz, 2H), 4.52 (dd, J = 12.1, 8.9 Hz,
1H), 5.28 (dd, J = 8.9, 4.1 Hz, 1H), 7.22 (m, 10 H).
1H NMR (CDCl3, 300 MHz): d = 3.37 (dd, J = 9.7, 6.8 Hz, 1H), 3.61
(s, 3H), 3.97 (dd, J = 9.8, 3.1 Hz, 1H), 4.16 (dd, J = 11.4, 3.1 Hz,
1H), 4.22 (d, J = 9.7 Hz, 1H), 4.43 (dd, J = 11.4, 9.8 Hz, 1H), 5.61
(d, J = 6.8 Hz, 1H), 7.3 (m, 15H).
13C NMR (CDCl3, 75.43 MHz): d = 13.8, 14.1, 60.7, 61.7, 64.9,
65.4, 125.4, 126.8, 127.7, 129.9, 133.3, 136.7, 148.8, 162.5.
13C NMR (CDCl3, 75.43 MHz): d = 52.4, 61.1, 62.1, 65.2, 69.9,
73.9, 128.3, 133.7, 135.8, 141.0, 150.1, 170.8.
MS (CI, NH3): 409 (MH+).
MS (CI, NH3): 429 (MH+).
calcd. HRMS for C26H25N2O4 : 429.1814. Found : 429.1811.
(4R,6R,7S,8R)-1-Oxo-4,6-diphenyltetrahydropyrazolo[1,2-
c][1,3,4]oxadiazine-7,8-dicarboxylic Acid Dimethyl Ester (10)
(Method B, Silica gel, cyclohexane/EtOAc 9:1).
[a]D20 -142 (CHCl3, c = 1.1); mp = 178-180 °C (EtOAc, cyclohex-
ane).
(4R,6R,8S)-4,6,8-Triphenyltetrahydropyrazolo[1,2-c][1,3,4]
oxadiazin-1-one (14) (method B, Silica gel, cyclohexane/EtOAc
8:2)
diastereomers were not separated
IR (cm-1): n = 1763, 1746, 1698.
IR (cm-1): n = 1693.
1H NMR (CDCl3, 300 MHz): d = 3.05 (s, 3H), 3.44 (s, 3H), 3.47 (dd,
J = 11.3, 8.8 Hz, 1H), 3.74 (dd, J = 10.0, 2.4 Hz, 1H), 4.13 (t, J =
10.2 Hz, 1H), 4.20 (dd, J = 10.5, 2.4 Hz, 1H), 4.59 (d, J = 11.3 Hz,
1H), 5.08 (d, J = 8.8 Hz, 1H), 7.0 (m, 10 H).
1H NMR (CDCl3, 300 MHz): d = 2.23 (ddd, J = 13.1, 10.9, 8.0 Hz,
1H), 2.94 (ddd, J = 13.1, 9.2, 6.5 Hz, 1H), 3.86 (m, 2H), 4.10 (dd, J
= 11.3, 3.1 Hz, 1H), 4.39 (dd, J = 11.3, 10.0 Hz, 1H), 5.36 (t, J = 8.5
Hz, 1H), 7.3 (m, 15H).
13C NMR (CDCl3, 75.43 MHz): d = 52.4, 52.9, 53.1, 60.5, 66.1,
70.5, 72.6, 128.3, 131.7, 136.2, 149.7, 167.8, 169.1.
13C NMR (CDCl3, 75.43 MHz): d = 44.6, 59.4, 65.6, 70.2, 73.3,
127.9, 134.0, 137.3, 142.5, 150.5.
MS (CI, NH3): 411 (MH+).
MS (CI, NH3): 371 (MH+).
calcd. HRMS for C22H23N2O6 : 411.1556. Found : 411.1548.
calcd. HRMS for C24H23N2O2 : 371.1759. Found : 371.1763.
(4R,6R,7S,8S)-1-Oxo-4,6-diphenyltetrahydropyrazolo[1,2-
c][1,3,4]oxadiazine-7,8-dicarboxylic Acid Dimethyl Ester (11)
(Method B, Silica gel, cyclohexane/EtOAc 9:1).
[a]D20 -49 (CH2Cl2, c = 1.25); mp = 52-54 °C (EtOAc, cyclohex-
ane).
(4R,6R,8R)-8-Hexyl-4,6-diphenyltetrahydropyrazolo[1,2-
c][1,3,4]oxadiazin-1-one (15) (Method B, Silica gel, cyclohex-
ane)
[a]D20 -29 (CH2Cl2, c = 1.12).
IR (cm-1): n = 1696.
IR (cm-1): n = 1742, 1694, 1640.
1H NMR (CDCl3, 300 MHz): d = 0.90 (t, J = 6.9 Hz, 3H), 1.34 (m,
8H), 1.69 (m, 1H), 1.88 (ddd, J = 13.0, 10.6, 7.6 Hz, 1H), 2.16 (m,
1H), 2.60 (ddd, J = 12.8, 8.5, 6.8 Hz, 1H), 3.71 (dd, J = 10.6, 6.8 Hz,
1H), 3.77 (dd, J = 9.6, 3.0 Hz, 1H), 4.07 (dd, J = 11.2, 3.0 Hz, 1H)
4.30 (dd, J = 11.2, 9.6 Hz, 1H), 4.31 (m, 1H), 6.94 (m, 10H).
13C NMR (CDCl3, 75.43 MHz): d = 14.0, 22.5, 25.3, 29.1, 31.7,
34.7, 40.9, 56.4, 65.0, 69.7, 72.7, 127.3, 128.2, 134.3, 138.0, 150.5.
1H NMR (C6D6, 300 MHz): d = 3.46 (dd, J = 8.4, 6.1 Hz, 1H), 3.66
(s, 3H), 3.86 (s, 3H) 3.95 (dd, J = 9.9, 2.9 Hz, 1H), 4.10 (d, J = 8.4
Hz, 1H), 4.17 (dd, J = 11.5, 2.9 Hz, 1H), 4.46 (t, J = 10.6 Hz, 1H),
5.18 (d, J = 6.1 Hz, 1H), 7.5 (m, 10H).
13C NMR (CDCl3, 75.43 MHz): d = 52.4, 52.6, 54.8, 59.4, 65.0,
70.4, 74.2, 128.1, 133.0, 136.2, 150.2, 169.7, 170.2.
MS (CI, NH3) : 379 (MH+).
MS (CI, NH3): 411 (MH+).
calcd. HRMS for C22H23N2O6 : 411.1556. Found : 411.1578.
(4R,6R,7S,8R)-1-Oxo-4-phenyl-6-pyridin-3-yltetrahydropyra-
zolo[1,2-c][1,3,4]oxadiazine-7,8-dicarboxylic Acid Dimethyl Es-
ter (16) (Method B, Aluminium oxide, cyclohexane/EtOAc 1/1
then CH2Cl2/MeOH, 98/2)
(4R,6R,7S)-1-Oxo-4,6-diphenyltetrahydropyrazolo[1,2-
c][1,3,4]oxadiazine-7-carboxylic Acid Methyl Ester (12) (Meth-
od B, Aluminium oxide, cyclohexane/EtOAc 8:2)
[a]D20 -82 (CHCl3, c = 1.08).
IR (cm-1): n = 1739, 1695.
1H NMR (C6D6, 300 MHz): d = 2.94 (ddd, J = 9.3, 8.1, 6.6 Hz, 1H),
3.13 (s, 3H), 3.47 (dd, J = 10.3, 3.2 Hz, 1H), 3.65 (dd, J = 11.1, 3.2
Hz, 1H), 3.77 (dd, J = 11.2, 9.3 Hz, 1H), 3.97 (dd, J = 11.1, 10.3 Hz,
[a]D20 -96 (CHCl3, c = 1.06), mp = 149-151 °C.
IR (cm-1): n = 3376, 2957, 1744, 1692, 1434, 1359.
1H NMR (CDCl3, 300 MHz): d = 3.57 (s, 3H), 3.64 (dd, J = 11.3,
8.7 Hz, 1H), 3.82 (s, 3H), 4.29 (dd, J = 10.8, 3.0 Hz, 1H), 4.29 (dd,
J = 11.2, 3.0 Hz, 1H), 4.48 (d, J = 11.3 Hz, 1H), 4.51 (t, J = 11.2 Hz,
1H), 5.03 (d, J = 8.7 Hz, 1H) 6.92 (dd, J = 7.9, 4.9 Hz, 1H), 6.95-
Synthesis 2000, No. 8, 1170–1179 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Diastereoselective Cycloadditions of Chiral Non-racemic Azomethine Imines
1177
7.05 (m, 5H), 7.27 (dt, J = 7.9, 1.9 Hz, 1H), 8.15 (s, 1H), 8.20 (d, J
= 3.9 Hz, 1H).
13C NMR (CDCl3, 75.43 MHz): d = 44.4, 59.4, 65.8, 70.1, 70.3,
122.6, 125.4-128.9, 133.3, 135.3, 148.6, 149.7.
13C NMR (CDCl3, 75.43 MHz): d = 52.7, 53.2, 60.4, 66.0, 68.1,
72.3, 122.9, 128.3, 129.2, 131.4, 132.3, 135.5, 148.9, 149.5, 167.4,
169.0.
Oxo-4-phenyl-6-pyridin-2-yltetrahydropyrazolo[1,2-
c][1,3,4]oxadiazine-7,8-dicarboxylic Acid Dimethyl Ester
(Method B, Silica gel, cyclohexane/EtOAc 1/1 then CH2Cl2/
MeOH, 98/2)
MS (CI, NH3): 412 (MH+).
diastereomer (4R,6S,7S,8S) (20a)
Anal. Calcd. for C21H21N3O6 : C 61.31, H 5.11, N 10.22. Found : C
61.37, H 5.08, N 10.08.
[a]D20 -96 (CHCl3, c = 0.90).
IR (cm-1): n = 2953, 2923, 2364, 1749, 1697, 1589, 1468, 1436.
1-Oxo-4-phenyl-6-pyridin-3-yltetrahydropyrazolo[1,2-
c][1,3,4]oxadiazine-7,8-dicarboxylic Acid Dimethyl Ester (17)
(Method B, Silica gel, cyclohexane/EtOAc 1/1 then CH2Cl2/
MeOH, 99/1)
1H NMR (CDCl3, 300 MHz): d = 3.36 (s, 3H), 3.44 (dd, J = 9.9, 3.1
Hz, 1H), 3.87 (s, 3H), 3.93 (dd, J = 8.6, 7.2 Hz, 1H), 4.05 (dd, J =
11.0, 3.1 Hz, 1H), 4.29 (dd, J = 11.0, 9.9 Hz, 1H), 4.61 (d, J = 7.2
Hz, 1H), 5.65 (d, J = 8.7 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 7.16-
7.27 (m, 3H), 7.33-7.40 (m, 3H), 7.58 (td, J = 7.7, 1.8 Hz, 1H), 8.6
(d, J = 3.9 Hz, 1H).
13C NMR (CDCl3, 75.43 MHz): d = 51.1, 52.1, 53.0, 53.8, 59.5,
66.2, 71.1, 123.2, 124.6, 128.0, 129.1, 133.9, 136.0, 150.0, 153.9,
171.2.
major diastereomer (4R,6R,7S,8S)
[a]D20 -44 (MeOH, c = 1.36).
IR (cm-1): n = 3447, 2955, 1742, 1698, 1467, 1434, 1306.
1H NMR (CDCl3, 300 MHz): d = 3.37 (dd, J = 8.9, 6.2 Hz, 1H), 3.61
(s, 3H), 3.82 (s, 3H), 3.94 (dd, J = 10.2, 3.0 Hz, 1H), 4.12 (d, J = 9.0
Hz, 1H), 4.14 (dd, J = 10.3, 3.0 Hz, 1H), 4.44 (dd, J = 10.2, 10.4 Hz,
1H), 5.17 (d, J = 6.2 Hz, 1H), 6.90 (m 1H), 6.96-7.07 (m, 5H), 7.38
(m, 1H), 8.20 (br s, 1H).
13C NMR (CDCl3, 75.43 MHz): d = 52.7, 52.9, 54.8, 59.5, 65.6, 70.,
72.0, 122.9, 128.3, 129.2, 131.4, 132.4, 135.5, 149.1, 149.4, 165.5,
173.7.
MS (CI, NH3): 412 (MH+).
diastereomer (4R,6S,7S,8S) (20c)
[a]D20 -50 (CHCl3, c = 1.06).
IR (cm-1): n = 2955, 2923, 2852, 1741, 1698, 1591, 1467, 1434.
1H NMR (CDCl3, 300 MHz): d = 3.69 (s, 3H), 3.80 (s, 3H), 3.90 (dd,
J = 7.5, 5.5 Hz, 1H), 4.06 (dd, J = 10.3, 3.0 Hz, 1H), 4.19 (dd, J =
11.1, 3.0 Hz, 1H), 4.35 (d, J = 7.5 Hz, 1H), 4.48 (dd, J = 11.1, 10.3
Hz, 1H), 5.26 (d, J = 5.5 Hz, 1H), 6.90-6.98 (m, 2H), 7.00-7.11 (m,
4H), 7.26 (m, 2H), 8.30 (d, J = 5.5 Hz, 1H).
13C NMR (CDCl3, 75.43 MHz): d = 52.7, 53.0, 60.2, 65.5, 71.4,
74.2, 122.7, 123.5, 128.3, 128.7, 135.8, 149.1, 155.6, 169.3, 170.3.
MS (CI, NH3): 412 (MH+).
MS (CI, NH3): 412 (MH+).
minor isomer (4R,6R,7R,8R)
1H NMR (CDCl3, 300 MHz): d = 3.32 (s, 3H), 3.33 (dd, J = 7.4, 2.1
Hz, 1H), 3.83 (s, 3H), 4.15 (dd, J = 10.3, 3.0 Hz, 1H), 4.28 (dd, J =
11.0, 3.0 Hz, 1H), 4.48 (d, J = 7.4 Hz, 1H), 4.61 (t, J = 10.8, 1H),
4.98 (d, J = 2.1 Hz, 1H), 6.83-6.95 (m, 1H), 6.96-7.07 (m, 5H),
7.32-7.40 (m, 1H), 8.20 (s, 2H).
13C NMR (CDCl3, 75.43 MHz): d = 52.4, 53.2, 60.7, 66.4, 68.5,
72.0, 122.3, 128.3, 129.2, 130.7, 131.8, 135.5, 149.0, 149.7, 169.3,
170.4.
(4R,6R,7S,8R)-1-Oxo-4-phenyl-6-pyridin-2-yltetrahydropyra-
zolo[1,2-c][1,3,4]oxadiazine-7,8-dicarboxylic Acid Dimethyl Es-
ter (21) (Method B, Aluminium oxide, cyclohexane/EtOAc 1/1
then CH2Cl2/MeOH, 99.5/0.5)
(4R,6R,7R)-1-Oxo-4-phenyl-6-pyridin-3-yltetrahydropyrazo-
lo[1,2-c][1,3,4]oxadiazine-7-carboxylic Acid Methyl Ester (18)
(Method B, Aluminium oxide, cyclohexane/EtOAc 1/1 then
CH2Cl2/MeOH, 98/2)
[a]D20 -131 (CH2Cl2, c = 0.98), mp = 98-100 °C.
IR (cm-1): n = 3427, 2953, 2359, 1744, 1692, 1593, 1468, 1434.
1H NMR (CDCl3, 300 MHz): d = 3.56 (s, 3H), 3.82 (s, 3H), 4.22 (dd,
J = 11.0, 9.0 Hz, 1H), 4.24 (dd, J = 11.0, 2.9 Hz, 1H), 4.30 (dd, J =
10.1, 2.9 Hz, 1H), 4.48 (t, J = 10.3 Hz, 1H), 4.56 (d, J = 11.0 Hz,
1H), 5.04 (d, J = 9.0 Hz, 1H), 6.43 (d, J = 7.8 Hz, 1H), 6.90-7.10
(m, 7H), 8.60 (d, J = 4.6 Hz, 1H).
13C NMR (CDCl3, 75.43 MHz): d = 50.9, 52.4, 53.0, 60.2, 65.9,
70.7, 72.4, 122.5, 124.8, 128.1, 128.6, 132.3, 135.8, 149.4, 154.5,
167.9, 169.6.
[a]D20 -73 (CH2Cl2, c = 1.2).
IR (cm-1): n = 3445, 2954, 1737, 1692, 1469.
1H NMR (CDCl3, 300 MHz): d = 3.30 (td, J = 9.2, 7.2 Hz, 1H), 3.64
(s, 3H), 3.99 (dd, J = 10.3, 3.2 Hz, 1H), 4.04 (dd, J = 11.2, 9.2 Hz,
1H), 4.18 (dd, J = 11.0, 3.2 Hz, 1H), 4.20 (d, J = 9.2 Hz, 1H), 4.26
(dd, J = 11.2, 7.2 Hz, 1H), 4.40 (dd, J = 11.0, 10.3 Hz, 1H), 6.92 (dd,
J = 4.8, 7.7 Hz, 1H), 6.95-7.10 (m, 5H), 7.34 (dt, J = 7.9, 1.9 Hz,
1H), 8.23 (dd, J = 4.8, 1.9 Hz, 1H), 8.24 (s, 1H).
13C NMR (CDCl3, 75.43 MHz): d = 47.0, 50.2, 52.5, 65.7, 70.9,
71.1, 122.7, 128.3, 128.8, 132.5, 133.2, 135.2, 148.8, 149.3, 170.5.
MS (CI, NH3): 354 (MH+).
MS (CI, NH3): 412 (MH+).
Anal. Calcd. for C21H21N3O6, 1/2 H2O : C 59.99, H 5.27, N 9.99.
Found : C 60.05, H 5.24, N 9.99.
(1R,3S,7R)-Phenyl-1,3-dipyridin-2-yldihydro-2,5-dioxa-3a,7a-
diazainden-4-one (22) (Method B, Silica gel, cyclohexane/
EtOAc 1/1 then CH2Cl2/MeOH, 98/2)
4,8-Diphenyl-6-pyridin-3-yltetrahydropyrazolo[1,2-c][1,3,4]
oxadiazin-1-one (19) (Method B, Silica gel, cyclohexane/EtOAc
1/1 then CH2Cl2/MeOH, 98/2)
[a]D20 = 21 (CH2Cl2, c = 1.20).
major diastereomer (4R,6R,8S)
IR (cm-1): n = 3388, 3061, 2923, 2851, 2360, 2343, 1702, 1591,
1508, 1458, 1437.
1H NMR (CDCl3, 300 MHz): d = 4.17 (dd, J = 10.0, 3.3 Hz, 1H),
4.28 (dd, J = 11.2, 3.3 Hz, 1H), 4.44 (dd, J = 11.2, 10.0 Hz, 1H),
5.28 (s, 1H), 6.73 (s, 1H), 6.91-7.14 (m, 4H), 7.20-7.50 (m, 5H),
7.70-7.86 (m, 2H), 8.09 (d, J = 4.5 Hz, 1H), 8.70 (d, J = 4.5 Hz,
1H).
1H NMR (CDCl3, 300 MHz): d = 2.18 (ddd, J = 13.0, 10.9, 8.1 Hz,
1H), 3.00 (ddd, J = 13.0, 8.9, 6.8 Hz, 1H), 3.87 (m, 2H), 4.16 (dd, J
= 11.3, 2.9 Hz, 1H), 4.46 (t, J = 10.8 Hz, 1H), 5.38 (t, J = 8.5 Hz,
1H), 6.80 (dd, J = 7.4, 4.7 Hz, 1H), 6.95-7.10 (m, 5H), 7.26-7.44
(m, 5H), 7.52 (d, J = 7.4 Hz, 1H), 8.13 (d, J = 3.2 Hz, 1H), 8.23 (s,
1H).
Synthesis 2000, No. 8, 1170–1179 ISSN 0039-7881 © Thieme Stuttgart · New York

1178
F. Roussi et al.
FEATURE ARTICLE
13C NMR (CDCl3, 75.43 MHz): d = 61.5, 70.5, 88.7, 99.7, 121.7,
123.3, 124.1, 127.9, 128.4, 132.3, 135.8, 136.9, 148.1, 149.7, 153.4,
156.1.
11.4, 3.2 Hz, 1H), 4.30 (dd, J = 11.4, 10.2 Hz, 1H), 5.19 (m, 1H),
7.35 (10 H).
13C NMR (CDCl3, 75.43 MHz): d = 13.8, 18.7, 34.6, 40.5, 58.8,
64.9, 69.3, 70.5, 127.4, 136.1, 142.7, 149.2.
MS (CI, NH3): 375 (MH+).
MS (CI, NH3) : 337 (MH+).
(4R,6S,7S,8R)-1-Oxo-4-phenyl-6-propyltetrahydropyrazolo
[1,2-c][1,3,4]oxadiazine-7,8-dicarboxylic Acid Dimethyl Ester
(23) (Method B or C, Silica gel, cyclohexane/EtOAc 8/2 then
CH2Cl2/MeOH, 98/2)
1-Oxo-4-phenyl-6-propyltetrahydropyrazolo[1,2-c][1,3,4]oxa-
diazine-7,8-dicarboxylic Acid Dimethyl Ester (31) (Method C,
Silica gel, cyclohexane/EtOAc 9/1)
[a]D20 -144 (CHCl3, c = 1.0).
major diastereomer (4R,6S,7R,8S)
IR (cm-1): n = 1737, 1693.
1H NMR (CDCl3, 300 MHz): d = 0.47 (t, J = 6.9 Hz, 3H), 1.04 (m,
4H), 3.23 (m, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 3.91 (dd, J = 10.3, 3.2
Hz, 1H), 4.17 (dd, J = 11.2, 3.2 Hz, 1H), 4.42 (dd, J = 11.2, 10.3 Hz,
1H), 5.16 (d, J = 4.7 Hz, 1H), 7.45 (m, 5H).
1H NMR (CDCl3, 300 MHz): d = 0.47 (t, J = 7.1 Hz, 3H), 0.57 (m,
1H), 0.98 (m, 3H), 3.35 (dd, J = 11.2, 8.9 Hz, 1H), 3.56 (ddd, J =
11.2, 6.1, 2.6 Hz, 1H), 3.71 (s, 3H), 3.74 (s, 3H), 4.18 (dd, J = 10.6,
3.2 Hz, 1H), 4.26 (dd, J = 11.1, 3.2 Hz, 1H), 4.49 (t, J = 10.8 Hz,
1H), 4.79 (d, J = 8.9 Hz, 1H), 7.45 (m, 5H).
13C NMR (CDCl3, 75.43 MHz): d = 13.6, 16.0, 32.1, 48.4, 52.5,
52.7, 60.1, 65.1, 66.2, 72.1, 128.1, 129.1, 133.6, 149.7, 168.8,
169.1.
13C NMR (CDCl3, 75.43 MHz): d = 13.4, 16.8, 33.5, 50.2, 52.8,
52.9, 59.7, 65.6, 70.2, 70.9, 128.1, 129.1, 134.5, 150.1, 169.7,
171.3.
MS (CI, NH3): 377 (MH+).
MS (CI, NH3): 377 (MH+).
Acknowledgement
calcd. HRMS for C24H23N2O2 : 377.1713. Found : 377.1725.
One of us (F. R.) thanks the "Ligue Nationale contre le Cancer" for
a grant. We gratefully thank Dr. A. Chiaroni and Dr. C. Riche for
X-ray structures.
1-Oxo-4-phenyl-6-propyltetrahydropyrazolo[1,2-c][1,3,4]oxa-
diazine-7-carboxylic Acid Methyl Ester (24) (Method B or C,
Aluminium oxide, cyclohexane/EtOAc 8/2 )
major diastereomer (4R,6S,7R).
IR (cm-1): n = 1694.
1H NMR (CDCl3, 300 MHz): d = 0.38 (t, J = 6.9 Hz, 3H), 0.79 (m,
4H), 2.45 (ddd, J = 8.8, 5.9, 4.4 Hz, 1H), 3.11 (m, 1H), 3.24 (s, 3H),
3.36 (m, 1H), 3.51 (dd, J = 10.4, 3.3 Hz, 1H), 3.59 (dd, J = 10.0, 3.3
Hz, 1H), 3.89 (t, J = 10.4 Hz, 1H), 4.44 (dd, J = 10.4, 4.3 Hz, 1H),
7.05 (m, 5H).
13C NMR (CDCl3, 75.43 MHz): d = 13.4, 17.4, 34.7, 46.1, 47.2,
51.5, 64.1, 68.7, 70.5, 127.3, 128.6, 135.7, 150.0, 172.4.
MS (CI, NH3): 319 (MH+).
References and Notes :
(1) Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952,
Stereoselective Synthesis, G. Helmchen, R. W. Hoffmann, J.
Mulzer, E. Schaumann, Eds., Vol. E21c, 2735, Thieme:
Stuttgart, 1995.
W. Oppolzer, Comprehensive Organic Synthesis, B. M. Trost,
I. Fleming, Eds., Vol. 5, 315, Pergamon: Oxford, 1991.
C. P. Dell, J. Chem. Soc. Perkin Trans. 1 1998, 3873.
(2) K. N. Houk, Y. Li, J. D. Evanseck, Angew. Chem. Int. Ed.
Engl. 1992, 31, 682.
K. N. Houk, J. Sims, R. E. Duke Jr., R. W. Strozier, J. K.
Georges, J. Am. Chem. Soc. 1973, 95, 7287.
K. N. Houk, J. Sims, C. R. Watts, L. J. Luskus, J. Am. Chem.
Soc. 1973, 95, 7301.
(1R,3S,7R)-7-Phenyl-1,3-dipropyldihydro-2,5-dioxa-3a,7a-di-
azainden-4-one (25)
Compound 6 (802 mg, 4.51 mmol) and butyraldehyde (1.6 mL,
18.02 mmol) were stirred for 16 h in toluene at 60 °C. The mixture
was concentrated under vacuo to give 25 as an oil (1.34 g, 98 %, d.e.
>95%).
[a]D20 -42 (CH2Cl2, c = 0.95).
IR (cm-1): n = 1698.
1H NMR (CDCl3, 300 MHz): d = 0.61 (t, J = 7.3 Hz, 3H), 0.98 (t, J
= 7.3 Hz, 3H), 1.0 (m, 2H), 1.29 (m, 2H), 1.53 (m, 2H), 1.81 (m,
1H), 1.94 (m, 1H), 3.72 (dd, J = 10.1, 3.2 Hz, 1H), 4.04 (dd, J = 6.2,
2.9 Hz, 1H), 4.17 (dd, J = 11.2, 11.2, 3.3 Hz, 1H), 4.30 (t, J = 11.2
Hz, 1H), 5.54 (dd, J = 6.2, 3.6 Hz, 1H), 7.38 (m, 5H).
(3) S. Kobayashi, S. Komiyama, H. Ishitani, Angew. Chem. Int.
Ed. 1998, 37, 979 and references herein.
(4) K. V. Gothelf, K. A. Jorgensen, Chem. Rev. 1998, 98, 863.
A. Padwa in Comprehensive Organic Synthesis, B. M. Trost,
I. Fleming, Eds., Vol. 4, 1069, Pergamon: Oxford, 1991.
A. Padwa, (Ed.), 1,3-Dipolar Cycloaddition Chemistry,
Wiley: New York, 1984.
(5) H. Dorn, A. Otto, Chem. Ber. 1968, 101, 3287.
H. Dorn, R. Ozegowski, E. Gründemann, J. Prakt. Chem.
1979, 565.
H. Dorn, Tetrahedron Lett. 1985, 26, 5123.
(6) W. Oppolzer, Tetrahedron Lett. 1972, 17, 1707.
W. Oppolzer, Tetrahedron Lett. 1970, 2199.
(7) E. C. Taylor, N. F. Haley, R. J. Clemens, J. Am. Chem. Soc.,
1981, 103, 7743.
13C NMR (CDCl3, 75.43 MHz): d = 13.7, 13.9, 16.6, 17.0, 33.6,
36.1, 61.5, 70.4, 87.6, 97.7, 128.9, 134.6, 150.3.
MS (CI, NH3): 305 (MH+).
E. C. Taylor, R. J. Clemens, H. M. L. Davies, J. Org. Chem.
1983, 48, 4567.
calcd. HRMS for C24H23N2O2 : 305.1865. Found : 305.1875.
E. C. Taylor, H. M. L. Davies, J. Org. Chem. 1984, 49, 4415.
L. N. Jugheim, D. B. Boyd, J. M. Indelicato, C. E. Pasini, D.
A. Preston, W. E. Alborn, Jr., J. Med. Chem. 1991, 34, 1732.
R. Grigg, M. Dowling, M. W. Jordan, V. Sridharan,
Tetrahedron 1987, 43, 5586.
4,8-Diphenyl-6-propyltetrahydropyrazolo[1,2-c][1,3,4]oxadiaz-
in-1-one (26) (Method B, Silica gel, cyclohexane/EtOAc 8/2)
major diastereomer (relative configuration unknown)
1H NMR (CDCl3, 300 MHz): d = 0.57 (t, J = 3.3 Hz, 3H), 0.98 (m,
3H), 1.72 (m, 1H), 1.81 (m, 1H), 2.73 (ddd, J = 15.4, 6.2, 3.0 Hz,
1H), 2.92 (m, 1H), 3.85 (dd, J = 10.2, 3.2 Hz, 1H), 4.10 (dd, J =
R. Huisgen, R. Temme, Eur. J. Org. Chem. 1998, 387.
For (3++ 2) cycloadditions, see also T. Shimizu, Y. Hayashi,
Synthesis 2000, No. 8, 1170–1179 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Diastereoselective Cycloadditions of Chiral Non-racemic Azomethine Imines
1179
M. Miki, K. Teramura, J. Org. Chem. 1987, 52, 2277 and
references herein.
(8) B. Stanovnik, B. Jelen, C. Turk, M. Zlicar, J. Svete, J. Het.
Chem. 1998, 35, 1187.
(11) For similar competitive 1-4 addition in azomethine ylid series,
see : A. S. Anslow, L. M. Harwood, H. Philipps, D. Watkin,
L. F. Wong, Tetrahedron: Asymm. 1991, 2, 1343.
(12) For use of aldehydes as dipolarophile, see : L. M. Harwood, J.
Macro, D. Watkin, C. E. Williams, l. F. Wong, Tetrahedron:
Asymm. 1992, 3, 1127.
J. Svete, A. Preseren, B. Stanovnik, L. Golic, S. Golic-
Grdadolnik, J. Heterocyclic Chem. 1997, 34, 1323.
M. Zlicar, B. Stanovnik, M. Tisler, Tetrahedron 1992, 48,
7965.
(13) G. Bianchi, C. De Micheli, R. Gandolfi, Angew. Chem. Int.
Ed. Engl. 1979, 18, 721.
M. Zlicar, B. Stanovnik, M. Tisler, J. Heterocyclic Chem.
1993, 30, 1209.
(14) For synthetic use of cycloreversion reaction, see : V. V.
Khaus, M. J. Martinelli, Tetrahedron Lett. 1996, 37, 4323.
(9) F. Roussi, M. Bonin, A. Chiaroni, L. Micouin, C. Riche, H.-P.
Husson, Tetrahedron Lett. 1999, 40, 3727.
(10) For preliminary report on the preparation of 6 , see : F. Roussi,
M. Bonin, A. Chiaroni, L. Micouin, C. Riche, H.-P. Husson,
Tetrahedron Lett. 1998, 39, 8081.
Article Identifier:
1437-210X,E;2000,0,08,1170,1179,ftx,en;E03500SS.pdf
Synthesis 2000, No. 8, 1170–1179 ISSN 0039-7881 © Thieme Stuttgart · New York