Synthesis and cycloaddition reactions of new captodative olefins n-substituted 5-alkylidene-1,3-oxazolidine-2,4-diones

Article abstract of DOI:10.3987/com-00-9094

An efficient and straightforward synthesis of the new captodative olefins N-substituted 5-alkylidene-1,3-oxazolidine-2,4-diones (8-10) is described, by a chemoselective oxidative cleavage of the novel exo-2-oxazolidinone dienes (3, 4, and 7), respectively

Full text of DOI:10.3987/com-00-9094

HETEROCYCLES, Vol. 55, No. 3, 2001, pp. 469 - 485, Received, 26th October, 2000
SYNTHESIS AND CYCLOADDITION REACTIONS OF
NEW CAPTODATIVE OLEFINS N-SUBSTITUTED 5-
ALKYLIDENE-1,3-OXAZOLIDINE-2,4-DIONES
Adriana Benavides, Rafael Martínez, Hugo A. Jiménez-Vázquez,
Francisco Delgado, and Joaquin Tamariz*
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas,
I.P.N. Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico. E-mail:
jtamariz@woodward.encb.ipn.mx
Abstract - An efficient and straightforward synthesis of the new captodative olefins
N-substituted 5-alkylidene-1,3-oxazolidine-2,4-diones (8-10) is described, by a
chemoselective oxidative cleavage of the novel exo-2-oxazolidinone dienes (3, 4,
and 7), respectively. A study of the reactivity and selectivity of olefins (8-10), was
carried out in Diels-Alder cycloadditions to cyclic and unsymmetric acyclic olefins.
In all reactions, the corresponding adducts were obtained in high stereo- and
regioselectivity. These results have been rationalized in terms of FMO theory by ab
initio calculations. 1,3-Dipolar additions of nitrones to olefin (8a) were also highly
regioselective, yielding only the C-5 substituted adducts.
In the last decade, an intense effort has been displayed in the synthesis and study of reactivity of outer-ring
1
o-xylylenes. In particular, exo-heterocyclic dienes (1) have been prepared looking for new heteroatom
2
combinations, and by original and more efficient synthetic methods. An interesting class of compounds
3
related to these dienes, which would be considered as heterodienes, are the exo-heterocyclic enones (2).
4
5
Their significant biological activity, natural occurrence, and attractive structure as potential chiral
6
7
synthons, have prompted the development of new and more versatile synthetic strategies. Among them,
the aldol-type condensation of the heterocyclic carbonylic species with the corresponding aldehyde has
8
been widely used for the preparation of these molecules (Scheme 1). The exocyclic enone moiety may be
9
expected to behave not only as a Michael acceptor, but also as a captodative olefin in Diels-Alder and
10
11
12
1,3-dipolar additions.
Recently, we described a highly convergent method to prepare the novel N-substituted exo-2-oxazolidinone
13,14
dienes (3) and (4).
This strategy involved the concept of a tandem interaction between two species
15
bearing both, potential nucleophilic and electrophilic centers, by using α-diketones (5) and isocyanates
(6) (Scheme 2). These dienes proved to be very reactive, regio- and stereoselective in Diels-Alder
14
cycloadditions. A synthetic application of some of the corresponding adducts resulted in a new method
16
for the preparation of the carbazole skeleton.

Y
Y
Y
O
X
Z
X
Z
X
Z
+
(-)
H
R
O
R
O
1
2
Scheme 1
In order to devise an efficient and versatile synthetic methodology for the preparation of exo-heterocyclic
enones (8-10), dienes (3, 4, and 7) might be suitable substrates, inasmuch as the enamide-like C-4
17
methylene could be transformed into a carbonyl group by an efficient oxidizing agent (Scheme 2).
O
O
2
3
R'
R'
O
O
1
N
O
N
O
+
4
R'-NCO
5
R
O
R
Ha
R
6
6
7
Hb
5a, R = H
5b, R = Me
5c, R = Et
8, R = H
9, R = Me
10, R = Et
3, R = H
4, R = Me
7, R = Et
Scheme 2
Herein, we describe the preparation of the new N-substituted 5-alkylidene-1,3-oxazolidine-2,4-diones (8-9)
by selective C-4 methylene cleavage of dienes (3) and (4). The behavior of these compounds as captodative
olefins in Diels-Alder and 1,3-dipolar cycloadditions, with cyclic and unsymmetric non-cyclic dienes, and
nitrones, respectively, is also reported. In order to synthesize diones (10), it has been necessary to prepare
the novel (5Z)-4-methylene-5-propenylene-2-oxazolidinones (7). We disclose MO calculations as well,
which rationalize the regioselectivity observed in the [4+2] addition processes.
RESULTS AND DISCUSSION
Diones (8-10) were readily available by oxidation of dienes (3, 4, and 7) with m-chloroperbenzoic acid
(MCPBA) in methylene chloride at room temperature for 3 h (Table 1). The conversion was almost
1
complete, since the analysis ( H NMR and MS spectrometries) of the crude reaction mixtures did not reveal
any further product. The modest yields of compounds (8-10) are mainly due to their decomposition under
column chromatography with silica gel. The latter had to be impregnated with methanol in order to
1
minimize decomposition of the dione. The chemoselectivity was confirmed by H NMR spectra, because
the methyl or ethyl groups remained in the double bond.
Dienes (7a) and (7b) were prepared in fair yields, following the general procedure for the preparation of
dienes (4), by using 2,3-hexanedione (5c) as the starting α-diketone. As in the case of dienes (3) and (4),
1
the H NMR spectral analysis of the crude mixtures of dienes (7) did not give evidence of the presence of
any other isomer.

This selective oxidation reflects a high difference in reactivity among the exocyclic double bonds of the
dienes. This is probably due to the higher polarizability of the nitrogen lone pair, as seems to be the case for
14
Diels-Alder additions, and for Michael conjugate additions.
18
In general, olefins are readily epoxidized with MCPBA, and the mechanism seems to be concerted and
19 20
stereospecific. However, the oxidative cleavage of the olefin by this reagent is not common, unless the
double bond is strongly activated by electron-donor groups, and the peracid is used in excess, to give the
21
corresponding carbonyl products. As many other oxidizing methods, the cleavage may give rise either to
22
the aldehyde or to the acid. In the case of the enamidic double bond of dienes (3, 4, and 7), the reaction
23
would lead to the carbonylic compounds (8-10), and, on the other side, to the oxidized formyl fragment.
Table 1. Reaction Conditions and Yields in the
a
Preparation of Oxazolidindiones (8-10).
O
O
2
3
N
4
R'
R'
1
N
O
O
MCPBA
5
25 °C, 3 h
R
O
R
6
3, R = H
4, R = Me
7, R = Et
8, R = H
9, R = Me
10, R = Et
b
Diene
R'
Dione mp (°C) Yield (%)
3a
3b
3c
4a
4b
7a
7b
Ph
8a
8b
108-109
131-132
90-91
25
53
41
58
69
69
76
p-ClC H
6
4
p-MeC H
6
8c
4
Ph
9a
112-113
122-123
105-106
113-114
p-ClC H
6
9b
4
Ph
10a
10b
p-ClC H
6
4
a
b
CH Cl as the solvent, with MCPBA (1.5 mol eq).
2
2
After column chromatography and recrystallization.
Since the formyl fragment was not unambiguously detected, neither as formaldehyde nor formic acid, we
decided to carry out the same experiment with a cyclic diene, in order to isolate both oxidized fragments of
the olefin. Diene (12) was prepared in low yield (18%) by the tandem condensation of 1,2-
cyclohexanedione (11) with phenyl isocyanate (6a) in the presence of triethylamine and lithium carbonate
(25 °C, 12 h) (Scheme 3). Treatment of 12 with MCPBA provided aldehyde (13) in 36% yield. Neither the
acid nor other isomeric products were detected in the crude reaction mixture.
Oxazolidine-2,4-diones (8-10) were evaluated in terms of reactivity and selectivity towards cyclic and
unsymmetrical acyclic dienes in Diels-Alder reactions. Thus, diones (8a) and (8b) reacted with a large
excess of isoprene (14) under thermal (190 °C) conditions (Table 2), to give mixtures of regioisomers
(15a/16a) and (15b/16b), respectively, in comparable ratios (Scheme 4).

O
O
O
O
Ph
Ph
N
O
N
O
Et3N
MCPBA
CH2Cl2
+
Ph-NCO
Li2CO3
18%
O
25 °C, 12 h
36%
O
H
11
6a
12
13
Scheme 3
Similar results were obtained under sonication for both olefins (Entries 3 and 4), giving the major para
(1,4-) isomer (15), but olefin (8b) was slightly less selective. In contrast, substituted olefins (9a) and (10a)
were not reactive enough toward the addition of 14 neither under these conditions nor under Lewis acid
catalysis. Likely, the presence of the alkyl group deactivates the double bond, as we have observed with
24
several β-substituted captodative olefins.
a
Table 2. Diels-Alder Cycloadditions of Olefins (8a) and (8b) with Dienes (14, 17, and 19).
b
c
d
Entry
Olefin
Diene
Solvent T (°C) t (h)
Products (ratio)
Yield (%)
1
2
8a
8b
8a
8b
8a
8a
14
14
14
14
17
19
xylene
xylene
---
190
190
65
198
216
168
216
120
72
15a/16a (75:25)
15b/16b (77:23)
15a/16a (80:20)
15b/16b (75:25)
18
89
93
96
97
53
73
e
3
e
4
---
65
5
xylene
---
160
65
e
6
20/21 (100:0)
a
b
All under N atmosphere, and in the presence of 1-2% hydroquinone. 20 Mol equiv with diene
2
(14) under thermal, and 38 mol equiv with diene (14) under sonication; 2 mol equiv with diene (17),
c
1
d
and 19 mol equiv with diene (19). Calculated by H NMR from the crude reaction mixtures.
Corresponding to the isomeric mixture after column chromatography and recrystallization.
Reactions carried out without solvent, in a sonicated water-bath.
e
Ar
Ar
O
O
N
N
O
O
O
O
+
O
Ph
Ar = Ph
Ar = p-ClC6H4
15a
15b
16a
16b
O
14
N
Ar
N
O
O
O
OSiMe3
O
17
O
O
8a, Ar = Ph
8b, Ar = p-ClC6H4
18
O
Ph
N
O
19
O
N
O
O
Ph
20
21
Scheme 4

An increase in regioselectivity was observed when the 2-substituted diene (17), which is bearing a stronger
electron-donor group, was used; hence the para adduct was exclusively obtained, and isolated as its
hydrolyzed product (18) (Scheme 4). The hydrolysis took place under column chromatography with silica
gel. Olefin (8a) underwent a highly stereoselective addition towards cyclopentadiene (19) by means of
sonication to give the bicyclic exo-adduct (20) in good yield; no endo-adduct (21) was detected.
The structures of the major isomers (15a, 15b, and 20) were characterized by spectroscopy, and the crystal
25
structure of 15a was determined by X-Ray diffraction (Figure 1). Adducts (15a) and (20) were also
hydrolyzed (NaOH, EtOH, 25 °C, 2 h) to their corresponding α-hydroxy N-benzamides (22) and (23) with
the goal of facilitating their characterization. The exo configuration of compound (20) and its derivative
1
(23) was assigned in agreement with H NMR spectroscopic arguments. Thus, the spectra of both
compounds exhibit the vicinal proton syn to the amide carbonyl group, H-3x, shifted down-field with
respect to proton H-3n. This deshielding effect produced by the carbonyl group upon the syn H-3 proton is
26
characteristic of the skeleton of norbornene derivatives. This stereochemistry was also supported by low-
27
resolution X-Ray diffraction data of a monocrystal of benzamide (23). For the spiro ketone (18), its
1
13
symmetrical structure was easily recognized in the H and C NMR spectra.
Figure 1. ORTEP Structure of 15a.
Hs
Ha
7
OH
O
O
H
N
6
1
2
Ph
5
Ph
N
H
4
Hx
OH
3
Hn
22
23
We also examined the outcome of 1,3-dipolar cycloadditions of olefin (8a) with nitrones (24a) and (24b), in
12
order to test their regio- and stereoselectivities. Thus, 8a undergoes a smooth cycloaddition to 24a (2.0
mol equiv) on gentle heating (C H , 60 ｡C) for 12 h to give a mixture of the endo/exo stereoisomers
6
6

(25a/26a) in 72:28 ratio (68%) (Scheme 5). Interestingly, a single regioisomer was detected in the crude
reaction mixture, and assigned to the C-5 substituted isoxazolidine. This is in agreement with additions of
28
other captodative olefins to the same nitrone. The same regiochemistry was obtained in carrying the
reaction (C H , 80 °C, 24 h) with the N-benzylnitrone (24b), however, the stereoisomeric ratio 25b/26b
6
6
(57:43) (80%) was lower than that of 24a. The greater motion of the benzyl group of 24b, in comparison
with that of the phenyl group of 24a, may be at the origin of this decrease in selectivity. The relative
configuration of major stereoisomers (25) was attributed in accordance with the endo preference displayed
29 1
by captodative olefins in the addition to nitrones (24). H NMR spectra of adducts (25) and (26) appear to
29
support this attribution, considering the unambiguously established structure of many analogous adducts.
Thus, for 25, the geminal coupling constant for protons H-4 is larger than that of 26; besides, the vicinal
coupling constants of these protons with H-3 are generally smaller for the endo adducts (25), than those of
the exo adducts (26). This behavior is due to differences among these stereiosomers in ring and torsion
angles between the H-3 and H-4 protons, arising from the preferential conformation assumed by the
29,30
isoxazolidine rings when they have an oxygenated function attached to the anomeric carbon C-5;
i.e.
the oxygen of the carbamate function takes the pseudo-axial position, leaving the amide carbonyl group in a
pseudo-equatorial orientation.
OMe
O
O
9
O
Ph
O
4
Ar
R
8
Ph
O
Ar
R
3
Ph
C6H6
N
O
O
N
7
N
5
+
+
+
N
N
N
O
O6
O
O
-
2
R
1
O
8a
24a, R = Ph
24b, R = Bn
25a, R = Ph
25b, R = Bn
26a, R = Ph
26b, R = Bn
Ar = p-OMeC H
6
4
Scheme 5
We have been able to explain satisfactorily the regioselectivity of Diels-Alder cycloadditions of captodative
31
olefins, 27 among them, by FMO theory. Therefore, this model should be useful as well to correlate the
10
energies and coefficients of the frontier molecular orbitals of olefins (8-10) with those of diene (14).
Frontier orbitals of olefins (8-10) were obtained from ab initio RHF calculations. Geometries were fully
32
optimized at the AM1 semiempirical method, and employed as the starting point for optimization using
33
the 3-21G and 6-31G* basis sets. The orbital energies derived from these calculations are summarized in
10
Table 3, and compared to those previously calculated for olefin (27). It appears that the normal electron
34
demand interaction, HOMO-diene/LUMO-dienophile, is largely preferred [3.12 eV (3-21G); 3.66 eV (6-
31G*)] for all the interactions between olefins (8-10). The energies for the LUMO of olefins (9) and (10)
are higher than those of β-unsubstituted olefins (8), at both 3-21G and 6-31G* levels. Consequently, olefins
(8) should be more reactive and selective in [4+2] cycloadditions with diene (14). Indeed, olefins (9) and
(10) did not react with this diene under thermal and catalytic conditions.

Table 3. Ab initio RHF/3-21G, and 6-31G* Frontier Molecular Orbital Energies of Olefins
(8a-8c, 9a-9b, 10a-10b, and 27), and Diene (14).
3-21G
6-31G*
E (eV)
3-21G
E (eV)
6-31G*
E (eV)
Compound
FMO
E (eV)
Compound
10a
FMO
a
a
8a
8a
8b
8b
8c
8c
9a
9a
9b
9b
-10.9570
1.8553
-10.7127
2.2564
-10.4375
2.0810
-10.2365
2.4724
HOMO
LUMO
HOMO
LUMO
10a
a
a
-11.1518
1.6360
-10.8770
2.0613
10b
-10.6188
1.8708
-10.3924
2.2791
HOMO
LUMO
HOMO
LUMO
10b
b
a
-10.9153
1.9034
-10.6718
2.3064
HOMO
LUMO
HOMO
LUMO
-11.0460
2.2417
-11.0123
2.4588
HOMO
LUMO
27
b
27
a
c
-10.4977
2.0749
-10.2762
2.4782
-8.7107
3.5451
-8.6193
3.5337
HOMO
LUMO
14
c
14
a
-10.6833
1.8607
-10.4348
2.2810
HOMO
LUMO
a
b
These values are for the 2NHOMO, since the HOMO does not have any p contribution on the diene π system. Of the most
z
c
stable nonplanar s-trans conformation; see ref. 10. See ref. 10.
Oxazolidine-2,4-diones (8a) and (8b) proved to be as regioselective as the captodative olefin (27)
(para/meta, (1,4-/1,3-) isomers, 75:25) when the addition was carried out with isoprene (14). This behavior
is foreseen from the point of view of coefficients, because the difference between coefficents C and C are
1
2
also similar (Table 4). However, they were less reactive, since olefin (27) adds to 14 at 130 °C for 35 h.
This does not agree with FMO theory, inasmuch as the LUMOs of captodative olefins (8a-8c) are more
stable than the LUMO of olefin (27) (Table 3), thereby they should be more reactive. This unexpected
reactivity seems to be due to an interplay of electronic and steric effects, associated with their distinct
structural features, rather than only to an FMO factor.
Table 4. Ab initio RHF/6-31G* Coefficients (C ) of the Frontier Molecular Orbitals for
i
a
Diones (8a-8b), Olefin (27), and Diene (14).
O
O 4
4
3
Ar
O
Ar
3
N
3
O
2
2
1
O
2
1
1
4 O
14
8a, Ar = Ph
8b, Ar = p-ClC H
27, Ar = p-NO C H
2 6 4
6
4
HOMO
LUMO
b
b
Compound
C
1
C
2
C
3
C
4
ΔC
C
1
C
2
C
3
C
4
ΔC
i
i
c
8a
0.356
0.356
0.337 -0.004 -0.156
0.339 -0.004 -0.156
0.019
0.017
0.003
0.089
0.295 -0.226 -0.298
0.291 -0.219 -0.298
0.294 -0.239 -0.289
0.259 -0.224 -0.231
0.243
0.242
0.280
0.069
0.072
0.055
c
8b
d
27
-0.359 -0.356
0.024
0.168
d
14
0.375 0.252 -0.218 -0.286
0.279 -0.020
a
b
These are the values of the 2p coefficients, the relative 2p ' contributions and their ΔC are analogous.
z
z
i
c
Carbon 1 - carbon 4 for the diene and carbon 1 - carbon 2 for the olefins. These values are for the 2NHOMO,
d
the HOMO does not have any p contribution. See ref. 10.
z

It is noteworthy that the substitution on the N-aryl ring modifies the energy of the LUMOs of these
molecules, suggesting a long-range electronic effect upon the orbital energies of the exocyclic π system.
Thus, the methyl group in the N-phenyl ring destabilises the FMOs in 8c, in comparison with the
unsubstituted enone (8a). On the other hand, the chlorine atom affects the energy of LUMO by stabilizing
it. This is probably due to the inductive effect of the substituent. However, in accord with the experimental
results, these effects would be negligible. A similar observation was done in the cycloaddition of dienes (3)
14
and (4) with several dienophiles. This was explained by the fact that the aryl ring molecular π orbitals
cannot overlap efficiently with the nitrogen lone-pair, because they are almost orthogonal, as shown by X-
14
Ray diffraction of these dienes.
The regioselectivity found for captodative olefins (8a) and (8b) agrees with recent reports describing Diels-
11a
Alder additions of analogous olefins. Interestingly, the exo stereoselectivity shown by 8a appears to be
common for this kind of exocyclic captodative olefins, as displayed by some other olefins with
11a-11c
cyclopentadiene (19), though, to a lesser extent.
In addition, exo/endo ratio seems to be kinetically
11b
controlled.
The high preference for the exo adducts in cycloadditions of 19 with exocyclic captodative
11c
olefins (8) is in sharp contrast with that observed for the acyclic counterparts,
such as 27. In this case,
26
addition to 19 is not stereoselective under similar reaction conditions.
Recently, we have shown that FMO theory was unable to predict the regiochemistry between captodative
35 29
olefins like 27 and dipoles such as nitrile oxides, and nitrones. A successful theoretical approach has
been found in the DFT-HSAB model, which is based on the estimation of the local-global hardnesses in
29b
both π-systems.
The orientation seems to be controlled by a hard-hard interaction between the
unsubstituted terminus of the olefin and the carbon atom center in the dipoles. The hardness of the olefin is
mainly induced by the electron-donor group. Consequently, the regioselectivity observed for dipolarophile
(8a) and nitrones (24a) and (24b) would be rationalized following the same arguments.
In summary, dienes (3, 4, and 7) showed a high chemoselectivity when they were treated with MCPBA.
Thus, the enamide-like moiety of the exocyclic diene suffered selective oxidative fission to yield the new
N-substituted 5-alkylidene-1,3-oxazolidine-2,4-diones (8-10). Highly reactive and selective Diels-Alder
and 1,3-dipolar cycloadditions were undergone by these exocyclic captodative olefins with diverse dienes
and nitrones. These results were consistent with the behavior of analogous captodative olefins. The
regioselectivity of the Diels-Alder additions of alefins (8) with diene (14) was rationalized by FMO theory,
suggesting that their control can be ascribed to the electronic interactions involved during the process.
EXPERIMENTAL
General. Melting points are uncorrected. IR spectra were recorded on a Perkin-Elmer 1600
1
spectrophotometer. NMR spectra were recorded at 270, 300, and 400 MHz for H, and at 67.9, 75.4, and
13
100.0 MHz for C, on a JEOL GSX-270 (270 MHz), Varian Gemini-300 (300 MHz), and JEOL-400 (400
MHz) instruments, using TMS as internal standard. MS spectra (EI) were obtained at 70 eV on a Hewlett-

Packard 5971A spectrometer. X-Ray analyses were collected on a P-4 Siemens diffractometer, using Mo
Kα radiation (graphite crystal monochromator, λ = 0.71073 Å). Microanalyses were performed by M-H-W
Laboratories (Phoenix, AZ). Analytical TLC was carried out using E. Merck silica gel 60 F
coated 0.25
254
plates, visualizing by long- and short-wavelength UV lamp. All air moisture sensitive reactions were
carried out under nitrogen using oven-dried glassware. Dioxane, and xylene were freshly distilled from
sodium, and methylene chloride from calcium hydride, prior to use. Li CO was dried overnight at 120 °C
2
3
before using. Triethylamine was freshly distilled from NaOH. All other reagents were used without further
purification.
General Procedure for the Preparation of N-Substituted (5Z)-4-Methylene-5-propylidene-2-
oxazolidinones (7a and 7b). To a stirred solution of triethylamine (0.71 g, 7.0 mmol) in dry dioxane (2
mL) containing dry Li CO (0.31 g, 4.2 mmol), under an N atmosphere, and at rt, a solution of 2,3-
3
2
2
hexanedione (5c) (0.40 g, 3.5 mmol) in dry dioxane (1 mL) was slowly added. After stirring for 30 min at
the same temperature, a solution of the isocyanate (6) (5.2 mmol) in dry dioxane (2 mL) was added
dropwise, and the mixture was stirred for 12 h at rt. The solution was filtered and the solvent was removed
under vacuum. The residue was purified by column chromatography over silica gel impregnated with
triethylamine (10%) in hexane (hexane/EtOAc, 9:1) to give dienes (7a-7b).
(5Z)-4-Methylene-N-phenyl-5-propylidene-2-oxazolidinone (7a). Using the general procedure with 0.62
g (5.2 mmol) of phenyl isocyanate (6a) gave 0.30 g (40%) of 7a as colorless crystals (CH Cl /hexane, 7:3):
2
2
-
R 0.55 (hexane/EtOAc, 9:1); mp 55-56 °C; IR (KBr) 1773, 1691, 1620, 1495, 1397, 1288, 1206, 1031 cm
f
1 1
; H NMR (270 MHz, CDCl ) δ 1.10 (t, J = 7.5 Hz, 3H, H-9), 2.33 (dt, J = 7.7, 7.5 Hz, 1H, H-8), 4.19 (d,
3
J = 2.9 Hz, 1H, H-6a), 4.59 (d, J = 2.9 Hz, 1H, H-6b), 5.38 (t, J = 7.7 Hz, 1H, H-7), 7.30-7.54 (m, 5H,
13
PhH); C NMR (67.5 MHz, CDCl ) δ 13.7 (C-9), 18.6 (C-8), 81.8 (C-6), 106.0 (C-7), 127.0 (C-11), 128.6
3
+
(C-13), 129.7 (C-12), 133.2 (C-10), 139.2 (C-4), 142.0 (C-5), 151.8 (C-2); MS (70 eV) 215 (M , 4), 170
(2), 156 (2), 118 (59), 104 (8), 91 (11), 77 (96), 55 (63), 51 (100). Anal. Calcd for C H NO : C, 72.54;
13 13
2
H, 6.09; N, 6.51. Found: C, 72.73; H, 6.22; N, 6.48.
(5Z)-N-(p-Chlorophenyl)-4-methylene-5-propylidene-2-oxazolidinone (7b). Using the general procedure
with 0.79 g (5.2 mmol) of p-chlorophenyl isocyanate (6b) gave 0.52 g (60%) of 7b as colorless crystals
(CH Cl /hexane, 7:3): R 0.59 (hexane/EtOAc, 9:1); mp 64-65 ｡C; IR (KBr) 1778, 1686, 1637, 1495, 1402,
2
2
f
-1 1
1299, 1037 cm ; H NMR (300 MHz, CDCl ) δ 1.09 (t, J = 7.5 Hz, 3H, H-9), 2.35 (dt, J = 7.7, 7.5 Hz,
3
1H, H-8), 4.20 (d, J = 3.1 Hz, 1H, H-6a), 4.62 (d, J = 3.1 Hz, 1H, H-6b), 5.40 (t, J = 7.7 Hz, 1H, H-7),
13
7.27-7.35 (m, 2H, ArH), 7.45-7.52 (m, 2H, ArH); C NMR (75.4 MHz, CDCl ) δ 13.6 (C-9), 18.5 (C-8),
3
81.8 (C-6), 106.4 (C-7), 128.3 (C-11), 129.9 (C-12), 131.7 (C-10), 134.4 (C-13), 138.8 (C-4), 141.8 (C-5),
+
152.4 (C-2); MS (70 eV) 249 (M , 8), 204 (6), 152 (76), 138 (10), 125 (14), 111 (84), 90 (20), 75 (100), 63
(30), 55 (40). Anal. Calcd for C H NO Cl: C, 62.53; H, 4.84; N, 5.61. Found: C, 62.70; H, 4.97; N, 5.61.
13 12
2
General Procedure for the Preparation of N-Substituted 5-Alkylidene-1,3-oxazolidine-2,4-diones. 5-
Methylene-N-phenyl-1,3-oxazolidine-2,4-dione (8a). To a stirred solution of 0.831 g (4.82 mmol) of
MCPBA (77% max.) in dry CH Cl (3 mL), under an N atmosphere, 0.60 g (3.2 mmol) of 3a in dry
2
2
2
CH Cl (6 mL) was added dropwise through a cannula at rt. The mixture was stirred at the same
2
2

temperature for 3 h, diluted with CH Cl (20 mL), and washed with a saturated solution of NaHCO (3 x
2
2
3
10 mL), and with cold water until neutral. The organic layer was dried (Na SO ), and the solvent was
2
4
removed under vacuum. The residue was purified by column chromatography on silica gel impregnated
with dry MeOH (15 g, hexane/CH Cl , 9:1) to give 0.152 g (25%) of 8a as colorless crystals. R 0.25
-1 1
2
2
f
(hexane/EtOAc, 8:2); mp 108-109 °C; IR (KBr) 1845, 1753, 1681, 1406, 1277 cm ; H NMR (300 MHz,
13
CDCl ) δ 5.46 (d, J = 3.4 Hz, 1H, H-6), 5.75 (d, J = 3.4 Hz, 1H, H-6), 7.42-7.56 (m, 5H, PhH); C NMR
3
(75.4 MHz, CDCl ) δ 99.4 (C-6), 125.5, 129.3, 129.6, 130.5, 145.2, 150.8 (C-2), 160.1 (C-4); MS (70 eV)
3
+
m/z 189 (M , 60), 119 (100), 91 (31), 77 (5), 64 (14). Anal. Calcd for C H NO : C, 63.49; H, 3.73; N,
10
7
3
7.40. Found: C, 63.21; H, 4.00; N, 7.19.
N-(p-Chlorophenyl)-5-methylene-1,3-oxazolidine-2,4-dione (8b). The same procedure as for 8a was
used, with 0.709 g (3.20 mmol) of 3b to give 0.379 g (53%) of 8b as colorless crystals (hexane/EtOAc,
-1 1
9:1): R 0.48 (hexane/EtOAc, 8:2); mp 131-132 ｡C; IR (KBr) 1810, 1743, 1680, 1496, 1400 cm ; H
f
NMR (300 MHz, CDCl ) δ 5.47 (d, J = 3.5 Hz, 1H, H-6), 5.75 (d, J = 3.5 Hz, 1H, H-6), 7.42-7.52 (m, 4H,
3
13
ArH); C NMR (75.4 MHz, CDCl ) δ 99.5 (C-6), 126.4, 128.9, 129.6, 135.0, 144.8, 150.2 (C-2), 159.6
3
+
+
(C-4); MS (70 eV) m/z 225 (M +2, 22), 223 (M , 65), 153 (100), 125 (29), 90 (25). Anal. Calcd for
C H NO Cl: C, 53.71; H, 2.70; N, 6.26. Found: C, 53.51; H, 2.76; N, 6.39.
10
6
3
5-Methylene-N-(p-tolyl)-1,3-oxazolidine-2,4-dione (8c). The same procedure as for 8a was used, with
0.643 g (3.20 mmol) of 3c to give 0.266 g (41%) of 8c as colorless crystals (hexane/CH Cl , 9:1): R 0.46
2
2
f
-1 1
(hexane/EtOAc, 8:2); mp 90-91 °C; IR (KBr) 1839, 1819, 1739, 1680, 1411 cm ; H NMR (300 MHz,
CDCl ) δ 2.40 (s, 3H, MeAr), 5.44 (d, J = 3.4 Hz, 1H, H-6), 5.73 (d, J = 3.4 Hz, 1H, H-6), 7.27-7.35 (m,
3
13
4H, ArH); C NMR (75.4 MHz, CDCl ) δ 21.2 (CH Ar), 98.9 (C-6), 125.2, 127.7, 130.0, 139.4, 145.2,
3
3
+
150.7 (C-2), 160.1 (C-4); MS (70 eV) m/z 203 (M , 79), 188 (1), 158 (1), 134 (9), 133 (100), 104 (28), 91
(13), 77 (17). Anal. Calcd for C H NO : C, 65.02; H, 4.46; N, 6.89. Found: C, 65.11; H, 4.62; N, 7.06.
11
9
3
(5Z)-5-Ethylidene-N-phenyl-1,3-oxazolidine-2,4-dione (9a). The same procedure as for 8a was used,
with 0.643 g (3.20 mmol) of 4a to give 0.376 g (58%) of 9a as colorless crystals (hexane/EtOAc, 9:1): R
f
-1 1
0.41 (hexane/EtOAc, 8:2); mp 112-113 °C; IR (KBr) 1813, 1746, 1693, 1499, 1399 cm ; H NMR (300
MHz, CDCl ) δ 2.00 (d, J = 7.4 Hz, 3H, CH CH=), 6.23 (q, J = 7.4 Hz, 1H, H-6), 7.41-7.58 (m, 5H, ArH);
3
3
13
C NMR (75.4 MHz, CDCl ) δ 11.2 (CH CH=), 113.8 (C-6), 125.4, 128.9, 129.4, 130.6, 140.3, 151.0 (C-
3
3
+
2), 159.9 (C-4); MS (70 eV) m/z 203 (M , 66), 119 (100), 91 (29), 56 (82). Anal. Calcd for C H NO : C,
11
9
3
65.02; H, 4.46; N, 6.89. Found: C, 65.05; H, 4.55; N, 6.60.
(5Z)-N-(p-Chlorophenyl)-5-ethylidene-1,3-oxazolidine-2,4-dione (9b). The same procedure as for 8a was
used, with 0.753 g (3.40 mmol) of 4b to give 0.523 g (69%) of 9b as colorless crystals (hexane/EtOAc, 9:1):
-1 1
R 0.42 (hexane/EtOAc, 8:2); mp 122-123 °C; IR (KBr) 1822, 1745, 1692, 1500, 1409, 1313 cm ; H
f
NMR (300 MHz, CDCl ) δ 1.99 (d, J = 7.4 Hz, 3H, MeCH=), 6.23 (q, J = 7.4 Hz, 1H, H-6), 7.42-7.50 (m,
3
13
4H, ArH); C NMR (75.4 MHz, CDCl ) δ 11.2 (CH CH=), 114.2 (C-6), 126.4, 129.1, 129.5, 134.6, 140.1,
3
3
+
+
150.5 (C-2), 159.6 (C-4); MS (70 eV) m/z 239 (M +2, 17), 237 (M , 51), 155 (29), 153 (87), 127 (7), 125
(21), 90 (20). Anal. Calcd for C H NO Cl: C, 55.60; H, 3.93; N, 5.89. Found: C, 55.84; H, 3.55; N, 5.78.
11
8
3

(5Z)-N-Phenyl-5-propylidene-1,3-oxazolidine-2,4-dione (10a). The same procedure as for 8a was used,
with 0.688 g (3.20 mmol) of 7a to give 0.479 g (69%) of 10a as a colorless crystalline powder
(hexane/EtOAc, 8:2): R 0.53 (hexane/EtOAc, 8:2); mp 105-106 °C; IR (KBr) 1814, 1739, 1689, 1500,
f
-1 1
1404 cm ; H NMR (300 MHz, CDCl ) δ 1.17 (t, J = 7.6 Hz, 3H, CH ), 2.37-2.50 (m, 2H, CH CH=),
3
3
2
13
6.19 (t, J = 7.9 Hz, 1H, H-6), 7.42-7.56 (m, 5H, PhH); C NMR (75.4 MHz, CDCl ) δ 12.8 (CH ), 19.3
3
3
(CH ), 120.0 (C-6), 125.4, 128.9, 129.4, 130.6, 139.0, 151.0 (C-2), 160.2 (C-4). Anal. Calcd for
2
C H NO : C, 66.35; H, 5.04; N, 6.45. Found: C, 66.24; H, 5.24; N, 6.36.
12 11
3
(5Z)-N-(p-Chlorophenyl)-5-propylidene-1,3-oxazolidine-2,4-dione (10b). The same procedure as for (8a)
was used, with 0.789 g (3.2 mmol) of 7b to give 0.611 g (76%) of 10b as a white powder (hexane/EtOAc,
-1 1
8:2): R 0.38 (hexane/EtOAc, 8:2); mp 113-114 °C; IR (KBr) 1832, 1745, 1697, 1500, 1418 cm ; H RMN
f
(300 MHz, CDCl ) δ 1.17 (t, J = 7.6 Hz, 3H, CH ), 2.37-2.50 (m, 2H, CH CH=), 6.19 (t, J = 7.9 Hz, 1H,
3
3
2
13
H-6), 7.45-7.56 (m, 4H, ArH); C RMN (75.4 MHz, CDCl ) δ 12.8 (CH ), 19.3 (CH ), 120.5 (C-6),
3
3
2
+
+
126.5, 129.2, 129.5, 134.7, 138.8, 150.6 (C-2), 159.8 (C-4); MS (70 eV) m/z 253 (M +2, 16), 251 (M ,
46), 223 (2), 179 (1), 153 (66), 127 (5), 125 (16), 90 (18), 70 (91), 55 (100). Anal. Calcd for
C H NO Cl: C, 57.27; H, 4.00; N, 5.56. Found: C, 57.23; H, 4.06; N, 5.37.
12 10 3
N-Phenyl-5,6-dihydrobenzoxazol-2-one (12). Using the general procedure of preparation of dienes 7, with
0.39 g (3.5 mmol) of 11, and 0.62 g of phenyl isocyanate (6a) gave 0.13 g (18%) of 12 as colorless crystals
(CH Cl /hexane, 1:1); R 0.55 (hexane/EtOAc, 7:3); mp 81-82 °C; IR (KBr) 1779, 1655, 1493, 1408, 1193,
2
2
f
-1 1
1123 cm ; H NMR (300 MHz, CDCl ) δ 2.33-2.51 (m, 4H, H-5, H-6), 4.94-4.98 (m, 1H, H-4), 5.25-5.29
3
13
(m, 1H, H-7), 7.32-7.50 (m, 5H, PhH); C NMR (75.4 MHz, CDCl ) δ 21.2 (C-5), 21.3 (C-6), 95.3 (C-4),
3
96.8 (C-7), 125.2 (C-9), 127.8 (C-11), 129.4 (C-10), 131.9 (C-3a), 133.6 (C-8), 142.7 (C-7a), 155.8 (C-2);
+
MS (70 eV) 213 (M , 9), 157 (3), 130 (4), 119 (78), 93 (100), 78 (11). Anal. Calcd for C H NO : C,
13 11
2
73.22; H, 5.20; N, 6.57. Found: C, 73.09; H, 5.16; N, 6.65.
(5E)-5-(4-Oxobutylidene)-3-phenyl-1,3-oxazolidine-2,4-dione (13). The same procedure as for 8a was
used, with 0.44 g (2.55 mmol) of MCPBA (77% max.), and 0.18 g (0.84 mmol) of 12 in dry CH Cl (2
2
2
mL). The mixture was stirred at rt for 12 h, and the purification by column chromatography on silica gel (6
g, hexane/EtOAc, 99:1) yielded 0.074 g (36%) of 13 as a white powder. R 0.25 (hexane/EtOAc, 7:3); mp
f
-1 1
81-82 ｡C; IR (KBr) 1802, 1730, 1679, 1405, 1185 cm ; H NMR (300 MHz, CDCl ) δ 2.72 (t, J = 7.0 Hz,
3
2H, CH CHO), 3.00-3.05 (dt, J = 8.4, 7.0 Hz, 2H, CH C=), 6.15 (t, J = 8.4 Hz, 1H, H-6), 7.42-7.50 (m,
2
2
13
5H, PhH), 9.79 (s, 1H, CHO); C NMR (75.4 MHz, CDCl ) δ 18.0 (CH C=), 42.6 (CH CHO), 120.8
3
2
2
(CH=), 125.4, 128.9, 129.2, 130.3, 139.0 (C-5), 150.4 (C-2), 160.0 (C-4), 200.0 (CHO); MS (70 eV) m/z
+
245 (M , 60), 216 (32), 190 (10), 126 (25), 119 (100), 91 (43), 70 (62). Anal. Calcd for C H NO : C,
13 11
4
63.67; H, 4.52; N, 5.71. Found: C, 63.61; H, 4.45; N, 5.60.
General Procedure for the Preparation of Adducts (15/16). 8-Methyl-3-phenyl-1-oxa-3-
azaspiro[4.5]dec-7-ene-2,4-dione (15a). 7-Methyl-3-phenyl-1-oxa-3-azaspiro[4.5]dec-7-ene-2,4-dione
(16a). Method A. A mixture of 0.05 g (0.26 mmol) of 8a, 0.34 g (5.0 mmol) of 14, and hydroquinone (3
mg) in dry xylene (1 mL), was placed in a threaded ACE glass pressure tube with a sealed Teflon screw cap,
under an N atmosphere, and in the dark. The mixture was stirred and heated to 190 °C for 198 h. The
2

solvent was removed under vacuum, and the residue was purified by column chromatography on silica gel
(8 g, hexane/EtOAc, 99:1) to give 0.06 g (89%) of a mixture of 15a/16a (75:25). This mixture was
recrystallized (hexane/CH Cl , 2:1) to give 15a as a white crystalline powder.
2
2
Method B. In a threaded ACE glass pressure tube with a sealed Teflon screw cap, under an N atmosphere,
2
and in the dark, a mixture of 0.05 g (0.26 mmol) of 8a, 0.68 g (0.01 mol) of 14, and hydroquinone (3 mg),
was placed in a sonicated water bath, controlling the temperature at 65 °C for 168 h. The excess of 14 was
removed under vacuum, and the residue was purified by column chromatography on silica gel (10 g,
hexane/EtOAc, 99:1) to give 0.065 g (96%) of a mixture of 15a/16a (80:20). This mixture was
recrystallized (hexane/CH Cl , 2:1) to give 15a as a white crystalline powder: R 0.65 (hexane/EtOAc,
2
2
f
-1 1
8:2); mp 119-121 °C; IR (KBr) 1817, 1750, 1500, 1415 cm ; H NMR (300 MHz, CDCl ) δ 1.75 (s, 3H,
3
MeC=), 2.01-2.23 (m, 3H), 2.27-2.47 (m, 2H), 2.70-2.84 (m, 1H), 5.37 (br s, 1H, CH=), 7.32-7.52 (m, 5H,
13
PhH); signals attributed to isomer 16a: 5.57 (br s, CH=); C NMR (75.4 MHz, CDCl ) δ 23.1 (CH C=),
3
3
25.5 (CH ), 28.7 (CH ), 32.3 (CH ), 83.3 (C-5), 115.0 (CH=), 125.4, 128.6, 129.1, 130.9, 133.7
2
2
2
(CH CH=), 153.4 (C-2), 174.5 (C-4). Anal. Calcd for C H NO : C, 70.02; H, 5.88; N, 5.44. Found: C,
3
3
15 15
69.89; H, 6.02; N, 5.55.
3-(p-Chlorophenyl)-8-methyl-1-oxa-3-azaspiro[4.5]dec-7-ene-2,4-dione (15b). 3-(p-Chlorophenyl)-7-
methyl-1-oxa-3-azaspiro[4.5]dec-7-ene-2,4-dione (16b). Method A. The same procedure as for 15a was
used, with 0.05 g (0.22 mmol) of 8b and 0.34 g (5.0 mmol) of 14. The reaction was carried out at 190 °C
for 216 h. Column chromatography on silica gel (8 g, hexane/EtOAc, 99:1) yielded 0.061 g (93%) of a
mixture of 15b/16b (77:23). This mixture was recrystallized (hexane/CH Cl , 2:1), to give 15b as a
2
2
colorless crystalline powder. Method B. The same procedure as for 15a was used, with 0.05 g (0.22 mmol)
of 8b and 0.34 g (5.0 mmol) of 14. The reaction was carried out at 65 °C for 216 h. Column
chromatography on silica gel (8 g, hexane) yielded 0.063 g (96%) of a mixture of 15b/16b (75:25). This
mixture was recrystallized (hexane/CH Cl , 2:1) to give 15b as a colorless crystalline powder: R 0.70
2
2
f
-1 1
(hexane/EtOAc, 8:2); mp 140-141 °C; IR (KBr) 1816, 1753, 1498, 1415 cm ; H NMR (300 MHz, CDCl )
3
δ 1.78 (s, 3H, MeC=), 2.02-2.25 (m, 3H), 2.26-2.45 (m, 2H), 2.67-2.83 (m, 1H), 5.39 (br s, 1H, CH=), 7.35-
13
7.53 (m, 4H, ArH); signals attributed to isomer 16b: 5.58 (br s, CH=); C NMR (75.4 MHz, CDCl ) δ 24.1
3
(CH C=), 26.8 (CH ), 30.0 (CH ), 33.8 (CH ), 84.5 (C-5), 116.0 (CH=), 127.8, 129.8,
3
2
2
2
130.6, 133.8, 134.8, 154.2 (C-2), 174.8 (C-4); signals attributed to isomer 16b: 22.0, 29.3, 37.6, 85.0; MS
+
+
(70 eV) m/z 293 (M +2, 12), 291 (M , 35), 246 (86), 232 (19), 153 (46), 119 (32), 94 (91), 79 (100). Anal.
Calcd for C H NO Cl: C, 61.97; H, 4.85; N, 4.82. Found: C, 61.77; H, 5.13; N, 4.76.
15 14
3
3-Phenyl-1-oxa-3-azaspiro[4.5]decane-2,4,8-trione (18). The same procedure as for 15a (Method A) was
used, with 0.05 g (0.26 mmol) of 8a and 0.074 g (0.52 mmol) of 17. The reaction was carried out at 160 °C
for 120 h. Column chromatography on silica gel (6 g, hexane) yielded 0.036 g (53%) of 18 as a white
crystalline powder: R 0.36 (hexane/EtOAc, 8:2); mp 221-223 °C; IR (KBr) 1821, 1739, 1719, 1498, 1418,
f
-1 1
1193 cm ; H NMR (400 MHz, CDCl ) δ 2.28-2.40 (m, 2H), 2.42-2.53 (m, 2H), 2.57-2.66 (m, 2H), 2.67-
3
13
2.82 (m, 2H), 7.40-7.56 (m, 5H, PhH); C NMR (100 MHz, CDCl ) δ 32.3 (2CH ), 36.0 (2CH ), 82.9 (C-
3
2
2
+
5), 125.4, 129.2, 129.4, 130.6, 153.0 (C-2), 173.2 (C-4), 206.4 (C-8); MS (70 eV) m/z 259 (M , 37), 214

(75), 187 (33), 130 (60), 119 (100), 112 (40), 91 (48). Anal. Calcd for C H NO : C, 64.86; H, 5.05; N,
14 13
4
5.40. Found: C, 64.76; H, 5.16; N, 5.34.
(1R*,2R*,4R*)-4-Phenylspiro[bicyclo[2.2.1]hept-5-ene-2,2'-oxazolidine]-3',5'-dione (20). In a threaded
ACE glass pressure tube with a sealed Teflon screw cap, under an N atmosphere, and in the dark, a
2
mixture of 0.15 g (0.79 mmol) of 8a, 1.0 g (0.015 mol) of 19, and hydroquinone (3 mg), was placed in a
sonicated water bath, controlling the temperature at 65 °C for 72 h. The excess of 19 was removed under
vacuum, and the residue was purified by column chromatography on silica gel (15 g, hexane/EtOAc, 99:1)
to give 0.148 g (73%) of 20 as a white powder: R 0.52 (hexane/EtOAc, 8:2); mp 156-157 °C; IR (KBr)
f
-1 1
1816, 1741, 1415, 1164 cm ; H NMR (270 MHz, CDCl ) δ 1.53-1.72 (m, 2H, H-7s, H-3n), 2.18 (br d, J
3
= 8.9 Hz, 1H, H-7a), 2.42 (dd, J = 12.4, 3.5 Hz, 1H, H-3x), 3.09 (br s, 1H, H-4), 3.22 (br s, 1H, H-1), 6.21
13
(dd, J = 5.5, 3.0 Hz, 1H, H-6), 6.56 (dd,J = 5.5, 3.0 Hz, 1H, H-5), 7.36-7.51 (m, 5H, PhH); C NMR (67.9
MHz, CDCl ) δ 40.3 (C-3), 42.4 (C-4), 48.0 (C-7), 52.0 (C-1), 91.0 (C-2), 125.6, 128.8, 129.3, 131.2, 132.9
3
+
(C-6), 141.0 (C-5), 153.8 (C-5'), 175.5 (C-3'); MS (70 eV) m/z 255 (M , 4), 190 (10), 119 (15), 91 (15), 77
(10), 66 (100). Anal. Calcd for C H NO : C, 70.58; H, 5.13; N, 5.49. Found: C, 70.68; H, 5.00; N, 5.51.
15 13
3
1- Hydroxy-4-methylcyclohex-3-ene-1-carboxylic acid N-phenylamide (22). A solution of 0.23 g (0.89
mmol) of 15a in dry EtOH (2 mL), under an N atmosphere and at rt, was treated with a solution of 0.18 g
2
(4.5 mmol) of NaOH in dry EtOH (0.5 mL). After being stirred for 2 h at rt, and the solvent was removed
under vacuum. The residue was dissolved in CH Cl (20 mL), and the mixture was washed with aqueous
2
2
5% HCl (3 x 20 mL), with saturated solution of NaHCO (3 x 20 mL), and with cold water until neutral.
3
The organic layer was dried (Na SO ), and the solvent was removed under vacuum. The residue was
4
2
purified by column chromatography on silica gel (10 g, hexane/EtOAc, 99:1) to give 0.07 g (34%) of 22 as
a white crystalline powder: R 0.59 (hexane/EtOAc, 7:3); mp 189-191 °C; IR (KBr) 3301, 1649, 1601,
f
-1 1
1555, 1443, 1099 cm ; H NMR (400 MHz, CDCl /DMSO) δ 1.57 (br s, 3H, CH C=), 1.59-1.67 (m, 1H),
3
3
1.65-1.88 (m, 1H), 1.89-2.00 (m, 2H), 2.00-2.17 (m, 1H), 2.53-2.68 (m, 1H), 4.65 (s, 1H, -OH), 5.20 (br s,
1H, H-3), 6.89-6.96 (m, 1H, PhH), 7.12-7.19 (m, 2H, PhH), 7.42-7.48 (m, 2H, PhH), 8.92 (br s, 1H, NH);
13
C NMR (100 MHz, CDCl /DMSO) δ 23.5 (CH ), 26.0 (CH ), 30.7 (CH ), 35.1 (CH ), 73.1 (C-1), 117.4
3
3
2
2
2
+
(C-3), 119.4, 123.8, 128.8, 133.0, 137.9, 175.2 (CON); MS (70 eV) m/z 231 (M , 3), 212 (17), 121 (47), 93
(100), 77 (44). Anal. Calcd for C H NO : C, 72.70; H, 7.41; N, 6.06. Found: C, 72.94; H, 7.21; N, 5.94.
14 17
2
(1R*,2R*,4R*)-2-Hydroxybicyclo[2.2.1]hept-5-ene-2-carboxylic acid N-phenylamide (23). The same
procedure as for 22 was used, with 0.14 g (0.55 mmol) of 20 and 0.18 g (4.5 mmol) of NaOH. The
purification by column chromatography on silica gel yielded 0.044 g (35%) of 23 as a white powder: R
f
-1 1
0.57 (hexane/EtOAc, 7:3); mp 149-150 °C; IR (KBr) 3359, 3306, 1656, 1599, 1540, 1441 cm ; H NMR
(400 MHz, CDCl ) δ 1.15 (dd, J = 12.0, 3.7 Hz, 1H, H-7s), 1.56-1.62 (m, 1H, H-3n), 2.19 (br s, 1H, OH),
3
2.33 (br d, J = 8.8 Hz, 1H, H-3x), 2.64 (dd, J = 12.0, 3.7 Hz, H-7a), 3.02 (br s, 1H, H-4), 3.07 (br s, 1H, H-
1), 6.25 (dd, J = 5.5, 3.0 Hz, 1H, H-6), 6.64 (dd, J = 5.5, 3.0 Hz, 1H, H-5), 7.07-7.14 (m, 1H, PhH), 7.29-
13
7.37 (m, 2H, PhH), 7.56-7.62 (m, 2H, PhH), 8.80 (br s, 1H, NH); C NMR (100 MHz, CDCl ) δ 42.9 (C-
4), 43.4 (C-7), 49.8 (C-3), 53.7 (C-1), 82.5 (C-2), 119.7, 124.1, 129.0, 133.0 (C-6), 137.9, 143.5 (C-5),
3

+
173.6 (CON); MS (70 eV) m/z 229 (M , 1), 201 (2), 163 (4), 118 (15), 93 (100), 77 (38). Anal. Calcd for
C H NO : C, 73.34; H, 6.59; N, 6.11. Found: C, 73.50; H, 6.57; N, 6.20.
14 15
2
(3R*,5R*)-3-(p-Anisyl)-2,8-diphenyl-1,6-dioxa-2,8-diazaspiro[4.4]nonane-7,9-dione (25a). (3S*,5R*)-
3-(p-Anisyl)-2,8-diphenyl-1,6-dioxa-2,8-diazaspiro[4.4]nonane-7,9-dione (26a). A mixture of 0.05 g
(0.26 mmol) of 8a, 0.12 g (0.53 mmol) of 24a, and hydroquinone (3 mg) in dry benzene (1.5 mL), was
placed in a threaded ACE glass pressure tube with a sealed Teflon screw cap, under an N atmosphere, and
2
in the dark. The mixture was stirred and heated to 60 °C for 12 h. The solvent was removed under vacuum,
and the residue was purified by column chromatography on silica gel (8 g, hexane/EtOAc, 99:1) to give
0.075 g (68%) of a mixture of 25a/26a (72:28). This mixture was recrystallized (hexane/CH Cl , 2:1) to
2
2
give 25a as a white crystalline powder: R 0.5 (hexane/EtOAc, 7:3); mp 179-180 °C; IR (KBr) 1826, 1749,
f
-1 1
1501, 1417, 1250, 1170 cm ; H NMR (300 MHz, CDCl ) δ 3.02 (dd, J = 13.8, 8.2 Hz, 1H, H-4β), 3.47
3
(dd, J = 13.8, 8.1 Hz, 1H, H-4α), 3.84 (s, 3H, MeO), 4.68 (dd, J = 8.2, 8.1 Hz, 1H, H-3), 6.91-6.96 (m, 2H,
ArH), 7.10-7.15 (m, 3H, PhH), 7.23-7.29 (m, 2H, PhH), 7.41-7.46 (m, 2H, ArH), 7.47-7.56 (m, 5H, PhH);
13
signals attributed to isomer 26a: 3.25 (dd, J = 12.9, 11.4 Hz, H-4), 4.79 (dd, J = 11.4, 5.9 Hz, H-3);
C
NMR (75.4 MHz, CDCl ) δ 47.6 (C-4), 55.5 (MeO), 71.6 (C-3), 105.3 (C-5), 114.6, 119.8, 125.7, 125.8,
3
128.8, 128.9, 129.0, 129.4, 129.6, 130.7, 148.0, 152.1 (C-7), 160.0, 167.2 (C-9); signals attributed to
+
isomer 26a: 69.3, 118.5, 125.7, 128.7; MS (70 eV) m/z 189 (M -227, 27), 119 (100), 91 (48), 77 (10).
Anal. Calcd for C H N O : C, 69.22; H, 4.84; N, 6.73. Found: C, 69.23; H, 5.03; N, 6.64.
24 20 2 5
(3R*,5R*)-2-Benzyl-3-(p-anisyl)-8-phenyl-1,6-dioxa-2,8-diazaspiro[4.4]nonane-7,9-dione (25b).
(3S*,5R*)-2-Benzyl-3-(p-anisyl)-8-phenyl-1,6-dioxa-2,8-diazaspiro[4.4]nonane-7,9-dione (26b). The
same procedure as for 25a was used, with 0.025 g (0.13 mmol) of 8a and 0.064 g (0.265 mmol) of 24b in
dry benzene (1.0 mL). The reaction was carried out at 80 °C for 24 h. Column chromatography on silica gel
(5 g, hexane) yielded 0.045 g (80%) of a mixture of 25b/26b (57:43) as a white powder. This mixture was
recrystallized (hexane/CH Cl , 2:1) to give 25b as a white crystalline powder: R 0.53 (hexane/EtOAc,
f
2
2
-1 1
7:3); mp 167-168 °C; IR (KBr) 1822, 1745, 1514, 1413, 1248, 1177, 1147 cm ; H NMR (270 MHz,
CDCl ) δ 2.91 (dd, J = 13.7, 9.8 Hz, 1H, H-4β), 3.28 (dd, J = 13.7, 7.6 Hz, 1H, H-4α), 3.82 (s, 3H, MeO),
3
3.90 (d, J = 15.0 Hz, 1H, CH Ph), 4.04-4.30 (m, 2H, H-3, CH Ph), 6.91-6.96 (m, 1H, ArH), 7.23-7.54 (m,
2
2
13
12H, ArH); signals attributed to 26b: 3.15 (dd, J = 12.9, 11.4 Hz, H-4), 3.82 (s, MeO); C NMR (67.9
MHz, CDCl ) δ 47.6 (C-4), 55.4 (MeO), 59.7 (CH Ph), 71.1 (C-3), 105.4 (C-5), 114.4, 125.6, 127.5, 128.3,
3
2
128.4, 128.7, 129.2, 129.4, 129.7, 130.7, 136.7, 152.6 (C-7), 160.1, 167.9 (C-9); signals attributed to 26b:
+
68.5, 127.6, 127.7, 127.8, 129.0, 136.4, 160.0; MS (70 eV) m/z 189 (M -241, 48), 119 (100), 91 (43). Anal.
Calcd for C H N O : C, 69.76; H, 5.15; N, 6.51. Found: C, 69.60; H, 5.14; N, 6.50.
25 22 2 5
X-Ray Structure Determination of Compound 15a. Crystal data: C H NO ; M = 313.34; monoclinic;
18 19
4
space group P2 /c; a = 6.9818(7), b = 10.3225(9), c = 22.655(2) Å; α = 90°, β = 90.961(8)｡, γ= 90｡; V =
1
3
1632.5(3) Å , Z = 4; D = 1.275 mg/m ; No. of reflections collected: 4062, No. of observed reflections:
3
2
2873; R = 0.0441, R = 0.0661; goodness of fit on F = 1.049; largest residual peak = 0.210 e Å .
-3 25
w

ACKNOWLEDGEMENTS
We are grateful to Dr. Gerardo Zepeda for helpful comments. We thank Fernando Labarrios for his help in
spectrometric measurements. J.T. acknowledges DEPI/IPN (Grant 916510) and CONACYT (Grants 1203-
E9203 and 32273-E) for financial support. A.B. thanks CONACYT for a graduate scholarship awarded.
R.M. thanks CGPI/IPN for a scholarship, and Ludwig K. Hellweg Foundation for a scholarship
complement. H.A.J.V. acknowledges support from CONACYT (Grant 3251P).
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14 15
2
P2 /c; unit cell parameters: a, 12.242 (6), b, 8.265 (3), c, 12.309 (4) (Å); α, 90, β, 102.33 (3), γ, 90
1
3
(deg); temp. (°K): 293 (2); Z: 4; D = 1.252 mg/m ; R: 0.1403; GOF: 1.052.
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29a
33. RHF/3-21G calculations were performed using MacSpartan, and at the 6-31G* level with Gaussian
29b
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