Nitroalkylation and nitroalkenylation reactions of γ-lactone enolates. A facile ring switch from polysubstituted γ-lactones to polysubstituted γ-lactams

Article abstract of DOI:10.1016/j.tet.2004.07.084

Michael addition of lithium enolates of γ-butyrolactone 1 and α-methyl-γ-butyrolactone 1′ to (E)-1-nitropropene 2, (E)-β-nitrostyrene 3 and (E)-2-nitro-1-phenylpropene 4 is described. Reactions of the lithium enolate of 1′ with 2 and 4 occurred with high

Full text of DOI:10.1016/j.tet.2004.07.084

Tetrahedron 60 (2004) 11011–11027
Nitroalkylation and nitroalkenylation reactions of g-lactone
enolates. A facile ring switch from polysubstituted g-lactones to
polysubstituted g-lactams
a
a,
b
b
b
C. Forzato,a P. Nitti,a, G. Pitacco, E. Valentin, S. Morganti, E. Rizzato, D. Spinelli,
*
*
C. Dell’Erba,c G. Petrilloc and C. Tavanic
a
`
Dipartimento di Scienze Chimiche, Universita di Trieste, via L. Giorgieri 1, I-34127 Trieste, Italy
`
b
Dipartimento di Chimica Organica ‘A. Mangini’, Universita di Bologna, via San Donato 15, I-40127 Bologna, Italy
c
`
Dipartimento di Chimica e Chimica Industriale, Universita di Genova, Via Dodecaneso 31, I-16146 Genova, Italy
Received 11 June 2004; revised 5 July 2004; accepted 28 July 2004
Available online 7 October 2004
Abstract—Michael addition of lithium enolates of g-butyrolactone 1 and a-methyl-g-butyrolactone 10 to (E)-1-nitropropene 2, (E)-b-
nitrostyrene 3 and (E)-2-nitro-1-phenylpropene 4 is described. Reactions of the lithium enolate of 10 with 2 and 4 occurred with high
diasteroselectivity (80 and 92% d.e., respectively). Reactions of the zinc enolate of 10 with two b-nitroenamines and two methylthio-
substituted 1-amino-2-nitro-1,3-dienes were also examined. Catalytic reduction of the nitroalkylated and nitroalkenylated products allowed
the achievement of functionalized g-lactams and/or cyclic hydroxamic acids.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
whether the position a to the carbonyl group was substituted
or not.
Polyfunctionalized g-lactones are frequently encountered in
the literature,1 owing to the fact that many natural products,
in particular those belonging to the sesquiterpene series,2
contain the g-lactone ring in their structure. Many examples
of a-functionalization and a,a-difunctionalization of g-
lactone rings are present in the literature3 and among them a
new class of anticonvulsant drugs can be mentioned.4 a-
Nitroalkenylation reactions were extensively studied,5 with
the aim of preparing compounds possessing quaternary
stereocentres,6 whereas no examples of nitroalkylation
reactions of g-lactones can be found. On the contrary,
Enders and co-workers7 obtained excellent results in the
diastereo- and enantio-selective Michael additions of
enolates of g-lactams to aliphatic and aromatic nitroolefins.
Seebach and coworkers8 investigated the nitroalkylation
reactions of lithium enolates of other five-membered ring
heterocycles, such as chiral non-racemic 2-t-butyl-1,3-
dioxolan-4-ones, 2-t-butylimidazolidin-4-ones and 2-t-
butyloxazolidin-5-ones, to verify the 1,3 asymmetric
induction on the reaction products. In all cases examined
the diastereoselectivity was high, depending however on
In this paper we describe the nitroalkylation reactions of the
lithium enolates of g-butyrolactone 1 and a-methyl-g-
butyrolactone 10 with a few conjugated nitroolefins, such as
(E)-1-nitropropene 2, (E)-b-nitrostyrene 3 and (E)-2-nitro-
1-phenylpropene 4. Nitroalkenylation reactions have also
been carried out, by reacting the zinc enolate of compound
10 with the b-nitroenamines 59 and 610 as well as with the
12
nitrodienes 7,11,12 and 70 (Fig. 1).
2. Results and discussion
2.1. Nitroalkylation reactions
The butanolides 1 and 10 were enolized with lithium
diisopropylamide in THF at K78 8C to the corresponding
lithium enolates 8 and 80, which reacted with the nitroolefins
2, 3, and 4, to provide the corresponding nitronate salts 9–14
(Scheme 1).
No attempt to isolate the lithium nitronate intermediates 9–
14 was undertaken. Treatment of the crude reaction
mixtures with a weak acid afforded the corresponding
nitroalkylated lactones 15–20. The nitroalkylated lactones
15, 16, 17 and 18, for which R2ZH, were mixtures of syn/
Keywords: Substituted nitroalkenes; Substituted nitroalkadienes; g-Lac-
tams; Cyclic hydroxamic acids.
* Corresponding authors. Tel.: C39-040-5583917; fax: C39-040-
5583903; e-mail: valentin@dsch.univ.trieste.it
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.084

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C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
Figure 1.
anti diastereomers, a and b respectively, owing to the
presence of two adjacent chiral centres, while 19 was a
mixture of four diastereomers and 20 was a mixture of three
diastereomers out of the four possible ones. In order to
evaluate the diastereoselectivity of the reaction, the syn and
anti descriptors were also used for 19 and 20, to indicate the
relative configurations of the two stereocentres of the newly
formed C–C bond.
acids 27–31,16 using 10% Pd/C as the catalyst. The latter
compounds proved better substrates for NOE measure-
ments, which supported the stereochemical assignments
previously made on the lactam derivatives. All resonances
of each compound were identified by means of 2D
correlated experiments.
2.2. Reactions of enolates 8 and 80 with (E)-1-nitro-
propene 2
Since for the nitroalkylated g-lactones 15–20 the syn/anti
stereochemical assignments were not straightforward, a
stereochemical correlation was desirable: therefore, such
lactones were converted into the corresponding trans and cis
lactam derivatives 21–26 to take advantage of the more rigid
polysubstituted lactams to determine the configurations of
the stereocentres. On the other hand, g-lactams themselves
are attractive targets because they possess a variety of
biological activities13 and have been used to produce
g-aminobutyric acid (GABA) analogues by hydrolysis.14
Thus, reduction of the nitro group of compounds 15–20 with
hydrogen on Raney Ni and subsequent cyclization15 of the
corresponding aminoalkyl lactone intermediates, which
were not isolated, afforded the corresponding lactam
derivatives 21–26 (Scheme 1). In this manner, the stereo-
chemical assignments were made on the lactam derivatives
21–26 either by a comparison of their 13C NMR spectra or
by means of NOE measurements. When this latter method
was unsatisfactory, the nitroalkylated g-lactones 15–19
were transformed into the corresponding cyclic hydroxamic
The reaction of lithium enolate 8 with (E)-1-nitropropene 2
led, after acidification with aqueous satd. NH4Cl, to the
formation of two diastereomeric (nitroalkyl)lactones 15a
and 15b in 2:3 ratio, which were separated by flash
chromatography (Scheme 2). They were assigned the syn
and anti configuration, respectively, after transformation
into the corresponding lactams 21a and 21b whose
geometries were demonstrated to be trans and cis,
respectively. In fact the 13C NMR spectrum of 21b showed
an upfield shift for the methyl group with respect to the same
resonance in 21a, thus demonstrating its cis relationship
with the hydroxyethyl chain (Table 1). The same trans/cis
assignment was made for the corresponding cyclic hydro-
xamic acids 27a and 27b that were obtained in admixture
with the corresponding lactams 21a and 21b when the
reduction was performed using Pd on carbon as the catalyst.
Similarly, the reaction between the enolate 80 and 2 afforded
the corresponding nitroalkylated products 16a and 16b in
Scheme 1.

C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
11013
Scheme 2.
1:9 ratio, as determined by HRGC analysis of the crude
reaction mixture. However, since in this case the two
diastereomers were not separable by flash chromatography,
the subsequent reductions of the nitro group were performed
on the mixture. When Raney Ni was used as the catalyst, a
1:9 mixture of the corresponding lactams 22a and 22b was
isolated. They were assigned the (3R*,4R*) and (3R*,4S*)
configurations, respectively, by comparison of their 13C
NMR spectra (Table 1): an upfield shift was always
observed for those carbon atoms which suffered from steric
effects.17 Thus, the methyl group at C-3 resonated at
15.1 ppm in 22a and at 20.5 ppm in 22b, as a consequence
of a less constrained situation in the latter diastereomer.
When the reduction of 16a,b was performed using Pd on
carbon, two cyclic hydroxamic acids, namely 28a and 28b,
were obtained in 1:9 ratio (Scheme 2). The relevant
configurations were assigned on the basis of NOE
measurements performed on the major product 28b, which
was separated in pure form by fractional crystallization.
Irradiation of its methyl singlet at 1.18 ppm enhanced the
signal of H-4 (5%), while irradiation of the a-methylene
hydrogens of the hydroxyethyl chain at 1.74 and 1.50 ppm
produced enhancement of the methyl doublet at 1.04 ppm
(2%). The NOE enhancement values were low, however this
assignment was supported by a comparison of the 13C NMR
spectra of the two isomers, whose significant digits are
reported in Table 1. Again an upfield shift was observed for
those carbon atoms which suffered from steric effects. Thus
the methyl group at C-3 is shifted to higher field in 28a,
being cis to the methyl group at C-4. The same trend was
observed for the a-methylene hydrogens of the hydroxy-
ethyl chain in 28b. As a consequence, the configuration of
the chiral centres in compounds 22a and 28a is (3R*,4R* or
like18) and that of 22b and 28b is (3R*,4S* or unlike18). The
same configurations can be assigned to the corresponding
parent lactones 16a and 16b, whose relative configurations
are therefore syn and anti respectively.
2.3. Reactions of enolates 8 and 80 with (E)-b-nitro-
styrene 3
The reactions between the nitroalkene 3 and the enolates 8

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C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
In a similar manner, the NOE experiments performed on the
diastereomeric cyclic hydroxamic acids 30a and 30b,
allowed the correct syn and anti attributions to the parent
lactones 18a and 18b to be made. Thus, the configuration of
the cyclic hydroxamic acid 30a, derived from 18a, was
proved to be (3R*,4R*) and that of 30b, derived from 18b,
was (3R*,4S*). In fact, upon irradiation of the methyl group
at 1.30 ppm in 30b, the H-4 signal was enhanced (10%). On
the other hand, irradiation of the H-4 signal at 3.63 ppm in
30a caused enhancement of the a-methylene protons of the
chain (5%), while irradiation of the methyl group at
0.74 ppm enhanced the aromatic o-hydrogens (6%). All
these assignments were also supported by a comparison of
the 13C NMR spectra of each pair of diastereomers, as
shown in Table 1.
Scheme 3.
It should be noted that in spite of the fact that the geometries
of the products are the same as those observed for the
products of the reaction between 8 or 80 with 1-nitropro-
pene, the descriptors are different, owing to a different
priority of the groups.
and 80 were poorly diastereoselective, as the former reaction
afforded a ca. 1:1 mixture of diastereomers 17a and 17b
(Scheme 3), and the latter reaction gave a ca. 2:1 mixture of
18a and 18b (Scheme 4). In both cases the diastereomers
could not be completely separated: anyway, for an easier
stereochemical assignment, different mixtures of 17a,b or
18a,b, enriched in either diastereomer, were converted into
the corresponding lactams (23a,b or 24a,b) or cyclic
hydroxamic acids (29a,b or 30a,b).
2.4. Reactions of enolates 8 and 80 with (E)-2-nitro-1-
phenylpropene 4
In the reaction between the enolate 8 and (E)-2-nitro-1-
phenylpropene 4 four diastereomers, namely 19a, 19b, 19c,
and 19d were formed, in 53:22:14:11 relative ratio
(Scheme 5), as determined by HRGC analysis of the crude
reaction mixture. Their separation on chromatographic
column allowed the isolation of all stereoisomers as pure
compounds with the exception of 19c which was isolated in
admixture with 19a. Treatment under basic conditions
(DBU in chloroform) of the pure diastereomer 19a afforded
a 1:1 mixture of 19a and 19b, thus demonstrating that they
differed in the configuration of the nitromethine carbon
atom. The same was proved for compounds 19c and 19d.
The trans and cis stereochemical assignments for the
g-lactams 23a and 23b and for the cyclic hydroxamic
acids 29a and 29b were based on 13C NMR spectra (Table
1). The carbon resonances for the cis diastereomers 23b and
29b were shifted upfield with respect to those for the trans
diastereomers 23a and 29a. Furthermore, NOE measure-
ments carried out on 29a and 29b confirmed the previous
assignments. Irradiation of the H-3 signal at 2.71 ppm in
29a produced enhancement (4%) of the ortho hydrogens of
the phenyl ring, while irradiation of the H-3 signal at
2.95 ppm in 29b enhanced the H-4 signal at 3.64 ppm (5%).
Therefore, since the configuration of 23a and 29a is
(3R*,4S*) and that of 23b and 29b is (3R*,4R*), the relative
configurations of lactones 17a and 17b, from which they are
derived, are syn and anti, respectively.
As above, the stereochemical assignments for 19a and 19b
were made on the corresponding lactam 25a and on the
cyclic hydroxamic acid 31b, respectively. Reduction of 19a
with hydrogen on Raney Ni afforded lactam 25a as a single
Scheme 4.

C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
11015
Scheme 5.
diastereomer, while reduction of 19b using 10% Pd/C as the
catalyst afforded a mixture of lactam 25b and cyclic
hydroxamic acid 31b in the 1:3 ratio. The stereochemistry of
25a was established by means of NOE measurements. In
fact, irradiation of the H-4 signal enhanced the signals of H-
3 (4%) and H-5 (5%). Compound 31b was less soluble than
the corresponding lactam 25b in ethyl acetate and therefore
it could be separated from the mixture in pure state. The
NOE experiment carried out on 31b revealed that the
hydroxyalkyl chain was cis to the phenyl group which in
turn was trans to the methyl group. In fact, irradiation of the
methyl group enhanced the signal of H-4 (6%) as well as
that of H-3 (3%), while irradiation of H-4 enhanced the
signals of H-3 (8%) and that of the methyl group (6%). Its
configuration was therefore (3R*,4R*,5R*) and, accord-
ingly, the relative configuration of 19b was assigned as anti,
anti. Since the stereochemical relationship between 19a and
19b was known from the previous equilibration reaction, the
configuration of 19a must be anti, syn.
of 20a, carried out under basic conditions with DBU at room
temperature, partially converted it into 20b, thus demon-
strating that 20a and 20b differed in the configuration of the
nitromethine carbon atom.
Reduction of a 1:1 mixture of lactones 20a and 20b using
Raney Ni as catalyst furnished a 1:1 mixture of lactams 26a
and 26b. The stereochemistry of lactam 26a was assigned
by means of NOE measurements: irradiation of the
a-methylene hydrogens of the hydroxyethyl chain at
1.90 ppm produced enhancement of the signal of H-4
(5%) as well as that of H-5 (8%) indicating that the
hydroxyalkyl chain was trans to the phenyl group, which in
turn was cis to the methyl group at C-5. Its configuration
was therefore (3R*,4R*,5R*) and that of 26b was
(3R*,4R*,5S*). Accordingly, the relative configuration of
20a was assigned as syn, syn and that of 20b as syn, anti,
both deriving from the same type of attack of the enolate
onto the nitroolefin. The diastereoselective excess of the
reaction, with reference to the syn configuration around the
newly formed C–C bond, was 92%.
The reaction between the enolate 80 and the nitroolefin 4
was somewhat more complicated by the fact that acidifica-
tion of the nitronate salt intermediate 14 (Scheme 1)
required strictly controlled conditions and the use of a weak
acid (see Section 4) in order to obtain the nitroalkylated
lactones 20. When glacial acetic acid in THF was used, a
61:35:4mixture of20a, 20b and 20c was obtained(Scheme 6),
which were isolated by flash chromatography. Equilibration
2.5. Products of the Nef reaction
The nitronate salt intermediates 13 (RZH) and 14 (RZMe)
(Scheme 1) were treated with 3 N HCl,19 with the aim of
obtaining the corresponding Nef products.20 Thus, a 75:25
diastereomeric mixture of 13 furnished 32a (isolated in19%
Scheme 6.

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C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
yield) and 32b in a ca. 3:2 ratio, in admixture with the oxime
34 (isolated in 15% yield), the latter most likely resulting
from the autoxidation–reduction of the not detected nitronic
acid intermediate 36.21 Acidic equilibration of the 3:2
mixture of 32a and 32b changed its composition to 3:1. The
thermodynamically more stable 32a was tentatively
assigned the (3R*,10R*) configuration, by a comparison of
the values of the 3J coupling constants between H-3 and the
benzylic proton in the two isomers: 7.7 and 5.1 Hz for 32a
and 32b, respectively.22 In the 13C NMR spectra, the only
significant difference between the two diastereomers was
the resonance value of C-3, 42.8 ppm for 32b and 41.3 ppm
for 32a, suggesting a slightly more crowded situation for the
latter compound.
compounds 16, for which the anti diastereomer largely
prevailed, and for compound 20, for which the syn
diastereomer was formed almost exclusively.
Formation of the syn and anti diastereomers would involve a
different topological approach of the donor and acceptor.23
Thus the Re*,Re* (like) approach of the enolate to the
nitroolefin would lead to the syn products, while the Re*,Si*
(unlike) one would give the anti products. It appears that the
unlike approach was slightly preferred over the like one
when the lactone enolate was unsubstituted (RZH) (entries
1, 3, 5). When R was methyl (entries 2, 4, 6) the reactions
showed the opposite diastereoselection, with the exception
of the reaction of 1-nitropropene. The following simplified
model transition states A and B (Fig. 3), in which the
pyramidalization of the reacting carbon atoms is ignored as
are the role of the solvent and the state of aggregation of the
lithium enolates,24 would account for the different selectiv-
ity observed. When R and R2 are hydrogens no remarkable
differences in the transition states exist, and the resulting
products syn and anti 15 and syn and anti 17 are formed in
almost equal amount. Substitution of a hydrogen for a
methyl group (R2ZMe) slightly disfavours the like
approach of the reactants and in fact compound anti-19
was formed with 50% d.e. When the lactone bears a methyl
group at the a-position, the steric situation seems to be
dominated by the presence of the phenyl group (R1ZPh),
which disfavours the unlike approach and consequently
favours the formation of the syn products (30% d.e. for 18
and 92% d.e. for 20).
From the nitronic salt intermediates 14 (96:4 diastereomeric
ratio) a single Nef product 33 (isolated in 17% yield) and a
single oxime 35 (isolated in 10% yield) were obtained by
the same acid treatment as above.
Remarkably, when acidification of the crude reaction
mixture was performed with a saturated solution of
ammonium chloride, followed by separation of the organic
phase, the subsequent treatment of the mother liquors with
3 N HCl afforded the nitronic acid 37 (isolated in 10%
yield). This latter compound was separated as a white solid,
stable at K20 8C. It must be underlined that reduction of the
nitronic acid 37 with Raney Ni afforded the same lactams
26a and 26b, in the ratio of 7:3, as previously obtained from
20a and 20b, thus demonstrating their stereochemistry. The
relative configuration reported in Figure 2 for the products
of the Nef reaction are correlated with the diastereomeric
values of the nitronate lithium salt formation.
The prevalent formation of compound 16 in anti configur-
ation from 1-nitropropene is not in accordance with the
results found for the Michael addition of cyclohexanone
lithium enolate to the same nitroolefin25 which always
afforded the syn-product under several reaction conditions.
Probably this is due to the fact that in our case the presence
of the heterocyclic oxygen atom allows the unlike or endo
orientation of the nitroolefin.
2.6. Mechanism of the nitroalkylation reactions
The results relating to the geometry of the products are
summarized in Table 2 (the syn and anti descriptors are also
used for 19 and 20, to indicate the relative configurations of
the two stereocentres of the newly formed C–C bond). The
diastereoselectivity observed is generally low except for
2.7. Nitroolefination and nitrodienylation reactions
Table 2. Diastereomeric ratios and yields for the nitroalkylated lactones
15–20
The reactivity of lithium enolates of g- and d-lactones
bearing no substituent at a-position with a few b-
nitroenamines has already been reported26 to lead to the
corresponding Nef products20 and not to the desired
nitroolefinated lactones. On the contrary, when the lactone
bears a substituent at the a-position, nitroolefination of the
lithium enolate by b-nitroenamines proceeds diastereo- and
enantio-selectively, as proved by Severin and coworkers.5a,27
An exchange of the counter ion from lithium to zinc had the
Entry
Product
syn/anti
40/60
Yield (%)
1
2
3
4
5
6
15
16
17
18
19
20
70
60
62
80
64
45
10/90
45/55
65/35
25/75
96/4
Figure 2.

C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
11017
Figure 3.
effect of increasing the reactivity and the enantioselectivity
of the reactions when a chiral non-racemic b-nitroenamine
derived from (S)-prolinol was used.28 In particular, when the
zinc enolate29 of lactone 10 reacted with (E)-1-(1-morpho-
linyl)-2-nitroethene and (E)-1-(1-morpholinyl)-2-nitropro-
pene5c the corresponding addition–elimination products in
(E) configuration were obtained.
measurements. Irradiation of the methyl group signal at
1.33 ppm in 40a caused enhancement of the H-5 signal at
4.75 ppm (6%). On the contrary, under the same conditions,
the nitroalkenylated lactones 39 furnished the correspond-
ing oxime 41. Using Raney Ni as the catalyst, both mixtures
38 and 39 afforded the same diastereomeric mixture of
lactams 40a and 40b, as a result of the concomitant
hydrogenolysis of the methylthio group in 39. Reduction
with sodium borohydride was not satisfactory, even using
the reagent supported on Amberlystw A 26, which is known
to reduce regioselectively the carbon–carbon double bond
of the nitrovinyl moiety to the corresponding nitroalkane.31
Herein an analogous reaction has been carried out on the
lithium enolate 80 with the nitroenamines (E)-1-(1-morpho-
linyl)-2-nitro-2-phenylethene 5 and (E)-1-(1-pyrrolidinyl)-
2-nitro-2-[2-(methylthio)phenyl]ethene 6 (Scheme 7). The
corresponding products, 38 and 39, were obtained as 85:15
1
and 65:35 E/Z mixtures, respectively, as determined by H
The same conditions as above were used for the nitroalk-
enylation reaction of the enolate 80 with the dienes 7 and 70
to afford the corresponding addition–elimination products
42 and 43, isolated from the respective reaction mixtures in
52 and 70% yield, the former as the (E,Z) diastereomer, the
latter as the (E) isomer (Scheme 8).
NMR analysis of the crude reaction mixtures. In fact, when
the vinyl proton was cis to the nitro group, it resonated at
lower field (7.75 ppm for 38 and 7.81 ppm for 39) than in
the case it was trans to it (6.43 ppm for 38 and 7.73 ppm for
39).12,30
The E/Z mixtures 38 and 39 were reduced under different
conditions. When Pd on carbon was used as the catalyst,
lactones 38 afforded a 4:1 mixture of cis and trans
diastereomers of lactam derivatives 40a and 40b. Differ-
ently from the cases previously reported for the nitroalky-
lated g-lactones, no traces of the corresponding cyclic
hydroxamic acid derivatives were detected. The geometry
of the lactams 40a and 40b was established by NOE
Interestingly, in deuteriated chloroform, compound 42
slowly equilibrated into a 4:1 mixture of (E,Z) and (Z,Z)-
diastereomers. This equilibration did not occur in the parent
nitrodienamine 70. In the major isomer the H-1 vinyl proton
resonated at 7.24 ppm, while in the minor isomer it absorbed
at 6.29 ppm, values which are consistent with the cis and
trans relationship of the same proton with the nitro group.
DIFNOE measurements supported the Z geometry for the
Scheme 7.

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C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
Scheme 8.
1
C(3)–C(4) double bond, as it was originally in the reagent.
On the contrary, an analogous equilibration between the (E)
and (Z) forms was not observed for compound 43, under the
same conditions.
FT-IR spectrometer. H NMR and 13C NMR spectra were
run on a Jeol EX-400 spectrometer (400 MHz for proton,
100.5 MHz for carbon) and on a Jeol EX-270 (270 MHz for
proton, 67.9 MHz for carbon), using deuteriochloroform as
a solvent and tetramethylsilane as the internal standard.
Coupling constants are given in Hz. Mass spectra were
recorded on a VG 7070 (70 eV) spectrometer and on an ion
trap instrument Finnigan GCQ (70 eV). GLC analyses were
run on a Carlo Erba GC 8000 instrument, the capillary
columns being OV 1701 (25 m!0.32 mm) (carrier gas He,
40 KPa, split 1:50). TLC’s were performed on Polygramw
Sil G/UV254 silica gel pre-coated plastic sheets (eluant: light
petroleum–ethyl acetate). CHN analyses were run on a
Carlo Erba 1106 Elemental Analyser. Flash chromato-
graphy was run on silica gel 230–400 mesh ASTM
(Kieselgel 60, Merck). Light petroleum refers to the fraction
with bp 40–70 8C and ether to diethyl ether. g-Butyro-
lactone 1, a-methyl-g-butyrolactone 10 and (E)-2-nitro-
styrene 3 were purchased from Aldrich. (E)-1-Nitropropene
2,34 (E)-2-nitro-1-phenylpropene 4,35 (E)-1-(2-methylthio-
phenyl)-1-nitro-2-pyrrolidinoethene 6,10 (1E,3Z)-4-
methylthio-2-nitro-1-pyrrolidino-1,3-butadiene 711 and 4,4-
bis(methylthio)-2-nitro-1-pyrrolidino-1,3-butadiene7012 were
prepared according to the literature.
Reductions with hydrogen and metal, as a catalyst, were
unsatisfactory as furnished complex mixtures of products
not identified as yet. Treatment of compound 43 with
polymer-supported borohydride resulted in the reduction of
the sole C(1)–C(2) double bond,31 affording a 3:2 44a,b
diastereomeric mixture which was assigned the structure
indicated in Scheme 8. These compounds however were not
stable in CDCl3 solution and were converted into the fully
conjugated system 45 in (E) configuration. In this manner a
conjugated ketene S,S-acetal was obtained whose reactivity
as a precursor of an acyl anion32 will be further investigated.
3. Conclusions
Differently from the cases of lithium enolates and enamines
from cycloalkanones, for which the Michael addition of
nitroolefins proceeded with high diastereoselectivity,24,33 in
general the lactone lithium enolates 1 and 10 showed low to
moderate diastereoselectivity, with the exception of the case
in which both reactants were substituted by bulky groups.
The stereochemical assignments were made either on the
lactam derivatives or on the cyclic hydroxamic acids formed
by reduction of the nitro group under different reaction
conditions. The reduction with Raney Ni however needed
milder conditions than those reported in the literature for
other heterocyclic nitroalkylated compounds.8b,15
4.1.1. (E)-2-Morpholinyl-1-nitro-1-phenylethene 5.9 The
synthesis was accomplished in accordance with a literature
procedure,36 using phenylnitromethane37 as the nitroalipha-
tic component. Thus phenylnitromethane (0.09 mol,
12.3 ml), triethyl orthoformate (0.1 mol, 17 ml), morpho-
line (0.09 mol, 7.8 ml) and p-toluenesulfonic acid (0.09 g,
0.5 mmol) were heated under reflux for 1 h. Then the
solvent was evaporated, the residue diluted with dichloro-
methane and purified through an alumina column (30!
2.5 cm) using dichloromethane as eluting agent. Although
the crude reaction mixture contained both diastereomers,
the nitroenamine 5 was isolated as pure E-isomer and
crystallized from ethanol. 21% Yield, mp 150–152 8C, [lit.9
The nitroolefination reaction proceeded smoothly and
quantitatively on the zinc enolates of 10 and afforded new
a,b-unsaturated nitroderivatives in E and Z configurations,
the percentage of the latter increasing with the size of the
substituent on the carbon bearing the nitro group.
for a 1:1 mixture of E- and Z-isomers, mp 125 8C]; IR (cmK1
,
nujol): 3056 (]CH), 1626, 1592, 1573, 785, 772, 725, 696
4. Experimental
4.1. General
1
(Ph), 1488, 1377 (NO2); H NMR (d, ppm): 8.41 (1H, s,
H–C]C), 7.42 (3H, m, Ph), 7.26 (2H, m, Ph) 3.59 (4H, s,
CH2–O), 3.14 (4H, s, CH2–N).
IR spectra were recorded on a Thermo Nicolet Avatar 320

C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
11019
4.2. General procedure for the Michael addition of
nitroalkenes to lactone enolates
J2Z12.4 Hz, CHNO2), 1.22 (3H, s, CH3), 1.05 (3H, d, JZ
7.0 Hz, CH3); 13C NMR (d, ppm): 180.0 (s), 77.6 (t,
CH2NO2), 64.8 (t, C-5), 44.5 (s, C-3), 36.9 (d, CHCH3),
32.8 (t, C-4), 18.7 (q, CH3 at C-3), 13.5 (q, CH3 of the
chain).
To a solution of lithium diisopropylamide (3.5 mmol, 2.3 ml
of a 1.5 M solution in THF) in THF (16 ml), a solution of the
g-lactone (2.9 mmol) in 2.5 ml of THF was slowly added, at
K78 8C. The mixture was stirred at K78 8C for 1 h and the
appropriate nitroalkene (3.5 mmol) dissolved in 2.5 ml of
THF was added dropwise. The mixture was stirred at
K78 8C for 2 h, the temperature was allowed to raise to
K40 8C and the reaction mixture was kept at this
temperature for 2 h. The reaction was quenched by addition
of a saturated aqueous solution of NH4Cl. The aqueous
phase was extracted three times with CH2Cl2. The combined
organic phases were dried over anhydrous Na2SO4. After
removal of the solvent, the residue was analysed by HRGC
and purified by flash chromatography (light petroleum/ethyl
acetate).
1
Compound 16b. H NMR (d, ppm): 4.53 (1H, dd, J1Z
4.0 Hz, J2Z12.1 Hz, CHNO2), 4.33 (1H, dd, J1Z10.4 Hz,
J2Z12.1 Hz, CHNO2), 4.26 (2H, m, 2H-5), 2.63 (1H, m,
CHCH3), 2.22 (1H, dt, J1Z13.2 Hz, J2ZJ3Z8.8 Hz, H-4),
1.98 (1H, ddd, J1Z4.0 Hz, J2Z7.3 Hz, J3Z13.2 Hz, H-4),
1.31 (3H, s, CH3), 1.10 (3H, d, JZ7.0 Hz, CH3); 13C NMR
(d, ppm): 179.5 (s), 78.2 (t, CH2NO2), 65.0 (t, C-5), 44.6 (s,
C-3), 37.6 (d, CHCH3), 32.5 (t, C-4), 21.5 (q, CH3 at C-3),
13.1 (q, CH3 of the chain).
4.2.3. Reaction of lactone 1 with (E)-2-nitrostyrene 3. syn
and anti-4,5-Dihydro-3-(2-nitro-1-phenylethyl)-2(3H)-
furanone 17a and 17b. The isomers 17a and 17b (62%
yield) were obtained as a 45:55 inseparable mixture, white
solid, mp 65–69 8C, IR (cmK1, nujol): 1762 (OC]O), 1603
(Ph), 1552, 1378 (NO2); 13C NMR (d, ppm): 176.9 (s), 176.8
(s), 136.7 (s), 135.4 (s), 129.2 (d), 129.1 (d), 128.5 (d), 128.4
(d), 128.3 (d), 127.7 (d), and for 17a: 77.7 (t, CH2NO2), 66.3
(t, C-5), 44.3 (d, CHPh), 41.3 (d, C-3), 27.6 (t, C-4), and for
17b: 76.6 (t, CH2NO2), 66.7 (t, C-5), 43.8 (d, CHPh), 41.7
(d, C-3), 26.1 (t, C-4). MS (m/z): 235 (MC., 2), 217 (8), 189
(21), 188 (66), 160 (23), 145 (51), 143 (22), 131 (18), 130
(100), 128 (19), 118 (34), 116 (34), 106 (26), 105 (90), 103
(33), 91 (85), 86 (13), 78 (18), 77 (30). Anal. Calcd for
C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C, 61.3; H,
5.50; N, 6.04.
4.2.1. Reaction of the lactone 1 with (E)-1-nitropropene
2. syn- and anti-4,5-Dihydro-3-(1-methyl-2-nitroethyl)-
2(3H)-furanone 15a and 15b. The isomers 15a and 15b
(70% yield) were only partially separable by column
chromatography, yellow oil, IR (cmK1, neat): 1760
(OC]O), 1550, 1380 (NO2); MS (m/z): 126 (7), 86 (56),
83 (10), 82 (16), 81 (10), 69 (14), 68 (16), 67 (34), 55 (100).
Anal. Calcd for C7H11NO4: C, 48.55; H, 6.40; N, 8.09.
Found: C, 48.4; H, 6.20; N, 7.89.
1
Compound 15a. H NMR (d, ppm): 4.73 (1H, dd, J1Z
6.6 Hz, J2Z12.8 Hz, CHNO2), 4.48 (1H, dd, J1Z7.1 Hz,
J2Z12.8 Hz, CHNO2), 4.39 (1H, dt, J1Z2.4 Hz, J2ZJ3Z
9.0 Hz, H-5), 4.24 (1H, dt, J1Z6.9 Hz, J2ZJ3Z9.0 Hz,
H-5), 2.74 (2H, m, H-3 and CHCH3), 2.42 (1H, m, H-4),
2.14 (1H, m, H-4), 1.15 (3H, d, JZ6.6 Hz, CH3); 13C NMR
(d, ppm): 176.7 (s), 78.5 (t, CH2NO2), 66.5 (t, C-5), 41.2 (d,
C-3), 32.4 (d, CHCH3), 26.2 (t, C-4), 13.3 (q, CH3).
For clarity sake the NMR values are given separately for
each isomer.
1
Compound 17a. H NMR (d, ppm): 7.30 (5H, m, Ph), 5.44
(1H, dd, J1Z5.5 Hz, J2Z13.2 Hz, CHNO2), 4.80 (1H, dd,
J1Z9.9 Hz, J2Z13.2 Hz, CHNO2), 4.25 (1H, dt, J1Z
2.8 Hz, J2ZJ3Z8.8 Hz, H-5), 4.12 (1H, m, H-5), 3.80 (1H,
m, CHPh), 2.92 (1H, q, JZ9.8 Hz, H-3), 1.98 (2H, m, 2H-
4); 1H NMR (d, ppm, CDCl3Cdrops of C6D6): 7.20 (5H, m,
Ph), 5.33 (1H, dd, J1Z5.3 Hz, J2Z12.9 Hz, CHNO2), 4.67
(1H, dd, J1Z9.9 Hz, J2Z12.9 Hz, CHNO2), 4.06 (1H, dt,
J1Z2.5 Hz, J2ZJ3Z8.8 Hz, H-5), 3.93 (1H, m, H-5), 3.63
(1H, m, CHPh), 2.69 (1H, dt, J1Z8.8 Hz, J2ZJ3Z10.2 Hz,
H-3), 1.84 (1H, m, H-4), 1.71 (1H, m, H-4).
1
Compound 15b. H NMR (d, ppm): 4.71 (1H, dd, J1Z
6.2 Hz, J2Z12.4 Hz, CHNO2), 4.51 (1H, dd, J1Z7.1 Hz,
J2Z12.4 Hz, CHNO2), 4.38 (1H, dt, J1Z1.8 Hz, J2ZJ3Z
9.0 Hz, H-5), 4.21 (1H, dt, J1Z6.7 Hz, J2ZJ3Z9.0 Hz,
H-5), 2.79 (1H, sept, JZ6.9 Hz, CHCH3), 2.69 (1H, ddd,
J1Z11.3 Hz, J2Z8.4 Hz, J3Z6.9 Hz, H-3), 2.36 (1H, m, H-
4), 2.10 (1H, m, H-4), 1.08 (3H, d, JZ6.9 Hz, CH3); 13C
NMR (d, ppm): 177.1 (s), 78.9 (t, CH2NO2), 66.3 (t, C-5),
41.2 (d, C-3), 32.5 (d, CHCH3), 25.3 (t, C-4), 14.5 (q, CH3).
1
Compound 17b. H NMR (d, ppm): 7.30 (5H, m, Ph), 5.20
4.2.2. Reaction of the lactone 10 with (E)-1-nitropropene
2. syn- and anti-4,5-Dihydro-3-methyl-3-(1-methyl-2-
nitroethyl)-2(3H)-furanone 16a and 16b. The isomers
16a and 16b (60% yield) were obtained as a 1:9 inseparable
mixture, yellow oil, IR (cmK1, neat): 1764 (OC]O), 1550,
1380 (NO2); MS (m/z): 140 (3), 100 (35), 97 (8), 96 (18), 83
(10), 82 (16), 81 (34), 71 (10), 69 (29), 67 (24), 57 (20), 55
(100). Anal. Calcd for C8H13NO4: C, 51.33; H, 7.00; N,
7.48. Found: C, 51.4; H, 6.92; N, 7.19.
(1H, dd, J1Z7.3 Hz, J2Z13.5 Hz, CHNO2), 5.05 (1H, dd,
J1Z8.4 Hz, J2Z13.5 Hz, CHNO2), 4.12 (1H, m, H-5), 3.80
(2H, m, CHPh, H-5), 3.06 (1H, dt, J1Z4.6 Hz, J2ZJ31Z
9.4 Hz, H-3), 2.38 (1H, m, H-4), 1.98 (1H, m, H-4); H
NMR (d, ppm, CDCl3Cdrops of C6D6): 7.20 (5H, m, Ph),
5.07 (1H, dd, J1Z6.9 Hz, J2Z13.4 Hz, CHNO2), 4.93 (1H,
dd, J1Z8.0 Hz, J2Z13.4 Hz, CHNO2), 3.93 (1H, m, H-5),
3.71 (1H, dt, J1Z4.5 Hz, J2ZJ3Z8.0 Hz, CHPh), 3.63 (1H,
m, H-5), 2.85 (1H, dt, J1Z4.5 Hz, J2ZJ3Z9.3 Hz, H-3),
2.10 (1H, m, H-4), 1.84 (1H, m, H-4).
For clarity sake the NMR values are given separately for
each isomer.
4.2.4. Reaction of lactone 10 with (E)-2-nitrostyrene 3.
syn- and anti-4,5-Dihydro-3-methyl-3-(2-nitro-1-phenyl-
ethyl)-2(3H)-furanone 18a and 18b. The isomers 18a and
1
Compound 16a. H NMR (d, ppm): 4.93 (1H, dd, J1Z
4.0 Hz, J2Z12.4 Hz, CHNO2), 4.19 (1H, dd, J1Z9.9 Hz,

11020
C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
18b (80% yield), obtained in the ratio of 65:35 were not
separable by flash chromatography, white solid, mp 99–
101 8C; IR (cmK1, nujol): 1756 (OC]O), 1602 (Ph), 1548,
1339 (NO2); MS (m/z): 250 (MHC, 1), 204 (4), 203 (13),
143 (16), 129 (13),128 (10), 116 (14), 114 (13), 106 (26),
105 (100), 104 (18), 101 (85), 100 (10), 98 (10), 92 (40), 85
(15), 83 (11), 78 (13), 77 (26), 71 (23), 69 (20), 57 (40), 56
(12), 55 (34). Anal. Calcd for C13H15NO4: C, 62.64; H,
6.07; N, 5.62. Found: C, 62.5; H, 6.17; N, 5.81.
J2Z11.1 Hz, CHPh), 2.88 (1H, dt, J1Z4.2 Hz, J2ZJ3Z
8.5 Hz, H-3), 2.46 (1H, m, H-4), 1.91 (1H, dq, J1Z12.8 Hz,
J2ZJ3ZJ4Z8.5 Hz, H-4), 1.33 (3H, d, JZ6.7 Hz, CH3);
13C NMR (d, ppm): 176.8 (s), 135.0 (s), 129.4 (d), 129.3 (d),
128.6 (d), 83.5 (d, CHNO2), 66.6 (t, C-5), 50.6 (d, CHPh),
40.5 (d, C-3), 26.5 (t, H-4), 19.5 (q, CH3); MS (m/z): 249
(MC., 3), 203 (26), 202 (36), 143 (14), 131 (37), 129 (27),
118 (38), 117 (100), 115 (29), 105 (15), 91 (67), 84 (13), 77
(14). Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N,
5.62. Found: C, 62.9; H, 6.23; N, 5.33.
For clarity sake the NMR values are given separately for
each isomer.
Compound 19c (in admixture with 19a). 1H NMR (d, ppm):
7.21 (5H, m, Ph), 5.68 (1H, dq, J1Z5.5 Hz, J2ZJ3ZJ4Z
6.6 Hz, CHNO2), 4.13 (2H, m, 2H-5), 3.40 (2H, m, CHPh
and H-3), 2.12 (1H, m, H-4), 1.85 (1H, m, H-4), 1.54 (3H, d,
JZ6.6 Hz, CH3); 13C NMR (d, ppm): 177.5 (s), 134.6 (s),
128.7 (d), 128.6 (d), 128.2 (d), 82.5 (d, CHNO2), 66.2 (t,
C-5), 50.1 (d, CHPh), 39.7 (d, C-3), 27.2 (t, H-4), 17.5 (q,
CH3).
1
Compound 18a. H NMR (d, ppm): 7.28 (5H, m, Ph), 5.28
(1H, dd, J1Z4.0 Hz, J2Z13.4 Hz, CHNO2), 4.93 (1H, dd,
J1Z11.5 Hz, J2Z13.4 Hz, CHNO2), 4.17 (1H, m, H-5),
4.08 (1H, m, H-5), 3.82 (1H, dd, J1Z4.0 Hz, J2Z11.5 Hz,
CHPh), 2.28 (1H, m, H-4), 1.72 (1H, ddd, J1Z5.5 Hz, J2Z
7.3 Hz, J3Z13.2 Hz, H-4), 1.29 (3H, s, CH3); 13C NMR (d,
ppm): 179.8 (s), 135.0 (s), 128.8 (d), 128.5 (d), 128.3 (d),
75.2 (t, CH2–NO2), 64.8 (t, C-5), 47.3 (d, CHPh), 44.6 (s,
C-3), 34.0 (t, C-4), 19.6 (q, CH3).
Compound 19d. Oil, 6% yield; IR (cmK1, neat): 1766, 1712
(OC]O), 1602 (Ph), 1550, 1390 (NO2); 1H NMR (d, ppm):
7.34 (3H, m, Ph), 7.16 (2H, m, Ph), 5.31 (1H, dq, J1Z
9.1 Hz, J2ZJ3ZJ4Z6.6 Hz, CHNO2), 4.13 (2H, m, 2H-5),
3.87 (1H, dd, J1Z6.2 Hz, J2Z9.1 Hz, CHPh), 2.84 (1H, dt,
J1Z6.2 Hz, J2ZJ3Z9.6 Hz, H-3), 2.34 (1H, m, H-4), 2.09
(1H, m, H-4), 1.45 (3H, d, JZ6.6 Hz, CH3); MS,(m/z): 203
(15), 202 (34), 176 (19), 148 (28), 143 (15), 131 (46), 130
(47), 129 (36), 118 (35), 117 (100), 116 (20), 115 (42), 105
(18), 104 (14), 103 (10), 91 (95), 77 (22).
1
Compound 18b. H NMR (d, ppm): 7.28 (5H, m, Ph), 5.09
(1H, dd, J1Z11.2 Hz, J2Z13.2 Hz, CHNO2), 4.89 (1H, dd,
J1Z4.2 Hz, J2Z13.2 Hz, CHNO2), 4.08 (1H, m, H-5), 3.70
(1H, dd, J1Z4.2 Hz, J2Z11.2 Hz, CHPh), 3.59 (1H, dt,
J1ZJ2Z9.0 Hz, J3Z4.8 Hz, H-5), 2.28 (1H, m, H-4), 1.98
(1H, ddd, J1Z4.8 Hz, J2Z8.1 Hz, J3Z12.8 Hz, H-4), 1.36
(3H, s, CH3); 13C NMR (d, ppm): 179.9 (s), 135.8 (s) 129.0
(d), 128.4 (d), 128.3 (d), 76.5 (t, CH2–NO2), 65.5 (t, C-5),
50.2 (d, CHPh), 45.5 (s, C-3), 33.3 (t, C-4), 23.4 (q, CH3).
4.2.6. Reaction of the lactone 10 with (E)-2-nitro-1-
phenylpropene 4. 4,5-Dihydro-3-methyl-3-(2-nitro-1-
phenylpropyl)-2(3H)-furanone 20a,b,c. The isomers 20a,
20b and 20c (61%, 35% and 4% relative ratio) were
obtained acidifying the reaction mixture with 0.43 ml
(7 mmol) of glacial acetic acid in 1.5 ml of THF, at
K78 8C. The temperature was allowed to raise to K40 8C
and, after 15 min, 25 ml of water was added. The aqueous
phase was extracted three times with CH2Cl2. The combined
organic phases were dried over anhydrous Na2SO4. After
removal of the solvent, the crude reaction mixture was
purified by flash chromatography (light petroleum/ethyl
acetate) to give the mixture of lactones 20a,b,c (45% yield)
which could not be separated. White solid, mp 89–92 8C, IR
(cmK1, nujol): 1755 (OC]O), 1602 (Ph), 1545, 1334
(NO2); MS (m/z): 263 (MC$, 0.8), 221 (10), 206 (44), 145
(14), 131 (18), 129 (13), 119 (100), 118 (39), 116 (21), 106
(42), 102 (13), 101 (75), 99 (10), 91 (48), 77 (20), 69 (14),
57 (36), 56 (16), 55 (43). Anal. Calcd for C14H17NO4: C,
63.87; H, 6.51; N, 5.32. Found: C, 64.0; H, 6.74; N, 5.31.
4.2.5. Reaction of the lactone 1 with (E)-2-nitro-1-
phenylpropene 4. 4,5-Dihydro-3-(2-nitro-1-phenylpro-
pyl)-2(3H)-furanone 19a,b,c,d. Four isomers 19a, 19b,
1
19c and 19d in 53:22:14:11 ratio were identified in the H
NMR spectrum of the crude reaction mixture. They were
separated by flash chromatography.
Compound 19a. 30% Yield, white solid, mp 125–126 8C,
from ether; IR (cmK1, nujol): 1756, (OC]O), 1546, 1377
(NO2); H NMR (d, ppm): 7.28 (5H, m, Ph), 5.72 (1H, dq,
1
J1Z11.0 Hz, J2ZJ3ZJ4Z6.6 Hz, CHNO2), 4.09 (1H, q,
JZ8.2 Hz, H-5), 3.64 (1H, dt, J1Z4.8 Hz, J2ZJ3Z8.2 Hz,
H-5), 3.45 (1H, dd, J1Z4.8 Hz, J2Z11.0 Hz, CHPh), 3.12
(1H, dt, J1Z4.8 Hz, J2ZJ3Z8.2 Hz, H-3), 2.38 (1H, m, H-
4), 1.92 (1H, dq, J1Z13.0 Hz, J2ZJ3ZJ4Z8.2 Hz, H-4),
1.82 (3H, d, JZ6.6 Hz, CH3), 13C NMR (d, ppm): 177.0 (s),
135.6 (s), 128.9 (d), 128.5 (d), 128.4 (d), 85.4 (d, CHNO2),
66.8 (t, C-5), 50.0 (d, CHPh), 39.9 (d, C-3), 26.1 (t, C-4),
18.6 (q, CH3); MS (m/z): 250 (MHC, 4), 203 (26), 202 (31),
144 (25), 143 (63), 142 (38), 131 (29), 129 (21), 118 (100),
116 (27), 106 (19), 103 (31), 102 (29), 91 (57), 79 (13), 77
(19). Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N,
5.62. Found: C, 62.5; H, 5.87; N, 5.28.
For clarity sake the NMR values are given separately for
each isomer.
1
Compound 20a. H NMR (d, ppm): 7.31 (3H, m, Ph), 7.23
(2H, m, Ph), 5.31 (1H, quintet, J1Z6.6 Hz, CHNO2), 4.18
(1H, dt, J1Z8.0 Hz, J2Z9.2 Hz, H-5), 4.02 (1H, ddd, J1Z
4.8 Hz, J2Z8.0 Hz, J3Z9.2 Hz, H-5), 3.44 (1H, d, JZ
6.6 Hz, CHPh), 2.44 (1H, dt, J1Z8.0 Hz, J2Z13.2 Hz,
H-4), 2.08 (1H, ddd, J1Z4.8 Hz, J2Z8.0 Hz, J3Z13.2 Hz,
Compound 19b. 17% Yield; white solid, mp 95–97 8C, IR
(cmK1, nujol): 1762, (OC]O), 1600 (Ph), 1550, 1388
(NO2); H NMR (d, ppm): 7.36 (3H, m, Ph), 7.26 (2H, m,
Ph), 5.89 (1H, dq, J1Z11.1 Hz, J2ZJ3ZJ4Z6.7 Hz,
CHNO2), 4.06 (1H, q, JZ8.5 Hz, H-5), 3.70 (1H, dt, J1Z
4.3 Hz, J2ZJ3Z8.5 Hz, H-5), 3.44 (1H, dd, J1Z4.2 Hz,
1
H-4), 1.59 (3H, d, JZ6.6 Hz, CH3), 1.50 (3H, s, CH3); 13
C
NMR (d, ppm): 180.2 (s), 135.6 (s), 130.0 (d), 128.7 (d),

C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
11021
128.1 (d), 83.2 (d, CHNO2), 64.8 (t, C-5), 54.3 (d, CHPh),
45.7 (s, C-3), 33.3 (t, C-4), 22.2 (q, CH3), 19.9 (q, CH3).
129.3 (d), 128.7 (d), 127.9 (d), 66.6 (t, C-5), 58.2 (d, CHPh),
42.8 (d, C-3), 29.1 (q, CH3), 25.1 (t, C-4).
1
Compound 20b. H NMR (d, ppm): 7.33 (5H, m, Ph), 5.22
4.3.3. 4,5-Dihydro-3-methyl-3-(2-oxo-1-phenylpropyl)-
2(3H)-furanone 33. 17% Yield; white solid, mp 67–
70 8C; IR (cmK1, nujol): 1772 (OC]O), 1701(C]O),
(1H, dq, J1Z9.5 Hz, J2ZJ3Z6.6 Hz, CHNO2), 4.18 (1H,
m, H-5), 4.10 (1H, ddd, J1Z4.8 Hz, J2Z8.4 Hz, J3Z
9.5 Hz, H-5), 3.62 (1H, d, JZ9.5 Hz, CHPh), 2.47 (1H, m,
H-4), 2.05 (1H, m, H-4), 1.34 (3H, d, JZ6.6 Hz, CH3), 1.26
(3H, s, CH3); 13C NMR (d, ppm): 179.4 (s), 135.3 (s), 129.8
(d), 128.6 (d), 128.2 (d), 83.6 (d, CHNO2), 65.1 (t, H-5),
53.4 (d, CHPh), 45.7 (s, C-3), 33.4 (t, H-4), 22.2 (q, CH3),
19.9 (q, CH3).
1
1580 (Ph); H NMR (d, ppm): 7.33 (3H, m, Ph), 7.28 (2H,
m, Ph), 4.27 (1H, s, CHPh), 4.06 (1H, q, J1Z8.6 Hz, H-5),
3.58 (1H, dt, J1Z5.1 Hz, J2Z8.6 Hz, H-5), 2.63 (1H, m, H-
4), 2.23 (1H, m, H-4), 2.12 (3H, s, CH3–CO), 1.38 (3H, s,
CH3); 13C NMR (d, ppm): 205.6 (s, C]O), 180.6 (s, COO),
133.4 (s), 130.0 (d), 128.9 (d), 128.2 (d), 65.6 (t, C-5), 62.7
(d, CHPh), 46.1 (s, C-3), 31.1 (q, CH3–CO), 30.9 (t, C-4),
23.3 (q, CH3); MS (m/z): [232 (MC$) at 20 eV], 190 (25),
175 (15), 162 (21), 144 (44), 129 (25), 117 (22), 115 (20),
106 (52), 105 (65), 91 (100), 77 (41), 65 (10), 57 (10). Anal.
Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.5; H,
6.80.
Compound 20c. Only a few signals were identified: 1H
NMR (d, ppm): 5.45 (1H, dq, J1Z6.6 Hz, J2Z9.5 Hz,
CHNO2), 3.89 (1H, dt, J1Z3.9 Hz, J2Z9.2 Hz, H-5), 3.61
(1H, d, JZ9.5 Hz, CHPh), 2.63 (1H, m, H-4), 1.93 (1H, m,
H-4), 1.29 (3H, d, JZ6.6 Hz, CH3); 13C NMR (d, ppm):
129.1 (d), 82.5 (d, CHNO2), 65.7 (t, C-5), 54.8 (d, CHPh),
32.6 (s).
4.3.4. 4,5-Dihydro-3-(2-hydroxyimino-1-phenylpropyl)-
2(3H)-furanone 34. 15% Yield; white solid, mp 127–
129 8C from light petroleum/ether; IR (cmK1, nujol): 3329
(OH), 1730 (OC]O), 1655 (C]N), 1600 (Ph); 1H NMR (d,
ppm): 8.00 (1H, bs, OH), 7.27 (5H, m, Ph), 4.40 (1H, dt,
J1Z3.0 Hz, J2ZJ3Z8.8 Hz, H-5), 4.16 (1H, q, JZ8.8 Hz,
H-5), 4.10 (1H, d, JZ5.9 Hz, CHPh), 2.99 (1H, dt, J1Z
5.9 Hz, J2ZJ3Z8.8 Hz, H-3), 2.66 (1H, dq, J1Z12.0 Hz,
J2ZJ3ZJ4Z8.8 Hz, H-4), 1.99 (1H, m, H-4), 1.75 (3H, s,
CH3); 13C NMR (d, ppm): 178.3 (s, COO), 155.8 (s, C]N),
138.5 (s), 128.8 (d), 128.4 (d), 127.4 (d), 66.7 (t, C-5), 50.4
(d, CHPh), 43.2 (d, C-3), 24.7 (t, C-4), 13.8 (q, CH3); MS
(m/z): 233 (MC$, 15), 216 (79), 185 (20), 175 (22), 174 (40),
173 (32), 172 (18), 170 (26), 157 (26), 156 (17), 149 (41),
148 (49), 147 (20), 132 (32), 130 (49), 128 (22), 121 (26),
118 (30), 116 (65), 92 (100), 89 (29), 81 (39),77 (65). Anal.
Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C,
67.2; H, 6.58; N, 6.02.
4.3. Acidification of the lithium nitronates 13 and 14 with
3 N HCl
The crude reaction mixture containing the lithium nitronate
was acidified with 20 ml of 3 N HCl, the mixture was stirred
overnight and extracted three times with CH2Cl2. The
combined organic phases were dried over anhydrous
Na2SO4. After removal of the solvent, the residue was
purified by flash chromatography (light petroleum/ethyl
acetate). In the case of nitronate 13, from the complex
mixture containing the Nef products 32a and 32b in 3:2 ratio
and the oxime 34, only 32a and 34 could be isolated as pure
compounds, by flash chromatography. In the case of
nitronate 14 the Nef product 33 and the oxime 35 could
be isolated by flash chromatography (see text).
4.3.1. 4,5-Dihydro-3-(2-oxo-1-phenylpropyl)-2(3H)-fura-
none 32a. 19% Yield, white solid, mp 87–88 8C from ether;
4.3.5. 4,5-Dihydro-3-methyl-3-(2-hydroxyimino-1-phe-
nylpropyl)-2(3H)-furanone 35. 10% Yield, white solid,
mp 117–119 8C. IR (cmK1, nujol): 3271 (OH), 1758
1
IR (cmK1, nujol): 1753 (OC]O), 1714 (C]O); H NMR
1
(d, ppm): 7.33 (3H, m, Ph), 7.21 (2H, m, Ph), 4.15 (2H, m,
2H-5), 4.08 (1H, d, JZ7.7 Hz, CHPh), 3.56 (1H, ddd, J1Z
7.7 Hz, J2Z8.7 Hz, J3Z12.1 Hz, H-3), 2.20 (3H, s, CH3),
2.12 (1H, m, H-4), 1.82 (1H, m, H-4); 13C NMR (d, ppm):
206.1 (s, C]O), 177.9 (s, COO), 134.7 (s), 129.0 (d), 128.8
(d), 128.0 (d), 66.9 (t, C-5), 58.3 (d, CHPh), 41.3 (d, C-3),
29.4 (q, CH3), 26.4 (t, C-4); MS (m/z): 218 (MC., 1), 176
(53), 149 (76), 148 (32), 132 (47), 131 (100), 118 (18), 117
(19), 116 (28), 105 (31), 92 (74), 77 (18). Anal. Calcd for
C13H14O3: C, 71.54; H, 6.47. Found: C, 71.3; H, 6.39.
(C]O), 1670 (C]N); H NMR (d, ppm): 7.80 (1H, bs,
OH), 7.30 (5H, m, Ph), 4.03 (1H, dt, J1Z7.3 Hz, J2Z
8.8 Hz, H-5), 3.89 (1H, s, CHPh), 3.56 (1H, dt, J1Z5.1 Hz,
J2Z8.8 Hz, H-5), 2.65 (1H, ddd, J1Z7.3 Hz, J2Z8.8 Hz,
J3Z13.6 Hz, H-4), 2.17 (1H, m, H-4), 1.79 (3H, s,
CH3C]N–OH), 1.45 (3H, s, CH3); 13C NMR (d, ppm):
181.4 (s, COO), 156.6 (s, C]N), 136.1 (s), 130.1 (d), 128.5
(d), 127.8 (d), 65.4 (t, C-5), 56.5 (d, CHPh), 46.7 (s, C-3),
31.7 (t, C-4), 24.5 (q, CH3), 15.5 (q, CH3); MS (m/z): 247
(MC.,16), 202 (10), 186 (18), 149 (43), 148 (100), 131 (25),
130 (42), 129 (26), 117 (19), 116 (15), 115 (33), 106 (25),
105 (17), 100 (13), 95 (17), 91 (42), 77 (25), 69 (10), 55(13).
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66.
Found: C, 67.9; H, 7.00; N, 5.56.
4.3.2. 4,5-Dihydro-3-(2-oxo-1-phenylpropyl)-2(3H)-fura-
none 32b. The lactone 19d was submitted to the Nef
reaction conditions according to the literature,19 furnishing
a 3:1 mixture of 32a and 32b.
4.3.6. 1-(Tetrahydro-3-methyl-2-oxofuryl)-1-phenylpro-
pan-2-ylideneazinic acid 37. The reaction between the
lithium enolate of 10 and (E)-2-nitro-1-phenylpropene 4,
carried out in accordance with the general procedure, was
quenched by addition of a saturated aqueous solution of
NH4Cl. The aqueous phase was extracted with CH2Cl2 three
times in order to separate the nitroalkylated lactones. From
1
Compound 32b. H NMR (d, ppm): 7.36 (5H, m, Ph), 4.48
(1H, dt, J1Z2.3 Hz, J2ZJ3Z9.0 Hz, H-5), 4.28 (1H, d, JZ
5.1 Hz, CHPh), 4.16 (1H, m, H-5), 2.89 (1H, ddd, J1Z
5.1 Hz, J2Z9.5 Hz, J3Z11.0 Hz, H-3), 2.56 (1H, quintet,
JZ10.4 Hz, H-4), 2.21 (1H, m, H-4), 2.08 (3H, s, CH3); 13
C
NMR (d, ppm): 206.3 (s, C]O), 177.8 (s, COO), 136.3 (s),

11022
C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
the mother liquors, acidified to pH 2 with 3 N HCl, the
nitronic acid 37 precipitated as a white solid which was
For clarity sake the NMR values of the two isomers are
given separately.
washed with ether. 10% Yield, mp 100–102 8C; IR (cmK1
,
1
1
Compound 22a in admixture with 22b. H NMR (d, ppm)
nujol): 2668 (OH); 1754 (COO), 1658 (C]N); H NMR
(DMSO-d6, d, ppm) 7.20 (5H, m, Ph), 4.70 (1H, s, CHPh),
4.18 (1H, q, JZ8.4 Hz, H-5), 3.93 (1H, dt, J1Z2.7 Hz, J2Z
J3Z8.4 Hz, H-5), 2.43 (1H, m, H-4), 2.12 (1H, m, H-4),
2.03 (3H, s, CH3), 1.23 (3H, s, CH3); 13C NMR (DMSO-d6,
d, ppm): 180.9 (s), 137.9 (s), 129.3 (d), 129.0 (d), 127.7 (d),
121.2 (s), 65.4 (t), 50.8 (d), 46.4 (t), 31.2 (s), 23.0 (q), 16.6
(q); MS (m/z): 262 (MKH·C, 0.3), 247 (0.4), 216 (1.3),
190 (30), 175 (18), 162 (13), 145 (27), 144 (58), 130 (35),
118 (27), 116 (28), 106 (44), 100 (10), 99 (5), 92 (100), 77
(47), 55 (7), 51 (17). Anal. Calcd for C14H17NO4: C, 63.87;
H, 6.51; N, 5.32. Found: C, 63.7; H, 6.71; N, 5.26.
(only few signals were identified): 6.97 (1H, bs, NH), 2.25
(1H, m, H-4), 1.70 (1H, ddd, J1Z5.8 Hz, J2Z10.2 Hz, J3Z
15.7 Hz, CHCH2OH), 1.42 (1H, m, CHCH2OH), 0.94 (3H,
s, CH3); 13C NMR (d, ppm): 184.5 (s), 58.7 (t, CH2OH),
47.0 (t, C-5), 45.9 (s, C-3), 39.7 (d, C-4), 38.2 (t,
CH2CH2OH), 15.1 (q, CH3 at C-3), 11.4 (q, CH3 at C-4).
Compound 22b. 1H NMR (d, ppm). 6.92 (1H, bs, NH), 3.82
(1H, m, CHOH), 3.79 (1H, bs, OH), 3.63 (1H, m, CHOH),
3.35 (1H, dd, J1Z8.2 Hz, J2Z9.0 Hz, H-5), 2.92 (1H, dd,
J1Z8.2 Hz, J2Z9.7 Hz, H-5), 2.13 (1H, m, H-4), 1.73 (1H,
ddd, J1Z5.3 Hz, J2Z9.0 Hz, J3Z14.1 Hz, CHCH2OH),
1.35 (1H, dt, J1Z4.7 Hz, J2Z14.1 Hz, CHCH2OH), 1.13
(3H, s, CH3), 0.96 (3H, d, JZ7.3 Hz, CH3); 13C NMR (d,
ppm): 184.0 (s), 58.9 (t, CH2OH), 46.6 (t, C-5), 44.6 (s,
C-3), 42.0 (d, C-4), 34.0 (t, CH2CH2OH), 20.5 (q, CH3 at
C-3), 12.6 (q, CH3 at C-4).
4.4. General procedure for the reduction with Raney Ni
The nitro compound (0.85 mmol) was dissolved in 1:1
EtOH/ethyl acetate (20 ml) and one teaspoon of Raney Ni
(Aldrich) was added. The apparatus was evacuated and
flushed with H2. The mixture was stirred at room
temperature under H2 atmosphere for 16 h, then filtered on
Celite and the solvent was evaporated.
4.4.3. (3R*,4S*)- and (3R*,4R*)-3-(2-Hydroxyethyl)-4-
phenyl-2-pyrrolidinone 23a and 23b. Treatment of the
crude reaction mixture with light petroleum/ethyl acetate
gave a 3:2 mixture of 23a and 23b as a white solid (70%
yield), mp 90–93 8C, IR (cmK1, nujol): 3366, 3262 (OH and
NH), 1693 (NHC]O), 1638 (Ph); MS (m/z): 206 (MHC,
16), 160 (100), 159 (90), 147 (13), 118 (13), 117 (43), 115
(33), 104 (16), 91 (13), 84 (14), 78 (11). Anal. Calcd for
C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.0; H,
7.11; N, 6.64.
4.4.1. (3R*,4R*)- and (3R*,4S*)-3-(2-Hydroxyethyl)-4-
methyl-2-pyrrolidinone 21a and 21b. Reduction of the
nitroalkylated lactone 15a gave the trans isomer 21a: 80%
yield, white solid, mp 78–80 8C, IR (cmK1, nujol): 3165
1
(OH and NH), 1672 (NHC]O); H NMR (d, ppm): 7.03
(1H, bs, NH), 4.9 (1H, bs, OH), 3.84 (1H, m, CHOH), 3.72
(1H, m, CHOH), 3.49 (1H, t, JZ9.0 Hz, H-5), 2.99 (1H, t,
JZ9.0 Hz, H-5), 2.18 (1H, m), 2.09 (1H, m), 1.78 (2H, m,
CH2CH2OH), 1.15 (3H, d, JZ6.9 Hz, CH3); 13C NMR (d,
ppm): 181.6 (s), 62.2 (t, CH2OH), 49.7 (d, C-3), 48.7 (t,
C-5), 37.1 (d, C-4), 32.4 (t, CH2CH2OH), 17.3 (q, CH3); MS
(m/z): 144 (MHC, 41), 126 (6), 113 (9), 112 (10), 99 (22), 98
(33), 96 (17), 85 (18), 84 (100), 67 (9). Anal. Calcd for
C7H13NO2: C, 58.72; H, 9.15; N, 9.78. Found: C, 58.5; H,
8.90; N, 9.59.
For clarity sake the NMR values of the isomeric mixture are
given separately for each isomer.
Compound 23a. 1H NMR (d, ppm): 7.64 (1H, bs, NH), 7.28
(5H, m, Ph), 4.5 (1H, bs, OH), 3.74–3.50 (3H, m, CH2OH,
H-5), 3.41 (1H, t, JZ9.5 Hz, H-5), 3.27 (1H, q, JZ9.5 Hz,
H-4), 2.70 (1H, dt, J1ZJ2Z9.5 Hz, J3Z4.0 Hz, H-3), 1.85
(1H, m, CHCH2OH), 1.74 (1H, m, CHCH2OH); 13C NMR
(d, ppm): 180.4 (s), 140.0 (s), 129.0 (2d), 128.7 (2d), 127.6
(d), 61.6 (t, CH2OH), 49.0 (d, C-3), 48.9 (t, C-5), 48.4 (d,
C-4), 32.4 (t, CH2CH2OH).
Reduction of nitroalkylated lactone 15b gave the cis isomer
,
21b: 80% yield, white solid, mp 62–65 8C, IR (cmK1
1
nujol): 3165 (OH and NH), 1672 (NHC]O); H NMR (d,
ppm): 6.77 (1H, bs, NH), 4.4 (1H, bs, OH), 3.82 (1H, m,
CHOH), 3.70 (1H, m, CHOH), 3.48 (1H, dd, J1Z6.0 Hz,
J2Z9.5 Hz, H-5), 2.94 (1H, bd, JZ9.5 Hz, H-5), 2.50 (2H,
m, H-3 and H-4), 1.70 (2H, m, CH2CH2OH), 0.97 (3H, d,
JZ6.9 Hz, CH3); 13C NMR (d, ppm): 180.3 (s), 62.2 (t,
CH2OH), 48.6 (t, C-5), 45.5 (d, C-3), 33.5 (d, C-4), 28.5 (t,
CH2CH2OH), 14.6 (q, CH3); MS (m/z): 144 (MHC, 49), 126
(14), 112 (22), 99 (27), 98 (69), 96 (23), 85 (23), 84 (100),
67 (22). Anal. Calcd for C7H13NO2: C, 58.72; H, 9.15; N,
9.78. Found: C, 58. 5; H, 9.00; N, 9.58.
Compound 23b. 1H NMR (d, ppm): 7.67 (1H, bs, NH), 7.28
(5H, m, Ph), 4.5 (1H, bs, OH), 3.79 (1H, dd, J1Z7.1 Hz,
J2Z9.7 Hz, H-5), 3.74–3.50 (4H, m, CH2OH, H-5, H-4),
2.92 (1H, dt, J1ZJ2Z8.7 Hz, J3Z5.0 Hz, H-3), 1.48 (1H,
m, CHCH2OH), 1.30 (1H, m, CHCH2OH); 13C NMR (d,
ppm): 181.2 (s), 140.4 (s), 127.8 (2d), 127.5 (2d), 127.3 (d),
61.4 (t, CH2OH), 48.0 (t, C-5), 45.3 (d, C-3), 44. 3 (d, C-4),
29.9 (t, CH2CH2OH).
4.4.4. (3R*,4R*)- and (3R*,4S*)-3-(2-Hydroxyethyl)-3-
methyl-4-phenyl-2-pyrrolidinone 24a and 24b. The 65:35
crude mixture of 24a and 24b (70% overall yield), obtained
from the reduction, was purified by flash chromatography.
The two isomeric lactams could be separated only partially.
Semisolid material, IR (cmK1, neat): 3260 (OH and NH),
1685 (NHC]O); MS (m/z): 220 (MHC, 20), 204 (27), 175
(100), 174 (69), 160 (68), 158 (28), 131 (14), 129 (18), 128
(15), 117 (11), 115 (19), 104 (21), 98 (54), 91 (16), 78 (11).
4.4.2. (3R*,4R*)- and (3R*,4S*)-3-(2-Hydroxyethyl)-3,4-
dimethyl-2-pyrrolidinone 22a and 22b. The two isomers
were obtained as a 1:9 inseparable mixture, 80% yield,
white solid, mp 88 8C (from light petroleum/ethyl acetate);
IR (cmK1, nujol): 3330 (OH and NH), 1680 (NHC]O); MS
(m/z): 158 (MCH·C, 13), 113 (40), 112 (54), 98 (100), 84
(17), 67 (11), 55 (22). Anal. Calcd for C8H15NO2: C, 61.12;
H, 9.62; N, 8.91. Found: C, 61.3; H, 9.41; N, 9.14.

C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
11023
Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39.
Found: C, 71.0; H, 7.88; N, 6.25.
J1Z6.2 Hz, H-4), 1.90 (2H, m, CH2CH2OH), 0.91 (3H, d,
JZ6.9 Hz, CH3), 0.81 (3H, s, CH3); 13C NMR (d, ppm):
183.0 (s), 136.9 (s), 130.1 (2d), 128.1 (2d), 127.7 (d), 59.2 (t,
CH2OH), 57.4 (d, C-4), 50.6 (d, C-5), 47.7 (s, C-3), 40.5 (t,
CH2CH2OH), 18.7 (q, CH3 at C-3), 17.1 (q, CH3 at C-5).
Compound 24a. 1H NMR (d, ppm). 7.33 (3H, m, m-,
p-ArH), 7.23 (2H, m, o-ArH), 6.31 (1H, bs, NH), 4.53 (1H,
dd, J1Z8.4 Hz, J2Z2.6 Hz, OH), 3.85–3.60 (4H, m,
CH2OH, 2H-5), 3.48 (1H, dd, J1Z10.1 Hz, J2Z7.8 Hz,
H-4), 1.90 (1H, m, CHCH2OH), 1.72 (1H, m, CHCH2OH),
0.93 (3H, s, CH3); 13C NMR (d, ppm): 183.4 (s), 136.4 (s),
129.1 (2d), 128.5 (2d), 127.7 (d), 58.6 (t, CH2OH), 51.3 (d,
C-4), 47.5 (s, C-3), 44.5 (t, C-5), 38.5 (t, CH2CH2OH), 17.4
(q, CH3).
1
Compound 26b. H NMR (CD3OD, d, ppm). 7.25 (3H, m,
m-, p-ArH), 7.12 (2H, bd, o-ArH), 4.12 (1H, dq, J1Z6.2 Hz,
J2Z9.9 Hz, H-5), 3.8–3.6 (2H, m, CH2OH), 3.07 (1H, d,
J1Z9.9 Hz, H-4), 1.70 (2H, m, CH2CH2OH), 1.15 (3H, d,
JZ6.2 Hz, CH3), 0.85 (3H, s, CH3); 13C NMR (d, ppm):
181.9 (s), 134.8 (s), 129.4 (2d), 128.5 (2d), 127.9 (d), 60.7
(d, C-4), 58.3 (t, CH2OH), 51.7 (d, C-5), 48.8 (s, C-3), 38.4
(t, CH2CH2OH), 19.7 (q, CH3 at C-3), 19.6 (q, CH3 at C-5).
Compound 24b. 1H NMR (d, ppm). 7.33 (3H, m, m-,
p-ArH), 7.21 (2H, m, o-ArH), 6.34 (1H, bs, NH), 3.85–3.60
(4H, m, CH2OH, H-5, H-4), 3.62 (1H, dd, J1Z2.1 Hz, J2Z
10.1 Hz, OH), 3.36 (1H, t, JZ7.7 Hz, H-5), 1.66 (1H, m,
CHCH2OH), 1.37 (3H, s, CH3), 0.98 (1H, m, CHCH2OH);
13C NMR (d, ppm): 183.6 (s), 137.8 (s), 128.7 (2d), 128.4
(2d), 127.6 (d), 58.7 (t, CH2OH), 53.6 (d, C-4), 46.5 (s, C-3),
44.4 (t, C-5), 35.7 (t, CH2CH2OH), 21.4 (q, CH3).
4.5. Reduction of the nitro group with 10% Pd on carbon
The appropriate nitroalkylated g-lactone (0.8 mmol) was
dissolved in 6 ml of MeOH and 10% Pd on activated carbon
(54 mg) was added. The mixture was stirred at room
temperature under H2 for 4 h. The mixture was filtered on
Celite and the solvent was evaporated.
4.4.5. (3R*,4R*,5S*)-3-(2-Hydroxyethyl)-5-methyl-4-
phenyl-2-pyrrolidinone 25a. The crude reaction mixture
obtained from the reduction of 19a was treated with light
petroleum/ethyl acetate to afford 25a (70% yield) as a white
solid, mp 123–125 8C; IR (cmK1, nujol): 3260 (OH and
4.5.1. (3R*,4R*)- and (3R*,4S*)-1-Hydroxy-3-(2-hydro-
xyethyl)-4-methyl-2-pyrrolidinone 27a and 27b. The two
isomers were obtained in admixture with the corresponding
lactams 21a and 21b from the corresponding parent lactones
15a and 15b. For clarity sake the NMR values of the
isomeric mixture are given separately for each isomer.
1
NH), 1690 (NHC]O), 1600 (Ph); H NMR (CD3OD, d,
ppm): 7.27 (3H, m, m-, p-ArH), 7.12 (2H, bd, o-ArH), 4.09
(1H, dq, J1Z6.6 Hz, J2Z5.8 Hz, H-5), 3.54 (1H, dd, J1Z
7.7 Hz, J2Z5.8 Hz, H-4), 3.45 (2H, m, CH2OH), 3.03 (1H,
ddd, J1Z8.9 Hz, J2Z7.7 Hz, J3Z5.8 Hz, H-3), 1.86 (1H,
m, CHCH2OH), 1.30 (1H, m, CHCH2OH), 0.83 (3H, d, JZ
6.6 Hz, CH3); 13C NMR (d, ppm): 183.7 (s), 139.3 (s), 132.5
(2d), 131.3 (2d), 130.4 (d), 65.1 (t, CH2OH), 56.0 (d), 54.2
(d), 51.2 (d, C-3), 32.4 (t, CH2CH2OH), 19.5 (q, CH3); MS
(m/z): 220 (MHC, 14), 175 (100), 174 (19), 131 (15), 118
(27), 117 (65), 115 (33), 91 (10). Anal. Calcd for
C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 69.9;
H, 7.41; N, 6.14.
1
Compound 27a. H NMR (d, ppm): 9.0 (1H, vbs, OH), 4.6
(1H, bs, OH), 3.75 (2H, m, CH2OH), 3.72 (1H, m, H-5),
3.22 (1H, bd, JZ9.1 Hz, H-5), 2.14 (2H, m, H-3 and H-4),
1.80 (2H, m, CH2CH2OH), 1.14 (3H, d, JZ6.2 Hz, CH3);
13C NMR (d, ppm): 172.4 (s), 61.5 (t, CH2OH), 55.2 (t, C-
5), 47.8 (d, C-3), 33.0 (t, CH2CH2OH), 31.5 (d, C-4), 17.6
(q, CH3).
1
Compound 27b. H NMR (d, ppm): 9.0 (1H, vbs, OH), 4.6
(1H, bs, OH), 3.75 (2H, m, CH2OH), 3.73 (1H, m, H-5),
3.21 (1H, dd, J1Z9.5 Hz, J2Z11.0 Hz, H-5), 2.66 (1H, m,
H-3), 2.52 (1H, m, H-4), 1.70 (2H, m, CH2CH2OH), 1.04
(3H, d, JZ7.0 Hz, CH3); 13C NMR (d, ppm): 172.0 (s), 61.5
(t, CH2OH), 55.5 (t, C-5), 43.4 (d, C-3), 28.8 (t, CH2CH2-
OH), 28.4 (d, C-4), 14.9 (q, CH3).
4.4.6. (3R*,4R*,5R*)- and (3R*,4R*,5S*)-3,5-Dimethyl-
3-(2-hydroxyethyl)-4-phenyl-2-pyrrolidinone 26a and
26b. A 1:1 mixture of nitroalkylated lactones 20a and 20b
was reduced under the above mentioned conditions to give a
1:1 mixture of the corresponding lactams 26a and 26b (70%
overall yield). The same compounds were obtained from the
reduction with Raney Ni of the nitronic acid 37, although in
a 7:3 molar ratio. The two isomers could not be separated.
White solid, mp 94–100 8C, IR (cmK1, CHCl3): 3336 (OH
and NH), 1680 (NHC]O), 1602 (Ph); MS (m/z): 234
(MHC, 14), 218 (49), 203 (16), 190 (27), 189 (100), 188
(82), 174 (62), 162 (28), 161 (14), 160 (15), 132 (28), 131
(87), 129 (42), 128 (20), 118 (28), 117 (55), 116 (22), 115
(37), 112 (35), 91 (46). Anal. Calcd for C14H19NO2: C,
72.07; H, 8.21; N, 6.00. Found: C, 71.9; H, 8.11; N, 5.89.
4.5.2. (3R*,4R*) and (3R*,4S*)-1-Hydroxy-3-(2-hydro-
xyethyl)-3,4-dimethyl-2-pyrrolidinone 28a and 28b. The
two isomers were obtained from the corresponding
nitroalkylated lactones 16a and 16b.The crude reaction
mixture was purified by flash chromatography (eluant: ethyl
acetate, 70% yield) and the isomer 28b crystallized on
standing at room temperature.
Compound 28a (in admixture with 28b). Oil, only a few
signals were identified; H NMR (d, ppm): 3.36 (1H, m),
1
2.95 (1H, m), 2.23 (1H, m, H-4), 0.94 (3H, s, CH3), 0.92
(3H, d, JZ7.3 Hz, CH3); 13C NMR (d, ppm): 58.5 (t,
CH2OH), 53.6 (t, C-5), 44.7 (s, C-3), 38.5 (t, CH2CH2OH),
33.8 (d, C-4), 16.0 (q, CH3 at C-3), 11.5 (q, CH3 at C-4).
For clarity sake the NMR values of the isomeric mixture are
given separately for each isomer.
1
Compound 26a. H NMR (CD3OD, d, ppm). 7.25 (3H, m,
m-, p-ArH), 7.12 (2H, bd, o-ArH), 4.25 (1H, dq, J1Z6.2 Hz,
J2Z6.9 Hz, H-5), 3.8–3.6 (2H, m, CH2OH), 3.38 (1H, d,
Compound 28b. White solid, mp 90–92 8C, IR (cmK1, neat):
3350 (OH), 1680 (NC]O); H NMR (d, ppm): 10.0 (1H,
1

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C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
vbs, NOH), 5.00 (1H, vbs, OH), 3.82 (1H, m, CHOH), 3.66
(2H, m, H-5 and CHOH), 3.29 (1H, t, JZ9.0 Hz, H-5), 2.18
(1H, sextet, JZ7.3 Hz, H-4), 1.74 (1H, m, CHCH2OH),
1.50 (1H, dt, J1ZJ2Z5.1 Hz, J3Z13.9 Hz, CHCH2OH),
1.18 (3H, s, CH3), 1.04 (3H, d, JZ7.3 Hz, CH3); 13C NMR
(d, ppm): 174.0 (s), 58.3 (t, CH2OH), 53.6 (t, C-5), 43.6 (s,
C-3), 37.3 (d, C-4), 35.0 (t, CH2CH2OH), 21.3 (q, CH3 at
C-3), 12.0 (q, CH3 at C-4). MS (m/z): 156 (MKOH·C, 12),
129 (18), 128 (34), 127 (11), 114 (100), 113 (33), 100 (14),
99 (68), 83 (21), 82 (39), 81 (13), 70 (22), 69 (66), 67 (65),
55 (80). Anal. Calcd for C8H15NO3: C, 55.47; H, 8.73; N,
8.09. Found: C, 55.4; H, 8.29; N, 7.89.
Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C,
66.5; H, 7.31; N, 5.81.
Compound 30b. 12% Yield; oil, IR (cmK1, film): 3200
(OH), 1681 (NC]O); H NMR (CD3OD, d, ppm): 7.31
1
(5H, m, Ph), 3.92 (1H, dd, J1Z7.9 Hz, J2Z9.3 Hz, H-5),
3.81 (1H, dd, J1Z7.7 Hz, J2Z9.2 Hz, H-5), 3.55 (1H, m,
CHOH), 3.35 (2H, m, CHOH and H-4), 1.57 (1H, ddd, J1Z
6.4 Hz, J2Z9.5 Hz, J3Z13.9 Hz, CHCH2OH), 1.30 (3H, s,
CH3), 1.15 (1H, ddd, J1Z5.2 Hz, J2Z9.4 Hz, J3Z14.1 Hz,
CHCH2OH); 13C NMR (CD3OD, d, ppm): 175.2 (s), 138.7
(s), 129.7 (d), 129.5 (d), 128.6 (d), 58.9 (t, CH2OH), 52.4 (t,
C-5), 46.5 (s, C-3), 45.0 (d, C-4), 37.0 (t, CH2CH2OH), 23.3
(q, CH3).
4.5.3. (3R*,4S*)- and (3R*,4R*)-1-Hydroxy-3-(2-hydro-
xyethyl)-4-phenyl-2-pyrrolidinone 29a and 29b. Treat-
ment of the crude reaction mixture, obtained by reduction of
17a and 17b, with ethyl acetate led to the crystallization of
the isomer 29a (6% yield). The isomer 29b was recovered in
1:1 admixture with 29a (89% yield).
4.5.5. (3R*,4R*,5R*)-1-Hydroxy-3-(2-hydroxyethyl)-5-
methyl-4-phenyl-2-pyrrolidinone 31b. Reduction of 19b
afforded a 1:3 mixture of the lactam 25b and the cyclic
hydroxamic acid 31b (80% yield), from which 31b was
isolated by treatment with ethyl acetate.
Compound 29a. White solid, mp 171–173 8C; IR (cmK1
,
1
1
Compound 25b not separated: H NMR (CDCl3CCD3OD,
nujol): 3210 (OH), 1685 (NC]O); H NMR (CD3OD, d,
ppm): 7.35 (5H, m, Ph), 3.85 (1H, t, JZ8.6 Hz, H-5), 3.66–
3.48 (3H, m, CH2OH and H-5), 3.25 (1H, q, JZ8.5 Hz,
H-4), 2.71 (1H, m, H-3), 1.94 (1H, sextet, JZ6.9 Hz,
d, ppm) (only a few signals were identified): 3.96 (1H, bq,
JZ5.7 Hz, H-5), 3.25 (1H, dd, J1Z4.6 Hz, J2Z8.6 Hz,
H-4), 1.29 (3H, d, JZ6.2 Hz, CH3); 13C NMR (CDCl3C
CD3OD, d, ppm): 180.1 (s), 138.8 (s), 128.6 (2d), 127.9
(2d), 127.1 (d), 61.0 (t, CH2OH), 54.8 (d, C-5), 52.1 (d,
C-4), 44.2 (d, C-3), 29.6 (t, CH2CH2OH), 20.6 (q, CH3).
CHCH2OH), 1.73 (1H, sextet, JZ6.9 Hz, CHCH2OH); 13
C
NMR (CD3OD, d, ppm): 173.3 (s), 141.2 (s), 129.9 (d),
128.6 (d), 128.4 (d), 60.6 (t, CH2OH), 56.3 (t, C-5), 46.4 (d,
C-3), 43.5 (d, C-4), 34.1 (t, CH2CH2OH); MS (m/z): 175
(19), 174 (13), 161 (93), 160 (43), 148 (16), 131 (25), 130
(16), 129 (16), 128 (11), 118 (26), 117 (100), 116 (33), 115
(48), 104 (67), 91 (48), 84 (30), 78 (17), 77 (25). Anal. Calcd
for C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.4;
H, 6.71; N, 6.16.
Compound 31b. White solid, mp 158 8C, 18% yield, IR
(cmK1, nujol): 3220 (OH), 1676 (NC]O); 1H NMR
(CDCl3CCD3OD, d, ppm): 7.24 (3H, m, Ph), 7.14 (2H, m,
Ph), 3.94 (1H, dq, J1Z4.4 Hz, J2ZJ3ZJ4Z6.2 Hz, H-5),
3.45 (2H, m, CH2OH,), 3.20 (1H, dd, J1Z4.4 Hz, J2Z
8.8 Hz, H-4), 2.91 (1H, dt, J1Z8.8 Hz, J2ZJ3Z6.2 Hz, H-
3), 1.47 (1H, m, CHCH2OH), 1.33 (3H, d, JZ6.2 Hz, CH3),
1.24 (1H, m, CHCH2OH); 13C NMR (CDCl3CCD3OD, d,
ppm): 171.3 (s), 138.3 (s), 128.7 (2d), 128.0 (2d), 127.3 (d),
60.8 (d, C-5), 60.7 (t, CH2OH), 47.6 (d, C-4), 41.7 (d, C-3),
30.0 (t, CH2CH2OH), 17.1 (q, CH3); MS (m/z): 217 (MK
H2O·C., 1), 216 (1), 176 (28), 175 (32), 148 (13), 133 (11),
132 (25), 131 (13), 119 (51), 118 (100), 117 (29), 116 (38),
1
Compound 29b. H NMR (CD3OD, d, ppm): 7.35 (5H, m,
Ph), 3.99 (1H, t, JZ8.2 Hz, H-5), 3.64 (2H, m, H-5 and
H-4), 3.47 (2H, m, CH2OH), 2.95 (1H, q, JZ7.7 Hz, H-3),
1.59 (1H, sextet, JZ7.2 Hz, CHCH2OH), 1.25 (1H, m,
CHCH2OH); 13C NMR (CD3OD, d, ppm): 172.9 (s), 141.6
(s), 129.6 (d), 128.2 (d), 128.1 (d), 60.6 (t, CH2OH), 55.8 (t,
C-5), 42.6 (d, C-3), 40.0 (d, C-4), 30.5 (t, CH2CH2OH).
92 (35), 77 (14); MS (m/z, 20 eV): 236 (MHC, 2), 235 (MC.
,
2). Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95.
Found: C, 66.5; H, 7.27; N, 5.90.
4.5.4. (3R*,4R*)- and (3R*,4S*)-1-Hydroxy-3-(2-hydro-
xyethyl)-3-methyl-4-phenyl-2-pyrrolidinone 30a and
30b. Treatment of the crude reaction mixture, obtained by
reduction of 18a and 18b, with ethyl acetate led to the
crystallization of the isomer 30a, while 30b was obtained by
flash chromatography of the mother liquors (eluant: ethyl
acetate).
4.6. Reactions of a-methyl-g-butyrolactone 10 with (E)-
2-morpholinyl-1-nitro-1-phenylethene (5), (E)-1-(2-
methylthiophenyl)-2-pyrrolidinyl-1-nitroethene (6),
(Z,E)-1-methylthio-4-pyrrolidinyl-2-nitrobutadiene (7)
and (E)-1,1-dimethylthio-4-pyrrolidinyl-2-
Compound 30a. 57% Yield, white solid, mp 175–178 8C; IR
(cmK1, nujol): 3200 (OH), 1681 (NC]O); 1H NMR
(CD3OD, d, ppm): 7.31 (5H, m, Ph), 3.90 (1H, dd, J1Z
8.4 Hz, J2Z9.1 Hz, H-5), 3.80 (1H, dd, J1Z7.8 Hz, J2Z
9.0 Hz, H-5), 3.77–3.66 (2H, m, CH2OH) 3.63 (1H, t, JZ
8.1 Hz, H-4), 1.80 (2H, m, CH2CH2OH), 0.74 (3H, s, CH3);
13C NMR (CD3OD, d, ppm): 175.3 (s), 138.7 (s), 129.9 (d),
129.5 (d), 128.4 (d), 59.3 (t, CH2OH), 52.5 (t, C-5), 47.1 (s,
C-3), 45.0 (d, C-4), 40.1 (t, CH2CH2OH), 19.5 (q, CH3); MS
(m/z): 218 (MKOH·C, 1), 190 (18), 189 (18), 175 (100),
174 (37), 160 (23), 131 (43), 129 (23), 117 (28), 116 (19),
115 (27), 104 (77), 98 (57), 91 (62), 78 (15), 77 (18). Anal.
nitrobutadiene (70). General procedure for the Michael
addition of nitroenamines to a-methyl-g-butyrolactone
zinc enolate 80
To a solution of lithium diisopropylamide (1.5 M solution in
THF) (2 mmol, 1.3 ml for the reaction with 5, 7 and 70;
3.5 mmol, 2.3 ml for the reaction with 6) in THF (1.3 ml), a
solution of the lactone 10 (0.162 g, 1.62 mmol) in 1.3 ml of
THF was slowly added, at K78 8C. The mixture was stirred
for 1 h at K78 8C. A solution of 1M ZnCl2 (1.62 ml) was
then added and the temperature was raised to K40 8C. After
1 h at this temperature, the solution was transferred to the

C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
11025
appropriate aminonitroalkene (0.81 mmol) dissolved in
5.2 ml of THF at K78 8C. The mixture was stirred at
K78 8C for 2 h, the temperature was allowed to raise and
the solution was kept overnight at room temperature. The
reaction mixture was then quenched with 2 N HCl and
extracted with dichloromethane. The organic phase was
dried over anhydrous Na2SO4. After removal of the solvent,
the residue was purified by flash chromatography (light
petroleum/ethyl acetate 3:2).
131.3 (d), 127.9 (s), 126.1 (d), 125.0 (d), 65.4 (t), 43.3 (s),
34.6 (t), 22.9 (q), 15.8 (q); MS (m/z): 293 (MC., 28), 248
(12), 247 (49), 220 (16), 219 (100), 201 (12), 194 (36), 191
(12), 189 (17), 186 (14), 174 (15), 173 (36), 161 (14), 151
(41), 149 (25), 148 (13), 147 (28), 129 (14), 128 (12), 115
(18), 83 (11). Anal. Calcd for C14H15NO4S: C, 57.32; H,
5.15; N, 4.77; S, 10.93. Found: C, 56.4; H, 5.19; N, 4.60.
4.6.3. cis- and trans-3-(2-Hydroxyethyl)-3-methyl-5-phe-
nyl-2-pyrrolidinone 40a and 40b. The nitroalkenylated
lactones 38 and 39 were reduced using Pd on carbon and
Raney Nickel as a catalyst as reported in the general
procedure.
4.6.1. (E)- and (Z)-4,5-Dihydro-3-methyl-3-(2-nitro-2-
phenylethenyl)-2(3H)-furanone 38. The crude reaction
mixture (88% yield), whose composition was 85:15 in
favour of the (E)-isomer, was treated with ether and ethanol
at 0 8C. The major isomer (E)-38 was isolated as pure
compound (30% yield), mp 90–92 8C; IR (cmK1, nujol):
1778 (COO), 1672 (C]C), 1528 (NO2). 1H NMR (d, ppm):
7.75 (1H, s, HC]C), 7.50 (3H, m, Ar–H), 7.32 (2H, m, Ar–
H), 4.13 (2H, m, 2H-5), 2.10 (1H, dt, J1Z9.3 Hz, J2Z
13.2 Hz, H-4), 1.60 (1H, ddd, J1Z2.9 Hz, J2Z6.2 Hz, J3Z
13.2 Hz, H-4), 1.41 (3H, s, CH3); 13C NMR (d, ppm): 177.8
(s, COO), 152.2 (s, C]CNO2), 137.6 (d, CH]CNO2),
130.7 (2d, o-Ar–H), 130.4 (2d, m-Ar–H), 129.1 (s), 128.6 (d,
p-Ar–H), 65.1 (t, C-5), 43.2 (s, C-3), 34.6 (t, C-4), 23.5 (q,
CH3). MS (m/z): 247 (MC$, 0.01), 201 (72), 174 (15), 173
(100), 171 (14), 170 (13), 156 (13), 155 (10), 145 (23), 143
(20), 142 (43), 141 (38), 130 (12), 129 (65), 128 (67), 127
(25), 117 (17), 115 (49), 105 (58), 104 (18), 103 (52), 102
(31), 99 (10), 91 (40), 84 (32), 77 (73), 76 (28), 75 (15), 69
(17), 65 (10), 63 (17), 56 (11), 55 (29), 51 (66), 53 (13).
Anal. Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.67.
Found: C, 63.0; H, 5.19; N, 5.90.
A 2:3 mixture of lactams 40a and 40b were obtained in 70%
yield. The two isomers were only partially separable by
flash chromatography; yellow oil, IR (cmK1, CHCl3): 3420,
3153 (NH and OH), 1685 (NHC]O); MS (m/z): 220
(MHC, 33), 219 (MC$, 38), 202 (10), 191 (65), 190 (46),
175 (100), 174 (69), 173 (35), 172 (29), 160 (40), 158 (40),
147 (18), 146 (49), 145 (17), 144 (13), 143 (14), 132 (13),
131 (41), 130 (26), 129 (34), 128 (32), 120 (11), 117 (12),
115 (23), 106 (16), 104 (21), 91 (26), 84 (11), 77 (14). Anal.
Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C,
70.5; H, 7.65; N, 6.30.
For sake of clarity the NMR values of the isomeric mixture
are given separately for each isomer.
1
Compound 40a. H NMR (d, ppm): 7.33 (5H, m, Ph), 6.23
(1H, bs, NH), 4.75 (1H, t, JZ6.6 Hz, H-5), 4.09 (1H, bd,
JZ6.2 Hz, OH), 3.92 (1H, m, CHOH), 3.70 (1H, m,
CHOH), 2.30 (1H, dd, J1Z6.6 Hz, J2Z12.6 Hz, H-4), 1.90
(2H, m, CHCH2OH and H-4), 1.71 (1H, m, CHCH2OH),
1.33 (3H, s, CH3); 13C NMR (d, ppm): 183.3 (s), 141.6 (s),
129.0 (2d), 128.0 (d), 125.7 (2d), 58.7 (t, CH2OH), 55.8 (d,
C-5), 46.6 (t, C-4), 44. 6 (s, C-3), 40.3 (t, CH2CH2OH), 21.8
(q).
The compound (Z)-38 was not isolated as pure isomer.
1H NMR (d, ppm): 7.43 (5H, m, Ar–H), 6.43 (1H, s,
HC]C), 4.44 (1H, dt, J1Z1.5 Hz, J2ZJ3Z9.2 Hz, H-5),
4.32 (1H, ddd, J1Z6.3 Hz, J2Z9.2 Hz, J3Z10.7 Hz, H-5),
2.51 (1H, ddd, J1Z9.2 Hz, J2Z10.7 Hz, J3Z12.8 Hz, H-4),
2.35 (1H, ddd, J1Z1.5 Hz, J2Z6.3 Hz, J3Z12.8 Hz, H-4),
1.58 (3H, s, CH3); 13C NMR (d, ppm): 178.2 (s), 152.2 (s),
137.6 (d), 128.8 (d), 128.5 (d), 128.2 (d), 65.3 (t, C-5), 43.8
(s, C-3), 32.9 (t, C-4), 22.7 (q, CH3); the singlet relative to
C-1 of the phenyl ring was hidden under other signals.
1
Compound 40b. H NMR (d, ppm): 7.38 (2H, m, Ph), 7.31
(3H, m, Ph), 5.94 (1H, bs, NH), 4.77 (1H, t, JZ7.3 Hz, H-
5), 3.94 (1H, m, CHOH), 3.75 (1H, m, CHOH), 2.97 (1H,
bd, OH), 2.55 (1H, dd, J1Z7.3 Hz, J2Z13.0 Hz, H-4), 2.02
(1H, m, CHCH2OH), 1.90 (1H, dd, J1Z7.3 Hz, J2Z
13.0 Hz, H-4), 1.71 (1H, m, CHCH2OH), 1.28 (3H, s,
CH3); 13C NMR (d, ppm): 183.3 (s), 142.2 (s), 129.1 (2d),
128.1 (d), 125.8 (2d), 59.4 (t, CH2OH), 55.0 (d, C-5), 46.8
(t, C-4), 43. 3 (s, C-3), 40.6 (t, CH2CH2OH), 23.5 (q).
4.6.2. (E)- and (Z)-4,5-Dihydro-3-methyl-3-[2-(2-
methylthiophenyl)-2-nitroethenyl]-2(3H)-furanone 39.
The crude reaction mixture, whose composition was 67:33
in favour of the (E)-isomer, was purified on flash
chromatography, 50% yield, yellow oil, IR (cmK1, neat):
1
1775 (COO), 1520, (C]C–NO2); H NMR (d, ppm): 7.81
4.6.4. 4,5-Dihydro-3-(2-(hydroxyimino)-2-(2-methylthio-
phenyl))ethyl-3-methyl-2(3H)-furanone 41. 51% Yield,
yellow oil, IR (cmK1) 3350 (OH), 1766 (COO), 1625
(C]N), 1587, 1560 (Ph), 1H NMR (d, ppm): 8.8 (1H, vbs,
OH), 7.27 (4H, m, Ph), 4.25 (2H, m, 2H-5), 3.21 (2H, AB
system, JZ13.2 Hz, CH2 of the chain), 2.44 (3H, s, SCH3),
2.30 (1H, dt, J1ZJ2Z7.6 Hz, J3Z12.9 Hz, H-4), 1.90 (1H,
ddd, J1Z5.1 Hz, J2Z7.3 Hz, J3Z12.9 Hz, H-4), 1.17 (3H,
s, CH3); 13C NMR (d, ppm): 181.0 (s), 156.7 (s), 137.7 (s),
135.7 (s), 129.4 (d), 129.1 (d), 126.6 (d), 124.9 (d), 65.3 (t,
C-5), 42.4 (s, C-3), 34.6 (t), 34.3 (t), 22.9 (q, CH3), 16.5 (q,
CH3); MS (m/z): 264 (MKCH·3C, 100), 262 (76), 247 (50),
232 (42), 229 (16), 203 (13), 188 (10), 164 (17), 152 (14).
(0.67H, s, C]CH), 7.73 (0.33H, s, C]CH), 7.47 (1H, m,
Ar–H), 7.31 (1H, bd, JZ7.7 Hz, Ar–H), 7.23 (2H, m, Ar–
H), 4.23 (0.67H, dt, J1Z9.0 Hz, J2Z2.6 Hz, H-5), 4.09
(1.33H, m, H-5), 2.45 (3H, s, SCH3), 2.26 (0.33H, dt, J1Z
8.9 Hz, J2Z13.1 Hz, H-4), 2.16 (0.67H, dt, J1Z9.1 Hz,
J2Z12.8 Hz, H-4), 1.78 (0.33H, ddd, J1Z3.7 Hz, J2Z
6.6 Hz, J3Z13.1 Hz, H-4), 1.48 (0.67H, ddd, J1Z2.4 Hz,
J2Z6.6 Hz, J3Z12.8 Hz, H-4), 1.43 (0.90H, s, CH3), 1.38
(2.1H, s, CH3); 13C NMR (d, ppm): (E)-39: 177.7 (s), 150.8
(s), 140.6 (s), 139.0 (d), 131.6 (d), 131.3 (d), 128.5 (s), 126.0
(d), 125.0 (d), 65.4 (t), 43.6 (s), 33.3 (t), 23.3 (q), 15.7 (q);
(Z)-39: 178.0 (s), 150.2 (s), 140.1 (s), 139.2 (d), 132.2 (d),

11026
C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
Anal. Calcd for C14H17NO3S: C, 60.19; H, 6.13; N, 5.01; S,
11.48. Found: C, 60.3; H, 6.25; N, 4.96.
2.31 (3H, s, SCH3), 2.03 (2H, m), 1.70 (1H, m), 1.29 (3H, s,
CH3).
Compound 44b. 1H NMR (d, ppm): 5.57 (1H, d, JZ8.4, H–
C]C), 4.58 (1H, ddd, J1Z3.0, J2Z8.4, J3Z10.6, CH–
NO2), 4.26 (2H, m, 2H-5), 2.44 (1H, m), 2.35 (3H, s, SCH3),
2.30 (3H, s, SCH3), 2.03 (2H, m), 1.70 (1H, m), 1.30 (3H, s,
CH3).
4.6.5. (E,Z)- and (Z,Z)-4,5-Dihydro-3-methyl-3-(4-
methylthio-2-nitrobutadienyl)-2(3H)-furanone 42. The
product (E,Z)-42 was purified on column chromatography
(52% yield). Oil, IR (cmK1, CHCl3): 1775 (COO), 1525
(C]C–NO2); 1H NMR (d, ppm): 7.32 (1H, d, JZ1.5 Hz, H-
1 of the chain), 6.64 (1H, d, JZ10.2 Hz, H-3 of the chain),
6.04 (1H, dd, J1Z10.2 Hz, J2Z1.5 Hz, H-4 of the chain),
4.32 (2H, m, 2H-5), 2.55 (1H, dt, J1Z8.5 Hz, J2Z13.1 Hz,
H-4), 2.32 (1H, m, H-4), 2.36 (3H, s, SCH3), 1.52 (3H, s,
CH3); 13C NMR (d, ppm): (E,Z)-42: 177.7 (s), 148.5 (s),
141.3 (d), 141.2 (d), 113.1 (d), 65.4 (t, C-5), 43.4 (s, C-3),
33.3 (t, C-4), 23.3 (q, SCH3), 15.7 (q, CH3); Anal. Calcd for
C10H13NO4S: C, 49.37; H, 5.39; N, 5.76; S, 13.18. Found:
C, 48.8; H, 5.49; N, 5.64. On standing in CDCl3, the (E,Z)-
isomer converted into its (Z,Z) isomer for an amount of
20%.
4.6.8. (E)-4,5-Dihydro-3-methyl-3-(4,4-dimethylthio)bu-
tadienyl-2(3H)-furanone 45. On standing in CDCl3, 44a
and 44b convert into the diene system 45. Oil. IR (cmK1
,
1
CHCl3): 1770 (COO), 1605, 1558 (C]C); H NMR (d,
ppm): 6.78 (1H, dd, J1Z15.7 Hz, J2Z10.2 Hz, H-2 of the
chain), 6.32 (1H, d, JZ10.2 Hz, H-3 of the chain), 5.77 (1H,
d, JZ15.7 Hz, H-1 of the chain), 4.29 (2H, m, 2H-5), 2.40
(1H, m, H-4), 2.33 (3H, s, SCH3), 2.32 (3H, s, SCH3), 2.17
(1H, m, H-4), 1.40 (3H, s, CH3); 13C NMR (d, ppm): 168.0
(s), 133.6 (s), 133.2 (d), 129.4 (d), 126.9 (d), 65.2 (t), 45.3
(s), 35.8 (t), 23.3 (q), 17.4 (q,), 16.7 (q); MS (m/z): 245
(MHC, 19), 244 (MC$, 21), 231 (19), 230 (24), 229 (100),
213 (13), 212 (15), 201 (36), 185 (12), 183 (43), 155 (10),
138 (10), 137 (13), 123 (10), 91 (19), 77 (12). Anal. Calcd
for C11H16O2S2: C, 54.06; H, 6.60; S, 26.24. Found: C, 55.0;
H, 6.67.
Compound (Z,Z)-42. 1H NMR (d, ppm) (a few signals were
hidden under those of the (E)-isomer): 6.54 (1H, d, JZ
11.0 Hz, H-3 of the chain), 6.29 (1H, s, H-1 of the chain),
6.09 (1H, d, JZ11.0 Hz, H-4 of the chain), 4.44 (1H, dt,
J1Z1.5 Hz, J2Z9.2 Hz, H-5), 2.41 (3H, s, SCH3), 1.57 (3H,
s, CH3); 13C NMR (d, ppm): 180.6 (s), 147.5 (s), 137.9 (d),
132.6 (d), 115.2 (d), 65.4 (t, C-5), 43.6 (s, C-3), 34.3 (t, C-4),
23.9 (q, SCH3), 18.9 (q, CH3).
Acknowledgements
4.6.6. (E)-4,5-Dihydro-3-methyl-3-(4,4-dimethylthio-2-
nitro)butadienyl-2(3H)-furanone 43. The product (70%
yield) was purified by flash chromatography (eluant: light
The authors wish to thank the Universities of Trieste,
Bologna, and Genova and M.I.U.R. (Rome) for financial
support to this research (PRIN 2001-2003).
petroleum:ethyl acetate, gradient), mp 82–84 8C; IR (cmK1
,
1
film): 1770 (COO), 1666 (C]C), 1528, 1368 (NO2); H
NMR (d, ppm): 7.24 (1H, d, JZ1.8 Hz, H-1 of the chain),
5.96 (1H, d, JZ1.8 Hz, H-3 of the chain), 4.32 (2H, dd, J1Z
6.0 Hz, J2Z7.7 Hz, 2H-5), 2.48 (1H, dt, J1Z7.7 Hz, J2Z
12.8 Hz, H-4), 2.45 (3H, s, SCH3), 2.35 (3H, s, SCH3), 2.30
(1H, dt, J1Z6.0 Hz, J2Z12.8 Hz, H-4), 1.51 (3H, s, CH3);
13C NMR (d, ppm): 177.7 (s), 149.8 (s), 147.9 (s), 137.0 (d,
C-1 of the chain), 111.0 (d, C-3 of the chain), 65.3 (t, C-5),
43.2 (s, C-3), 35.9 (t, C-4), 22.6 (q, CH3), 16.4 (q, SCH3),
16.2 (q, SCH3); MS (m/z): 289 (MC$, 3), 243 (100), 215
(48), 195 (11), 167 (22), 139 (11), 91 (11). Anal. Calcd for
C11H15NO4S2: C, 45.66; H, 5.22; N, 4.84; S, 22.16. Found:
C, 46.5; H, 5.35; N, 4.76.
References and notes
1. (a) Fischer, N. H.; Olivier, E. J.; Fischer, H. D. In Progress in
the Chemistry of Organic Natural Compounds, Herz, W.,
Grisebach, H., Kirby G. W., Eds.; Springer Verlag, New York:
1979, 38, ch. 2. (b) Devon, T. K.; Scott, A. I. In Handbook of
Naturally Occurring Compounds, Academic, New York,
1975; Vol. 1.
2. (a) Yoshoka, H.; Mabry, T. J.; Timmermann, B. N.
Sesquiterpene Lactones: Chemistry, NMR and Plant Distri-
bution, University Tokyo Press, Tokyo, Japan, 1973. (b)
Hoffmann, H. M. R.; Raabe, J. Angew. Chem., Int. Ed. Engl.
1985, 24, 94–110.
4.6.7. 4,5-Dihydro-3-methyl-3-[(4,4-dimethylthio-2-
nitro)but-3-enyl]-2(3H)-furanone 44a,b. To a solution of
the nitrodiene 43 (0.04 g, 0.14 mmol) in MeOH (7 ml),
0.105 g of supported borohydride (2 mmol/g of Amberlyst
A26, Aldrich product) was added under stirring and the
reaction was monitored by TLC. After 15 min, the polymer
was filtered off and washed with MeOH, the filtrated was
evaporated and purified by flash chromatography. Com-
pounds 44a and 44b (60 and 40%, respectively) were not
separable by flash chromatography. For sake of clarity the
NMR values of the isomeric mixture are given separately
for each isomer.
3. (a) Hormuth, S.; Deissig, H.-U.; Dorsch, D. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1449–1450. (b) Maritani, Y.; Ukita, T.;
Nishitani, T.; Seki, M.; Iwasaki, T. Tetrahedron Lett. 1990, 31,
3615–3618. (c) Tomioka, K.; Cho, Y.-S.; Sato, F.; Koga, K.
J. Org. Chem. 1988, 53, 4094–4098.
4. (a) Klunk, W. E.; McKeon, A. C.; Coney, D. F.; Ferrendelli,
J. A. Science 1982, 217, 1040–1042. (b) Peterson, E. M.; Xu,
K.; Holland, K. D.; McKeon, A. C.; Rothman, S. M.;
Ferrendelli, J. A.; Coney, D. F. J. Med. Chem. 1994, 37,
275–286 and references therein.
5. (a) Node, M.; Nagasawa, H.; Naniwa, Y.; Fuji, K. Synthesis
1987, 729–732. (b) Fuji, K.; Node, M.; Nagasawa, H.; Naniwa,
Y.; Terada, S. J. Am. Chem. Soc. 1986, 108, 3855–3856. (c)
Nishide, K.; Kurosaki, R.; Hosomi, K.; Imazato, H.; Inoue, T.;
Compound 44a. 1H NMR (d, ppm): 5.52 (1H, d, JZ8.8 Hz,
H–C]C), 4.50 (1H, dt, J1ZJ2Z8.8 Hz, J3Z4.8 Hz, CH–
NO2), 4.26 (2H, m, 2H-5), 2.44 (1H, m), 2.35 (3H, s, SCH3),

C. Forzato et al. / Tetrahedron 60 (2004) 11011–11027
11027
`
¨
Node, M.; Ohmori, T.; Fuji, K. Tetrahedron 1995, 51,
10857–10866. (d) Katoh, T.; Nishide, K.; Node, M.; Ogura,
H. Heterocycles 1999, 50, 833–841.
19. Thominiaux, C.; Rousse, S.; Desmaele, D.; d’Angelo, J.;
Riche, C. Tetrahedron: Asymmetry 1999, 10, 2015–2021.
20. Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–1047 and
references cited therein.
6. (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed.
Engl. 1998, 37, 388–401. (b) Ramachandran, P. V.; Chen,
G. M.; Brown, H. C. J. Org. Chem. 1996, 61, 88–94. (c) Fuji,
K. Chem. Rev. 1993, 93, 2037–2066. (d) Isaka, M.; Nakamura,
E. J. Am. Chem. Soc. 1990, 112, 7428–7430. (e) Martin, S. F.
Tetrahedron 1980, 36, 419–460.
21. Breuer, E.; Aurich, H. G.; Nielsen, A. Nitrones, nitronates and
nitroxides. In The Chemistry of Functional Groups; Patai, S.,
Rappoport, Z., Eds.; Wiley: Chichester, 1989.
22. Jackmann, L. M.; Sternhell, S. Application of Nuclear
Magnetic Resonance Spectroscopy in Organic Chemistry.
2nd ed.; Pergamon: London, 1969.
7. Enders, D.; Teschner, D.; Raabe, G. Synlett 2000, 637–640.
8. (a) Fitzi, R.; Seebach, D. Tetrahedron 1988, 44, 5277–5292.
(b) Calderari, G.; Seebach, D. Helv. Chim. Acta 1985, 68,
1592–1604.
23. (a) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia
1979, 33, 1–18. (b) Stevens, R. W.; Mukaiyama, T. Chem.
Lett. 1985, 855–856.
24. Oare, D. A.; Heathcock, C. H. Stereochemistry of the base
promoted Michael addition reaction. In Topics in Stereo-
chemistry; Eliel, E. L., Wiley, S. H., Eds.; Wiley: New York,
1989; Vol. 19.
9. Pavlova, Z. F.; Lipina, E. S.; Kasem, Ya. A.; Kuz’mina,
N. V. Russ. J. Org. Chem 1999, 35, 1321–1325.
10. Surage, S. S.; Rajappa, S. Tetrahedron Lett. 1998, 39,
7169–7172.
25. Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay,
T.; Simson, M.; Seebach, D. Synthesis 1993, 1271–1290.
¨
26. Lerche, H.; Konig, D.; Severin, Th. Chem. Ber. 1974, 107,
11. Surage, S. S.; Kumarau, G.; Rajappa, S.; Rajalakshmi, K.;
Pattabhi, V. Tetrahedron 1997, 53, 8531–8540.
12. Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.;
Cosimelli, B.; Spinelli, D. Tetrahedron 2001, 57, 8159–8165.
13. (a) Shih, N. Y.; Lupo, A. T. Jr.; Aslanian, R.; Orlando, S.;
Piwinski, J. J.; Green, M. J.; Ganguly, A. K.; Clark, M. A.; Tozzi,
S.; Kreutner, W.; Hey, J. A. J. Med. Chem. 1995, 38,
1593–1599. (b) Corey, E. J.; Li, W.; Reichard, G. A. J. Am.
Chem. Soc. 1998, 120, 2330–2336.
1509–1517.
27. (a) Severin, Th.; Konig, D. Chem. Ber. 1974, 107, 1499–1508.
¨
(b) Severin, T.; Kullmer, H. Chem. Ber. 1971, 104, 440–448.
28. Fuji, K.; Node, M. Synlett 1991, 603–610.
29. Fuji, K.; Kawabata, T.; Naniwa, Y.; Ohmori, T.; Node, M.
Chem. Pharm. Bull. 1994, 42, 999–1001.
30. (a) Kawai, Y.; Inaba, Y.; Tokitoh, N. Tetrahedron: Asymmetry
2001, 12, 309–318. (b) Dell’Erba, C.; Mele, A.; Novi, M.;
Petrillo, G.; Stagnaro, P. Tetrahedron 1992, 48, 4407–4418.
31. Goudgaon, N. M.; Wadgaonkar, P. P.; Kabalka, G. W. Synth.
Commun. 1989, 19, 805–808.
14. (a) Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry
1992, 3, 1213–1221. (b) McGeer, P. L.; McGeer, E. G. Basic
Neurochemistry: Molecular, Cellular and Medical Aspects,
4th ed.; Siegel, G. J., Agranoff, B., Albens, R. W., Molinoff, P.,
Eds.; Raven: New York, 1989.
¨
32. Grobel, B.-Th.; Seebach, D. Synthesis 1977, 357–402.
15. Otto, A.; Abegaz, B.; Ziemer, B.; Liebscher, J. Tetrahedron:
Asymmetry 1999, 10, 3381–3389.
33. Oare, D. A.; Heathcock, C. H. Acyclic stereocontrol in
Michael addition reactions of enamines and enol ethers. In
Topics in Stereochemistry; Eliel, E. L., Wiley, S. H., Eds.;
Wiley: New York, 1991; Vol. 20.
16. (a) Bapat, J. B.; Black, D. St. C.; Brown, R. F. C. In Advances
in Heterocyclic Chemistry, 1969; Vol. 10, pp 199–240. (b)
Thomas, A.; Rajappa, S. Tetrahedron 1995, 51, 10571–10580.
17. Grant, D. M.; Cheney, B. V. J. Am. Chem. Soc. 1967, 89,
5319–5327.
34. Buckley, G. D.; Scaife, C. W. J. Chem. Soc. 1947, 1471–1472.
35. Boberg, F.; Schultze, G. R. Chem. Ber. 1957, 90, 1215–1225.
36. Falques, M.; Rene, L.; Royer, R. Synthesis 1982, 260–261.
37. Black, A. P.; Babers, F. H. Organic Syntheses; Collect. Wiley:
New York; Vol. 2, pp 412 and 512.
18. Seebach, D.; Prelog, W. Angew. Chem., Int. Ed. Engl. 1982,
21, 654–660.