Condensed 2-pyrrolidinone-1,2-oxazines from lithium enolate of 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid and β-aryl, β-nitroenamines

Article abstract of DOI:10.1016/j.tet.2006.06.106

The reaction of the lithium enolate of 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid 3 with a series of β-aryl, β-nitroenamines unexpectedly afforded 6-aryl-2-benzyl-4-oxa-1-oxo-3a-methoxycarbonyl-2,5-diazaindenes 9a-d, whose structure was determined by analytical and NMR spectroscopical analysis. The structure of 9b was further confirmed by X-ray analysis. A reasonable mechanism for their formation is given.

Full text of DOI:10.1016/j.tet.2006.06.106

Tetrahedron 62 (2006) 8787–8791
Condensed 2-pyrrolidinone-1,2-oxazines from lithium enolate
of 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid and
b-aryl, b-nitroenamines
b
Fulvia Felluga,a Valentina Gombac,a Giuliana Pitacco,a Ennio Valentin,a, Ennio Zangrando,
*
Stefano Morganti,c Egon Rizzato,c Domenico Spinellic and Giovanni Petrillod
aDipartimento di Scienze Chimiche, Universitaꢀ di Trieste, Via L. Giorgieri 1, I-34127 Trieste, Italy
bCentro di Eccellenza in Biocristallografia, Universitaꢀ di Trieste, Via L. Giorgieri 1, I-34127 Trieste, Italy
cDipartimento di Chimica Organica ‘A. Mangini’, Universitaꢀ di Bologna, Via San Giacomo 11, I-40126 Bologna, Italy
dDipartimento di Chimica e Chimica Industriale, Universitaꢀ di Genova, Via Dodecaneso 31, I-16146 Genova, Italy
Received 28 March 2006; revised 9 June 2006; accepted 29 June 2006
Available online 24 July 2006
Abstract—The reaction of the lithium enolate of 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid 3 with a series of b-aryl, b-nitroenamines
unexpectedly afforded 6-aryl-2-benzyl-4-oxa-1-oxo-3a-methoxycarbonyl-2,5-diazaindenes 9a–d, whose structure was determined by
analytical and NMR spectroscopical analysis. The structure of 9b was further confirmed by X-ray analysis. A reasonable mechanism for their
formation is given.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
(4a–e),10 under strongly basic conditions, with the aim of ob-
taining new a-functionalized aza paraconic acid derivatives.
The g-lactam nucleus (2-pyrrolidinone) characterizes
several compounds with biological and pharmaceutical
activities.1 Furthermore, 2-pyrrolidinones are also useful
intermediates in organic synthesis.2 In particular, polyfunc-
tionalized g-lactams have been synthesized to obtain g-amino-
butyric acid (GABA) analogues by hydrolysis under either
acidic or basic conditions.3 GABA4 is a major inhibitory
neurotransmitter in the mammalian central nervous system
(CNS) and several psychiatric and neurological diseases
are correlated with a disfunctioning of the GABA system,
which acts in opposition to excitatory systems such as gluta-
mate.5 Many unnatural g-amino acids have been designed
for their promising therapeutic use in the treatment of these
diseases, acting either as specific agonists at post-synaptic
GABAA receptors6 or as inhibitors of the GABA-uptake
mechanism.7 Within the frame of our research in the field
of g-lactams bearing a b-carboxylic group (such as 1,8 i.e.,
the aza analogue of paraconic acid 29), (Fig. 1) we have ex-
amined the reactivity of 1-benzyl-5-oxo-3-pyrrolidinecar-
boxylic acid (3)8b with a series of b-aryl, b-nitroenamines
As a matter of fact, b-nitroenamines11 react under strongly
basic conditions with ketones, esters, and lactones 5 con-
taining active hydrogens at the a-position to give the
corresponding 2-aci-nitroalkylidene derivatives 6 as a conse-
quence of a conjugative addition–elimination reaction
(Scheme 1).12
The fate of these intermediates depends on the structure of
both the substrate and the nitroenamine as well as on the
type of the final treatment. With ketones,12a linear esters,12b
and lactones the corresponding 1,4-dicarbonyl compounds 7
were isolated (for R3¼Me), as a result of a Nef reaction,12a,13
while by treatment with a suitable alkylating reagent nitronic
HOOC
O2N
Ar
HOOC
O
N
O
N
R
O
R = H: 1
2
4a–e
R = Bn: 3
a: Ar = C6H5-
b: Ar = o-MeS-C6H4-
c: Ar = o-EtS-C6H4-
s
d: Ar = o-Bu S-C6H4-
Keywords: g-Lactams; b-Nitroenamines; Michael addition; Intramolecular
redox process; Electrocyclic reaction; Condensed 1,2-oxazines.
* Corresponding author. Tel.: +39 040 558 3917; fax: +39 040 558 3903;
e-mail: valentin@dsch.units.it
e: Ar = o-BnS-C6H4-
Figure 1. Reactants 3 and 4a–e.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.106

8788
F. Felluga et al. / Tetrahedron 62 (2006) 8787–8791
R2
R3
R1
NO2Me
(Et)
O
8
Me2SO4
(Et3OBF4)
R3
R3
R2
R2
Me2N
R1
NO2
1
R
-
+
NO2 M
NaH or EtO-K
+
O
5
O
i
or LiN(Pr )Cy
6
R1 = alkyl, aryl, O-alkyl
R2 = H, Me;
silica gel
R2
R3 = Me
R3
R1,R2 = (CH2)2,(CH2)3
Figure 2. X-ray crystal structure of the 1,2-oxazine derivative 9b.
Table 1. The main NMR spectroscopic data for compounds 9a–d
R
3 = H, Me
R1
Cy = cyclohexyl
O
O
7
Compd
H-3
H-7
C-3
C-3a
C-6
C-7
Scheme 1. General reactivity of carbonyl compounds and acidic derivatives
with nitroenamines.
9a
9b
9c
9d (two
diast.)
3.60, 3.80
3.60, 3.82
3.60, 3.81
3.59, 3.81
7.07
6.83
6.81
6.81,
6.83
46.8
46.6
46.5
46.6
74.4
74.4
74.2
74.3
155.0
156.4
156.7
156.8,
156.9
112.0
115.1
115.2
115.62,
115.57
alkyl esters of the type 8 were the products, which could
undergo further transformations.
2. Results and discussion
ortho-benzylthio group, was found unreactive, probably
due to steric reasons, allowing the complete recovery of
the reagents.
Lactamic acid 3 (twofold excess) in THF was treated with
LDA (or n-butyllithium) (2.2–2.5 molar ratio with respect
to 3) under an inert atmosphere, at ꢀ78 ꢁC. The b-nitro-
enamines 4a–e were then added and the mixture was heated
for 1 h. The crude reaction mixtures were acidified to pH 2
and subsequently esterified with methanol, in the presence
of trimethylchlorosilane,14 in order to separate esters 9a–d
from the methyl ester of substrate 3 (Scheme 2). No other
products were detected.
Compounds 9a–d are unknown in the literature as yet. In
fact, formations of 6H-1,2-oxazine derivatives are reported
to proceed by a hetero Diels–Alder reaction of suitable
alkenes with a-nitroso alkenes.16,17 a-Nitro alkenes are
known to give smoothly 1,2-oxazine-N-oxide derivatives
in their reactions with enamines,18 whereas silyl enol ethers,
vinyl ethers, and isolated dienes react only in the presence of
Lewis acid promoters.19,20,21
Ar
6
1) BuLi, THF,
-78°C
N
In order to gain information on the mechanism of the reac-
tion observed, several attempts have been made to isolate
at least one of the possible intermediates. To this purpose,
the reaction work-up was performed with acids weaker
than mineral acids and attempts to trap the expected nitro-
nate intermediate of the type 6 (Scheme 1) with ethyl acryl-
ate22 and ethylidene malonate22 were also made, but
unsuccessfully. Anyway, on the basis of the expected reac-
tivity of the reagents, the mechanism reported in Scheme 3
is proposed to account for the formation of these unusual
bicyclic 1,2-oxazine derivatives 9a–d.
O
3
7
7a
2) 64°C, 1h
MeOOC
3
+ 4a–e
3)H3O+
4) MeOH,
Me3SiCl
3a
O
N
1
Bn
9a–d
Scheme 2. Formation of the 1,2-oxazine derivatives 9a–d.
The structures of compounds 9a–d were attributed on the
basis of 1H and 13C NMR spectra, as well as by HRMS data,
and definitively confirmed by a single crystal X-ray crystal-
lographic analysis performed on 1,2-oxazine 9b (Fig. 2).15
As a matter of fact, we can assume that the lithium enolate of
3 adds to the b-nitroenamines 4 by the usual 1,4-conjugate
Michael addition to give nitronate salt 10. By acidification
to pH 2, i.e., under the conditions of Nef reaction,13 10 gives
11, which converts into 12 via the usual acid-catalyzed elimi-
nation of the secondary amine.
1H and 13C NMR spectra of compounds 9a–d show very
strict resemblances, in particular for protons and carbon
atoms of the heterocyclic skeleton. The variations range
within 0.3 ppm for protons and within less than 4 ppm for
carbons (Table 1).
The E-configuration of the carbon–carbon double bond in 12
is necessary for the subsequent reaction steps. In fact, a fast
cascade reaction can conceivably occur due to the simulta-
neous presence of the allylic proton and oxidizing nitronic
acid function,23 suitably positioned for an intramolecular
In the reaction of chiral racemic b-nitroenamine 4d, the re-
sulting product 9d was about 1:1 mixture of two diastereo-
mers, which could not be separated. Strangely enough, the
b-nitroenamine 4e, whose aromatic ring contains the

F. Felluga et al. / Tetrahedron 62 (2006) 8787–8791
Ar
8789
Ar
HO
samples and for CHCl3 solutions on a Jasco FTIR 200 spec-
trophotometer. 1H and 13C NMR spectra were run on either
a 300 MHz Varian Inova 300 instrument or a Jeol EX-400
spectrometer (400 MHz for proton), using deuteriochloro-
form as the solvent and tetramethylsilane as the internal
standard. Coupling constants are given in hertz. Mass spectra
were recorded on a VG 7070 (70 eV) spectrometer. HRMS
spectra were performed on a Finnigan MAT95XP spectro-
meter. TLC analyses were performed on PolygramÒ Sil G/
UV254 silica gel pre-coated plastic sheets (eluant:
dichloromethane–ethyl acetate). Flash chromatography
was run on silica gel 230–400 mesh ASTM (Kieselgel 60,
Merck). THF was distilled over benzophenone ketyl before
each use.
+
LiO2N
LiOOC
N
+
-O
HOOC
N
NH
H
+
+H3O
O
O
N
N
Bn
Bn
11
10
+
–R2NH2
Ar
HO
Ar
HO
+
H
N
N
-O
HOOC
H-O
HOOC
O
O
N
N
Bn
13
Bn
12
–H2O
Ar
Reagents: 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid 3
was prepared in accordance with the literature.26 Analytical
and spectroscopic data for (S)-(+)-3 are given in Ref. 8b.
Ar
N
O
N
O
HOOC
HOOC
b-Nitroenamines 4a10a and 4b10b were synthesized accord-
ing to the literature. Compounds 4c–e were obtained follow-
ing the synthetic procedure used for 4b;10c the silver salt
derived from the ring-opening of 3-nitrobenzo[b]thio-
phene27 has been treated with a large excess of ethyl iodide,
2-iodobutane, and benzyl bromide, respectively.
O
O
N
N
Bn
Bn
15a–d
14
Scheme 3. Proposed mechanism of formation of the acidic forms 15a–d of
the 1,2-oxazine derivatives 9a–d.
4.1.1. (1E,3Z)-Ethylthio-2-nitro-1-pyrrolidino-1,3-buta-
diene (4c). Yield 42%; yellow solid; mp 112–113 ꢁC; IR
redox process. The resulting intermediate 13 would in turn
lose a molecule of water from the –N(OH)2 grouping, thus
forming 14. Finally, a 6p-thermal electrocyclization, involv-
ing the 1-nitroso-1,3-butadiene system24,25 would afford the
acids 15a–d, isolated as their respective methyl esters 9a–d.
As to the intermediate 14, very little is known about aliphatic
nitrosodienes.24 However, recent computational studies car-
ried out on the cyclization pathways of 1-nitroso-1,3-buta-
diene25 indicate that, although, 1,5-electrocyclization
leading to pyrrole derivative is thermodynamically more
favored than the 1,6-electrocyclization giving the 6H-1,2-
oxazine, formation of this latter system is slightly faster
than that of the former one.
(CHCl3) 1617, 1487, 1457, 1400, 1244 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 1.32 (1H, t, J¼7.5 Hz), 1.82 (4H, br
band), 2.71 (2H, br band), 2.93 (2H, q, J¼7.5 Hz), 3.66
(2H, br band), 7.12–7.19 (1H, m), 7.24–7.30 (2H, m),
7.32–7.39 (1H, m), 8.67 (1H, s); 13C NMR (75 MHz,
CDCl3) d 13.8, 24.3, 25.9, 26.2, 47.9, 55.0, 122.5, 125.8,
129.5, 130.9, 133.5, 140.8, 145.9; ESIMS, m/z 301.0
[M+Na]+; MS (70 eV) m/z 278 (4), 232 (12), 216 (22), 203
(14), 163 (59), 148 (30), 135 (100), 108 (16), 99 (17);
HRMS (EI) calcd for C14H18N2O2S (M+): 278.1084; found:
278.1086.
4.1.2. (1E,3Z)-sec-Butylthio-2-nitro-1-pyrrolidino-1,3-
butadiene (4d). Yield 12%; yellow oil; IR (film) 1618,
1487, 1455, 1399, 1256, 1219 cmꢀ1; H NMR (300 MHz,
1
3. Conclusions
CDCl3) d 0.94–1.04 (m, 3H), 1.28 (3H, d, J¼6.6 Hz),
1.46–1.73 (2H, m), 1.81 (4H, br band), 2.67 (2H, br band),
3.25 (1H, m), 3.66 (2H, br band), 7.14–7.40 (4H, m), 8.66
(1H, s); 13C NMR (75 MHz, CDCl3) d 11.3, 20.1, 20.4,
24.2, 25.8, 29.2, 29.3, 43.1, 48.0, 54.9, 122.7, 124.8,
124.9, 127.9, 128.3, 129.28, 129.32, 132.1, 132.3, 133.45,
133.52, 139.8, 140.1, 145.8; ESIMS m/z 328.9 [M+Na]+;
MS (70 eV) m/z 306 (1), 260 (10), 217 (21), 191 (11), 163
(5), 147 (8), 135 (100), 121 (6), 108 (5), 99 (7). HRMS
(EI) calcd for C16H22N2O2S (M+): 306.1400; found:
306.1402.
The peculiar reactivity of the arylated b-nitroenamines 4
with the lithium enolate of the lactamic acid 3 leads to the
heterocyclic derivatives 9, which are to the best of our
knowledge, the first examples of aza paraconic acid deriva-
tives condensed with a six-membered heterocyclic ring. The
key step in the reaction is likely to be the formation of the
intermediate 12 of the proposed mechanism, from which
the a-butenolides 13 and 14 are produced, thus allowing
the heterodiene with an intramolecular inverse electron
demand Diels–Alder reaction to occur.
4.1.3. (1E,3Z)-Benzylthio-2-nitro-1-pyrrolidino-1,3-
butadiene (4e). Yield 27%; yellow solid; mp 128–129 ꢁC;
4. Experimental
4.1. General
IR (CHCl3) 1616, 1487, 1456, 1399, 1256, 1220 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 1.81 (4H, br band), 2.54
(2H, br band), 3.63 (2H, br band), 4.12 (2H, m), 7.14–7.38
(9H, m), 8.65 (1H, s); 13C NMR (75 MHz, CDCl3) d 24.0,
25.7, 37.0, 47.9, 54.9, 122.2, 124.8, 126.7, 127.0,
128.2, 128.7, 129.3, 131.2, 133.2, 136.8, 140.1, 145.6;
€
Melting points were measured using a Buchi 510 apparatus
and were uncorrected. IR spectra were recorded for neat

8790
F. Felluga et al. / Tetrahedron 62 (2006) 8787–8791
Found: C ESIMS m/z 363.0 [M+Na]+; MS (70 eV) m/z
294 (11), 225 (22), 134 (14), 91 (100), 65 (13); HRMS
(EI) calcd for C19H20N2O2S (M+): 340.1247; found:
340.1247.
HRMS (EI) calcd for C22H20N2O4S (M+): 408.1144; found:
408.1146.
4.2.1.3. 2-Benzyl-6-(2-ethylthiophenyl)-3a-methoxy-
carbonyl-4-oxa-1-oxo-2,5-diazaindene (9c). Yield 100 mg
(47%); mp 147–149 ꢁC; IR (CHCl3) 1730, 1695,
4.2. Reactions between lactamic acid 3 and
nitroenamines 4a–d
1525 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.25 (3H,
;
t, SCH2CH3), 2.84 (2H, dq, SCH2CH3), 3.60 (1H, d, J¼
10.6 Hz, H-3), 3.72 (3H, s, OCH3), 3.81 (1H, d, J¼
10.6 Hz, H-3), 4.52 (1H, d, J¼14.9 Hz, PhCH2N), 4.77
(1H, d, J¼14.9 Hz, PhCH2N), 6.81 (1H, s, H-7), 7.26–7.50
(9H, m, Ar-H); 13C NMR (100 MHz, CDCl3) d 14.3 (q,
SCH2CH3), 28.6 (t, SCH2CH3), 46.5 (t, C-3), 53.0 (q,
OCH3), 54.0 (t, CH2Ph), 74.2 (s, C-3a), 115.2 (d, C-7),
126.5 (d), 128.0 (2d), 128.1 (2d), 128.8 (d), 129.5 (d),
130.3 (d), 130.4 (s), 130.4 (d), 134.4 (s), 134.8 (s), 135.8
(s), 156.7 (s, C-6), 163.2 (s, O–C]O), 169.0 (s, N–C]O);
4.2.1. General procedure. A solution of lithium diisopro-
pylamide (2.5 mmol) in THF (3.5 mL) [or a solution of
sec-butyllithium (2.2 mmol) in cyclohexane] was slowly
added to a solution of 3 (1 mmol) in THF (23 mL), at
ꢀ78 ꢁC, under argon. The reaction mixture was stirred at
ꢀ78 ꢁC for 3 or 4 h, then it was slowly added to a solution
of the appropriate nitroenamine 4 (0.5 mmol) in THF
(2 mL) at the same temperature, by means of a double-ended
needle. The mixture was gradually warmed to room tempera-
ture and then heated to reflux for 1 h. After cooling to room
temperature, the mixture was further stirred overnight. The
reaction mixture was quenched by the addition of 3 M
HCl. The aqueous phase was extracted three times with
CH2Cl2. The combined organic layers were washed with
saturated NaHCO3, the aqueous phase was acidified to pH
2 with 3 M HCl solution, and extracted three times with
CH2Cl2. The combined organic layers were dried on anhy-
drous Na2SO4 and the solvent was removed to give the crude
product (200–220 mg). This was esterified with methanol in
trimethylchlorosilane and purified by flash column chroma-
tography (silica gel, eluent: ethyl acetate–dichloromethane,
gradient from 0% up to 10%) to afford 9a–d as white crys-
talline solids in yields varying from 26 to 47%.
ꢂ
MS (70 eV) m/z 422 (M+ , 33), 390 (50), 392 (54), 361
(34), 363 (85), 335 (23), 332 (27), 274 (34), 246 (34), 91
(100), 65 (10); HRMS (EI) calcd for C23H22N2O4S (M+):
422.1300; found: 422.1300.
4.2.1.4. 2-Benzyl-6-(2-(2-methyl)propylthiophenyl)-
3a-methoxycarbonyl-4-oxa-1-oxo-2,5-diazaindene (9d).
Yield 59 mg (26%), two diastereomers; mp 128–132 ꢁC;
1
IR (CHCl3) 1730, 1697, 1523 cmꢀ1; H NMR (400 MHz,
CDCl3) d 0.94 (3H, t, J¼7.33 Hz, CH2CH3), 0.94 (3H, t, J¼
7.32 Hz, CH2CH3), 1.18 (3H, d, J¼6.23 Hz, CHCH3), 1.20
(3H, d, J¼6.59 Hz, CHCH3), 1.40–1.53 (2H, m, CH3CH2),
1.53–1.68 (2H, m, CH3CH2), 3.04–3.17 (1H, m, CH3CH),
3.59 (1H, d, J¼10.6 Hz, H-3), 3.72 (3H, s, OCH3), 3.81
(0.5H, d, J¼10.6 Hz, H-3), 3.80 (0.5H, d, J¼11.0 Hz,
H-3), 4.51 (0.5H, d, J¼15.0 Hz, PhCH2N), 4.52 (0.5H, d,
J¼15.0 Hz, PhCH2N), 4.77 (1H, d, J¼15.0 Hz, PhCH2N),
6.81 (0.5H, s, H-7), 6.83 (0.5H, s, H-7), 7.20–7.51 (9H, m,
2Ar-H); 13C NMR (100 MHz, CDCl3) d 11.2, 11.3 (2q,
CH3CH), 20.3 (2q, CH2CH3), 29.4, 29.5 (2t, CH2CH3),
45.4, 45.8 (2d, CH3CHCH2), 46.6 (2t, C-3), 52.98, 53.00
(2q, OCH3), 54.1 (2t, CH2Ph), 74.3 (2s, C-3a), 115.57,
115.62 (2d, C-7), 127.1, 127.3 (2d), 128.1 (2d), 128.2 (4d),
128.9 (4d), 129.70, 129.75 (2d), 129.8, 129.9 (2s), 130.41,
130.43 (2d), 133.2, 132.7 (2d), 134.8 (2s), 135.0, 135.1
(2s), 135.8, 136.7 (2s), 156.8 (2s, C-6), 156.9 (2s, C-6),
163.4 (2s, O–C]O), 169.1 (2s, N–C]O); MS (70 eV)
4.2.1.1. 2-Benzyl-3a-methoxycarbonyl-4-oxa-1-oxo-6-
phenyl-2,5-diazaindene (9a). Yield 47 mg (26%); mp
156–158 ꢁC; IR (CHCl3): 1730, 1695, 1525 cmꢀ1 1H
;
NMR (400 MHz, CDCl3) d 3.60 (1H, d, J¼11.0 Hz, H-3),
3.69 (3H, s, OCH3), 3.80 (1H, d, J¼11.0 Hz, H-3), 4.55
(1H, d, J¼15.0 Hz, PhCH2N), 4.77 (1H, d, J¼15.0 Hz,
PhCH2N), 7.07 (1H, s, H-7), 7.26–7.48 (10H, m, Ar-H);
13C NMR (100 MHz, CDCl3) 46.8 (t, C-3), 53.3 (q,
OCH3), 54.3 (t, CH2Ph), 74.6 (s, C-3a), 112.0 (d, C-7),
126.5 (d), 128.3 (d), 129.0 (d), 130.9 (s), 133.8 (s),
134.6 (s), 155.2 (s, C-6), 163.4 (s, O–C]O), 169.0 (s,
ꢂ
N–C]O); MS (70 eV) m/z 362 (M+ , 7.5), 332 (MꢀNO,
ꢂ
22), 303 (MꢀCH3COꢂ2, 17), 200 (14), 156 (7.5), 91 (100);
HRMS (EI) calcd for C21H18N2O4 (M+): 362.1266; found:
362.1263.
m/z 450 (M+ , 20), 420 (12), 391 (23), 393 (48), 395 (18),
361 (34), 334 (23), 335 (100), 275 (18), 245 (13), 246
(32), 249 (15), 215 (15), 200 (12), 91 (86); HRMS (EI) calcd
for C25H26N2O4S (M+): 450.1613; found: 450.1611.
4.2.1.2. 2-Benzyl-6-(2-methylthiophenyl)-3a-methoxy-
carbonyl-4-oxa-1-oxo-2,5-diazaindene (9b). Yield 92 mg
(45%); mp 153–154 ꢁC; IR (CHCl3) 1728, 1697,
4.2.1.5. Crystal data for 9b. Data collected on a rotating
˚
anode (Cu Ka 1.54178 A). Monoclinic, space group P21/n,
1
1524 cmꢀ1; H NMR (400 MHz, CDCl3) d 2.43 (3H, s,
a¼8.161(2), b¼27.296(4), c¼9.950(3) A, b¼113.25(2) ,
ꢁ
˚
3
V¼2036.4(8) A , Z¼4, rcalcd¼1.332 Mg mꢀ3, qmax¼64.76ꢁ,
˚
SCH3), 3.60 (1H, d, J¼11.0 Hz, H-3), 3.73 (3H, s, OCH3),
3.82 (1H, d, J¼11.0 Hz, H-3), 4.55 (1H, d, J¼14.6 Hz,
PhCH2N), 4.75 (1H, d, J¼14.6 Hz, PhCH2N), 6.83 (1H, s,
H-7), 7.25–7.48 (9H, m, Ar-H); 13C NMR (100 MHz,
CDCl3) d 17.1 (q, SCH3), 46.6 (t, C-3), 53.1 (q, OCH3),
54.0 (t, CH2Ph), 74.4 (s, C-3a), 115.1 (d, C-7), 125.7 (d),
127.7 (d), 128.2 (d), 128.3 (2d), 128.9 (2d), 129.4 (d),
130.7 (d), 131.0 (s), 132.8 (s), 134.8 (s), 138.0 (s), 156.4
(s, C-6), 163.3 (s, O–C]O), 169.1 (s, N–C]O); MS
temp¼293(2) K, no. of measured and independent reflec-
tions: 21461/3318, no. of parameters¼264, R1¼0.0492,
3
˚
wR2¼0.1422, max residual electron density: 0.214 e/A .
Acknowledgements
Financial supports from M.I.U.R. (Rome), PRIN 2004, and
the Universities of Bologna, Genova, and Trieste are grate-
fully acknowledged.
ꢂ
(70 eV) m/z 408 (M+ , 24), 393 (21), 379 (22), 378 (85),
349 (58), 348 (12), 274 (17), 246 (25), 91 (100), 65 (10);

F. Felluga et al. / Tetrahedron 62 (2006) 8787–8791
8791
Valentin, E. Targets in Heterocyclic Systems, Chemistry and
ꢀ
References and notes
Properties; Attanasi, O. A., Spinelli, D., Eds.; Societa
Chimica Italiana: Rome, 1999; Vol. 3, pp 93–115; (c) Mori,
K. Tetrahedron 1983, 39, 3107–3109 and references therein.
10. (a) Boberg, F.; Schultze, G. R. Chem. Ber. 1957, 90, 1215–
1225; (b) Surage, S. S.; Rajappa, S. Tetrahedron Lett. 1998,
39, 7169–7172; (c) Dell’Erba, C.; Gabellini, A.; Novi, M.;
Petrillo, G.; Tavani, C.; Cosimelli, B.; Spinelli, D.
Tetrahedron 2001, 57, 8159–8165.
1. (a) Donohoe, T. J.; Sintin, H. O.; Sisangia, L.; Harling, J. D.
Angew. Chem., Int. Ed. 2004, 43, 2293–2296; (b) Corey,
E. J.; Li, W.-D. Z.; Nagamitsu, T.; Fenteany, G. Tetrahedron
1999, 55, 3305–3316; (c) Corey, E. J.; Li, W.-D. Z. Chem.
Pharm. Bull. 1999, 47, 1–10; (d) Ghelfi, F.; Bellesia, F.;
Forti, L.; Ghirardini, G.; Grandi, R.; Libertini, E.;
Montemaggi, M. C.; Pagnoni, U. M.; Pinetti, A.; De Buick,
L.; Parsons, A. F. Tetrahedron 1999, 55, 5839–5852; (e)
Bryans, J. S.; Large, J. M.; Parsons, A. F. J. Chem. Soc.,
Perkin Trans. 1 1999, 2905–2910; (f) Moody, C. M.; Young,
D. W. Tetrahedron Lett. 1994, 35, 7277–7280; (g) Meyers,
A. I.; Sneyder, L. J. Org. Chem. 1993, 58, 36–42; (h)
Nilsson, B. M.; Ringdhal, B.; Hocksell, U. A. J. Med. Chem.
1990, 33, 580–584; (i) Bergmann, R.; Gericke, R. J. Med.
Chem. 1990, 33, 492–504.
2. (a) Mandal, A. K.; Hines, J.; Kuramoki, K.; Crews, C. M.
Bioorg. Med. Chem. Lett. 2005, 15, 4043–4047; (b) Bowman,
W. R.; Cloonan, M. O.; Krintel, S. L. J. Chem. Soc., Perkin
Trans. 1 2001, 2885–2902; (c) Masse, C. E.; Morgan, A. J.;
Adams, J.; Panek, J. S. Eur. J. Org. Chem. 2000, 2513–2528;
(d) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J. F.
J. Am. Chem. Soc. 1997, 119, 4565–4566; (e) Sardina, F. J.;
Rappoport, H. Chem. Rev. 1996, 96, 1825–1872.
11. (a) Rajappa, S. Tetrahedron 1999, 55, 7065–7114; (b) Rajappa,
S. Tetrahedron 1981, 37, 1453–1480.
€
12. (a) Severin, Th.; Konig, D. Chem. Ber. 1974, 107, 1499–1508;
(b) Lerche, H.; Konig, D.; Severin, Th. Chem. Ber. 1974, 107,
€
1509–1517.
13. (a) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–1047;
(b) Severin, Th.; Kullmer, H. Chem. Ber. 1971, 104, 440–448.
14. Brook, M. A.; Chan, T. H. Synthesis 1983, 201–203.
15. Crystallographic data (excluding structural factors) for com-
pound 9b have been deposited at the Cambridge Crystallo-
graphic Data Centre as supplementary publication number
CCDC 602404. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44 1223 336033 or e-mail: deposit@
ccdc.cam.ac.uk].
16. (a) Davies, D. E.; Gilchrist, T. L.; Roberts, T. G. J. Chem. Soc.
Perkin Trans. 1 1983, 1275–1281; (b) Gilchrist, T. L.; Roberts,
T. G. J. Chem. Soc., Perkin Trans. 1 1983, 1283–1292.
17. (a) Homan, K.; Angermann, J.; Collas, M.; Zimmer, R.; Reibig,
H.-U. J. Prakt. Chem. 1998, 340, 649–655; (b) Zimmer, R.;
Angermann, J.; Hain, U.; Hiller, F.; Reibig, H.-U. Synthesis
1997, 1467–1474; (c) Arnold, T.; Orschel, B.; Reibig, H.-U.
Angew. Chem., Int. Ed. Engl. 1992, 31, 1033–1035 and refer-
ences therein; (d) Gilchrist, T. L.; Moxey, J. R.; Yagoub,
A. K. J. Chem. Res., Miniprint 1987, 3030–3041.
´
ꢁ
3. (a) Rodrıguez, V.; Sanchez, M.; Quintero, L.; Sartillo-Piscil, F.
Tetrahedron 2004, 60, 10809–10815; (b) Blazecka, P. G.;
Davidson, J. G., III; Zhang, J. PCT Int. Appl. WO
2003093220; Chem. Abstr. 139, 381742. (c) Herdeis, C.;
Hubmann, H. P. Tetrahedron: Asymmetry 1992, 3, 1213–1221.
4. (a) Mc Geer, P. L.; Mc Geer, 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, NY, 1989; (b) GABA-Neurotransmitters. Pharma-
cochemical, Biochemical and Pharmacological Aspects;
Krogsgaard-Larsen, P., Scheel-Kruger, J., Kofod, H., Eds.;
Munksgaard: Copenhagen, 1979.
18. (a) Pitacco, G.; Pizzioli, A.; Valentin, E. Synthesis 1996,
€
242–248; (b) Chincilla, R.; Backvall, J.-E. Tetrahedron Lett.
1992, 33, 5641–5644 and references therein.
19. Seebach, D.; Lyapkalo, I. M.; Dahinden, R. Helv. Chim. Acta
1999, 82, 1829–1842.
20. (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96,
137–165; (b) Denmark, S. E.; Thorarensen, A. J. Org. Chem.
1994, 59, 5672–5680.
5. (a) Goodman and Gilman’s The Pharmacological Basis of
Therapeutics, 10th ed.; Hardman, J. G., Limbird, L. E.,
Goodman Gilman, A., Eds.; McGraw-Hill: New York, NY,
2001; Section III; (b) Nielsen, L.; Brehm, L.; Krogsgaard-
Larsen, P. J. Med. Chem. 1990, 33, 71–77.
21. Denmark, S. E.; Guagnano, V.; Dixon, J. A.; Stolle, A. J. Org.
Chem. 1997, 62, 4610–4628.
6. (a) Krogsgaard-Larsen, P.; Frolund, B.; Ebert, B. The GABA
Receptors, 2nd ed.; Humana: Totowa, New Jersey, 1997;
pp 37–81; (b) Bowery, N. G.; Hudson, A. L.; Price, G. W.
Neuroscience 1987, 20, 365–383; (c) Hill, D. R.; Bowary,
N. G. Nature 1981, 290, 149–152.
7. (a) Krogsgaard-Larsen, P.; Hjeds, H.; Falch, E.; Jorgensen,
F. S.; Nielsen, L. Adv. Drug Res. 1988, 17, 381–456; (b)
Krogsgaard-Larsen, P.; Falch, E.; Larsson, O. M.; Schoushoe,
A. Epilepsy Res. 1987, 1, 77–93.
22. Posner, G. H.; Crouch, R. D. Tetrahedron 1990, 46, 7509–7530.
23. Breuer, E.; Aurich, H. G.; Nielsen, A. The Chemistry of
Functional Groups: Nitrones, Nitronates and Nitroxides;
Patai, S., Rappoport, Z., Eds.; Wiley: New York, NY, 1989,
Chapter 1.
24. Gowenlock, B. G.; Richter-Addo, G. B. Chem. Rev. 2004, 104,
3315–3340.
25. Davies, I. W.; Guner, V. A.; Houk, K. N. Org. Lett. 2004, 6,
743–746.
26. Zilka, A.; Rachman, E. S.; Rivlin, J. J. Org. Chem. 1961, 26,
376–380.
27. Zahradnik, R.; Parkanyi, C.; Horak, V.; Koutecky, J. Collect.
Czech. Chem. Commun. 1963, 28, 776–798.
8. (a) Felluga, F.; Fermeglia, M.; Ferrone, M.; Pitacco, G.; Pricl,
S.; Valentin, E. Helv. Chim. Acta 2002, 85, 4046–4054; (b)
Felluga, F.; Pitacco, G.; Prodan, M.; Pricl, S.; Visintin, M.;
Valentin, E. Tetrahedron: Asymmetry 2001, 12, 3241–3249.
9. (a) Bandichhor, R.; Nosse, B.; Reiser, O. Top. Curr. Chem.
2005, 243, 43–72; (b) Forzato, C.; Nitti, P.; Pitacco, G.;