Stereoselective dimerization of 3-arylisoxazoles to cage-shaped bis-β-lactams syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.02,5]octan-4,8-diones induced by hindered lithium amides

Article abstract of DOI:10.1016/j.tet.2007.09.040

3-Arylisoxazoles react with hindered lithium amides giving syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.0^2,5]octan-4,8-diones in good to fair yields. Stereochemistry of the so-obtained cage-shaped bis-β-lactams was assigned by X-ray diffraction analysis. Concerning the mechanism of formation of such hitherto unknown molecules, dimerization of an azetinone anion intermediate stereoselectively induced by Li⁺ chelation is suggested.

Full text of DOI:10.1016/j.tet.2007.09.040

Tetrahedron 63 (2007) 12388–12395
Stereoselective dimerization of 3-arylisoxazoles to cage-shaped
bis-b-lactams syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.02,5]-
octan-4,8-diones induced by hindered lithium amides
a
a
a
Leonardo Di Nunno,a, Paola Vitale, Antonio Scilimati, Laura Simone
*
and Francesco Capitellib
aDipartimento Farmaco-Chimico, Universitaꢀ degli Studi di Bari, Via E. Orabona 4, 70125 Bari, Italy
bIstituto di Cristallografia (IC-CNR), Via Amendola 122/o, 70125 Bari, Italy
Received 11 July 2007; revised 5 September 2007; accepted 20 September 2007
Available online 23 September 2007
Abstract—3-Arylisoxazoles react with hindered lithium amides giving syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.02,5]octan-4,8-diones in good
to fair yields. Stereochemistry of the so-obtained cage-shaped bis-b-lactams was assigned by X-ray diffraction analysis. Concerning the
mechanism of formation of such hitherto unknown molecules, dimerization of an azetinone anion intermediate stereoselectively induced
by Li+ chelation is suggested.
Ó 2007 Elsevier Ltd. All rights reserved.
O
H
1) RLi
1. Introduction
PhCN
+
C
O
2) NH4Cl aq.
Ph
R
b-Lactams and their derivatives are used in a very large
number of clinically important therapeutic areas in defence
against bacterial infection.1 In organic and medicinal chem-
istry they are used as building blocks,2 synthons for short
peptides,3 natural products,4 and b-amino acids synthesis.5
fragmentation
Ph
Ph
Ph
H
Ph
H2N
1) RLi
C
RLi
N
N
N
C R
O
-78°C
O
2) NH4Cl aq.
O
O
Cage-shaped bis-b-lactams constitute a new class of
compounds not explored as yet. Herein, a novel one-pot
stereoselective synthetic approach from 3-arylisoxazoles to
cage-shaped bis-azetidinones different from the classical
b-lactam structures and that could find applications at least
in the above mentioned fields is reported.
1a
2a
cyclization
Ph
Ph
Ph
1) PhCN
N
N
N
2) RLi
O
Previous investigations6 concerning the reactivity of 3-
phenylisoxazole (1a) with alkyllithiums ascertained a rather
complex behaviour (Scheme 1).
3) NH4Cl aq.
R
4
(R=Et,Me)
3a
Scheme 1. Reaction of 3-phenylisoxazole (1a) with RLi.
In all cases the starting reaction is represented by C5–H
abstraction by RLi, followed by ring-opening to form
lithium iminoketene 2a. This, in turn, is assumed as the
common intermediate precursor of all the isolated products
deriving from fragmentation or further nucleophilic addition
of RLi.
Among other formed products and concerning some alkyl-
lithiums (MeLi, EtLi) we isolated alkyldiphenylpyrimidines
4, arising from a preliminary cyclization of lithium imino-
ketene 2a to azetinone anion 3a and subsequent reaction
with PhCN and RLi.6
It must be pointed out that C5–H abstraction from 3-phenyl-
isoxazole (1a) was previously described also using LTMP as
a base. In such a case, only products of fragmentation were
reported (Scheme 2).7
Keywords: 3-Arylisoxazoles; Cage-shaped bis-b-lactams; Hindered lithium
amides; Lithium iminoketene; Azetinone anion.
* Corresponding author. Tel.: +39 80 5442734; fax: +39 80 5442231;
e-mail: dinunno@farmchim.uniba.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.040

L. Di Nunno et al. / Tetrahedron 63 (2007) 12388–12395
12389
Ph
Ph
And this, presumably, is also an important factor favouring
the formation of bis-azetidinone 5a. Lack of any nucleo-
philic addition by lithium amides should in fact directly or
indirectly enhance the availability of azetinone anion 3a,
so determining the best conditions for dimerization.
Ph
H
C N
LTMP
-60°C
+
N
N
Me3Si
Me3Si
1)
LTMP
O
O
C
C O
C
C O
1a
2) Me3SiCl
Scheme 2. Reaction of 3-phenylisoxazole (1a) with LTMP.7
However, another important factor promoting the dimeriza-
tion seems also to be involved. X-ray diffraction analysis
(see Section 2) established in fact that the isolated bis-azeti-
dinone 5a has exclusively the syn geometry, as represented
in Figure 1.
2. Results and discussion
We have now repeated the reaction with LTMP at various
temperatures, extending it also to other lithium amides
(LDA, LHMDS).
And this strongly suggests an important role of Li+
chelation during the dimerization (Scheme 4). The above
hypothesis seems to be very reasonable, as stereoselective
reactions promoted by intramolecular Li+ chelation are
not new.8
In all cases no products of nucleophilic addition subsequent
both to isoxazole ring-opening (i.e., onto lithium imminoke-
tene 2a and azetinone anion 3a) and ring-fragmentation (i.e.,
onto PhCN) were found, as instead observed (Scheme 1) for
reactions carried out with alkyllithiums. At variance, syn
2,6-diphenyl-3,7-diazatricyclo[4.2.0.02,5]octan-4,8-dione (5a),
plausibly formed by dimerization of azetinone anion intermedi-
ate 3a, was isolated in high yields (Scheme 3 and Table 1).
Besides, we could obtain a direct evidence of the above
hypothesis by performing the reaction of 3-phenylisoxazole
(1a) with bis(trimethylsilyl)amides with different metal
counterions (Na+, K+) (Table 2). In this case, formation of
bis-azetidinone 5a largely decreases with NaHMDS and is
completely suppressed with KHMDS.
H
6a
PhCN
+
O
C
fragmentation
Correspondingly, fragmentation is progressively favoured,
as indicated by the increasing amounts of PhCN 6a (in this
case not further reacted with R2NLi, as expected).
Ph
H
Ph
Ph
R2NLi
2a
N
C
O
The observed behaviour parallels the decreasing bind-
ing affinity on going from Li+ to K+, as determined in other
cases (e.g., in the case of various azines).9 So, this strongly
supports the leading role of chelation in the dimerization
of 3a.
N
N
O
1a
O
cyclization
Ph
N
H
Ph
O
dimerization
Ph
O
N
N
When in fact such an interaction is less important, dimeriza-
tion becomes correspondingly more difficult, so that other
possible reactions (fragmentation, in our case) can compete
or even prevail.
O
H
3a
Scheme 3. Reaction of 3-phenylisoxazole (1a) with R2NLi.
5a
Only small amounts of such a dimer could seldom be
observed, on the contrary, in reactions with alkyllithiums.
On the other hand, the observed dimerization is not a special
behaviour of 3-phenylisoxazole (1a).
Reactions of a number of other arylisoxazoles10 bearing
either electron-withdrawing or electron-donating groups11
indicate in fact similar results, the yields of bis-azetidinones
depending on the nature of the substituent (Table 3).
Concerning the absence of products of subsequent nucleo-
philic addition of R2NLi, it was clearly expected by consid-
ering the well-known non-nucleophilic character of the used
lithium amides.
Table 1. Percentages of products formed in the reaction of 3-phenylisoxazole (1a) and lithium amides
Entry
Base
1a/Base
T (ꢀC)
t (h)
1a (%)
5aa (%)
6ab (%)
1
2
3
4
5
6
7
8
9
10
LTMP
LTMP
LTMP
LHMDS
LHMDS
LHMDS
LHMDS
LDA
1:2
ꢁ60/rt
0.7
1
1
1
0.5
1
1
1
1
1
—
—
75
78
<1
7
1:1.5
1:1.5
1:1
1:1.1
1:1.1
1:1.5
1:1.5
1:1.5
1:1.5
ꢁ78
0
—
85
<1
<1
<1
<1
<1
<1
10
2
ꢁ78
84c
50c
34c
—
16c
50c
66c
83
0
0
0
0
—
—
—
80
68
80
LDA
LDA
0/rt
ꢁ78
a
Isolated yields (unless otherwise indicated).
Detected by GC on reaction crudes and then distilled off in vacuo.
b
c
Percentages determined by 1H NMR spectra recorded on reaction crudes.

12390
L. Di Nunno et al. / Tetrahedron 63 (2007) 12388–12395
Figure 1. (a) ORTEP view of crystal structure of bis-azetidinone 5a. (b) View of enantiomers of bis-azetidinone 5a; symmetry: I) x, ꢁy+1/2, +z+1/2 (related by
inversion centre).
H
N
O
N
H
NH4Cl
H2O
cyclization
LiNR2
ring-opening
dimerization
Li
H
O
N
N
N
C
O
O
O
O
Li
N
H
O
1a
2a
N
fragmentation
5a
Scheme 4. Proposed mechanism of dimerization of 3-phenylisoxazole (1a) induced by R2NLi.
Table 2. Yields of products from the reaction of 3-phenylisoxazole (1a) with
In particular, electron-withdrawing groups again give high
yields of the above azetidinones, while electron-donating
groups lower the yields in favour of the fragmentation prod-
ucts, seemingly to an extent depending on the magnitude of
the electron-donating effect of the substituent. The above
results seem to be related to the lower stability of the lithium
imminoketene intermediate in the presence of electron-
donating groups, which should actually favour the frag-
mentation, just as observed. Further investigations are in
progress on this point.
bis(trimethylsilyl)amidesa
Entry
Base
Bis-azetidinone
PhCN
5ab (%)
6ab (%)
1
2
3
LHMDS
NaHMDS
KHMDS
83
<1c
57d
90
43d
—
a
Reactions were conducted in THF at 0 ꢀC for 1 h, with isoxazole 1a/base
ratio¼1:1.5.
b
c
d
Isolated yields (unless otherwise indicated).
Detected by GC on reaction crudes and then distilled off in vacuo.
Percentages determined by 1H NMR spectra recorded on reaction crudes.
In conclusion, the present investigation has disclosed a new
interesting reaction involving 3-arylisoxazoles, with forma-
tion of a type of b-lactams hitherto unknown.
Table 3. Percentages of products formed in the reaction of 3-arylisoxazoles
1a–e with LDAa
Next investigations will concern a further expansion of the
scope of the reaction, as well as a study of the chemical
and biological properties of such cage-shaped bis-b-lactams.
Entry
Ar
Bis-azetidinones
ArCN
6a–e (%)
5a–eb (%)
1
2
3
4
5
Phenyl- (1a)
80
<1c
38d
56d
—
4-Methylphenyl- (1b)
4-Methoxyphenyl- (1c)
4-Fluorophenyl- (1d)
4-Trifluoromethylphenyl-
(1e)
58d
33d
79
3. Experimental section
3.1. General methods
80
—
a
Reactions were conducted in THF at 0 ꢀC for 1 h, with isoxazole 1a–e/
base ratio¼1:1.5.
Melting points taken on Electrothermal apparatus were
uncorrected. 1H NMR and 13C NMR spectra were recorded
on a Varian-Inova-400 MHz spectrometer and on a Bruker-
Aspect 3000 console-500 MHz spectrometer, and chemical
shifts are reported in parts per million (d). 19F NMR spectra
were recorded by using CFCl3 as internal standard. Absolute
b
c
d
Isolated yields (unless otherwise indicated).
Detected by GC on reaction crudes and then distilled off in vacuo.
Percentages determined by 1H NMR spectra recorded on reaction crudes;
some unreacted 3-arylisoxazole (ꢂ4 and ꢂ11% for 1b and 1c, respec-
tively) was also detected.

L. Di Nunno et al. / Tetrahedron 63 (2007) 12388–12395
12391
values of the coupling constant are reported. Infrared spectra
were recorded on a FT Perkin–Elmer 681 spectrometer. GC
analyses were performed by using a HP1 column (methyl
siloxane; 30 mꢃ0.32 mmꢃ0.25 mm film thickness) on a
HP 6890 model, Series II. Thin-layer chromatography
(TLC) was performed on silica gel sheets with fluorescent in-
dicator, the spots on the TLC were observed under ultraviolet
light or were visualized by I2 vapour. Chromatography was
conducted by using silica gel 60 with a particle size distribu-
tion 40–63 mm and 230–400 mesh ASTM. GC–MS analyses
were performed on an HP 5995C model and elemental anal-
yses on an Elemental Analyzer 1106-Carlo Erba-instrument.
ESI-MS analyses were performed on Agilent 1100 LC/MSD
trap VL system. Crystallographic data (excluding structure
factors) for the structure in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC 615266. Copies of the data
can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: +44
(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
(M+, 100), 134 (22), 108 (58), 92 (21), 77 (29), 63 (17),
51 (9).
3.2.3. 4-Fluorobenzaldehyde oxime.14–16 Yield: 88%
(3.483 g). Yellow solid. Rf¼0.4 (petroleum ether/ethyl
acetate¼80:20). 1H NMR (400 MHz, CDCl3, d): 9.40–8.60
(br s, 1H, OH: exchanges with D2O), 8.15 (s, 1H), 7.58–
7.54 (m, 2H, aromatic protons), 7.10–7.06 (m, 2H, aromatic
protons). 13C NMR (100 MHz, CDCl3, d): 163.8 (d,
3
1J19F–13C¼249 Hz), 149.3, 128.9 (d, J19F–13C¼8.5 Hz),
4
2
128.0 (d, J19F–13C¼3.2 Hz), 116.0 (d, J19F–13C¼21.8 Hz).
19F NMR (376 MHz, CDCl3, d): ꢁ110.3.
3.2.4. 4-(Trifluoromethyl)benzaldehyde oxime.15,17 Yield:
92% (3.814 g). White crystals. Rf¼0.5 (petroleum ether/
ethyl acetate¼70:30). Mp 100–101 ꢀC. IR (neat): 3293,
2922, 1618, 1413, 1325, 1067, 971, 940, 872, 834 cmꢁ1
.
1H NMR (500 MHz, CDCl3, d): 9.40–9.10 (br s, 1H, OH:
exchanges with D2O), 8.21 (s, 1H), 7.70–7.63 (m, 4H,
aromatic protons). 13C NMR (100 MHz, CDCl3, d): 149.2,
2
135.1, 131.7 (q, J19F–13C¼32.5 Hz), 127.2, 125.7 (q,
1
3.2. Materials
3J19F–13C¼3.7 Hz), 123.8 (q, J19F–13C¼270.8 Hz). 19F
NMR (376 MHz, CDCl3, d): ꢁ63.2.
Tetrahydrofuran (THF) from commercial source was puri-
fied by distillation (twice) from sodium wire under nitrogen.
DMF from commercial source was purified by distillation
from CaH2 under reduced pressure. Standardized (2.5 M)
n-butyllithium in hexanes was purchased from Aldrich
Chemical Co. and its titration was performed with N-piva-
loyl-o-toluidine.12 NaHMDS in THF (1.0 M) and KHMDS
in toluene (0.5 M) were purchased from Aldrich Chemical
Co. Bis(trimethylsilyl)amine, diisopropylamine and 2,2,6,6-
tetramethylpiperidine were purified by distillation from
CaH2. All other chemicals and solvents were of commercial
grade and further purified by distillation or crystallization
prior to use.
3.3. Synthesis of N-Hydroxybenzimidoyl chlorides:
general procedure
In a round-bottom flask equipped with magnetic stirring the
suitable benzaldoxime (3.483 g, 0.0251 mol) was dissolved
in anhydrous DMF (60 mL), then the solution was cooled to
0 ꢀC. NCS (3.686 g, 0.0276 mol) was slowly added and the
suspension was stirred at 0 ꢀC. When the reaction was
complete (TLC), water was added to the reaction mixture
that became a limpid yellow solution. The aqueous layer
was extracted three times with ethyl acetate. The combined
organic extracts were washed with water to remove succini-
mide, then the solution was dried over anhydrous Na2SO4.
N-Hydroxybenzimidoyl chlorides (obtained in 77–90%
yield after evaporation of the solvent under vacuum) had
analytical and spectroscopic data identical to those ones pre-
viously reported and commercially available compounds.
All the used 3-arylisoxazoles 1a–e were prepared via the
corresponding 3-aryl-5-hydroxy-2-isoxazolines 7a–e (see
below), by using the previously described procedure.10 Aryl-
nitrile oxides were prepared from aldehydes through their
conversion into the corresponding oximes and then into N-
hydroxybenzimidoyl chloride.10,13 These were finally con-
verted into nitrile oxides by treatment with NEt3, followed
by vacuum filtration of NEt3$HCl from the solution.10,13
Oximes, prepared from reaction of aldehydes/EtOH and
NH2OH$HCl/aq NaOH, had analytical and spectroscopic
data identical to those previously reported or commercially
available.
3.3.1. N-Hydroxy-4-methylbenzimidoyl chloride.18 Yield:
90% (2.305 g). Yellow solid. Rf¼0.8 (petroleum ether/ethyl
acetate¼70:30). 1H NMR (CDCl3, 400 MHz, d): 9.60–9.00
(s, 1H, br s, 1H, OH: exchanges with D2O), 7.74–7.72 (m,
2H, aromatic protons), 7.21–7.19 (m, 2H, aromatic protons),
2.38 (s, 3H). 13C NMR (75 MHz, CDCl3): 141.1, 140.5,
129.6, 129.2, 127.1, 21.3.
3.2.1. 4-Methylbenzaldehyde oxime.14 Yield: 60%
(2.182 g). Yellow solid. Rf¼0.5 (petroleum ether/ethyl
3.3.2. N-Hydroxy-4-methoxybenzimidoyl chloride.18–20
Yield: 77% (2.282 g). Oil. Rf¼0.7 (petroleum ether/ethyl
acetate¼70:30). 1H NMR (CDCl3, 400 MHz, d): 8.35–8.30
(br s, 1H, OH: exchanges with D2O), 7.78–7.76 (m, 2H,
aromatic protons, J¼8.8 Hz), 6.92–6.90 (m, 2H, aromatic
protons, J¼8.8 Hz), 3.84 (s, 3H). 13C NMR (75 MHz,
CDCl3): 161.5, 139.6, 132.0, 128.7, 113.8, 55.4.
1
acetate¼80:20). H NMR (400 MHz, CDCl3, d): 8.10 (s,
1H), 7.46–7.43 (m, 2H, aromatic protons), 7.18–7.16 (m,
2H, aromatic protons), 2.35 (s, 3H). 13C NMR (75 MHz,
CDCl3): 150.3, 140.3, 129.5, 129.1, 127.0, 21.4.
3.2.2. 4-Methoxybenzaldehyde oxime.14,15 Yield: 67%
(2.428 g). White solid. Rf¼0.5 (petroleum ether/ethyl
acetate¼80:20). 1H NMR (400 MHz, CDCl3, d): 8.20–7.80
(br s, 1H, OH: exchanges with D2O), 8.09 (s, 1H), 7.50–
7.47 (m, 2H, aromatic protons), 6.89–6.86 (m, 2H, aromatic
protons), 3.78 (s, 3H). GC–MS (70 eV) m/z (rel int.): 151
3.3.3. N-Hydroxy-4-fluorobenzimidoyl chloride.21 Yield:
88%. Yellow crystals. Mp 74–75 ꢀC. Rf¼0.8 (petroleum
ether/ethyl acetate¼90:10). 1H NMR (400 MHz, CDCl3,
d): 9.80–9.20 (br s, 1H, OH: exchanges with D2O), 7.85–
7.79 (m, 2H, aromatic protons), 7.10–7.04 (m, 2H, aromatic

12392
L. Di Nunno et al. / Tetrahedron 63 (2007) 12388–12395
protons). 13C NMR (100 MHz, CDCl3, d): 164.1 (d,
Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90.
Found: C, 67.40; H, 6.28; N, 7.74.
3
1J19F–13C¼250 Hz), 138.3, 129.1 (d, J19F–13C¼8.5 Hz),
4
2
128.8 (d, J19F–13C¼3.2 Hz), 115.5 (d, J19F–13C¼22.0 Hz).
19F NMR (376 MHz, CDCl3, d): ꢁ110.1.
3.4.2. 5-Hydroxy-3-(4-methoxyphenyl)-2-isoxazoline
(7c). Yield: 85% (2.018 g). Yellow oil. Rf¼0.3. IR (neat):
3200, 2924, 2850, 1606, 1518, 1465, 1363, 1257, 1180,
3.3.4. N-Hydroxy-4-trifluoromethylbenzimidoyl chlo-
ride.17,19 Yield: 83%. Yellow solid. Rf¼0.8 (petroleum
ether/ethyl acetate¼90:10). Mp 90–92 ꢀC.19 IR (neat):
3308, 2919, 2853, 1618, 1410, 1326, 1129, 1068, 1015,
1077, 1020, 923, 898, 847, 832, 745 cmꢁ1 1H NMR
.
(400 MHz, CDCl3, d): 7.63–7.61 (m, 2H, aromatic protons),
6.93–6.90 (m, 2H, aromatic protons), 6.02 (dd, 1H, J¼1.0,
6.4 Hz), 3.84 (s, 3H), 3.7–3.3 (br s, 1H, OH: exchanges
with D2O), 3.43 (dd, 1H, J¼6.4, 17.3 Hz), 3.32 (dd, 1H,
J¼17.3, 1.0 Hz). 13C NMR (100 MHz, CDCl3, d): 161.2,
156.3, 128.5, 121.5, 114.1, 97.7, 55.3, 42.8. GC–MS
(70 eV) m/z (rel int.): 193 (M+, 100), 176 (35), 175 (32),
164 (84), 149 (31), 133 (64), 132 (71), 121 (15), 108 (25),
90 (24), 77 (31), 64 (19). Anal. Calcd for C10H11NO3: C,
62.17; H, 5.74; N, 7.25. Found: C, 62.40; H, 5.68; N, 7.30.
940, 846 cmꢁ1 1H NMR (400 MHz, CDCl3, d): 10.50–
.
10.10 (br s, 1H, OH: exchanges with D2O), 7.88–7.85 (m,
2H, aromatic protons), 7.55–7.54 (m, 2H, aromatic protons).
19F NMR (376 MHz, CDCl3, d): ꢁ63.5.
3.4. Synthesis of 3-arylisoxazoles (1a–e): general
procedure10
A solution of the enolate ion of acetaldehyde in anhydrous
THF (10 mL) was dropwise added at room temperature to
a solution of arylnitrile oxide in THF (10 mL) contained in
a nitrogen-flushed three-necked flask equipped with a mag-
netic stirrer. After the reaction was completed, the reaction
mixture was quenched by adding aq NH4Cl. The two phases
were separated and the aqueous phase was extracted three
times with ethyl acetate. The organic extracts were com-
bined, dried over anhydrous Na2SO4 and then the solvent
evaporated under reduced pressure. Column chromato-
graphy (silica gel, petroleum ether/ethyl acetate¼70:30) of
the residue afforded the 3-aryl-5-hydroxy-2-isoxazolines
7a–e in 60–85% yields.
3.4.3. 3-(4-Fluorophenyl)-5-hydroxy-2-isoxazoline (7d).
Yield: 70% (2.109 g). Mp 109–111 ꢀC. Yellow crystals.
Rf¼0.3. IR (KBr): 3370, 3073, 2960, 2930, 2854, 1603,
1514, 1415, 1356, 1235, 1159, 1081, 921, 890, 872,
1
836 cmꢁ1. H NMR (400 MHz, CDCl3, d): 7.62–7.57 (m,
2H, aromatic protons), 7.10–7.00 (m, 2H, aromatic protons),
6.02 (dd, 1H, J¼6.7, 1.7 Hz), 5.3–4.8 (br s, 1H, OH: ex-
changes with D2O), 3.34 (dd, 1H, J¼6.7, 17.4 Hz), 3.17
(dd, 1H, J¼17.4, 1.7 Hz). 13C NMR (100 MHz, CDCl3, d):
1
3
163.9 (d, J19F–13C¼250 Hz), 156.1, 128.9 (d, J19F–13C
¼
4
2
8.5 Hz), 125.1 (d, J19F–13C¼3.5 Hz), 115.9 (d, J19F–13C
¼
21.9 Hz), 98.1, 42.4. 19F NMR (376 MHz, CDCl3, d):
ꢁ105.5. GC–MS (70 eV) m/z (rel int): 181 (M+, 58), 164
(21), 163 (87), 153 (52), 152 (96), 135 (38), 134 (37), 121
(80), 109 (38), 107 (39), 101 (19), 96 (21), 95 (100), 75
(56), 63 (11), 57 (17), 50 (14). Anal. Calcd for C9H8FNO2:
C, 59.67; H, 4.45; N, 7.73. Found: C, 59.40; H, 4.50; N, 7.55.
In a round-bottom flask with magnetic stirrer, MeONa
(0.654 g, 12.7 mmol) was added to a solution of 3-aryl-5-hy-
droxy-2-isoxazolines 7a–e (1.885 g, 11.5 mmol) in MeOH
(30 mL). The reaction mixture was then heated under reflux.
After the reaction was completed, the reaction mixture was
quenched by adding aq NH4Cl. The MeOH was evaporated
under reduced pressure and aqueous layer was extracted
three times with ethyl acetate. The combined organic
extracts were dried over anhydrous Na2SO4 and the solvent
evaporated under reduced pressure. Column chromato-
graphy (silica gel, petroleum ether/ethyl acetate¼10:1) of
the residue afforded 3-arylisoxazoles 1a–e in 65–94% yields.
5-Hydroxy-3-phenyl-2-isoxazoline (7a),10 3-phenylisox-
azole (1a),10 3-(p-tolyl)isoxazole (1b),22 3-(p-anisyl)isox-
azole (1c),23 3-(p-fluorophenyl)isoxazole (1d)24 and 3-(p-
trifluoromethylphenyl)isoxazole (1e)25 had analytical and
spectroscopic data identical to those previously reported.
3.4.4. 5-Hydroxy-3-(4-trifluoromethylphenyl)-2-isoxazo-
line (7e). Yield: 84% (3.313 g). Mp 116.0–118.0 ꢀC. Yellow
crystals. Rf¼0.3. IR (KBr): 3341, 2927, 2853, 1618, 1413,
1
1326, 1169, 1127, 1068, 1017, 844, 770 cmꢁ1. H NMR
(500 MHz, CDCl3, d): 7.79–7.77 (m, 2H, aromatic protons),
7.67–7.64 (m, 2H, aromatic protons), 6.10 (dd, 1H, J¼6.3,
1.6 Hz), 4.5–3.5 (br s, 1H, OH: exchanges with D2O), 3.44
(dd, 1H, J¼6.3, 17.4 Hz), 3.26 (dd, 1H, J¼17.4, 1.6 Hz).
13C NMR (100 MHz, CDCl3, d): 155.9, 132.3, 132.1 (q,
2J19F–13C¼32.7 Hz), 127.1, 125.7 (q, 3J19F–13C
¼
1
3.8 Hz), 123.8 (q, J19F–13C¼272.3 Hz), 98.4, 42.1. 19F
NMR (376 MHz, CDCl3, d): ꢁ63.3. GC–MS (70 eV) m/z
(rel int.): 231 (M+, 51), 214 (16), 213 (54), 212 (87), 203
(59), 202 (77), 194 (10), 185 (28), 171 (31), 158 (21), 145
(100), 125 (14), 95 (15), 75 (16). Anal. Calcd for
C10H8F3NO2: C, 51.96; H, 3.49; N, 6.06. Found: C, 52.30;
H, 3.68; N, 6.30.
3.4.1. 5-Hydroxy-3-(4-methylphenyl)-2-isoxazoline (7b).
Yield: 60% (1.444 g). Mp 120.8–121.4 ꢀC. Yellow crystals.
Rf¼0.3. IR (KBr): 3223, 3033, 2954, 2939, 1609, 1595,
1517, 1444, 1411, 1357, 1336, 1270, 1240, 1177, 1080,
1
928, 900, 844, 810, 786, 737 cmꢁ1. H NMR (400 MHz,
CDCl3, d): 7.57–7.54 (m, 2H, aromatic protons), 7.20–7.18
(m, 2H, aromatic protons), 6.03 (d, 1H, J¼6.6 Hz), 4.3–3.9
(br s, 1H, OH: exchanges with D2O), 3.36 (dd, 1H, J¼6.6,
7.6 Hz), 3.23 (d, 1H, J¼17.6 Hz), 2.37 (s, 3H). 13C NMR
(75 MHz, CDCl3, d): 156.9, 140.7, 129.5, 126.9, 126.1,
97.9, 42.6, 21.5. GC–MS (70 eV) m/z (rel int.): 177 (M+,
97), 160 (23), 159 (19), 158 (18), 148 (100), 133 (27), 132
(31), 131 (23), 130 (18), 117 (57), 116 (25), 115 (32), 104
(16), 103 (12), 91 (74), 89 (22), 77 (24), 65 (31), 51 (13).
3.4.5. 3-(4-Methylphenyl)isoxazole (1b).22 Yield: 84%
(1.013 g). Yellow oil. Rf¼0.5 (petroleum ether/ethyl
acetate¼94:6). IR (neat): 3020, 2923, 1619, 1552, 1524,
1426, 1381, 1126, 1097, 881, 824, 777, 721, 689 cmꢁ1. 1H
NMR (400 MHz, CDCl3, d): 8.42 (d, 1H, J¼1.5 Hz), 7.72
(d, 2H, aromatic protons, J¼8.0 Hz), 7.27 (d, 2H, aromatic
protons, J¼8.0 Hz), 6.63 (d, 1H, J¼1.5 Hz), 2.40 (s, 3H).
13C NMR (100 MHz, CDCl3, d): 161.7, 158.9, 140.4,
129.8, 127.0, 126.1, 102.6, 21.6. GC–MS (70 eV) m/z (rel

L. Di Nunno et al. / Tetrahedron 63 (2007) 12388–12395
12393
int.): 159 (M+, 100), 158 (88), 131 (91), 130 (56), 116 (9),
103 (14), 91 (35), 89 (12), 77 (13), 65 (20), 51 (10).
diones 5a–e as indicated in Scheme 3 and Tables 1 and 3.
1H NMR signal (d¼4.10O4.35 ppm) attributed to the proton
at C5 was a doublet with long-range coupling constant
4J¼2.2/2.6 Hz. 4J (s0 Hz) was due to the ‘W conformation’
of the four s bonds between H5 and Hamidic. Hamidic peak was
not split by H5, its signal was broadened by the quadrupolar
interaction. Aromatic nitriles 6a–c, isolated as product of
the reaction mentioned above, had the same analytical and
spectroscopic data of the commercially available com-
pounds.
3.4.6. 3-(4-Methoxyphenyl)isoxazole (1c).23 Yield: 94%
(1.541 g). Mp 48.0–49.0 ꢀC. Yellow crystals. Rf¼0.5 (petro-
leum ether/ethyl acetate¼91:9). 1H NMR (400 MHz,
CDCl3, d): 8.40 (d, 1H, J¼1.5 Hz), 7.75 (d, 2H, aromatic
protons, J¼8.8 Hz), 6.97 (d, 2H, aromatic protons,
J¼8.0 Hz), 6.59 (d, 1H, J¼1.5 Hz), 3.84 (s, 3H). GC–MS
(70 eV) m/z (rel int.): 175 (M+, 100), 174 (38), 160 (21),
147 (26), 146 (35), 132 (51), 104 (9), 92 (8), 77 (16), 63 (9).
3.6. Reaction of 3-phenylisoxazole (1a) with
bis(trimethylsilyl)amides: general procedure
3.4.7. 3-(4-Fluorophenyl)isoxazole (1d).24 Yield: 65%
(1.099 g). Colourless oil. Rf¼0.8 (petroleum ether/ethyl
acetate¼80:20). IR (KBr): 3147, 3129, 3073, 2927, 2855,
1607, 1521, 1435, 1379, 1236, 1160, 1125, 1098, 1043,
A solution of 3-phenylisoxazole (1a) (50 mg, 0.331 mmol)
in THF (1 mL) was added to a solution of NaHMDS (or
KHMDS) (0.496 mmol) in THF (1 mL) at 0 ꢀC under nitro-
gen, using a nitrogen-flushed three-necked flask equipped
with a magnetic stirrer and a nitrogen inlet. The brown reac-
tion mixture was stirred at 0 ꢀC for 1 h (Table 2), and then
quenched by adding aq NH4Cl. The two phases were sepa-
rated and the aqueous layer was extracted three times with
ethyl acetate. The organic extracts combined were dried
over anhydrous Na2SO4 and then the solvent evaporated
under reduced pressure.
1
1016, 947, 886, 842, 777, 685 cmꢁ1. H NMR (500 MHz,
CDCl3, d): 8.44 (d, 1H, J¼1.8 Hz), 7.82–7.79 (m, 2H, aro-
matic protons), 7.16–7.12 (m, 2H, aromatic protons), 6.61
(d, 1H, J¼1.8 Hz). 13C NMR (100 MHz, CDCl3, d): 163.7
1
3
(d, J19F–13C¼250 Hz), 160.5, 159.0, 128.7 (d, J19F–
4
2
¼8.6 Hz), 124.9 (d, J19F–13C¼2.9 Hz), 116.0 (d, J19F–
¼21.9 Hz), 102.3. GC–MS (70 eV) m/z (rel int.): 163
13C
13C
(M+, 100), 162 (78), 135 (21), 134 (39), 121 (12), 108
(18), 107 (32), 95 (40), 75 (23). 19F NMR (376 MHz,
CDCl3, d): ꢁ114.8.
3.6.1. syn 2,6-Bis(phenyl)-3,7-diazatricyclo [4.2.0.02,5]-
octan-4,8-dione (5a). Yield: 85% (0.045 g). Mp 132.0–
133.0 ꢀC (dec). Yellow crystals. Rf¼0.2. IR (KBr): 3279,
3091, 1760, 1738, 1498, 1447, 1365, 1308, 1161, 1038,
3.4.8. 3-(4-Trifluoromethylphenyl)isoxazole (1e).25 Yield:
94% (2.900 g). Mp 99.0–101.0 ꢀC. Yellow crystals. Rf¼0.8
(petroleum ether/ethyl acetate¼91:9). IR (KBr): 3159,
3138, 1620, 1554, 1435, 1330, 1166, 1113, 1067, 891,
1
748, 693 cmꢁ1. H NMR (500 MHz, CDCl3, d): 8.16–8.04
856, 842, 787, 688, 597 cmꢁ1
.
1H NMR (400 MHz,
(br s, 2H, NH: exchange with D2O), 7.44–7.38 (m, 8H, aro-
matic protons), 7.38–7.32 (m, 2H, aromatic protons), 4.25
(d, 2H, J¼2.4 Hz). 13C NMR (125 MHz, CDCl3, d): 167.2,
137.0, 129.3, 128.7, 126.1, 64.1, 52.3. LC–MS (ESI+): 313
[M+Na]+. Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86;
N, 9.65. Found: C, 74.40; H, 5.01; N, 9.36.
CDCl3, d): 8.46 (d, 1H, J¼1.7 Hz), 7.90 (d, 2H, J¼8.1 Hz,
aromatic protons), 7.67 (d, 2H, J¼8.1 Hz, aromatic protons),
6.66 (d, 1H, J¼1.7 Hz). 13C NMR (100 MHz, CDCl3, d):
2
160.3, 159.4, 132.2, 131.7 (q, J19F–13C¼32.5 Hz), 127.1,
3
1
125.8 (q, J19F–13C¼3.7 Hz), 123.8 (q, J19F–13C
¼
270.8 Hz), 102.5. GC–MS (70 eV) m/z (rel int.): 213 (M+,
78), 212 (100), 194 (14), 185 (10), 184 (20), 171 (8), 145
(41), 95 (9), 75 (9). 19F NMR (376 MHz, CDCl3, d): ꢁ63.2.
3.6.2. syn 2,6-Bis(4-methylphenyl)-3,7-diazatricy-
clo[4.2.0.02,5]octan-4,8-dione (5b). Yield: 58% (0.029 g).
Mp 150.1–151.3 ꢀC. Yellow powder. Rf¼0.2. IR (KBr):
3.5. Reaction of 3-arylisoxazoles (1a–e) with lithium
amides: general procedure (the amount of 3-arylisoxa-
zoles, LiNR2 and solvent indicated below refer to a
substrate/LiNR2 ratio=1:1.5. See Table 1 for other
substrate/LiNR2 ratios)
3238, 2923, 2855, 1756, 1516, 1347, 1043, 812, 734 cmꢁ1
.
1H NMR (400 MHz, CDCl3, d): 8.35–8.25 (br s, 2H, NH:
exchange with D2O), 7.32–7.30 (m, 4H, aromatic protons),
7.24–7.21 (m, 4H, aromatic protons), 4.17 (d, 2H,
J¼2.5 Hz), 2.37 (s, 6H). 13C NMR (100 MHz, CDCl3, d):
167.3, 138.3, 133.9, 129.6, 125.8, 63.8, 51.9, 21.1.
LC–MS (ESI+): 341 [M+Na]+. Anal. Calcd for
C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.52;
H, 5.95; N, 8.70.
A 2.5 M solution of n-BuLi in hexanes (0.310 mL,
0.776 mmol) was added to a solution of the dialkylamine
or bis(trimethylsilyl)amine (0.776 mmol) in THF (2 mL) at
0 ꢀC under nitrogen, using a nitrogen-flushed three-necked
flask equipped with a magnetic stirrer and a nitrogen inlet.
After 10 min, the solution of the 3-arylisoxazole 1a–e
(75 mg, 0.517 mmol) in THF (1 mL) was added dropwise
and the obtained brown reaction mixture kept at 0 ꢀC was
stirred for the time indicated in Tables 1 and 3, and then
quenched by adding aq NH4Cl. The two phases were sepa-
rated and the aqueous layer was extracted three times with
ethyl acetate. The organic extracts combined were dried
over anhydrous Na2SO4 and then the solvent evaporated
under reduced pressure. Column chromatography (silica gel,
petroleum ether/ethyl acetate¼6:4) of the residue afforded
the syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.02,5]octan-4,8-
3.6.3. syn 2,6-Bis(4-methoxyphenyl)-3,7-diazatricy-
clo[4.2.0.02,5]octan-4,8-dione (5c). Yield: 32% (0.016 g).
Mp 132.0–133 ꢀC. Orange powder. Rf¼0.2. IR (KBr):
3262, 3173, 2924, 2852, 1750, 1729, 1610, 1515, 1255,
1
1178, 1031, 823 cmꢁ1. H NMR (400 MHz, CDCl3, d):
8.20–8.10 (br s, 2H, NH: exchange with D2O), 7.35–7.31
(m, 4H, aromatic protons, J¼8.6 Hz), 6.95–6.92 (m, 4H,
aromatic protons, J¼8.6 Hz), 4.16 (d, 2H, J¼2.4 Hz), 3.82
(s, 6H). 13C NMR (100 MHz, CDCl3, d): 167.2, 159.6,
128.7, 127.2, 114.3, 63.8, 55.4, 51.7. LC–MS (ESI+): 373
[M+Na]+. Anal. Calcd for C20H18N2O4: C, 68.56; H, 5.18;
N, 8.00. Found: C, 68.59; H, 5.17; N, 7.98.

12394
L. Di Nunno et al. / Tetrahedron 63 (2007) 12388–12395
3.6.4. syn 2,6-Bis(4-fluorophenyl)-3,7-diazatricyclo-
[4.2.0.02,5]octan-4,8-dione (5d). Yield: 79% (0.071 g).
Mp 168–169 ꢀC (dec). Yellow powder. Rf¼0.2. IR (KBr):
3273, 3166, 2922, 2847, 1753, 1732, 1599, 1514, 1514,
COLLECT;26 cell refinement and data reduction: Evalccd.27
The structure was solved through the direct method proce-
dure of SIR9728 and refined by a full-matrix least-squares
technique based on F2, SHELXL-97.29 The non-hydrogen
atoms were refined with anisotropic displacement para-
meters. The hydrogen atoms were localized through differ-
ence-Fourier map and refined isotropically. The final cycle
of least-squares refinement included 255 parameters
(weighting scheme applied: wꢁ1¼[s2(Fo2)+(0.0497P)2+
0.2881P], with P¼[(Fo2+2F2c)/3]). The final residuals
[I>2s(I)] were R1¼0.0588 and wR2¼0.1081. Crystal data
and structure refinement of 5a are reported in Table 4; frac-
tional atomic coordinates and equivalent isotropic parame-
ters, bond lengths and angles are reported in Tables 5 and
6 in Supplementary data.
1
1375, 1224, 1160, 1044, 836 cmꢁ1. H NMR (400 MHz,
(CD3)2CO3, d): 8.35–8.30 (br s, 2H, NH: exchange with
D2O), 7.61–7.57 (m, 4H, aromatic protons), 7.24–7.20 (m,
4H, aromatic protons), 4.35 (d, 2H, J¼2.6 Hz). 13C
NMR (100 MHz, (CD3)2CO3, d): 169.5, 167.5 (d,
4
1J19F–13C¼250 Hz), 139.6 (d, J19F–13C¼3.2 Hz), 133.4 (d,
2
3J19F–13C¼8.4 Hz), 120.7 (d, J19F–13C¼21.9 Hz), 69.7,
55.6. LC–MS (ESI+): 349 [M+Na]+. Anal. Calcd for
C18H12F2N2O2: C, 66.26; H, 3.71; N, 8.59. Found: C,
66.20; H, 3.72; N, 8.80.
3.6.5. syn 2,6-Bis-(4-trifluoromethylphenyl)-3,7-diazatri-
cyclo[4.2.0.02,5]octan-4,8-dione (5e). Yield: 80% (0.072 g).
Mp 145–146 ꢀC (dec). Yellow crystals. Rf¼0.2. IR (KBr):
3273, 2923, 2853, 1760, 1746, 1620, 1412, 1326, 1165,
Acknowledgements
1
1116, 1068, 1017, 827 cmꢁ1. H NMR (500 MHz, CDCl3,
This work was financially supported by National Project
‘Stereoselezione in Sintesi Organica, Metodologie ed Appli-
cazioni’ MiUR (Rome), and the University of Bari. Thanks
are due to Istituto di Chimica dei Composti OrganoMetallici
(ICCOM-CNR, Bari) for NMR facilities.
d): 8.60–8.50 (br s, 2H, NH: exchange with D2O), 7.74–
7.71 (m, 4H, aromatic protons), 7.58–7.55 (m, 4H, aromatic
protons), 4.29 (d, 2H, J¼2.2 Hz). 13C NMR (100 MHz,
4
CDCl3, d): 166.5, 140.4 (d, J19F–13C¼1.1 Hz), 131.1 (q,
3
2J19F–13C¼32.9 Hz), 126.4, 126.2 (q, J19F–13C¼3.8 Hz),
1
123.7 (q, J19F–13C¼272.5 Hz), 64.1, 51.9. 19F NMR
(376 MHz, CDCl3, d): ꢁ63.0. LC–MS (ESIꢁ): 425
[MꢁH]ꢁ (27), 382 (100). Anal. Calcd for C20H12F6N2O2:
C, 56.35; H, 2.84; N, 6.57. Found: C, 56.20; H, 3.22; N, 6.80.
Supplementary data
1H and 13C NMR spectra for the new compounds and X-ray
crystal structure data for 5a. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2007.09.040.
3.7. X-ray crystallography data for compound (5a)
X-ray data were collected at 293(2) K on microscope-
selected single crystals using a Nonius Kappa CCD area
detector diffractometer, with Mo Ka radiation (l¼
References and notes
˚
0.71073 A), in f and u scan modes; data collection:
1. (a) Southgate, R. Contemp. Org. Synth. 1994, 1, 417–431; (b)
Neu, H. C. The Chemistry of b-Lactams; Page, M. I., Ed.;
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Table 4. Crystal data and structure refinement for syn 2,6-diphenyl-3,7-
diazatricyclo[4.2.0.02,5]octan-4,8-dione (5a)
Empirical formula
Formula weight
Temperature
C18H14N2O2
290.31
293(2) K
0.71073 A
Monoclinic; P21/c
80; 4.15–19.39ꢀ
˚
Wavelength
Crystal system; space group
Unit cell refl; q range
Unit cell dimensions
˚
˚
a¼14.3880(10) A
b¼11.8830(10) A
ꢁ
Balentova, E.; Jimenez, A.; Oyarbide, J.; Fratila, M. R.;
Miranda, J. J. Org. Lett. 2007, 9, 101–104.
˚
c¼8.7360(10) A
b¼97.276(7)ꢀ
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3
˚
Volume
1481.6(2) A
Z; calculated density
Absorption coefficient
F(000)
4; 1.302 mg mꢁ3
0.086 mmꢁ1
608
Crystal size
q range for data collection
Limiting indices
0.04 mmꢃ0.04 mmꢃ0.07 mm
5.01–27.49ꢀ
ꢁ18ꢂhꢂ12
ꢁ14ꢂkꢂ15
ꢁ11ꢂlꢂ11
Reflections collected/unique
Completeness (q¼27.49ꢀ)
Refinement method
11,827/3378[R(int)¼0.0534]
99.1% (q¼27.49ꢀ)
Full-matrix least-squares on F2
3378/0/255
Data/restraints/parameters
Goodness-of-fit on F2
1.016
R1¼0.0588, wR2¼0.1081
Final R indices [I>2s(I)]
R indices (all data)
Largest diff. peak and hole
R1¼0.1364, wR2¼0.1329
ꢁ3
˚
0.230 and ꢁ0.180 eA

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