Effect of the aryl group substituent in the dimerization of 3-arylisoxazoles to syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.02,5]octan-4,8-diones induced by LDA

Article abstract of DOI:10.1016/j.tet.2008.09.063

3-Arylisoxazoles react with LDA in THF at 0 °C affording syn-2,6-diaryl-3,7-diazatricyclo[4.2.0.0^2,5]octan-4,8-diones (bis-azetidinones), via stereoselective dimerization of an azetinone anion intermediate. A?fragmentation reaction affording arylnitriles may compete with electronic and steric effects of the substituent present in the aryl group being pivotal in determining the outcome of this reaction. An interesting behaviour with LDA of arylnitriles arising from the fragmentation reaction of some 3-arylisoxazoles was also observed. N,N-Diisopropylaminobenzonitriles were in fact formed (plausibly via a benzyne mechanism) from 3-(4-chlorophenyl)isoxazole and 3-(2-chlorophenyl)isoxazole, whereas 3-(2-methylphenyl)isoquinolin-1-amine was isolated starting from 3-(2-methylphenyl)isoxazole and LDA.

Full text of DOI:10.1016/j.tet.2008.09.063

Tetrahedron 64 (2008) 11198–11204
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Effect of the aryl group substituent in the dimerization of 3-arylisoxazoles
to syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.02,5]octan-4,8-diones induced by LDA
*
Leonardo Di Nunno , Paola Vitale, Antonio Scilimati
`
Dipartimento Farmaco-Chimico, Universita degli Studi di Bari, Via E.Orabona 4, 70125 Bari, Italy
a r t i c l e i n f o
a b s t r a c t
3-Arylisoxazoles react with LDA in THF at 0 ꢀC affording syn-2,6-diaryl-3,7-diazatricyclo[4.2.0.02,5]octan-
4,8-diones (bis-azetidinones), via stereoselective dimerization of an azetinone anion intermediate.
A fragmentation reaction affording arylnitriles may compete with electronic and steric effects of the
substituent present in the aryl group being pivotal in determining the outcome of this reaction. An
interesting behaviour with LDA of arylnitriles arising from the fragmentation reaction of some
3-arylisoxazoles was also observed. N,N-Diisopropylaminobenzonitriles were in fact formed (plausibly
via a benzyne mechanism) from 3-(4-chlorophenyl)isoxazole and 3-(2-chlorophenyl)isoxazole, whereas
3-(2-methylphenyl)isoquinolin-1-amine was isolated starting from 3-(2-methylphenyl)isoxazole and
LDA.
Article history:
Received 27 June 2008
Received in revised form 3 September 2008
Accepted 18 September 2008
Available online 30 September 2008
Keywords:
3-Arylisoxazoles
Cage-shaped bis-
LDA
b-lactams
Ó 2008 Elsevier Ltd. All rights reserved.
EDGs, EWGs
N,N-Diisopropylaminobenzonitriles
3-(2-Methylphenyl)isoquinolin-1-amine
1. Introduction
2. Results and discussion
We have recently reported the synthesis of previously unknown
syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.02,5]octan-4,8-diones (referred
to as bis-azetidinones from now on) by dimerization of 3-arylisox-
azoles induced by hindered lithium amides (LDA, LTMP, LHMDS)
(Scheme 1).1
Variously substituted 3-arylisoxazoles 1a–m were synthesized
following the procedure already reported by us,1,2 and outlined in
Scheme 2.
H
ArCN
+
C
O
In particular, we investigated the reaction of 3-phenylisoxazole 1
anda small numberof 3-(4-substituted-phenyl)isoxazolesobserving
high yields of the corresponding bis-azetidinones 4, except for iso-
xazoles containing electron-donor substituents (EDGs).
The latter compounds, in fact, depending on the magnitude of
the electron-donating effect, gave together with bis-azetidinones 4,
also variable amounts of the corresponding arylnitriles 5, arising
from a competitive fragmentation reaction plausibly favoured in
the presence of EDGs both for a diminished stability of lithium
iminoketenes 2, and a concomitant increased stability of arylni-
triles 5.
5
fragmentation
Ar
N
H
Ar
Ar
R2NLi
C
O
N
N
O
O
1
2
In this paper, we report a more extensive investigation of the
substituent effect on such a reaction, including other different
substituents and/or different substituted positions of the aryl
moiety.
cyclization
Ar
(R2NLi= LDA, LTMP, LHMDS)
N
H
Ar
O
dimerization
Ar
O
N
N
O
H
3
4
* Corresponding author. Tel.: þ39 80 5442734; fax: þ39 80 5442231.
E-mail address: dinunno@farmchim.uniba.it (L. Di Nunno).
Scheme 1. Reaction of 3-arylisoxazoles with R2NLi.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.063

L. Di Nunno et al. / Tetrahedron 64 (2008) 11198–11204
11199
Table 2
Ar
Ar
O
Li
Yields of bis-azetidinones (4a–m) and arylnitriles (5b, 5d, 5e, 5g and 5m) isolated by
n-BuLi
ArCNO
THF
MeONa
reaction of 3-arylisoxazoles (1a–m) with LDAa
N
N
r.t.
MeOH
reflux
OH
O
O
O
Entry Ar
Yield of
Yield of
Other
4a–m (%)b 5a–m (%)c products (%)
6a-m
1a-m
1
2
3
4
5
6
7
8
Phenyl (1a)
80 (4a)
58 (4b)
7 (4c)
33 (4d)
79 (4e)
70 (4f)
40 (4g)
79 (4h)
74 (4i)
80 (4l)
d
d
Scheme 2. Synthesis of 3-arylisoxazoles (1a–m) via 3-aryl-5-hydroxy-2-isoxazolines
(6a–m).
4-Methylphenyl- (1b)
2-Methylphenyl- (1c)
4-Methoxyphenyl- (1d)
3-Methoxyphenyl- (1e)
4-Chlorophenyl- (1f)
2-Chlorophenyl- (1g)
4-Fluorophenyl- (1h)
3-Fluorophenyl- (1i)
38 (5b)
d
d
80 (9)d
d
56 (5d)
18 (5e)
d
d
22e
21 (8)f
d
30 (5g)
d
In all cases, satisfactory yields of 3-arylisoxazoles 1a–m were
obtained, as reported in Table 1.
The synthesized 3-arylisoxazoles 1a–m include a variety of
substituents with different electronic effects and/or attached at
different positions of the aryl moiety.
9
10
11
d
d
4-(Trifluoromethyl)phenyl- (1l)
2-(Trifluoromethyl)phenyl- (1m) 31 (4m)
d
60 (5m)g
d
d
a
Reactions were conducted in THF at 0 ꢀC for 1 h, with isoxazole 1a–m/base
ratio¼1:1.5.
All the synthesized compounds (1a–m) were reacted with LDA
under the same previously reported conditions,1 observing also the
same behaviour (see Scheme 1), with relative percentages (%) of
the isolated products depending on the features and the position
of the substituent.
In some cases (aryl¼4-chlorophenyl-, 2-chlorophenyl- and 2-
methylphenyl-), variable amounts of additional products generated
by further reaction of the initially formed arylnitriles with LDA
were also isolated. The obtained results are summarized in Table 2.
Examination of the obtained results allows several comments to
be made. First of all, the previously observed trend concerning the
favourable effect of electron-withdrawing groups (EWGs) on the
dimerization reaction seems to be further supported. Comparison
of the behaviour of 3-(4-methoxyphenyl)isoxazole (1d) (entry 4)
with that of 3-(3-methoxyphenyl)isoxazole (1e) (entry 5) offers
a clear further confirmation of such a hypothesis.
b
Yields refer to the products actually isolated by chromatography.
Percentages determined by 1H NMR spectra recorded on reaction crudes; some
c
unreacted starting 3-arylisoxazole was also detected (1b, ꢂ4%; 1c, ꢂ11%; 1d, ꢂ11%).
d
2-Methylbenzonitrile (5b) in presence of LDA gives rise to dimerization to 3-(2-
methylphenyl)isoquinolin-1-amine (9) (Scheme 5).
e
4-(Diisopropylamino)benzonitrile (7) (15%) and of 3-(diisopropylamino)benzo-
nitrile (8) (7%) were also isolated (Scheme 4).
f
3-(Diisopropylamino)benzonitrile (8) was also isolated (Scheme 4).
Percentages determined by 19F NMR spectra recorded on reaction crudes.
g
iminoketene anions 2 to the detriment of their dimerization to
bis-azetidinones 4. And this, in turn, can conceivably be related to
their electronic effect destabilizing the iminoketene anion and at
the same time stabilizing one of the fragmentation products
(ArCN 5).
As it is well-known, a methoxy group is a typical substituent
with electronic effects that are markedly dependent on the oc-
cupied position: it behaves as an EDG when bonded to the para
position and an EWG when instead is present in the meta posi-
tion (see the corresponding Hammett s(OMe) values: sp¼ꢁ0.28;
sm¼0.10).3
However, together with the electronic effects, we decided to
also explore the steric effects of the substituent in the same re-
action. This can be evaluated by comparing, for a given substituent,
the behaviour of para versus ortho substituted 3-arylisoxazoles, by
assuming that the electronic effects should be not much different in
the two cases (comparison of sp with so
values).4
*
So, while 3-(4-methoxyphenyl)isoxazole (1d), as previously
reported,1 affords low yields (33%) of the bis-azetidinone (4d), 3-(3-
methoxyphenyl)-isomer (1e) gives high yields (79%) of 4e (Table 2).
As expected, not very different results are instead observed in
the reactions of 3-(4-fluorophenyl)- and 3-(3-fluorophenyl)iso-
xazole (79% and 74% yields of the corresponding bis-azetidinones
4h and 4i, respectively). In this case, in fact, the different position of
the substituent does not cause inversion of the sign of the elec-
tronic effect (the reported s(F) values are both positive: sp¼0.15;
sm¼0.34).3
Examination of data referring to both electron-donating (iso-
xazoles 1b,c) and electron-withdrawing substituents (isoxazoles
1f,g and 1l,m) clearly indicates, as expected, a marked dependence
of the reaction on the steric effects of the substituent.
In all cases, in fact, the presence of the substituent in the ortho
position disfavours the dimerization reaction and favours the
fragmentation (see Table 2, entries 2, 3, 6, 7,10 and 11: reference, for
a given substituent, to the relative increase of the corresponding
arylnitrile 5 and/or products of further reaction with LDA, on going
from para to ortho substituted 3-arylisoxazoles), to an extent also
Thus, as previously observed,1 the presence of electron-
donating groups is confirmed to favour the fragmentation of
roughly depending on the size of the group (calculated as
D volume,
as reported in Table 3).5
Similar conclusions can be drawn also by referring to different
parameters for steric effects of the same groups, such as Es values
(0, ꢁ0.97, ꢁ1.24 and ꢁ2.4 for H, Cl, CH3 and CF3, respectively).3
The observed behaviour can again be related to a diminished
stability of the iminoketene anion 2 compared to the fragmen-
tation product ArCN 5, caused, in this case, by steric effects
(Scheme 3).
Table 1
Yieldsa of 3-aryl-5-hydroxy-2-isoxazolines (6a–m) from ArCNO and of 3-arylisox-
azoles (1a–m) from 6a–m (reference to Scheme 2)
Entry
Ar
Yield of 6a–m (%)
Yield of 1a–m (%)
1
2
3
4
5
6
7
8
Phenyl
80 (6a)
60 (6b)
74 (6c)
85 (6d)
72 (6e)
73 (6f)
80 (6g)
70 (6h)
65 (6i)
84 (6l)
72 (6m)
80 (1a)
84 (1b)
75 (1c)
94 (1d)
85 (1e)
73 (1f)
85 (1g)
68 (1h)
78 (1i)
94 (1l)
74 (1m)
4-Methylphenyl-
2-Methylphenyl-
4-Methoxyphenyl-
3-Methoxyphenyl-
4-Chlorophenyl-
2-Chlorophenyl-
4-Fluorophenyl-
3-Fluorophenyl-
4-(Trifluoromethyl)phenyl-
2-(Trifluoromethyl)phenyl-
Table 3
Size relative to H of groups G attached to phenyl ring, calculated as
D
molecular
volume [(Ph–G)–(Ph–H)]5
Substituent (Ph–G)
CPK volume (Å3)
D
Volume (Å3)
9
10
11
Ph–H
Ph–Cl
Ph–CH3
Ph–CF3
99.1507433
112.323603
117.172886
131.654974
d
13.17
18.02
32.50
a
Yields refer to the products actually isolated by chromatography.

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L. Di Nunno et al. / Tetrahedron 64 (2008) 11198–11204
Thus, the observed behaviour may constitute an example of
benzyne mechanism not induced (as commonly established)6 by
the absence of an activating group, but only (or mainly) due to
a large steric hindrance of the nucleophile.
Finally, another observation concerned the reaction of 3-
(2-methylphenyl)isoxazole (1c) with LDA. In this case, as already
reported,7 the formed 2-methylbenzonitrile (5c) further reacts in
the presence of LDA giving rise to dimerization to 3-(2-methyl-
phenyl)isoquinolin-1-amine (9) (recently tested as an antitumour
agent),8 by the mechanism outlined in Scheme 5.
fragmentation
G
H
+
O C CH
sp2
N
G
sp
C
C
C
C
O
N
2
5
Scheme 3. The presence of a substituent in the ortho position favours the fragmen-
tation reaction.
Transformation of the iminoketene 2 into the corresponding
arylnitrile in the case of ortho substituted 3-arylisoxazoles is, in fact,
actually accompanied by a relief of the steric hindrance, due to the
smaller size and the linear geometry of the cyano group.
On the other hand, the present investigation also allowed us to
ascertain the interesting behaviour of some formed aromatic
nitriles in the presence of LDA.
The first one refers to arylnitriles derived from the fragmenta-
tion of 3-arylisoxazoles 1f and 1g with LDA: in both cases the
formed 4-chloro- and 2-chlorobenzonitrile, respectively, further
react to give (in part or completely) the products of diisopropyl-
amino-dehalogenation (Table 2, entries 6 and 7).
CH3
CH3
N
H
CH3
N
+
LDA
4c
O
O
O
N
H
1c
C
N
The latter reaction, however, conceivably due to the steric hin-
drance of the nucleophile (LDA), does not occur by SNAr mechanism
as expected by considering that the cyano group, unaffected (as it
appears) by LDA under the used conditions, could in principle
activate such a mechanism. So, in spite of the existing potential
activation for a SNAr reaction, a benzyne mechanism occurs instead,
as revealed by isolation of both 7 and 8 (the normal- and the cine-
substitution product, respectively) from 4-chlorobenzonitrile (5f),
and of cine-substitution product 8 in the case of 2-chlorobenzoni-
trile (5g) (Table 2 and Scheme 4). Accordingly, the same results
were found by reacting the commercially available chloro-
benzonitriles 5f and 5g with LDA under the same conditions.
Moreover, as expected for a benzyne mechanism, no products of
diisopropylamino-dehalogenation have instead been observed
starting from commercially available 4-fluorobenzonitrile (an un-
identified fluorinated material was obtained in this case).
CH3
5c
LDA
NH2
N
N
C
N
CH3
N
CH3
N
C
H+
CH2
H3C
9
Scheme 5. Reaction of 3-(2-methylphenyl)isoxazole (1c) with LDA.
N
CN
N
CN
7
Normal-substitution
product (main product)
more stable
intermediate
LDA
LDA
Cl
CN
CN
(a)
5f
N
N
CN
CN
Cine-substitution
product
8
Cl
LDA
LDA
CN
CN
(b)
N
N
CN
CN
5g
8
Cine-substitution
product
decidedly
more stable intermediate :
electronic and steric factors
Scheme 4. Proposed mechanism of formation of (a) 4-(diisopropylamino)benzonitrile (7) and 3-(diisopropylamino)benzonitrile (8) from 4-chlorobenzonitrile (5f) and (b) 3-
(diisopropylamino)benzonitrile (8) from 2-chlorobenzonitrile (5g) induced by LDA.

L. Di Nunno et al. / Tetrahedron 64 (2008) 11198–11204
11201
In conclusion, the present investigation confirmed the pre-
viously observed dependence of dimerization of 3-arylisoxazoles
on the electronic effects of the substituent present in the aryl
moiety (reactions of meta and para substituted isoxazoles). A clear
evidence of an important influence of the steric effects of
the substituent on the same reaction (reactions of ortho substituted
3-arylisoxazoles) is also presented and a plausible explanation of
both electronic and steric effects is provided.
In addition, concerning in particular the reaction of 3-(4-
chlorophenyl)isoxazole (1f) and 3-(2-chlorophenyl) isoxazole (1g),
an interesting behaviour with LDA of the corresponding chlor-
obenzonitriles generated by ring-fragmentation has also been
evidenced and discussed. This reaction appears also to be an al-
ternative synthetic approach to the N,N-diisopropylaminobenzo-
nitrile 7 (4-DIABN)9 and its isomer 8 (3-DIABN), widely used in
dual-fluorescence and intramolecular charge transfer (ICT) studies
as electron donor (D)/acceptor (A) molecules.10,11 Further in-
vestigations are in progress on this point as well as to elucidate the
chemical and biological properties of the synthesized cage-shaped
identical to those previously reported or commercially available
compounds.
3.2.1. 2-Methylbenzaldehyde oxime14,15
FTIR (neat): 3210, 3071, 2992, 2922, 2870, 2744, 1625, 1498,
1454, 1425, 1318, 1291, 1227, 1188, 978, 954, 874, 792, 751, 711 cmꢁ1
.
1H NMR (500 MHz, CDCl3,
d): 8.50–9.0 (br s, 1H, OH: exchanges
with D2O), 8.50 (s, 1H), 7.72–7.74 (m, 1H, aromatic proton), 7.32–
7.35 (m, 1H, aromatic proton), 7.25–7.29 (m, 2H, aromatic protons),
2.49 (s, 3H). 13C NMR (125 MHz, CDCl3,
d): 149.2, 136.8, 130.8, 130.1,
129.8, 126.6, 126.2, 19.6. GC–MS (70 eV) m/z (rel int.): 135 (Mþ, 69),
120 (59), 119 (11), 118 (92), 117 (100), 116 (22), 91 (56), 90 (38), 89
(39), 77 (13), 65 (25), 63 (21), 51 (11).
3.2.2. 3-Methoxybenzaldehyde oxime16
1H NMR (400 MHz, CDCl3,
d): 9.0–8.40 (br s, 1H, OH: exchanges
with D2O), 8.14 (s, 1H), 7.32–7.28 (m, 1H, aromatic proton), 7.17–7.12
(m, 2H, aromatic protons), 6.97–6.93 (m, 1H, aromatic proton), 3.83
(s, 3H). 13C NMR (100 MHz, CDCl3,
120.1, 116.4, 111.2, 55.3.
d): 159.8, 150.3, 133.2, 129.8,
bis-b-lactams.
3. Experimental section
3.1. General methods
3.2.3. 4-Chlorobenzaldehyde oxime14,17
1H NMR (400 MHz, CDCl3,
): 8.10 (s, 1H), 7.82–7.60 (m, 1H, OH:
exchanges with D2O), 7.53–7.50 (d, 2H, J¼8.4 Hz, aromatic protons),
7.37–7.34 (d, 2H, J¼8.4 Hz, aromatic protons). GC–MS (70 eV) m/z
(rel int.): 155 (Mþ, 100), 134 (22), 108 (58), 92(21), 77 (29), 63 (17),
51 (9).
d
Melting points were taken on an electrothermal apparatus. 1H
NMR and 13C NMR spectra were recorded on a Varian-Inova-
400 MHz spectrometer, on a Bruker-Aspect 3000 console-500 MHz
spectrometer and chemical shifts are reported in parts per million
3.2.4. 3-Fluorobenzaldehyde oxime18
(d
). 19F NMR spectra were recorded by using CFCl3 as internal
Yield 92%. Light semi-solid. FTIR (neat): 3307, 3017, 2934, 2854,
1584, 1489, 1448, 1326, 1271, 1257, 1140, 953, 946, 862, 779,
standard. Absolute values of the coupling constant are reported.
FTIR spectra were recorded on a Perkin–Elmer 681 spectrometer.
GC analyses were performed by using a HP1 column (methyl
678 cmꢁ1. 1H NMR (400 MHz, CDCl3,
d): 10.00–9.40 (br s, 1H, OH:
exchanges with D2O), 8.18 (s, 1H), 7.38–7.33 (m, 3H, aromatic pro-
siloxane; 30 mꢃ0.32 mmꢃ0.25
mm film thickness) on a HP 6890
tons), 7.12–7.06 (m,1H, aromatic proton).13C NMR (100 MHz, CDCl3,
4
model, Series II. Thin-layer chromatography (TLC) was performed
on silica gel sheets with fluorescent indicator; the spots on the TLC
were observed under ultraviolet light or were visualized by I2 va-
pour. Chromatography was conducted by using silica gel 60 with
d
): 162.8 (d, 1J19F–13C¼246 Hz), 149.5 (d, J19F–13C¼2.7 Hz), 133.8 (d,
3J19F–13C¼8.0 Hz), 130.3 (d, J19F–13C¼8.0 Hz), 123.1 (d, J19F–13C
3
4
¼3.0 Hz),117.0 (d, 2J19F–13C¼21.8 Hz),113.3 (d, 2J19F–13C¼22.9 Hz). 19
F
NMR (376 MHz, CDCl3,
d
): ꢁ116.4 (m).
a particle size distribution 40–63 mm and 230–400 ASTM. GC–MS
analyses were performed on an HP 5995C model and elemental
analyses on an Elemental Analyzer 1106-Carlo Erba-instrument.
MS-ESI analyses were performed on Agilent 1100 LC/MSD trap
system VL.
3.2.5. 2-(Trifluoromethyl)benzaldehyde oxime14,19
Yield 95%. FTIR (neat): 3306, 3080, 3026, 2927, 1580, 1495, 1450,
1317, 1280, 1180, 1157, 1111, 1036, 975, 875, 763, 670 cmꢁ1. 1H NMR
(400 MHz, CDCl3, d): 9.40–9.30 (br s, 1H, OH: exchanges with D2O),
8.61 (m, 1H), 7.99–7.97 (m, 1H, aromatic proton), 7.70–7.67 (m, 1H,
aromatic proton), 7.56–7.52 (m, 1H, aromatic proton), 7.49–7.45 (m,
3.2. Materials
1H, aromatic proton). 13C NMR (100 MHz, CDCl3,
d
): 147.4 (m),
2
Tetrahydrofuran (THF) from commercial source was purified
by distillation (twice) from sodium wire under nitrogen atmo-
sphere. 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-pivaloyl-o-toluidine.12
Diisopropylamine from Aldrich Chemical Co. was purified by
distillation from CaH2. All other chemicals and solvents were
commercial grade further purified by distillation or crystallization
prior to use.
All the used 3-arylisoxazoles 1a–m were prepared via the cor-
responding 3-aryl-5-hydroxy-2-isoxazolines 6a–m, by using the
previously described procedure.1,2 Arylnitrile oxides were prepared
from aldehydes through their conversion into the corresponding
oximes and then into benzohydroximinoyl chlorides.2,13 These
were finally converted into nitrile oxides by treatment with NEt3,
followed by vacuum filtration of the formed NEt3$HCl from the
reaction mixture.
132.0, 129.9 (m), 129.7, 128.4 (q, J19F–13C¼30.9 Hz), 127.3, 125.9 (q,
3J19F–13C¼5.5 Hz), 123.9 (q, 1J19F–13C¼273.7 Hz). 19F NMR (376 MHz,
CDCl3,
d
): ꢁ62.8.
3.3. Synthesis of benzohydroximinoyl chlorides: general
procedure2,13
In a round-bottom flask equipped with magnetic stirrer the
benzaldoxime (3.483 g, 0.0251 mol) was dissolved in anhydrous
DMF (60 mL), then the solution was cooled to 0 ꢀC. NCS (3.686 g,
0.0276 mol) was slowly added and the suspension was stirred to
0 ꢀC. When the reaction was completed, water was added to the
reaction mixture became a limpid yellow solution. The aqueous
layer was extracted three times with ethyl acetate. The combined
organic extracts were washed with water to remove succinimide
and then the solution was dried over anhydrous Na2SO4. Benzo-
hydroximinoyl chlorides (obtained in 77–90% yield after evapora-
tion of the solvent under vacuum) had analytical and spectroscopic
data identical to those previously reported or commercially avail-
able compounds.
Oximes, prepared from reaction of aldehydes/EtOH and
NH2OH$HCl/aq NaOH,1,2 had analytical and spectroscopic data

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L. Di Nunno et al. / Tetrahedron 64 (2008) 11198–11204
3.3.1. N-Hydroxy-2-methylbenzimidoyl chloride14,15
134 (11), 133 (19), 132 (22), 107 (17), 104 (13), 103 (10), 92 (29), 91
(13), 77 (44), 76 (13), 64 (16), 63 (17). Anal. Calcd for C10H11NO3: C,
62.17; H, 5.74; N, 7.25. Found: C, 62.30; H, 5.88; N, 7.33.
1H NMR (CDCl3, 400 MHz,
d): 8.30–8.50 (s, 1H, br s, OH: ex-
changes with D2O), 7.21–7.47 (m, 4H, aromatic protons), 2.43 (s,
3H). 13C NMR (75 MHz, CDCl3): 138.9, 137.0, 133.0, 130.8, 130.1,
129.5, 125.9, 20.2.
3.4.3. 3-(4-Chlorophenyl)-5-hydroxy-2-isoxazoline (6f)22
Yield 73%, 2.042 g. Mp 128.0–129.0 ꢀC. Light yellow crystals.
FTIR (KBr): 3344, 2921, 2404, 1852, 1917, 1741, 1595, 1491, 1462,
1404,1351,1274,1242,1175,1085,1012, 892, 874, 823 cmꢁ1. 1H NMR
3.3.2. 3-Fluoro-N-hydroxybenzimidoyl chloride20
Yield 86%. Light yellow oil. 1H NMR (500 MHz, CDCl3,
d): 9.70–
9.50 (br s, 1H, OH: exchanges with D2O), 7.60–7.58 (m, 1H, aromatic
proton), 7.52–7.49 (m, 1H, aromatic proton), 7.37–7.30 (m, 1H,
(300 MHz, CDCl3, d): 7.63–7.58 (m, 2H, aromatic protons), 7.39–7.35
(m, 2H, aromatic protons), 6.06 (dd, 1H, J¼6.5 and 1.65 Hz), 4.00–
3.80 (br s, 1H, OH: exchange with D2O), 3.40 (dd, 1H, J¼6.5 and
17.5 Hz), 3.21 (dd, 1H, J¼17.5 and 1.65 Hz). 13C NMR (75 MHz, CDCl3,
aromatic proton), 7.13–7.08 (m, 1H, aromatic proton). 13C NMR
4
(125 MHz, CDCl3,
d
): 162.4 (d, 1J19F–13C¼247 Hz), 138.3 (d, J19F–13C
¼3.3 Hz),134.3 (d, 3J19F–13C¼8.6 Hz),129.9 (d, 3J19F–13C¼8.1 Hz),122.7
d): 156.2, 136.7, 129.3, 128.4, 127.7, 98.4, 42.6. GC–MS (70 eV) m/z
4
2
2
(d, J19F–13C¼3.3 Hz), 117.5 (d, J19F–13C¼21.5 Hz), 114.0 (d, J19F–13C
¼
(rel int.): 197 (Mþ, 69),180 (19),178 (42),170 (26),168 (97),153 (35),
139 (34), 137 (100), 125 (22), 111 (45), 102 (44), 75 (43), 63 (15), 51
(25).
24.3 Hz). 19F NMR (376 MHz, CDCl3,
d
): ꢁ62.8.
3.3.3. N-Hydroxy-2-trifluoromethylbenzimidoyl chloride14,21
Yield 83%. White semi-solid.1H NMR (500 MHz, CDCl3,
d): 10.60–
3.4.4. 3-(3-Fluorophenyl)-5-hydroxy-2-isoxazoline (6i)
10.40 (br s,1H, OH: exchanges with D2O), 7.65–7.62 (m,1H, aromatic
proton), 7.54–7.45 (m, 3H, aromatic protons). 19F NMR (376 MHz,
Yield 65%, 2.679 g. Mp 167–168 ꢀC. Light yellow crystals. FTIR
(KBr): 3221, 3065, 2964, 2848, 1599, 1574, 1494, 1429, 1366, 1274,
1249, 1186, 1089, 918, 873, 790 cmꢁ1. 1H NMR (400 MHz, (CD3)2CO,
CDCl3,
d
): ꢁ62.9. 13C NMR (125 MHz, CDCl3,
d): 164.1, 135.0, 131.9 (q,
2
4J19F–13C¼1.9 Hz), 131.8, 130.9, 130.1, 128.4 (q, J19F–13C¼31.5 Hz),
d): 7.58–7.46 (m, 3H, aromatic protons), 7.25–7.19 (m, 1H, aromatic
proton), 6.2–6.05 (br s, 1H, OH: exchanges with D2O), 6.03 (dd, 1H,
126.3 (q, 3J19F–13C¼4.8 Hz), 123.3 (q, 1J19F–13C¼273.7 Hz).
J¼6.9 and 1.6 Hz), 3.52 (dd, 1H, J¼6.9 and 17.8 Hz), 3.20 (dd, 1H,
3.4. Synthesis of 3-aryl-5-hydroxy-2-isoxazolines (6a–m):
general procedure1,2
J¼17.8 and 1.6 Hz). 13C NMR (100 MHz, (CD3)2CO,
d): 164.6 (d,
4
3
1J19F–13C¼244 Hz), 157.0 (d, J19F–13C¼3.0 Hz), 134.3 (d, J19F–13C
3
4
¼8.0 Hz), 132.6 (d, J19F–13C¼8.4 Hz), 124.5 (d, J19F–13C¼3.0 Hz),
118.4 (d, 2J19F–13C¼21.4 Hz), 114.9 (d, 2J19F–13C¼23.3 Hz), 100.4, 43.4.
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 magnetic stirrer. After the re-
action 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 combined, dried over anhydrous Na2SO4 and then the
solvent evaporated under reduced pressure. Column chromatog-
raphy (silica gel, petroleum ether/ethyl acetate¼70:30) of the res-
idue afforded the 3-aryl-5-hydroxy-2-isoxazolines 6a–m in 60–85%
yields (Table 1). 5-Hydroxy-3-aryl-2-isoxazoline (6a,2 6b, 6d, 6g,2
6h, 6l)1 had analytical and spectroscopic data identical to those
previously reported.
19F NMR (376 MHz, (CD3)2CO,
d
): ꢁ109.2. GC–MS (70 eV) m/z (rel
int.): 181 (Mþ, 55), 164 (20), 163 (76), 162 (78), 153 (41), 152 (47),
135 (29), 134 (28), 122 (20), 121 (58), 109 (21), 108 (19), 107 (32),
101 (21), 96 (19), 95 (100), 81 (11), 75 (46), 57 (15), 50 (10). Anal.
Calcd for C9H8FNO2: C, 59.67; H, 4.45; N, 7.73. Found: C, 60.05; H,
4.53; N, 7.73.
3.4.5. 3-(2-(Trifluoromethyl)phenyl)-5-hydroxy-2-isoxazoline (6m)
Yield 82%, 3.247 g. Light yellow oil. FTIR (neat): 3382, 3077,
2962, 2927, 2851, 1606, 1451, 1316, 1271, 1175, 1116, 1079, 1036, 840,
770 cmꢁ1. 1H NMR (500 MHz, CDCl3,
d): 7.76–7.73 (m, 1H, aromatic
proton), 7.60–7.53 (m, 3H, aromatic protons), 6.05 (dd, 1H, J¼6.6
and 1.5 Hz), 4.4–3.9 (br s, 1H, OH: exchanges with D2O), 3.49 (dd,
1H, J¼6.6 and 17.9 Hz), 3.16 (dd, 1H, J¼17.9 and 1.5 Hz). 13C NMR
2
3.4.1. 3-(2-Methylphenyl)-5-hydroxy-2-isoxazoline (6c)
(125 MHz, CDCl3,
d
): 156.4, 132.0 (m), 129.9, 128.5 (q, J19F–13C
4
3
Yield 74%, 1.415 g. Light yellow oil. FTIR (KBr): 3383, 3063, 2960,
¼31.5 Hz), 128.3 (q, J19F–13C¼1.9 Hz), 126.6 (q, J19F–13C¼5.7 Hz),
2925, 1603, 1493, 1455, 1342, 1176, 1076, 921, 839, 758 cmꢁ1
.
1H
123.7 (q, J19F–13C¼273.4 Hz), 98.3, 46.0 (m). 19F NMR (376 MHz,
1
NMR (500 MHz, CDCl3,
d): 7.35–7.20 (m, 4H, aromatic protons), 6.00
CDCl3,
d
): ꢁ62.9. GC–MS (70 eV) m/z (rel int.): 231 (Mþ, 100), 214
(d, 1H, J¼6.7 Hz), 4.6–4.5 (br s, 1H, OH: exchanges with D2O), 3.46
(16), 213 (97), 212 (95), 188 (35), 185 (65), 184 (51), 183 (52), 171
(38), 168 (45), 166 (47), 165 (50), 164 (20), 163 (21), 162 (78), 152
(49), 151 (97), 145 (97), 133 (38), 121 (30), 95 (34), 75 (38). Anal.
Calcd for C10H8F3NO2: C, 51.96; H, 3.49; N, 6.06. Found: C, 51.70; H,
3.53; N, 6.30.
(dd, 1H, J¼6.7 and 17.5 Hz), 3.25 (d, 1H, J¼17.5 Hz), 2.54 (s, 3H). 13C
NMR (125 MHz, CDCl3, d): 157.8, 137.9, 131.4, 129.5, 129.1, 128.0,
125.7, 96.9, 44.9, 22.6. GC–MS (70 eV) m/z (rel int.): 177 (Mþ, 63),
162 (22), 160 (56), 134 (17), 133 (13), 132 (38), 131 (29), 130 (100),
117 (27), 116 (20), 115 (33), 104 (17), 103 (15), 91 (31), 89 (18), 78
(16), 77 (21), 65 (18), 63 (12). Anal. Calcd for C10H11NO2: C, 67.78; H,
6.26; N, 7.90. Found: C, 67.80; H, 6.24; N, 7.52.
3.5. Synthesis of 3-arylisoxazoles (1a–m): general
procedure1,2
3.4.2. 3-(3-Methoxyphenyl)-5-hydroxy-2-isoxazoline (6e)
In a round-bottom flask equipped with magnetic stirrer, MeONa
(0.654 g, 12.7 mmol) was added to a solution of 3-aryl-5-hydroxy-
2-isoxazolines 6a–m (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. MeOH was evaporated under reduced pressure and the
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 chroma-
tography (silica gel, petroleum ether/ethyl acetate¼10:1) of the
residue affords 3-arylisoxazoles 1a–m in 65–94% yields (Table 1). 3-
Yield 72%, 3.640 g. Light yellow oil. FTIR (neat): 3391, 3080,
2938, 2840, 1607, 1574, 1460, 1433, 1348, 1287, 1260, 1218, 1177,
1080, 1033, 881, 789, 689 cmꢁ1. 1H NMR (400 MHz, CDCl3,
d): 7.32–
7.27 (m, 2H, aromatic protons), 7.20–7.17 (m, 1H aromatic proton),
6.98–6.95 (m, 1H aromatic proton), 6.04 (dd, 1H, J¼6.6 and 1.5 Hz),
4.0–3.6 (br s, 1H, OH: exchanges with D2O), 3.82 (s, 3H), 3.41 (dd,
1H, J¼6.6 and 17.6 Hz), 3.23 (dd, 1H, J¼17.6 and 1.5 Hz). 13C NMR
(100 MHz, CDCl3, d): 159.6, 156.8, 130.2, 129.7, 119.6, 116.8, 114.1,
98.0, 55.3, 42.5. GC–MS (70 eV) m/z (rel int.): 193 (Mþ, 63), 176 (18),
175 (100), 174 (77), 165 (12), 150 (13), 149 (14), 147 (27), 146 (10),

L. Di Nunno et al. / Tetrahedron 64 (2008) 11198–11204
11203
Phenylisoxazole (1a),2 3-(4-methylphenyl)isoxazole (1b),1,23 3-(4-
methoxyphenyl) isoxazole (1d)1,24 and 3-(4-fluorophenyl)isoxazole
(1h),1,25 3-(4-trifluoromethyphenyl)isoxazole (1l)1,26 had analytical
and spectroscopic data identical to those previously reported.
Anal. Calcd for C10H6F3NO: C, 56.35; H, 2.84; N, 6.57. Found: C,
56.30; H, 2.88; N, 6.50.
3.6. Reaction of 3-arylisoxazoles (1a–m) with lithium
diisopropylamide: general procedure
3.5.1. 3-(2-Methylphenyl)isoxazole (1c)
Yield 75%, 0.820 g. Colourless oil. FTIR (neat): 3153, 3120, 2956,
A 2.5 M solution of n-BuLi in hexanes (0.310 mL, 0.776 mmol)
was added to a solution of the diisopropylamine (0.853 mmol) in
THF (2 mL) at 0 ꢀC under nitrogen atmosphere, using a nitrogen-
flushed three-necked flask equipped with a magnetic stirrer and
a nitrogen inlet. After 10 min, the solution of the 3-arylisoxazoles
1a–m (75 mg, 0.517 mmol) in THF (1 mL) was dropwise added and
the obtained brown reaction mixture, kept at 0 ꢀC, was stirred for
1 h and then quenched by adding aq NH4Cl. The two phases were
separated and the aqueous layer was extracted three times with
ethyl acetate. The combined organic extracts were dried over an-
hydrous 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-diones 4a–m as indicated in the
2925, 1606, 1553, 1460, 1386, 1120, 1086, 874, 762, 726. 1H NMR
(500 MHz, CDCl3,
d
): 8.39 (d, 1H, J¼1.5 Hz), 7.45–7.43 (m, 1H, aro-
matic proton), 7.28–7.20 (m, 3H, aromatic protons), 6.46 (d, 1H,
J¼1.5 Hz), 2.41 (s, 3H). 13C NMR (125 MHz, CDCl3,
d): 161.9, 157.9,
136.8, 131.0, 129.43, 129.40, 128.4, 125.9, 105.0, 21.0. GC–MS (70 eV)
m/z (rel int.): 159 (Mþ, 63), 158 (63), 130 (100), 103 (20), 91 (16), 89
(14), 77 (15), 65 (20), 51 (11). Anal. Calcd for C10H9NO: C, 75.45; H,
5.70; N, 8.80. Found: C, 75.40; H, 5.68; N, 8.50.
3.5.2. 3-(3-Methoxyphenyl)isoxazole (1e)
Yield 74%, 2.431 g. Light yellow oil. FTIR (neat): 3147, 3125, 3004,
2939, 2838, 1588, 1556, 1472, 1436, 1385, 1320, 1295, 1236, 1123,
1039, 885, 830, 777, 771, 688 cmꢁ1 1H NMR (400 MHz, CDCl3,
. d):
8.46 (d, 1H, J¼1.8 Hz), 7.41–7.40 (m, 1H, aromatic proton), 7.38–7.36
Scheme 3, Tables 1 and 2. 1H NMR signal (
d
¼4.10O4.35 ppm) at-
(d, 2H, aromatic protons), 7.01–6.98 (m, 1H, aromatic proton), 6.66
tributed to the proton at C5 was a doublet with long-range coupling
(d, 1H, J¼1.8 Hz), 3.87 (s, 3H). 13C NMR (100 MHz, CDCl3,
d
): 161.4,
constant 4J¼2.0O3.2 Hz. 4J (s0 Hz) was due to the ‘W conforma-
159.9, 158.9, 129.98, 129.96, 119.4, 116.1, 111.8, 102.6, 55.4. GC–MS
(70 eV) m/z (rel int.): 175 (Mþ, 100), 174 (75), 132 (16), 107 (12), 92
(22), 77 (32), 76 (10), 64 (12), 63 (13). Anal. Calcd for C10H9NO2: C,
68.56; H, 5.18; N, 8.00. Found: C, 68.41; H, 5.01; N, 7.86.
tion’ of the four s bonds between H5 and Hamidic. Hamidic peak was
not split by H5, its signal was broadened by the quadrupolar
interaction.
Analytical and spectroscopic data of syn 2,6-diaryl-3,7-diaza-
tricyclo[4.2.0.02,5]octan-4,8-diones 4a, 4b, 4d, 4h and 4l were
previously reported.1 Arylnitriles 5b, 5d, 5e, 5g and 5m, isolated as
product of the reaction mentioned above (Scheme 1 and Table 2)
had the same analytical and spectroscopic data of the commercially
available compounds.
3.5.3. 3-(4-Chlorophenyl)isoxazole (1f)22
Yield 73%, 0.160 g. Mp 70.0–71.0 ꢀC. Light yellow crystals. FTIR
(KBr): 3151, 3129, 3078, 2925, 2853, 1664, 1548, 1548, 1503, 1430,
1372,1274,1121,1099,1046,1014, 946, 887, 832, 782, 719, 683 cmꢁ1
.
1H NMR (400 MHz, CDCl3,
d
): 8.47 (d, 1H, J¼1.8 Hz), 7.76 (d, 2H,
J¼8.4 Hz, aromatic protons), 7.44 (d, 2H, J¼8.4 Hz, aromatic pro-
3.6.1. syn 2,6-Bis(2-methylphenyl)-3,7-diazatricyclo
[4.2.0.02,5]octan-4,8-dione (4c)
tons), 6.64 (d, 1H, J¼1.8 Hz). 13C NMR (100 MHz, CDCl3,
d): 160.5,
159.1, 136.0, 129.2, 128.1, 127.2, 102.3. GC–MS (70 eV) m/z (rel int.):
179 (Mþ, 140), 153 (11), 152 (15), 151 (30), 150 (32), 123 (15), 113
(15), 111 (36), 89 (22), 75 (34), 74 (11), 50 (12).
Yield 7%, 0.0036 g. Yellow semi-solid. FTIR (neat): 3200, 2922,
2847, 1742, 1453, 1350, 1257, 1237, 1093, 1030, 757, 730 cmꢁ1 1H
.
NMR (500 MHz, CDCl3, d): 8.85–8.75 (br s, 2H, NH protons: ex-
change with D2O), 7.30–7.26 (m, 4H, aromatic protons), 7.19–7.15
(m, 2H, aromatic protons), 7.11–7.08 (m, 2H, aromatic protons), 4.22
3.5.4. 3-(3-Fluorophenyl)isoxazole (1i)
Yield 78%, 1.790 g. Light oil. FTIR (neat): 3153, 3129, 3073, 2960,
2932, 2873, 1616, 1588, 1557, 1505, 1464, 1422, 1384, 1296, 1269,
(d, 2H, J¼3.2 Hz), 2.47 (s, 6H). 13C NMR (125 MHz, CDCl3,
d): 167.3,
136.3, 131.5, 130.9, 128.8, 126.2, 125.7, 61.6, 53.9, 19.5. LC–MS (ESIþ):
1207, 1122, 1097, 973, 881, 845, 775, 710, 681 cmꢁ1
.
1H NMR
341 [MþNa]þ.
(500 MHz, CDCl3,
d
): 8.48 (d, 1H, J¼1.4 Hz), 7.61–7.59 (m, 1H, aro-
matic proton), 7.56–7.53 (m, 1H, aromatic proton), 7.46–7.41 (m, 1H,
aromatic proton), 7.17–7.12 (m, 1H, aromatic proton), 6.65 (d, 1H,
3.6.2. syn 2,6-Bis(3-methoxyphenyl)-3,7-diazatricyclo
[4.2.0.02,5]octan-4,8-dione (4e)
J¼1.4 Hz). 13C NMR (125 MHz, CDCl3,
d
): 163.0 (d, 1J19F–13C¼247 Hz),
Yield 79%, 0.039 g. Mp 135.0–136 ꢀC. Light orange powder. FTIR
(KBr): 3432, 3242, 2924, 2853, 1750, 1609, 1581, 1450, 1384, 1321,
4
3
160.6 (d, J19F–13C¼2.9 Hz), 159.2, 130.8 (d, J19F–13C¼7.6 Hz), 130.6
3
4
2
(d, J19F–13C¼8.6 Hz), 122.6 (d, J19F–13C¼2.9 Hz), 116.9 (d, J19F–13C
1290, 1260, 1215, 1038, 789, 693 cmꢁ1. 1H NMR (400 MHz, CDCl3,
d):
¼21.0 Hz), 113.9 (d, J19F–13C¼22.9 Hz), 102.5. 19F NMR (376 MHz,
7.99–7.97 (br s, 2H, NH protons: exchange with D2O), 7.36–7.32 (m,
2H, aromatic protons), 7.00–6.94 (m, 4H, aromatic protons), 6.91–
6.88 (m, 2H, aromatic protons), 4.23 (d, 2H, J¼2.2 Hz), 3.83 (s, 6H).13C
2
CDCl3,
d
): ꢁ116.8. GC–MS (70 eV) m/z (rel int.): 163 (Mþ, 98), 162
(100), 135 (11), 134 (23), 108 (16), 107 (23), 95 (41), 75 (21). Anal.
Calcd for C9H6FNO: C, 66.26; H, 3.71; N, 8.59. Found: C, 65.90; H,
3.69; N, 8.50.
NMR (100 MHz, CDCl3, d): 166.8, 160.0, 138.3, 130.1, 118.1, 113.7, 111.8,
64.0, 55.4, 52.0. LC–MS (ESIþ): 373 [MþNa]þ. Anal. Calcd for
C20H18N2O4:C, 68.56;H, 5.18;N,8.00. Found:C,68.66;H, 5.27;N, 7.80.
3.5.5. 3-[2-(Trifluoromethyl)phenyl]isoxazole (1m)
Yield 82%, 2.117 g. Light yellow oil. FTIR (neat): 3160, 3130, 3076,
2929, 2856, 1609, 1584, 1555, 1504, 1427, 1392, 1316, 1266, 1176,
3.6.3. syn 2,6-Bis(4-chlorophenyl)-3,7-diazatricyclo
[4.2.0.02,5]octan-4,8-dione (4f)
1125, 1060, 1035, 888, 770, 690 cmꢁ1. 1H NMR (500 MHz, CDCl3,
d):
Yield 70%, 0.035 g. Pink powder. Mp 129.6–130.0 ꢀC (dec). FTIR
8.48 (d, 1H, J¼1.6 Hz), 7.81–7.79 (m, 1H, aromatic proton), 7.65–7.56
(KBr): 3425, 3278, 2924, 2856, 1760, 1734, 1091, 816, 745, 690 cmꢁ1
.
(m, 3H, aromatic protons), 6.58–6.56 (m, 1H). 13C NMR (125 MHz,
1H NMR (400 MHz, CDCl3,
d): 8.10–7.90 (br s, 2H, NH protons: ex-
CDCl3,
d
): 160.5, 158.3, 129.7, 128.9 (q, 2J19F–13C¼30.9 Hz), 128.1 (m),
change with D2O), 7.43–7.41 (m, 4H, aromatic protons), 7.35–7.33
3
1
126.4 (q, J19F–13C¼5.2 Hz), 123.7 (q, J19F–13C¼273.5 Hz), 105.9 (q,
(m, 4H, aromatic protons), 4.21 (d, 2H, J¼2.4 Hz). 13C NMR
5J19F–13C¼3.3 Hz). 19F NMR (376 MHz, CDCl3,
d): ꢁ62.4. GC–MS
(100 MHz, CDCl3, d): 167.0, 135.3, 135.0, 129.5, 129.1, 127.5, 64.2,
(70 eV) m/z (rel int.): 213 (Mþ, 100), 212 (97), 184 (31), 165 (29), 164
51.9. LC–MS (ESI-): 357 [MꢁH]ꢁ. Anal. Calcd for C18H12Cl2N2O2: C,
(18), 145 (35), 138 (7), 134 (10), 125 (10), 107 (6), 95 (10), 75 (10).
60.19; H, 3.37; N, 7.80. Found: C, 60.27; H, 3.42; N, 7.90.

11204
L. Di Nunno et al. / Tetrahedron 64 (2008) 11198–11204
3.6.4. syn 2,6-Bis(2-chlorophenyl)-3,7-diazatricyclo
[4.2.0.02,5]octan-4,8-dione (4g)
7.54–7.50 (m, 1H, aromatic proton), 7.45–7.43 (m, 1H, aromatic pro-
ton), 7.30–7.26 (m, 3H, aromatic protons), 7.09 (s, 1H aromatic pro-
ton), 5.90–5.70 (br s, 2H, NH: exchange with D2O), 2.40 (s, 3H). 13
NMR (125 MHz, CDCl3, ):155.4,150.9,137.7,136.0,130.7,130.6,129.6,
Yield 40%, 0.020 g. Light powder. Mp 207–208 ꢀC (dec). FTIR
C
(KBr): 3228, 2924, 2853, 1768, 1750, 1060, 759 cmꢁ1
.
1H NMR
d
(500 MHz, CDCl3,
d
): 8.30–8.10 (br s, 2H, NH protons: exchange
128.0,127.3, 126.2,125.7, 122.8,116.4, 112.0, 20.3. GC–MS (70 eV) m/z
with D2O), 7.46–7.43 (m, 2H, aromatic protons), 7.35–7.28 (m, 6H,
(rel int.): 234 (Mþ, 50), 233 (100), 216 (17), 189 (5), 116 (14).
aromatic protons), 4.45 (d, 2H, J¼2.0 Hz). 13C NMR (125 MHz, CDCl3,
d
): 166.2, 134.5, 133.2, 130.4, 130.2, 128.1, 127.1, 61.3, 53.3. LC–MS
Acknowledgements
(ESIþ): 381 [MþNa]þ. Anal. Calcd for C18H12Cl2N2O2: C, 60.19; H,
3.37; N, 7.80. Found: C, 60.20; H, 3.22; N, 7.80.
This work was financially supported by National Project ‘Ster-
eoselezione in Sintesi Organica, Metodologie ed Applicazioni’ MiUR
(Rome), and the University of Bari. Thanks are due to Istituto di
Chimica dei Composti OrganoMetallici (ICCOM-CNR, Bari) for NMR
facilities.
3.6.5. syn 2,6-Bis(3-fluorophenyl)-3,7-diazatricyclo
[4.2.0.02,5]octan-4,8-dione (4i)
Yield 74%, 0.037 g. Light crystals. Mp 158–160 ꢀC (dec). FTIR (KBr):
3435, 3246, 3087, 2957, 2924, 2854,1738,1613,1587,1487,1440,1383,
1261,1105, 794 cmꢁ1.1HNMR(400 MHz, CDCl3,
d):8.54–8.53(brs,2H,
Supplementary data
NHprotons:exchangewithD2O), 7.45–7.39(m, 2H, aromaticprotons),
7.22–7.19 (m, 2H, aromatic protons), 7.16–7.05 (m, 4H, aromatic pro-
NMR spectra for the new synthesized compounds are available
free of charge in the online version. Supplementary data associated
with this article can be found in the online version, at doi:10.1016/
j.tet.2008.09.063.
tons), 4.22(d, 2H, J¼2.2 Hz).13C NMR (100 MHz, CDCl3,
d): 166.8,163.0
1
3
3
(d, J19F–13C¼248 Hz), 139.2 (d, J19F–13C¼7.2 Hz), 130.8 (d, J19F–
4
2
¼8.4 Hz), 121.5 (d, J19F–13C¼3.0 Hz), 115.6 (d, J19F–13C¼21.0 Hz),
13C
2
4
113.2 (d, J19F–13C¼22.9 Hz), 64.0, 51.8 (d, J19F–13C¼2.3 Hz). LC–MS
(ESIþ): 349 [MþNa]þ. Anal. Calcd for C18H12F2N2O2: C, 66.26; H, 3.71;
N, 8.59. Found: C, 66.36; H, 3.82; N, 8.66.
References and notes
1. Di Nunno, L.; Vitale, P.; Scilimati, A.; Simone, L.; Capitelli, F. Tetrahedron 2007,
63, 12388–12395.
2. Di Nunno, L.; Scilimati, A. Tetrahedron 1987, 43, 2181–2189.
3.6.6. syn 2,6-Bis-3-(2-(trifluoromethyl)phenyl)-3,7-
diazatricyclo[4.2.0.02,5]octan-4,8-dione (4m)
3. For the Hammett
s values see: Smith, M. B.; March, J. March’s Advanced Organic
Yield 30%, 0.015 g (white solid). Mp 240.1–241.8 ꢀC (dec). FTIR
(KBr): 3240, 2923, 2853, 1759, 1607, 1450, 1315, 1263, 1170, 1123,
Chemistry: Reactions, Mechanisms and Structure, 6th ed.; John Wiley and Sons:
Hoboken, NJ, 2007, Chapter 9, p 404.
4. Taft, R. W., Jr. In Steric Effects in Organic Chemistry; Newman, M., Ed.; Wiley:
New York, NY, 1956, Chapter 13.
5. The molecular volumes discussed above (Table 3) have been calculated using
semiempirical PM3 calculations. The volume of an individual atom or G group
(where G¼Cl, CH3 or CF3) bonded to a phenyl ring was estimated as the dif-
ference between the molecular volume of Ph–G (Ph¼phenyl) and the mole-
cular volume of benzene. Semiempirical optimizations and the calculation of
the molecular volumes of CPK-type models were performed using SPARTAN
’04 (Wavefunction, 18401 Von Karman Suite 370, Irvine, CA 92612, USA,
Version 1.0.0).
6. Reference to the benzyne mechanism: Smith, M. B.; March, J. March’s Advanced
Organic Chemistry: Reactions, Mechanisms and Structure, 6th ed.; John Wiley and
Sons: Hoboken, NJ, 2007, Chapter 13, p 859.
7. 3-(2-Methylphenyl)isoquinolin-1-amine (9): Kaiser, E. M.; Petty, J. D.; Solter, L. E.;
Thomas, W. R. Synthesis 1974, 805–806.
8. Cho, W.-J.; Kim, E.-K.; Park, I. Y.; Jeong, E. Y.; Kim, T. S.; Le, T. N.; Kim, D.-D.; Lee,
E.-S. Bioorg. Med. Chem. 2002, 10, 2953–2961.
9. Demeter, A.; Druzhinin, S.; George, M.; Haselbach, E.; Roulin, J.-L.; Zachariasse,
K. A. Chem. Phys. Lett. 2000, 323, 351–360.
1109, 1033, 766 cmꢁ1. 1H NMR (400 MHz, (CD3)2CO3,
d): 8.30–8.16
(br s, 2H, NH protons: exchange with D2O), 7.90–7.85 (m, 2H, aro-
matic protons), 7.71–7.63 (m, 6H, aromatic protons), 4.65 (d, 2H,
J¼2.1 Hz). 13C NMR (125 MHz, (CD3)2CO3,
d): 164.0, 135.9 (m), 133.2,
129.5, 129.2,128.0 (q, 2J19F–13C¼31.5 Hz),127.9 (m),124.7 (q, 1J19F–13C
¼273.2 Hz), 63.3, 52.6. 19F NMR (376 MHz, CDCl3,
): ꢁ53.9. LC–MS
d
(ESIþ): 449 [MþNa]þ(100). Anal. Calcd for C20H12F6N2O2: C, 56.35;
H, 2.84; N, 6.57. Found: C, 56.31; H, 2.93; N, 6.43.
3.6.7. 4-(Diisopropylamino)benzonitrile (7)9
Yield 15%, 0.017 g. White crystals. Mp 85–86 ꢀC (lit. 81–84 ꢀC).9
FTIR (neat): 2969, 2925, 2851, 2212,1602,1517,1334,1302,1182,1156,
1120, 821 cmꢁ1. 1H NMR (400 MHz, CDCl3,
d): 7.41–7.39 (m, 2H, ar-
omatic protons), 6.78–6.75 (m, 2H, aromatic protons), 3.92 (septu-
plet, 2H, J¼6.8 Hz),1.30 (d,12H, J¼6.8 Hz).13C NMR (100 MHz, CDCl3,
10. Braun, M.; von Korff Schmising, C.; Kiel, M.; Zhavoronkov, N.; Dreyer, J.;
Bargheer, M.; Elsaesser, T.; Root, C.; Schrader, T. E.; Gilch, P.; Zinth, W.; Woerner,
M. Phys. Rev. Lett. 2007, 98, 248301–248304.
11. Daum, R.; Druzhinin, S.; Ernst, D.; Rupp, L.; Schroeder, J.; Zachariasse, K. A.
Chem. Phys. Lett. 2001, 347, 421–428.
d
): 150.9, 132.9, 120.7, 114.5, 96.9, 47.4, 20.7. GC–MS (70 eV) m/z (rel
int.): 202 (Mþ,17),187 (56),145 (100),129 (8),102 (15), 43 (8), 41 (7).
3.6.8. 3-(Diisopropylamino)benzonitrile (8)
12. Suffert, J. J. Org. Chem. 1989, 54, 509–510.
13. Di Nunno, L.; Vitale, P.; Scilimati, A.; Tacconelli, S.; Patrignani, P. J. Med. Chem.
2004, 47, 4881–4890.
14. Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45, 3916–3918.
15. Kapuriya, N.; Kapuriya, K.; Dodia, N. M.; Lin, Y.-W.; Kakadiya, R.; Wu, C.-T.;
Chen, C.-H.; Naliapara, Y.; Su, T.-L. Tetrahedron Lett. 2008, 49, 2886–2890.
16. Zamponi, G. W.; Stotz, S. C.; Staples, R. J.; Andro, T. M.; Nelson, J. K.; Hulubei, V.;
Blumenfeld, A.; Natale, N. R. J. Med. Chem. 2003, 46, 284–302.
17. Blackwell, M.; Dunn, P. J.; Graham, A. B.; Grigg, R.; Higginson, P.; Saba, I. S.;
Thornton-Pett, M. Tetrahedron 2002, 58, 7715–7725.
Yield 7–22%, 0.008–0.025 g. Yellow semi-solid. FTIR (neat):
2971, 2930, 2873, 2853, 2227, 1591, 1496, 1369, 1300, 1195, 1180,
999, 775, 689 cmꢁ1 1H NMR (400 MHz, CDCl3,
. d): 7.23–7.19 (m,
1H, aromatic proton), 7.03–7.00 (m, 2H, aromatic protons), 6.95–
6.92 (m, 1H, aromatic proton), 3.82 (septuplet, 2H, J¼6.8 Hz), 1.30
(d, 12H, J¼6.8 Hz). 13C NMR (100 MHz, CDCl3,
d): 148.3, 129.2,
120.9, 119.9, 119.3, 112.4, 47.5, 21.0. GC–MS (70 eV) m/z (rel int.):
202 (Mþ, 11), 187 (47), 159 (5), 146 (10), 145 (100), 129 (6), 117 (3),
102 (12), 43(7), 41(7). Anal. Calcd for C13H18N2: C, 77.18; H, 8.97;
N, 13.85. Found: C, 77.03; H, 8.83; N, 13.74.
18. 3-Fluorobenzaldehyde oxime: CAN [458-02-6].
19. Barfknecht, C. F.; Westby, T. R. J. Med. Chem. 1967, 10, 1192–1193.
20. Hamper, B. C.; Leschinsky, K. L.; Massey, S. S.; Bell, C. L.; Brannigan, L. H.; Prosch,
S. D. J. Agric. Food Chem. 1995, 43, 219–228.
21. Kim, J. N.; Ryu, E. K. J. Org. Chem. 1992, 57, 6649–6650.
´
22. Jazouli, M.; Baba, S.; Carboni, B.; Carrie, R.; Soufiaoui, M. J. Organomet. Chem.
3.6.9. 3-(2-Methylphenyl)isoquinolin-1-amine (9)7
1995, 498, 229–235.
23. Sheng, S.-R.; Xin, Q.; Liu, X.-L.; Sun, W.-K.; Guo, R.; Huang, X. Synthesis 2006,
2293–2296.
24. Shvekhgeimer, G. A.; Baranski, A.; Grzegozek, M. Synthesis 1976, 612–614.
25. Sheng, S.-R.; Liu, X.-L.; Xu, Q.; Song, C.-S. Synthesis 2003, 2763–2764.
26. Go1e˛biewski, W. M.; Gucma, M. J. Heterocycl. Chem. 2006, 43, 509–513.
Yield 80%, 0.029 g. FTIR (neat): 3329, 3199, 3056, 2954, 2924,
2853,1650,1632,1588,1564,1498,1432,1370,1337, 764, 727 cmꢁ1.1H
NMR (500 MHz, CDCl3,
d): 7.91–7.89 (m, 1H, aromatic proton), 7.75–
7.72 (m, 1H, aromatic proton), 7.68–7.64 (m, 1H, aromatic proton),