Uncommon 1,2-migration of a nitro group within a β-nitrostyryl moiety: Synthetic scope and mechanistic details

Article abstract of DOI:10.1002/ejoc.201300856

The unusual migration of a nitro group from the β- to the α-position of a β-aryl-α-nitroethenyl moiety, following a nitrocyclopropane to isoxazoline N-oxide isomerization, has been studied from a mechanistic and synthetic points of view. As a result, two series of isomeric isoxazoline N-oxides could be obtained under controlled conditions. When reacted with diazomethane, a model transposed isoxazoline cleanly furnished a new, interesting pyrazolylisoxazole. Copyright

Full text of DOI:10.1002/ejoc.201300856

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FULL PAPER
DOI: 10.1002/ejoc.201300856
Uncommon 1,2-Migration of a Nitro Group Within a β-Nitrostyryl Moiety:
Synthetic Scope and Mechanistic Details
Lara Bianchi,[a] Franco Ghelfi,[b] Gianluca Giorgi,[c] Massimo Maccagno,*[a]
Giovanni Petrillo,[a] Domenico Spinelli,[d] Marco Stenta,[e] and Cinzia Tavani[a]
Keywords: Synthetic methods / Heterocycles / Nitro group migration / Alkenes
The unusual migration of a nitro group from the β- to the α-
a result, two series of isomeric isoxazoline N-oxides could
position of a β-aryl-α-nitroethenyl moiety, following a nitro- be obtained under controlled conditions. When reacted with
cyclopropane to isoxazoline N-oxide isomerization, has been
studied from a mechanistic and synthetic points of view. As
diazomethane, a model transposed isoxazoline cleanly fur-
nished a new, interesting pyrazolylisoxazole.
Among the synthetic procedures already reported, reac-
Introduction
tion of dinitrobutadienes 2 with diazomethane represents
an interesting route[6] to 1,1Ј-bis(cyclopropane)s
3
Isoxazolines and isoxazoles are ubiquitous heterocycles
whose interest among chemists is testified by the continuous
appearance of articles, reviews, and/or monographs con-
cerning preparations,[1] synthetic applications[2] and bio-
logical/pharmacological relevance.[3]
In the context of a long-standing project on the synthetic
exploitation of highly functionalized dinitrobutadienes 2,
easily obtainable by ring-opening of 3,4-dinitrothiophene
(1) with diethylamine followed by arylation with Grignard
reagents (Scheme 1, Steps a and b),[4] we have published a
number of new approaches to linear, homo- and hetero-
cyclic compounds[5] over the last twenty years, which main-
tain the original four-carbon skeleton, thus sharing the
common feature of total “carbon-atom economy”. Some of
the derivatives obtained along the way also possess signifi-
cant pharmacological activity, thus justifying further devel-
opments of the project.[5g–5l]
(Scheme 1, Step c) and to corresponding isomeric 3,3Ј-bis(i-
soxazoline N-oxide)s 4, through a thermal iodide-assisted
process (Scheme 1, Step d).[7] Compounds 4 may in turn be
further modified by reduction of the N-oxide functionality
(Scheme 1, Step e), followed by aromatization with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; Scheme 1,
Step f), to give bis-isoxazoles 5[7] as ultimate products.
On the other hand, the reaction with diazomethane
proves of utility in chemically differentiating the two iden-
tical conjugated nitrovinylic moieties of dinitrobutadienes
2: thus, by a careful treatment with one molar equivalent
of reactant (Scheme 2, Step a), monocyclopropane deriva-
tives 6 were obtained as the main products together with
minor amounts of corresponding 3.[6]
As a logical extension of previously studied 3 to 4 isom-
erization, we studied the application of relevant methodol-
ogy to nitrovinylcyclopropanes 6 (Scheme 2), with the aim
of obtaining new isoxazoline derivatives. Nevertheless, pre-
liminary results[8] showed unexpected behavior whereby
NaI-catalyzed nitrocyclopropane to isoxazoline N-oxide re-
arrangement (Scheme 2, Step b) is followed by an unexpec-
ted migration of the residual nitro group of 7 (Scheme 2,
Step c) to afford α-nitrostyryl derivatives 8.
[a] Dipartimento di Chimica e Chimica Industriale, Università di
Genova,
Via Dodecaneso 31, 16146 Genova, Italy
Homepage: http://www.chimica.unige.it/page.php?v=
12&persona=Massimo-Maccagno&do=visua
[b] Dipartimento di Chimica, Università di Modena e Reggio
Emilia,
Hereinafter we report full details of this appealing pro-
cess, together with optimization of the experimental condi-
tions for the effective isolation of primarily formed products
7.
Via Campi 183, 41100 Modena, Italy
[c] Dipartimento di Chimica, Università di Siena,
Via A. Moro, 53100 Siena, Italy
[d] Dipartimento di Chimica “G. Ciamician”, Università di
Bologna,
Via Selmi 2, 40126 Bologna, Italy
Results and Discussion
[e] Ecole Polytechnique Fed. Lausanne, School of Life Science,
Lab. Biomol. Modeling, Inst. Bioengin.,
1015 Lausanne, Switzerland
Evidence for Sequential 6 to 7 to 8 Isomerizations
E-mail: massimo.maccagno@unige.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300856
Heating monocyclopropanes 6 in the presence of NaI un-
der the experimental conditions previously applied to bi-
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Scheme 1. (a) Et2NH (excess), EtOH, 0 °C, overnight; (b) ArMgBr (2.2 mol equiv.), THF, 0 °C, 15–45 min; then acidic (HCl) quenching;
(c) CH2N2 (excess), Et2O, 0 °C to room temp., overnight; (d) NaI (2 mol equiv.), DMSO, 60 °C, 4–22 h; (e) P(OMe)3, (40 mol equiv.),
anhydrous dioxane, heated to reflux under argon, 17–24 h; (f) DDQ (4–6 mol equiv.), dry toluene, heated to reflux under argon.
Scheme 2. (a) CH2N2 (1.2 mol equiv.), Et2O, 0 °C to room temp., overnight; (b) and (c) NaI, DMSO, 60 °C.
1
Table 1. H NMR spectroscopic study on the 6Ǟ7Ǟ8 conversion rate in [D6]DMSO in the presence of NaI.[a]
Entry
Ar in 6
t = 1 h
t = 2 h
t = 5 h
t = 24 h
Disappearance[c]
of 7 after:
6/7/8 ratio[b]
6/7/8 ratio[b]
6/7/8 ratio[b]
6/7/8 ratio[b]
1
2
3
4
5
6
7
8
9
6a: Ph
74:26:0
25:75:0
72:28:0
38:62:0
82:18:0
84:16:0
0:100:0
52:48:0
0:100:0
73:27:0
52:48:0
8:92:0
31:67:2
0:94:6
0:15:85
0:45:55
0:42:58
0:83:17
0:0:100
0:0:100
0:12:88
0:3:97
48 h
72 h
72 h
144 h
24 h
24 h
48 h
48 h
144 h
24 h
6b: 2-MeC6H4
6c: 4-MeC6H4
6d: 4-MeOC6H4
6e: 3-ClC6H4
6f: 4-ClC6H4
6g: 1-naphthyl
6h: 2-naphthyl
6i: 2-thienyl[d][e]
6j: 3-thienyl[e]
48:52:0
13:87:0
65:28:7
71:25:4
0:100:0
27:73:0
0:100:0
63:37:0
10:90:0
0:100:0
32:30:38
39:43:18
0:86:14
0:83:17
0:100:0
38:61:0
0:100:0
0:0:0
10
[a] At 60 °C; NaI: 1 mol-equiv. [b] Normalized. [c] The disappearance of 7 is due to the formation of 8 and/or to decomposition pathways.
[d] The substrate is relevant isoxazoline N-oxide 7i, as 6i isomerized to 7i during the chromatographic separation of the final mixture
from monocyclopropanation. [e] Increasing decomposition signals were observed until complete disappearance of 7i and 7j.
s(cyclopropane)s 3[7] brings to evidence (TLC, 1H NMR lated analogous structures 7 and 8, respectively, to be as-
spectroscopy) the accumulation of transient intermediate 7, signed (see Exp. Section).
which slowly converts to final product 8. Such behavior,
Although 7 is the expected result of the iodide-catalyzed
initially observed for model phenyl derivative 6a (Ar = Ph), nitrocyclopropane to isoxazoline N-oxide isomerization of
was found to be general over the series of substrates (6a– 6 (Scheme 2, Step b), the structure of 8 reveals an intriguing
6j) as the reaction scope was defined.
1,2-migration of a nitro group under relatively mild experi-
Preliminary tests to follow the progress of the reaction mental conditions (Scheme 2, Step c).
by NMR spectroscopy in [D6] dimethyl sulfoxide (DMSO;
cf. Table 1) defined the most convenient time for a work-up
finalized to the isolation of 7: a result which was eventually
obtained, at least in the most favorable cases, by chromatog-
Justification of the Nitro Group Transfer
raphy of the crude residue, with no attempt, at this time, to
The shift of a vinylic nitro group onto the adjacent Csp2
determine absolute yields (on this aspect, see “Solvent ef- atom is an example[9,10] of a well-known, more general pro-
fect”). Of course, final product 8 could be most easily iso- cess undergone by unsaturated systems characterized by the
lated from reactions extended until complete disappearance presence of a heteroatom directly bonded to a Csp2 atom.[11]
of both substrate 6 and 7 (Table 1).
As far as arylnitroethenyl (nitrostyryl) derivatives are con-
The structure of both 7 and 8 was assigned by means of cerned, the literature exclusively reports examples of
single-crystal X-ray analyses carried out on the products irreversible base-catalyzed rearrangements towards the iso-
isolated from the reaction on phenyl derivative 6a;[8] the mer that takes full thermodynamic advantage of the
ORTEP drawings are shown in Figure 1. Spectroscopic (1H through conjugation between the aryl and the nitro group
and 13C NMR) similarities with 7a and 8a allowed all iso- (i.e. Scheme 3, B).[9a]
2
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1,2-Migration of a Nitro Group Within a β-Nitrostyryl Moiety
Scheme 3.
In our case the nitro group migration proceeds in the
opposite direction to that shown in Scheme 3: thus the out-
come requires proper rationalization, for which both elec-
tronic and steric factors likely concur. To this end, in the
preliminary communication[8] we undertook a computa-
tional study at the DFT level[12] both in solution (DMSO)
and in the gas phase,[8] whereby the geometries of represen-
tative “critical” structures were optimized for a model
phenyl derivative (Ar = Ph; see, Figure 2). For isoxazoline
7a, the relief of repulsive interactions between the cyclic ni-
tronate and the nitro group allows significant through reso-
nance between the nitro group and Ph in the s-cis confor-
mation, corresponding to an effective stabilization of about
2 kcal/mol with respect to the s-trans conformation. When
considering analogous structures for isomerized isoxazoline
8a, whereas the s-cis conformation matches in energy (at
least in solution) s-cis-7a, the s-trans conformation seems
to minimize any steric and/or stereoelectronic interactions,
thus taking full advantage from a new extended through-
conjugation between the cyclic nitronate and the shifted ni-
tro group thanks to effective coplanarity.
Thus, we can rationalize the driving force for the nitro
group shift basically as a release of unfavorable through-
space interactions, whereas the nitro group/phenyl conjuga-
tion of 7 (highlighted in blue color in Figure 2) is replaced
Figure 1. ORTEP drawing of the crystal structure of 7a (top) and by a similarly effective nitro group/nitronate one through
8a (bottom). Ellipsoids are shown at 50% probability.
the ethenyl moiety (highlighted in red in Figure 2) in 8.
Figure 2. Calculated relative energies in DMSO and in the gas phase (in parentheses) for optimized geometries.
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It should be emphasized that, in the crystal structure, 7a fer. Incidentally, the data at t = 4 h clearly exclude (as ex-
adopts an apparently less stable s-trans-like conformation pected) any appreciable isotope effect for the 6 to 7 isomer-
(see Figure 1), whereas the spatial arrangement of 8a seems ization of Scheme 4.
to match the optimized s-trans geometry in solution.[13]
Table 2. Deuterium isotope effect in the 6Ǟ7Ǟ8 conversion for
4-methyl derivative 6c in [D6]DMSO in the presence of NaI.[a]
Entry Substrate
t = 4 h
t = 24 h
t = 48 h
Mechanistic Details, the Catalytic Role of NaI
6/7/8 ratio[b] 6/7/8 ratio[b] 6/7/8 ratio[b]
1[c]
6c
16:84:0
17:83:0
17:83:0
18:82:0
0:35:65
0:74:26
0:30:70
0:68:32
0:8:92
0:56:44
0:5:95
0:54:46
The catalytic significance of NaI in the nitrocyclopro-
pane to isoxazoline N-oxide ring-enlargement (6 to 7 isom- 2[c]
6c-d2
6c
3[d]
erization) has already been reported from our lab for the 3
6c-d2
to 4 transformation of Scheme 1, whereby the role of the
nucleophilic catalyst was attributed to the iodide anion
within a double SN2 process (Scheme 4) and on the grounds
of the observed diastereospecificity.[7]
1
[a] Reactions followed by H NMR spectroscopy. [b] Normalized.
[c] Parallel tests. [d] Competitive test, with both substrates in the
same sample tube.
Herein, it should be accepted that the role of the base
(Scheme 5, B) cannot be played by anything other than the
iodide anion. Accordingly, we could verify (cf. Table 3) that
(a) 7 to 8 isomerization does not proceed in the absence of
NaI (Table 3, Entries 6 and 8), and (b) with respect to the
standard conditions (NaI, 1.0 mol equiv.), 2 equiv. of NaI
significantly accelerates the 7 to 8 isomerization (Table 3,
Entries 3a and 4), whereas 0.5 equiv. slows it down (Table 3,
Entries 1b and 2c).
Scheme 4.
Herein, an analogous mechanism can be suggested, al-
though the fact that the substrate is represented by a race-
mic mixture prevents the same kind of stereochemical evi-
Substituent Effect on the Nitrocyclopropane to Isoxazoline
dence. Interestingly, in some cases, 7 is effectively formed in
the absence of NaI (Table 3, Entry 8), with complete 6 to 7
isomerization within 24 h for the 1-naphthyl derivative.
Thus, a concurrent, different pathway must be invoked in
these cases, represented by a SN1-like process involving a
particularly stable benzylic-like carbocation, as corrobo-
rated by the behavior of 6d and 6g (Table 3, Entries 6 and
8).
As far as the nitro group transfer is concerned, the litera-
ture claims for a base-catalyzed mechanism through a cyclic
intermediate (Scheme 5),[9a,9b] grounded on the results of
tests of isotopic labeling either of substrate (sizeable kinetic
deuterium isotope effect) or of added nitrite (absence of 15N
uptake into the product), find herein further support. Thus,
in agreement with the mechanistic hypothesis of
Scheme 5,[14] cyclopropyl derivative 6c-d2 (prepared from
dideuterated 3,4-dinitrothiophene 1-d2) furnished, by means
of comparative semi-quantitative tests with 6c (Table 2), a
significant kinetic isotope effect (kH/kD ≈ 3). Such an out-
come, which remains well above any reasonable secondary
isotope effect, clearly indicates that a proton transfer is in-
N-Oxide (6 to 7) Isomerization
Considering the data in Table 1, with respect to the
model substrate (Table 1, Entry 1; Ar = Ph), the 6 to 7 con-
Table 3. Effect of catalyst on the 7Ǟ8 conversion rate in DMSO.[a]
Entry Substrate Ar
Catalyst
Reaction time [h] and
(mol equiv.) 6/7/8 molar ratio[b]
1
2
6a
6a
Ph
Ph
NaI (1.0)
NaI (0.5)
a)
b) 24
3
36/64:0
0:15:85
58:42:0
39:58:3
9:18:63
0:42:58
0:8:92
0:0:100
0:83:17
0:59:41
43:57:0
11:89:0
0:12:88
0:0:100
2:98:0
a)
b)
c) 24
a) 24
b) 48
24
3
6
3
6c
4-MeC6H4
4-MeC6H4
NaI (1.0)
NaI (2.0)
4
5
6c
6d
4-MeOC6H4 NaI (1.0)
a) 24
b) 48
a) 24
b) 48
a) 24
b) 48
a) 24
b) 48
6
7
8
6d
6g
6g
4-MeOC6H4 none
1-naphthyl
1-naphthyl
NaI (1.0)
none
0:100:0[c]
volved in the rate-determining step of the nitro group trans- [a] At 60 °C. [b] Normalized. [c] No 8 detected after 140 h.
Scheme 5.
4
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1,2-Migration of a Nitro Group Within a β-Nitrostyryl Moiety
version becomes faster (a) when the aryl moiety carries elec- competitive decomposition pathways. To establish whether
tron-repulsive (Table 1, Entries 2 and 3) or electron-donat- kinetic or thermodynamic reasons prevent effective nitro-
ing substituents (Table 1, Entry 4), (b) in the presence of transfer, we evaluated the relative stabilities within the two
more extensively conjugated systems (Table 1, Entries 7 and couples of isomers, 7i versus 8i, and 7j versus 8j. Quanto-
8), or (c) when steric hindrance occurs (Table 1, Entries 2 mechanical calculations suggest that for both the 2- and 3-
and 7). It should also be noted that, for 2-thienyl derivative thienyl derivatives the stabilization achievable for the 7Ǟ8
6i (Table 1, Entry 9), the conversion to 7i is particularly fa- isomerization is considerably reduced (both in solution and
voured, because it takes place spontaneously at room tem- in the gas phase), relative to the case of the phenyl deriva-
perature during the chromatographic purification of the tive, and almost negligible in the case of 7i. This outcome
crude, possibly owing to the catalytic effect of silica gel agrees with a rationalization based on a lower gain from
itself. This is in line with the electron-rich nature of the steric-hindrance release for a five-membered ring relative to
thiophene ring.
a six-membered one.
However, a disfavouring effect is played by a chloro sub-
stituent in the aryl ring, either from the meta or from the
para position with respect to the vinyl moiety (Table 1, En-
tries 5 and 6, respectively).
Overall, the observed electronic effects upon the 6 to 7
isomerization process are in agreement with the fact that
Solvent Effect: an Optimized Approach to Intermediate
Isoxazoline N-Oxides 7
The substituent effect outlined above mirrors a conceiv-
the nitrocyclopropane ring-opening occurs as a heterolitic able significant polarity of the transition states for both the
breakage of the more substituted bond involving the ni- 6Ǟ7 and 7Ǟ8 isomerizations. Thus, for the overall pro-
trogroup-bearing carbon atom. Such a breakage, whether cess, but in particular as far as the second isomerization
iodide-assisted or not, generates an incipient positive charge is concerned (in which proton exchanges are involved), an
on the benzylic carbon atom which obviously takes advan- important role of the solvent (and of its proton affinity) is
tage of charge delocalization onto the aryl ring.[7] The oc- expected.
currence of significant uncatalyzed pathways (described in
In order to better understand such a role, we decided to
the mechanistic details above) could well find a rationale change the reaction medium, testing two solvents: methanol
in the weakening of the bond to be broken owing to the (a polar protic solvent) and acetonitrile [a polar aprotic sol-
stabilization (e.g. by a p-MeO group) of an incipient carbo- vent (ε = 35.94) “similar” to DMSO (ε = 46.45) but charac-
cation. In this regard, it should be recalled that a similar terized by a marked protophobicity].[10c]
uncatalyzed isomerization has already been observed on
Preliminary tests performed in CD3OD showed (1H
substrates bearing a PhSO2 group on the nitrated carbon. NMR spectroscopy) a rather awkward outcome, charac-
In that instance, the “weakening” of the bond to be broken terized by the formation of complex final mixtures for
is achieved by the concomitant effect of two strong elec- which minor signals attributable to structures different from
tron-withdrawing groups stabilizing the negative charge.[15]
7 or 8 were detected. Such a solvent seems to be a too reac-
tive medium and additional, competitive processes take
place.
Substituent Effect on the Nitro Group Migration (7 to 8)
Pleasingly, analogous tests performed in CD3CN re-
For the 1,2 nitro group migration, the trend is opposite vealed (Table 4) a remarkable opposite effect on the rate of
to that observed for the 6 to 7 isomerization. Only in the the two consecutive processes. The isoxazoline formation is
cases of the chloro substituted substrates (Table 1, Entries 5 significantly accelerated throughout, as evidenced by the
and 6) we observed the completion of the overall process data at differing reaction times in Table 1. In addition, a
after 24 h. Other systems, particularly the 4-methoxy substi- significant negative effect on the nitro group migration re-
tuted one (Table 1, Entry 4), lagged well behind. Thus, for sults in either a decreased isomerization rate (Table 4, En-
this second step, the approximate reactivity order: 3-Cl Ͼ tries 5, 6, and more markedly 1, 3), or in the total preven-
4-Cl Ͼ 2-Naph Ͼ Ph ≈ 1-Naph Ͼ 4-Me ≈ 2-Me Ͼ 4-MeO, tion of the process (Table 4, Entries 2, 4, 7 and 8). As al-
is in agreement with the increasing conjugative ability of ready observed in DMSO, in CD3CN, 3-thienyl derivative
the aryl group towards the β-nitrogroup within the nitro- 7j does not undergo any nitro transfer. For the 2-thienyl
styrenic moiety, and mirroring the reluctance of the system derivative, spontaneous 6Ǟ7 isomerization coupled with
to renounce a stabilizing effect in final product 8. It should failure of the 7Ǟ8 shift in DMSO, clearly voids the signifi-
be underlined that, even if the complete conversion to 8 cance of analogous tests.
(last column of Table 1) requires increasing times following
Overall, the preliminary results just described are gratify-
the reactivity order above, the process does definitely occur ing both from a mechanistic and synthetic point of view.
even in the least favourable case (e.g. the methoxy derivative The almost general, unfavourable effect of acetonitrile on
d). This fact proves that the release of steric and/or stereoe- the migration process supports the proposed mechanism,
lectronic strain is the most important factor underlying the that was supposed to require initial deprotonation of 7. In-
chemical outcome.
deed the protophobicity of such a solvent, with respect to
No isomerization to 8i and 8j was observed for the two DMSO, is well known and evidenced by the donicity pa-
thienyl derivatives 7i and 7j, which are consumed through rameters (0.36 and 0.77, respectively).[10c]
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1
Table 4. H NMR spectroscopic study on the 6Ǟ7Ǟ8 conversion rate in CD3CN in the presence of NaI.[a]
Entry
Ar in 6
t = 1 h
6/7/8
t = 2 h
6/7/8
t = 5 h
6/7/8
t = 24 h
6/:7/8
Last control
after:
ratio[b]
ratio[b]
ratio[b]
ratio[b][c]
1
2
3
4
5
6
7
8
9
6a: Ph
65:35:0
10:90:0
46:54:0
9:91:0
45:55:0
50:50:0
0:100:0
0:100:0
35:65:0
40:60:0
0:100:0
10:90:0
0:100:0
28:72:0
32:68:0
0:100:0
0:100:0
23:77:0
14:86:0
0:100:0
0:100:0
0:100:0
0:84:16
6:84:10
0:100:0
0:100:0
0:100:0[d]
0:86:14
0:100:0
0:95:5
0:100:0
0:21:79
0:17:83
0:100:0
0:100:0
0:0:0
48 h (0:68:32)
144 h (0:100:0)
168 h (0:37:63)
144 h (0:100:0)
48 h (0:0:100)
48 h (0:0:100)
96 h (0:100:0)
96 h (0:100:0)
24 h (0:0:0)
6b: 2-MeC6H4
6c: 4-MeC6H4
6d: 4-MeOC6H4
6e: 3-ClC6H4
6f: 4-ClC6H4
6g: 1-naphthyl
6h: 2-naphthyl
6j: 3-thienyl
[a] At 60 °C; NaI: 1 mol equiv. [b] Normalized. [c] Decomposition occurs throughout. [d] Significant decomposition.
Acetonitrile offers the possibility of stopping the process substituent effect for the 7 to 8 isomerization in DMSO
after formation of 7, prior to migration and thus could be (as explained above) is qualitatively confirmed by the gross
the solvent of choice to prepare isoxazoline N-oxide 7 in reaction times required for completion, reported in Table 5
pure form.
in the same solvent, and determined by TLC monitoring of
Table 5 shows yields of isolated isoxazoline N-oxides, re- disappearance of substrate.
ported for preparative reactions carried out in CH3CN typi-
cally at 60 °C, which were more than satisfactory. As far
as the 1-naphthyl derivative is concerned, the outcome of
Reaction of Isoxazoline 8c with Diazomethane: A Viable
Breakthrough to New, More Complex Bis-Heterocyclic
Systems
Table 5, Entry 7 represents an alternative to effective isola-
tion of 7g, which can be performed in DMSO in the ab-
sence of NaI. The entry relevant to the 2-thienyl derivative,
refers to the already mentioned (cf. Table 1) isomerization
of 6i to 7i during the chromatographic separation of the
final mixture from the cyclopropanation reaction.
Attempts to further exploit our system for heterocyclic
synthesis, e.g. assembling a new homo- or heterocycle with
the existing isoxazoline ring, by means of cyclopropanation
of the nitrovinylic moiety of 7c, met with little success.
A much more rewarding result was obtained when treat-
ing with diazomethane in tetrahydrofuran (THF) at 0 °C
transposed isoxazoline 8c, as pyrazolyl derivative 11c was
isolated in almost quantitative yields. Formation of 11c
(structure confirmed by NOE experiments, see Supporting
Information) can be explained by means of an initial re-
gioselective [3+2] dipolar cycloaddition between diazometh-
ane and the nitroethenyl moiety, followed by tautomeriz-
ation of the pyrazoline intermediate and aromatization by
nitrous acid elimination (Scheme 6).
Table 5. Results of experiments performed on preparative scale, at
60 °C.[a]
Entry Ar
6Ǟ7 (MeCN)
7Ǟ8 (DMSO)
Reaction 7: Yield% Reaction 8: Yield%
time
time
1
2
3
4
5
6
7
8
9
Ph
6 h
3 h
5 h
3 h
3 h
7a: 90%
7b: 88%
7c: 87%
7d: 98%
7e: 68%
7f: 73%
7g: 82%
7h: 78%
7i: 87%
7j: 74%
24 h
72 h
48 h
72 h
24 h
24 h
48 h
24 h
–
8a: 80%
8b: 68%
8c: 65%
8d: 75%
8e: 40%
8f: 44%
8g: 32%
8h: 53%
–
2-MeC6H4
4-MeC6H4
4-MeOC6H4
3-ClC6H4
4-ClC6H4
1-naphthyl
2-naphthyl
2-thienyl
3 h
2 h[b]
3 h
[c]
10
3-thienyl[d]
24 h
–
–
Conclusions
[a] In the presence of NaI (1 mol equiv.), if not otherwise stated.
[b] Isolation of 7g (89%) can also be performed in DMSO, after
1 h at 70 °C in the absence of NaI. [c] Complete isomerization to
7i occurs during the chromatographic separation of the final mix-
ture from the cyclopropanation reaction. [d] No catalyst was em-
ployed. Isomerization to 7j occurs on silica (50% after 24 h).
These results provide further support to the possibility
of the ring opening of 3,4-dinitrothiophene 1 as a window
to a vast range of heterocycles. The chemical differentiation
of the two nitrovinyl moieties of 2, obtained in this case
through monocyclopropanation to 3,[6] seems to guarantee
the possibility of new synthetic routes. The functionalities
of compounds 6, 7 or 8 could be in turn exploited to gain
As expected, treatment of isolated 7a–7h at 60 °C with access to targets for applications in, for example, pharma-
NaI (1 mol equiv.) in DMSO led to nitro group migration, cology. The easy high-yielding transformation of 8c into 11c
although some yields are less satisfactory: an outcome that represents a clear and valuable example of such potential,
can be attributed, in part, to some instability of both sub- leading to bis(heterocycle)s characterized by two differing
strate and final product. It should be remarked that the heterorings.[16]
6
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1,2-Migration of a Nitro Group Within a β-Nitrostyryl Moiety
Scheme 6.
(CD3SOCD3): δ = 1.62 (dd, J = 10.5, 4.8 Hz, 1 H), 2.39 (s, 3 H),
2.41 (s, 3 H), 2.47 (app. t part overlapped with the previous signal,
J = 6.9 Hz, 1 H), 4.04 (app. t, J = 10.0 Hz, 1 H), 6.42 (d, J =
7.4 Hz, 1 H), 7.00–7.12 (m, 1 H), 7.12–7.27 (m, 3 H), 7.33–7.60 (m,
3 H), 8.71 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 20.00, 20.12, 24.00,
35.96, 68.47, 123.70, 125.54, 126.37, 126.72, 128.13, 128.49, 129.38,
129.53, 131.09, 131.87, 138.14, 140.03, 140.81, 141.54 ppm.
HRMS: calcd. for C19H18N2O4 338.1267; found 338.1263.
Experimental Section
1
Materials and Methods: H NMR and 13C NMR spectra were re-
corded at 300 and 75 MHz, respectively. Chemical shifts are re-
ported relative to TMS as internal reference. IR spectra were re-
corded with a Perkin–Elmer 881 Infrared Spectrophotometer. MS
(ESI) analyses were recorded with a Micromass Z0MD Waters in-
strument (30 V, 13.2 KV). HRMS were recorded with a FINNI-
GAN MAT95XP apparatus. Melting points were determined with
a Büchi 535 apparatus. Petroleum ether and light petroleum refer
to the fractions with b.p. 40–60 and 80–100 °C, respectively. Silica
gel 230–400 mesh was used for column chromatography, all sol-
vents being distilled before use. THF was purified by standard
methods and distilled from potassium benzophenone ketyl before
use. All other commercially available reagents were used as re-
ceived. 4-Chlorophenyl- and 3-thienylmagnesium iodide were avail-
able as commercial THF or Et2O solutions, which were titrated just
before use.
(E)-1-Chloro-4-{2-[2-(4-chlorophenyl)-1-nitrocyclopropyl]-2-nitro-
vinyl}benzene (6f): Yellow solid, m.p. 214–215 °C (ethanol). 1H
NMR (CDCl3): major conformer δ = 1.52 (dd, J = 10.0, 7.0 Hz, 1
H, part overlapped with the signal of water), 2.50 (dd, J = 10.4,
7.0 Hz, 1 H), 3.96 (app. t, J = 9.7 Hz, 1 H), 6.86 and 7.22 (AAЈBBЈ,
J = 8.2 Hz, part overlapped with the signals of minor conformer,
2 H each), 7.37 and 7.52 (AAЈBBЈ, J = 8.1 Hz, part overlapped
with the signals of minor conformer, 2 H each), 8.39 (s, 1 H) ppm;
minor conformer δ = 1.98 (app. t, J = 8.2 Hz, 1 H), 2.94 (app. t, J
= 9.2 Hz, 1 H), 3.54 (t, J = 10.0 Hz, 1 H), 6.43 and 6.76 (AAЈBBЈ,
J = 8.0 Hz, 2 H each), 6.91 and 7.21 (AAЈBBЈ, J = 7.2 Hz, part
overlapped with the signals of major conformer, 2 H each), 8.25 (s,
1 H) ppm; (CD3SOCD3): major conformer δ = 1.92 (dd, J = 9.3,
7.6 Hz, 1 H), 2.75 (dd, J = 10.4, 7.6 Hz, 1 H), 4.11 (app. t, J =
9.9 Hz, 1 H), 7.09 and 7.32 (AAЈBBЈ, J = 8.5 Hz, part overlapped
with the signals of minor conformer, 2 H each), 7.66 (br. s, 4 H),
8.67 (s, 1 H) ppm; minor conformer δ = 2.65 (dd, J = 9.7, 7.5 Hz,
1 H), 2.85 (dd, J = 10.8, 7.5 Hz, 1 H), 3.83 (dd, J = 10.7, 9.7 Hz,
1 H), 6.91 (br. s, 4 H), 7.04 and 7.31 (AAЈBBЈ, J = 8.6 Hz, part
overlapped with the signals of major conformer, 2 H each), 8.45 (s,
1 H) ppm. The ratio major/minor conformer is 83:17 in CDCl3 and
77:23 in CD3SOCD3. 13C NMR (CDCl3): the sample is a mixture
of two conformers and only a few signals are unambiguously as-
signed: δ = 24.39 (major conformer), 25.87 (minor conformer),
37.76 (minor conformer), 38.34 (major conformer), 67.32 (minor
conformer), 67.36 (major conformer), 128.03, 128.19, 128.49,
129.03 (major conformer), 129.23, 129.37 (major conformer),
129.58, 129.92 (major conformer), 130.71, 131.63 (major con-
former), 134.81, 138.80, 141.32 (major conformer), 142.37 (minor
conformer) ppm. HRMS: calcd. for C17H12Cl2N2O4 378.0174;
found 378.0172.
Compounds 2a,[4b] b–e, g, i[17] and h[5h] have been already described.
Compounds 2f and 2j are new compounds, prepared according to
a reported procedure.[4b,17]
4,4Ј-[(1E,3E)-2,3-Dinitro-1,3-butadiene-1,4-diyl]bis(chlorobenzene)
(2f): Yellow solid, m.p. 155–156 °C (toluene). 1H NMR (CDCl3): δ
= 6.76 and 7.17 (AAЈBBЈ, J = 8.4 Hz, 4H each), 8.42 (s, 2 H) ppm.
13C NMR (CDCl3): δ = 127.88, 129.05, 129.99, 131.64, 139.19,
140.11 ppm. HRMS: calcd. for C16H10Cl2N2O4 364.0018; found
364.0014.
3,3Ј-[(1E,3E)-2,3-Dinitro-1,3-butadiene-1,4-diyl]dithiophene (2j):
Yellow solid, m.p. 144–145 °C (toluene/petroleum ether). 1H NMR
(CDCl3): δ = 7.15 (dd, J = 5.2, 1.4 Hz, 2 H), 7.34 (dd, J = 5.1,
2.9 Hz, 2 H), 7.80 (dd, J = 2.9, 1.2 Hz, 2 H), 8.58 (s, 2 H) ppm;
(CD3SOCD3): δ = 7.21 (dd, J = 5.1, 1.4 Hz, 2 H), 7.64 (dd, J =
5.1, 2.9 Hz, 2 H), 8.37–8.45 (m, 2 H), 8.82 (s, 2 H) ppm. 13C NMR
(CDCl3): δ = 126.66, 128.59, 131.50, 134.84, 135.57, 138.17 ppm.
HRMS: calcd. for C12H8N2O4S2 307.9925; found 307.9920.
Compounds 6a, 6c–e, 6g, 6i have been already described.[6]
Compounds 6b (80%), 6f (76%), 6h (67%) and 6j (62%) are new
and were prepared according to the same procedure.[6]
(E)-1-Methyl-2-{2-nitro-2-[1-nitro-2-(2-methylphenyl)cyclopropyl]- (E)-2-{2-[2-(2-Naphthyl)-1-nitrocyclopropyl]-2-nitrovinyl}naphth-
vinyl}benzene (6b): Yellow solid, m.p. 148–149 °C (ethanol). 1H
NMR (CDCl3): δ = 1.49 (t, J = 8.3 Hz, 1 H), 2.30 (dd, J = 10.7,
7.3 Hz,1 H), 2.43 (s, 3 H), 2.48 (s, 3 H), 4.07 (t, J = 10.0 Hz, 1 H),
6.28 (d, J = 7.6 Hz, 1 H), 6.92–7.52 (m, 7 H), 8.56 (s, 1 H) ppm;
alene (6h): Yellow oil. 1H NMR (CDCl3) major conformer: δ =
2.41 (dd, J = 8.8, 6.9 Hz, 1 H), 2.84 (dd, J = 10.5, 7.0 Hz, 1 H),
4.06 (app. t, J = 9.6 Hz, 1 H), 6.76–8.15 (m, 14 H), 8.57 (s, 1
H) ppm; minor conformer: δ = 1.75 (app. t, J = 8.0 Hz, 1 H), 2.60
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

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M. Maccagno et al.
FULL PAPER
(dd, J = 10.5, 7.2 Hz, 1 H), 4.06 (app. t, J = 9.6 Hz, 1 H), 6.76–
8.15 (m, 14 H), 8.39 (s, 1 H); the signals of the 14 aromatic H of
the two conformers overlap: 6.92–7.07, 7.08–7.18, 7.29–7.39, 7.40–
7.54, 7.55–7.62, 7.62–7.70, 7.70–7.80, 7.80–7.90, 7.90–8.30 (9m, 14
H in all) ppm; (CD3SOCD3): δ = 2.10 (app. t, J = 8.4 Hz, 1 H),
2.91 (dd, J = 10.4, 7.7 Hz, 1 H), 4.27 (app. t, J = 9.8 Hz, 1 H),
dichloromethane). IR (Nujol): ν = 3452, 1568, 1304, 1277, 1224,
˜
1149 cm–1. 1H NMR (CDCl3): δ = 3.40 (dd, J = 16.4, 7.0 Hz, 1 H),
3.84 (dd, J = 16.3, 9.7 Hz, 1 H), 5.91 (dd, J = 9.3, 6.9 Hz, 1 H),
7.29–7.55 (m, 10 H), 8.32 (s, 1 H); (CD3SOCD3): δ = 3.32 (dd, J
= 17.0, 6.5 Hz, 1 H, part overlapped with the signal of water), 3.88
(dd, J = 17.0, 9.6 Hz, 1 H), 6.11 (dd, J = 9.5, 6.5 Hz, 1 H), 7.36–
6.86–7.17, 7.17–7.32, 7.38–7.63, 7.64–7.76, 7.77–7.92 and 7.94–8.25 7.62 (m, 10 H), 8.48 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 39.59,
(6m, 14 H in all), 8.79 (s, 1 H) ppm; the ratio major/minor con-
former is 67:33 in CDCl3, whereas in CD3SOCD3 only one con-
77.84, 106.97, 125.86, 129.21, 129.30, 129.43, 130.70, 132.57,
137.25, 138.14, 140.83, 141.43 ppm; (CD3SOCD3): δ = 39.16,
former is present. 13C NMR (CD3SOCD3): δ = 14.25, 28.97, 64.81, 77.37, 107.53, 126.02, 128.01, 128.98, 129.23, 129.40, 130.79,
115.37, 120.22, 121.44, 121.59, 121.70, 122.01, 122.11, 122.18, 137.20, 138.65, 140.67, 142.16 ppm. MS (ESI): m/z = 349
123.22, 123.96, 124.22, 126.07, 126.97, 128.86, 132.55, 144.83 (6
C accidentally isochronous) ppm. HRMS: calcd. for C25H18N2O4
410.1267; found 410.1267.
[M + K]+, 644 [2M + Na]+, 659 [2M + K]+.
(E)-5-(2-Methylphenyl)-3-[2-(2-methylphenyl)-1-nitrovinyl]-4,5-dihy-
1
droisoxazole 2-Oxide (7b): Yellow oil. H NMR (CD3SOCD3): δ =
2.25 (s, 3 H), 2.38 (s, 3 H), 3.04 (dd, J = 17.0, 5.9 Hz, 1 H), 3.81
(dd, J = 17.0, 10.0 Hz, 1 H), 6.16 (dd, J = 9.9, 5.9 Hz, 1 H), 7.07–
7.17 (m, 2 H), 7.19–7.44 (m, 6 H), 8.49 (s, 1 H) ppm. 13C NMR
(CDCl3): δ = 19.11, 20.25, 38.80, 75.36, 106.75, 125.01, 126.70,
126.74, 127.96, 128.91, 129.64, 131.11, 131.16, 132.12, 134.49,
136.45, 138.61, 139.22, 139.36 ppm. HRMS: calcd. for C19H18N2O4
338.1267; found 338.1265.
(E)-3-{2-Nitro-2-[1-nitro-2-(thiophen-3-yl)cyclopropyl]vinyl}-
thiophene (6j): Yellow solid, m.p. 142–143 °C (diethyl ether). 1H
NMR (CDCl3): major conformer δ = 1.74 (dd, J = 8.9, 6.7 Hz, 1
H), 2.70 (dd, J = 10.4, 6.7 Hz, 1 H), 4.00 (dd, J = 10.4, 8.8 Hz, 1
H), 6.78 (dd, J = 5.0, 1.4 Hz, 1 H, part overlapped with the signals
of minor conformer), 6.87 (ddd, J = 3.0, 1.4, 0.7 Hz, 1 H), 7.16–
7.30 (m, part overlapped with the signals of minor conformer, 2
H), 7.51 (ddd, J = 5.1, 3.0, 0.6 Hz, 1 H), 7.74 (ddd, J = 3.0, 1.4,
0.7 Hz, 1 H), 8.39 (s, 1 H) ppm; minor conformer δ = 1.93 (dd, J
= 9.1, 7.4 Hz, 1 H), 2.97 (dd, J = 10.6, 7.3 Hz, 1 H), 3.76 (dd, J =
10.6, 9.1 Hz, 1 H), 6.33 (dd, J = 5.0, 1.4 Hz, 1 H), 6.57 (dd, J =
2.7, 1.4 Hz, 1 H), 6.93 (dd, J = 4.9, 2.9 Hz, 1 H), 8.26 (s, 1 H) ppm
(the remaining 3 aromatic H are covered by the signals of major
conformer); (CD3SOCD3): major conformer δ = 2.12 (dd, J = 9.1,
7.0 Hz, 1 H), 2.94 (dd, J = 10.5, 7.1 Hz, 1 H, part overlapped with
the signals of minor conformer), 4.05 (dd, J = 10.6, 9.1 Hz, 1 H,
part overlapped with the signals of minor conformer), 6.87 (dd, J
= 4.9, 1.5 Hz, 1 H), 7.29 (dd, J = 2.8, 1.3 Hz, 1 H), 7.38–7.44 (m,
2 H), 7.78 (dd, J = 5.0, 2.9 Hz, 1 H), 8.38 (dd, J = 3.0, 1.4 Hz, 1
H, part overlapped with the signals of minor conformer), 8.59 (s,
1 H) ppm; minor conformer δ = 2.46 (dd, J = 9.3, 7.1 Hz, 1 H,
part overlapped with the signal of solvent), 2.86 (dd, J = 10.7,
7.3 Hz, 1 H, part overlapped with the signals of major conformer),
4.06 (t, J 10.0 Hz, 1 H, part overlapped with the signals of major
conformer), 6.71 (dd, J = 5.0, 1.4 Hz, 1 H), 6.98 (dd, J = 5.0,
1.4 Hz, 1 H), 7.07 (dd, J = 5.0, 3.0 Hz, 1 H), 7.17 (dd, J = 2.7,
1.3 Hz, 1 H), 7.52 (dd, J = 5.1, 2.9 Hz, 1 H), 7.89 (dd, J = 3.0,
1.4 Hz, 1 H), 8.38 (s, 1 H, part overlapped with the signals of major
conformer) ppm; the ratio major/minor conformer is 81:19 in
CDCl3 and 7:3 in CD3SOCD3. 13C NMR (CDCl3): the sample is
a mixture of two conformers and only a few signals are unambigu-
ously assigned: δ = 26.44 (major conformer), 27.63 (minor con-
former), 29.85 (minor conformer), 34.66 (major conformer), 67.08
(major conformer), 67.85 (minor conformer), 123.30, 123.66 (major
conformer), 124.50, 125.03, 125.79, 126.60 (major conformer),
127.28, 127.67 (major conformer), 127.72, 128.04 (major con-
former), 128.15 (major conformer), 128.46, 131.31, 132.96, 133.03,
133.59, 133.99, 136.01 (major conformer), 137.62, 140.20 ppm.
HRMS: calcd. for C13H10N2O4S2 322.0082; found 322.0081.
(E)-5-(4-Methylphenyl)-3-[2-(4-methylphenyl)-1-nitrovinyl]-4,5-di-
hydroisoxazole 2-Oxide (7c): Yellow oil. 1H NMR (CDCl3): δ =
2.39 (s, 6 H), 3.39 (dd, J = 16.6, 7.4 Hz, 1 H), 3.76 (dd, J = 16.6,
9.4 Hz, 1 H), 5.85 (dd, J = 9.4, 7.5 Hz, 1 H), 7.20 (half AAЈBBЈ, J
= 8.1 Hz, 2 H), 7.23–7.31 (m, 4 H), 7.37 (half AAЈBBЈ, J = 8.1 Hz,
2 H), 8.27 (s, 1 H); (CD3SOCD3): δ = 2.35 (s, 3 H), 2.37 (s, 3 H),
3.31 (dd, J = 17.2, 7.1 Hz, 1 H, part overlapped with the signal of
water), 3.83 (dd, J = 17.0, 9.6 Hz, 1 H), 6.06 (app. t, J = 8.3 Hz, 1
H), 7.22–7.35 (m, 4 H), 7.38–7.48 (m, 4 H), 8.45 (s, 1 H) ppm [the
peaks are broad; global spectral deconvolution (GSD) analysis
shows the presence of a minor conformer with the same pattern of
signals almost completely overlapped with the main one]. 13C
NMR (CDCl3): δ = 21.31, 21.87, 39.50, 78.04, 107.46, 126.01,
127.10, 129.78, 130.21, 130.95, 134.95, 136.28, 139.25, 140.81,
143.79 ppm. HRMS: calcd. for C19H18N2O4 338.1267; found
338.1262.
(E)-5-(4-Methoxyphenyl)-3-[2-(4-methoxyphenyl)-1-nitrovinyl]-4,5-di-
hydroisoxazole 2-Oxide (7d): Yellow solid, m.p. 127–128 °C (petro-
leum ether/dichloromethane). IR (Nujol): ν = 1617, 1594, 1303,
˜
1
1259, 1173, 1024, 919, 837, 722 cm–1. H NMR (CDCl3): δ = 3.49
(dd, J = 16.6, 7.8 Hz, 1 H), 3.79 (dd, J = 16.6, 9.3 Hz, 1 H), 3.85
(s, 3 H), 3.88 (s, 3 H), 5.88 (dd, J = 9.2, 7.8 Hz, 1 H), 6.94 and
6.99 (AAЈBBЈ, J = 8.8 Hz, 2H each), 7.35 and 7.45 (AAЈBBЈ, J =
8.8 Hz, 2H each), 8.31 (s, 1 H); (CD3SOCD3): δ = 3.37 (dd, J =
17.1, 7.3 Hz, 1 H), 3.79 (s, 3 H), 3.80 (dd, J = 16.9, 9.1 Hz, 1 H,
part overlapped with the previous signal), 3.85 (s, 3 H), 6.04 (dd,
J = 9.4, 7.4 Hz, 1 H), 7.04 and 7.06 (AAЈBBЈ, J = 8.6 Hz, 2H
each), 7.49 and 7.53 (AAЈBBЈ, J = 8.6 Hz, 2H each), 8.44 (s, 1
H) ppm. 13C NMR (CDCl3): δ = 39.35, 55.40, 55.57, 77.99, 107.80,
114.41, 114.97, 122.22, 127.67, 129.51, 133.43, 134.43, 140.41,
160.34, 163.30 ppm. HRMS: calcd. for C19H18N2O6 370.1165;
found 370.1160.
Preparative Isomerization of 6 to 7: In a flask equipped with a mag-
netic stirring-bar, appropriate 6 (0.8 mmol) was dissolved in dry
CH3CN (20 mL) and NaI (120 mg, 0.8 mmol, 1 mol equiv.) was
added. The flask was then closed with a rubber septum equipped
with a silica-gel trap and kept at 60 °C as long as necessary. At the
end, the solvent was removed under vacuum to obtain a crude mix-
ture that was separated by column chromatography on silica gel.
(E)-5-(3-Chlorophenyl)-3-[2-(3-chlorophenyl)-1-nitrovinyl]-4,5-di-
hydroisoxazole 2-Oxide (7e): Yellow oil. 1H NMR (CDCl3): δ =
3.38 (dd, J = 16.6, 6.9 Hz, 1 H), 3.91 (dd, J = 16.4, 9.7 Hz, 1 H),
5.87 (dd, J = 9.6, 6.8 Hz, 1 H), 7.11–7.47 (m, 8 H), 8.24 (s, 1 H);
(CD3SOCD3): δ = 3.41 (dd, J = 17.3, 6.3 Hz, 1 H, part overlapped
with the signal of water), 3.95 (dd, J = 17.3, 9.8 Hz, 1 H), 6.11 (dd,
J = 9.7, 6.2 Hz, 1 H), 7.39–7.66 (m, 8 H), 8.48 (s, 1 H) ppm. 13C
NMR (CDCl3): δ = 35.84, 75.60, 118.00, 122.99, 123.02, 123.24,
123.63, 123.76, 124.17, 124.29, 124.54, 129.28, 130.68, 131.19,
(E)-3-(1-Nitro-2-phenylethenyl)-5-phenyl-4,5-dihydroisoxazole 2-
Oxide (7a):[8] Yellow solid, m.p. 104–105 °C (petroleum ether/
8
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1,2-Migration of a Nitro Group Within a β-Nitrostyryl Moiety
137.50, 138.13, 138.90 ppm. HRMS: calcd. for C17H12Cl2N2O4
378.0174; found 378.0171.
conformer with the same pattern of signals almost completely over-
lapped with the main one). 13C NMR (CDCl3): δ = 29.80, 39.34,
74.54, 127.45, 127.52, 127.70, 128.45, 128.98, 134.10, 135.27,
136.44, 138.34, 139.46 ppm. HRMS: calcd. for C13H10N2O4S2
322.0082; found 322.0079.
(E)-5-(4-Chlorophenyl)-3-(2-(4-chlorophenyl)-1-nitrovinyl)-4,5-di-
hydroisoxazole 2-Oxide (7f): Yellow solid, m.p. 83–84 °C (petro-
leum ether/dichloromethane). 1H NMR (CDCl3): δ = 3.39 (dd, J =
16.5, 6.9 Hz, 1 H), 3.86 (dd, J = 16.5, 9.4 Hz, 1 H), 5.87 (dd, J =
9.3, 7.0 Hz, 1 H), 7.20–7.31 (m, 2 H), 7.32–7.52 (m, 6 H), 8.26 (s,
1 H) ppm; (CD3SOCD3): δ = 3.34 (dd, J = 17.1, 6.7 Hz, 1 H, part
overlapped with the signal of water), 3.89 (dd, J = 17.0, 9.6 Hz, 1
H), 6.10 (dd, J = 9.5, 6.7 Hz, 1 H), 7.49–7.60 (m, 8 H), 8.49 (s, 1
H) ppm. 13C NMR (CDCl3): δ = 39.66, 76.23, 106.73, 127.29,
128.36, 129.52, 129.84, 131.80, 135.46, 136.44, 137.38, 139.07,
139.44 ppm. HRMS: calcd. for C17H12Cl2N2O4 378.0174; found
378.0168.
(E)-3-[1-Nitro-2-(3-thienyl)vinyl]-5-(3-thienyl)-4,5-dihydroisoxazole
2-Oxide (7j): Orange oil. 1H NMR (CDCl3): δ = 3.53 (dd, J = 16.5,
6.6 Hz, 1 H), 3.86 (dd, J = 16.3, 9.2 Hz, 1 H), 5.99 (dd, J = 9.1,
6.6 Hz, 1 H), 7.04 (dd, J = 5.1, 1.3 Hz, 1 H), 7.21 (d, J = 1.6 Hz,
1 H), 7.41 (dd, J = 5.1, 2.8 Hz, 1 H), 7.45 (dd, J = 5.1, 3.0 Hz, 1
H), 7.56 (dd, J = 5.1, 1.3 Hz, 1 H), 7.68 (dd, J = 3.4, 1.6 Hz, 1 H),
8.37 (s, 1 H) ppm; (CD3CN): δ = 3.46 (dd, J = 16.9, 6.6 Hz, 1 H),
3.83 (dd, J = 17.0, 9.3 Hz, 1 H), 6.06 (dd, J = 9.2, 6.6 Hz, 1 H),
7.11 (dd, J = 5.0, 1.5 Hz, 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 7.44 (d,
J = 5.5 Hz, 1 H), 7.53 (dd, J = 4.9, 2.1 Hz, 1 H), 7.60 (d, J =
3.0 Hz, 1 H), 7.88 (d, J = 5.6 Hz, 1 H), 8.41 (s, 1 H) ppm. 13C
NMR (CDCl3): δ = 37.37, 77.39, 117.72, 118.53, 119.56, 120.25,
120.89, 120.95, 127.09, 131.31, 131.58, 142.61, 144.07 ppm.
HRMS: calcd. for C13H10N2O4S2 322.0082; found 322.0085.
(E)-5-(1-Naphthyl)-3-[2-(1-naphthyl)-1-nitrovinyl]-4,5-dihydroisox-
azole 2-Oxide (7g): Yellow oil. 1H NMR (CDCl3): major conformer
δ = 3.16 (dd, J = 16.4, 5.5 Hz, 1 H), 3.92 (dd, J = 16.4, 9.8 Hz, 1
H, part overlapped with the signal of minor conformer), 6.40 (dd,
J = 9.8, 5.4 Hz, 1 H, part overlapped with the signal of minor
conformer), 7.16–7.34, 7.34–7.72 and 7.73–7.97 (3 m, 14H in all),
8.90 (s, 1 H) ppm; minor conformer δ = 3.46 (dd, J = 16.6, 7.0 Hz,
1 H), 3.99 (dd, J = 16.6, 9.7 Hz, 1 H, part overlapped with the
major conformer), 6.47 (dd, J = 9.9, 7.3 Hz, 1 H, part overlapped
with the major conformer), 8.67 (s, 1 H) ppm; (CD3SOCD3): major
conformer δ = 3.11 (dd, J = 16.9, 5.0 Hz, 1 H), 4.03 (dd, J = 16.9,
10.0 Hz, 1 H), 6.70 (dd, J = 9.8, 5.1 Hz, 1 H), 7.15–7.52, 7.55–7.65
and 7.89–8.11 (3 m, 14H in all), 8.95 (s, 1 H) ppm; minor con-
former δ = 3.79 (dd, J = 16.6, 7.2 Hz, 1 H), 4.37 (dd, J = 16.1,
9.4 Hz, 1 H), 6.81 (app. t, J = 8.4 Hz, 1 H), 8.84 (s, 1 H) ppm (the
signals of the 14 aromatic H of the minor conformer are hidden by
those of the major, both in CDCl3 and in CD3SOCD3); the ratio
major/minor conformer is 73:27 in CDCl3 and 19:1 in CD3SOCD3.
13C NMR (CD3SOCD3): δ = 34.64, 75.74, 115.52, 116.36, 116.39,
116.69, 117.02, 122.10, 122.24, 122.39, 122.42, 122.47, 122.53,
122.62, 122.87, 122.96, 123.03, 123.15, 123.28, 123.48, 123.56,
129.40, 135.62, 136.93, 138.22 ppm. HRMS: calcd. for C25H18N2O4
410.1267; found 410.1269.
Preparative Isomerization of 7 to 8: The reactions were performed
under the same conditions described above, except for the solvent
DMSO. After the required time, water was added, the mixture ex-
tracted with diethyl ether, washed with water, and dried with
Na2SO4. The solvent was then removed under vacuum to obtain a
crude mixture that was purified by column chromatography on sil-
ica gel.
(E)-3-(2-Nitro-2-phenylvinyl)-5-phenyl-4,5-dihydroisoxazole 2-Oxide
(8a):[8] Yellow solid, m.p. 180–181 °C (petroleum ether/dichloro-
methane). IR (Nujol): ν = 2722, 1305, 1156, 970, 891, 722 cm–1.
˜
1H NMR (CDCl3): δ = 2.50 (dd, J = 16.6, 8.1 Hz, 1 H), 2.79 (dd,
J = 16.6, 9.3 Hz, 1 H), 5.52 (dd, J = 9.3, 8.0 Hz, 1 H), 7.22–7.31
(m, 4 H), 7.35–7.50 (m, 6 H), 8.21 (s, 1 H) ppm; (CD3SOCD3): δ
= 2.45 (dd, J = 16.3, 8.3 Hz, 1 H, part overlapped with the signal
of solvent), 2.80 (dd, J = 16.3, 9.4 Hz, 1 H), 5.70 (app. t, J = 8.8 Hz,
1 H), 7.29–7.41 (m, 5 H), 7.41–7.56 (m, 5 H), 7.96 (s, 1 H) ppm;
(CD3COCD3): δ = 2.63 (dd, J = 16.5, 8.2 Hz, 1 H), 2.97 (dd, J =
16.4, 9.4 Hz, 1 H), 5.71 (dd, J = 9.3, 8.2 Hz, 1 H), 7.34–7.42 (m, 5
H), 7.45–7.53 (m, 5 H), 8.08 (s, 1 H) ppm. 13C NMR (CDCl3): δ =
37.74, 78.10, 113.59, 122.01, 125.95, 128.61, 129.07, 129.21, 129.51,
130.93, 131.01, 137.03, 150.26 ppm; (CD3SOCD3): δ = 36.92,
77.92, 114.93, 121.48, 126.61, 128.11, 128.64, 128.91, 129.24,
130.56, 131.18, 137.26, 149.79 ppm; (CD3COCD3): δ = 38.23,
79.05, 115.05, 122.47, 127.23, 129.05, 129.76, 130.00, 130.24,
131.32, 132.14, 138.71, 150.98 ppm. MS (ESI): m/z = 311 [M + H]
+, 349 [M + K]+, 644 [2M + Na]+, 659 [2M + K]+.
(E)-5-(2-Naphthyl)-3-[2-(2-naphthyl)-1-nitrovinyl]-4,5-dihydro-
isoxazole 2-Oxide (7h): Yellow oil. 1H NMR (CD3CN): δ = 3.47
(dd, J = 17.1, 6.5 Hz, 1 H), 3.96 (dd, J = 17.2, 9.8 Hz, 1 H), 6.18
(dd, J = 9.7, 6.5 Hz, 1 H), 7.35–7.70, 7.71–7.80, 7.80–7.89 and
7.90–8.11 (4m, 14H in all), 8.50 (s, 1 H) ppm; (CD3SOCD3): δ =
3.52 (dd, J = 17.1, 6.8 Hz, 1 H), 4.02 (dd, J = 17.6, 9.4 Hz, 1 H),
6.32 (dd, J = 9.7, 6.7 Hz, 1 H), 7.42–7.74, 7.80–7.94 and 7.95–8.16
(3m, 14H in all), 8.64 (s, 1 H) ppm. 13C NMR (CD3SOCD3): δ =
35.16, 74.91, 114.92, 116.56, 116.71, 121.59, 122.37, 122.73, 122.96,
123.06, 123.30, 123.92, 124.02, 124.82, 127.64, 136.73, 137.91,
138.22 ppm (7 C are accidentally isochronous). HRMS: calcd. for
C25H18N2O4 410.1267; found 410.1261.
(E)-5-(2-Methylphenyl)-3-[2-(2-methylphenyl)-2-nitrovinyl]-4,5-dihy-
droisoxazole 2-Oxide (8b): Yellow solid, m.p. 158–159 °C (light pe-
1
troleum/toluene). H NMR (CD3SOCD3): δ = 2.10 (s, 3 H), 2.18
(s, 3 H), 2.70 (dd, J = 16.4, 9.5 Hz, 1 H), 2.90 (dd, J = 16.2, 9.8 Hz,
1 H), 5.92 (dd, J = 16.0, 8.7 Hz, 1 H), 7.15–7.44 (m, 8 H), 8.01 (s,
1 H) ppm. 13C NMR (CD3SOCD3): δ = 14.40, 14.58, 34.64, 78.27,
115.22, 120.09, 121.33, 121.36, 121.70, 121.80, 124.77, 125.16,
126.04, 126.35, 130.50, 130.92, 133.75, 140.43, 142.38 ppm.
HRMS: calcd. for C19H18N2O4 338.1267; found 338.1261.
(E)-3-[1-Nitro-2-(2-thienyl)vinyl]-5-(2-thienyl)-4,5-dihydroisoxazole
2-Oxide (7i): Yellow oil. 1H NMR (CDCl3): δ = 3.70 (dd, J = 16.6,
8.5 Hz, 1 H), 3.84 (dd, J = 16.6, 9.2 Hz, 1 H), 6.18 (app. t, J =
8.8 Hz, 1 H), 7.07 (dd, J = 5.0, 3.6 Hz, 1 H), 7.21 (dd, J = 5.1,
3.8 Hz, 1 H), 7.30 (dd, J = 3.5, 1.1 Hz, 1 H), 7.44 (dd, J = 5.1,
1.2 Hz, 1 H), 7.53 (dd, J = 3.8, 1.4 Hz, 1 H), 7.81 (dd, J = 5.0,
1.1 Hz, 1 H), 8.57 (s, 1 H) ppm; (CD3SOCD3): δ = 3.58 (dd, J =
17.3, 8.0 Hz, 1 H), 3.91 (dd, J = 17.3, 9.5 Hz, 1 H), 6.40 (app. t, J
(E)-5-(4-Methylphenyl)-3-[2-(4-methylphenyl)-2-nitrovinyl]-4,5-dihy-
droisoxazole 2-Oxide (8c): Yellow solid, m.p. 165–166 °C (light pe-
troleum/toluene). IR (Nujol): ν = 1569, 1304, 1276, 1225, 1150,
˜
= 8.6 Hz, 1 H), 7.13 (dd, J = 5.0, 3.6 Hz, 1 H), 7.33 (dd, J = 8.6, 966, 892, 817, 772, 724 cm–1. H NMR (CDCl3): δ = 2.35 (s, 3 H),
1
3.6 Hz, 1 H), 7.40 (dd, J = 3.4, 1.3 Hz, 1 H), 7.71 (dd, J = 5.0,
1.4 Hz, 1 H), 7.92 (dd, J = 3.7, 1.4 Hz, 1 H), 8.23 (dd, J = 5.3,
1.2 Hz, 1 H), 8.87 (s, 1 H) ppm (Both in CDCl3 and CD3SOCD3
the peaks are broad: GSD analysis shows the presence of a minor
2.39 (s, 3 H), 2.55 (dd, J = 16.6, 8.2 Hz, 1 H), 2.78 (dd, J = 16.7,
9.2 Hz, 1 H), 5.48 (app. t, J = 8.8 Hz, 1 H), 7.03–7.28 (m, 8 H),
8.18 (s, 1 H) ppm (The peaks are broad: GSD analysis shows the
presence of a minor conformer with the same pattern of signals
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

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M. Maccagno et al.
FULL PAPER
almost completely overlap with the major one); (CD3SOCD3): δ =
2.27 (s, 3 H), 2.31 (s, 3 H), 2.42 (app. t, J = 12.5 Hz, 1 H, part
overlapped with the signal of the solvent), 2.78 (dd, J = 16.3,
with the signal of solvent), 6.34 (app. t, J = 8.9 Hz, 1 H, part over-
lapped with the signal of the second conformer), 8.28 (s, 1 H) ppm;
second conformer: δ = 2.57 (dd, J = 16.7, 8.5 Hz, 1 H, part over-
9.4 Hz, 1 H), 5.64 (app. t, J = 8.9 Hz, 1 H), 7.07–7.47 (m, 8 H), lapped with the signal of solvent), 3.12 (dd, J = 16.5, 9.9 Hz, 1 H),
7.92 (d, J = 2.1 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 21.34, 21.68, 6.39 (dd, J = 9.7, 5.8 Hz, 1 H, part overlapped with the signal of
37.79, 78.35, 113.96, 121.73, 126.09, 126.20, 129.31, 129.83, 130.89,
the first conformer), 8.26 (s, 1 H); the signals of the 14 aromatic H
133.92, 139.65, 141.29, 150.47 ppm. HRMS: calcd. for C19H18N2O4 of the two conformers overlap: 7.16 (app. d, J = 7.14 Hz, 1 H),
338.1267; found 338.1262.
7.33–7.37, 7.41–7.45, 7.47–7.52, 7.53–7.63, 7.69–7.71, 7.80–7.86,
7.89–7.96, 8.00–8.05 (8m, 13 H in all) ppm (The two conformers
have approximately the same abundance, both in CDCl3 and in
CD3SOCD3). 13C NMR (CDCl3): signals are not attributable to a
particular conformer: δ = 36.00, 36.50, 75.36, 75.85, 115.42, 116.64,
119.60, 120.86, 121.90, 122.09, 122.79, 123.18, 123.56, 123.58,
123.84, 124.26, 124.38, 124.61, 124.76, 124.86, 125.16, 125.35,
126.14, 126.29, 126.43, 126.82, 126.96, 127.06, 127.77, 128.13,
128.64, 129.00, 129.25, 129.40, 129.53, 129.78, 129.91, 129.95,
131.59, 132.16, 133.92, 148.90, 149.07 ppm. HRMS: calcd. for
C25H18N2O4 410.1267; found 410.1272.
(E)-5-(4-Methoxyphenyl)-3-[2-(4-methoxyphenyl)-2-nitrovinyl]-
4,5-dihydroisoxazole 2-Oxide (8d): Yellow solid, m.p. 169–170 °C
(light petroleum/toluene). IR (Nujol): ν = 1572, 1304, 1227, 1178,
˜
1151, 1032, 969, 924, 891, 840, 736, 686 cm–1. H NMR (CDCl3):
1
δ = 2.57 (dd, J = 16.7, 8.5 Hz, 1 H), 2.79 (dd, J = 16.7, 9.2 Hz, 1
H), 3.80 (s, 3 H), 3.84 (s, 3 H), 5.48 (app. t, J = 8.8 Hz, 1 H), 6.89
and 6.94 (AAЈBBЈ, J = 8.2 Hz, 2H each), 7.19 and 7.25 (AAЈBBЈ,
J = 8.5 Hz, 2H each), 8.17 (s, 1 H) ppm; (CD3SOCD3): δ = 2.56
(dd, J = 16.4, 8.7 Hz, 1 H), 2.78 (dd, J = 16.4, 9.3 Hz, 1 H), 3.74
(s, 3 H), 3.77 (s, 3 H), 5.65 (app. t, J = 8.9 Hz, 1 H), 6.94 and 6.99
(AAЈBBЈ, J = 8.2 Hz, 2H each), 7.32 and 7.41 (AAЈBBЈ, J =
8.3 Hz, 2H each), 7.91 (s, 1 H) ppm (The peaks are broad: GSD
analysis shows the presence of a minor conformer with the same
pattern of signals almost completely overlap with the major one).
13C NMR (CDCl3): δ = 37.80, 55.53, 55.55, 78.39, 114.04, 114.55,
114.91, 121.68, 127.67, 127.84, 128.62, 132.57, 150.30, 160.60,
161.42 ppm. HRMS: calcd. for C19H18N2O6 370.1165; found
370.1159.
(E)-5-(2-Naphthyl)-3-[2-(2-naphthyl)-1-nitrovinyl]-4,5-dihydro-
isoxazole 2-Oxide (8h): Yellow oil. 1H NMR (CDCl3): δ = 2.50 (dd,
J = 15.1, 8.7 Hz, 1 H), 2.84 (dd, J = 15.3, 8.1 Hz, 1 H), 5.61 (app.
t, J = 8.7 Hz, 1 H), 7.03–7.39, 7.40–7.64, 7.66–7.82, 7.83–7.99 and
8.00–8.15 (5m, 14H in all), 8.61 (s, 1 H) ppm; (CD3SOCD3): δ =
2.56 (dd, J = 16.1, 7.8 Hz, 1 H), 2.90 (dd, J = 16.2, 9.6 Hz, 1 H),
5.83 (dd, J = 9.3, 8.1 Hz, 1 H), 7.36–7.75, 7.77–7.92, 7.93–8.07 and
8.07–8.26 (4m, 14H in all), 8.60 (s, 1 H) ppm. 13C NMR
(CD3SOCD3): δ = 33.83, 74.83, 111.54, 115.08, 116.55, 116.71,
120.18, 121.59, 122.37, 122.42, 122.81, 122.87, 122.96, 123.59,
123.82, 123.92, 124.03, 124.82, 126.48, 127.64, 138.90, 143.74 (3 C
are accidentally isochronous) ppm. HRMS: calcd. for C25H18N2O4
410.1267; found 410.1267.
(E)-5-(3-Chlorophenyl)-3-[2-(3-chlorophenyl)-2-nitrovinyl]-4,5-di-
hydroisoxazole 2-Oxide (8e): Yellow oil. 1H NMR (CDCl3): δ =
2.49 (dd, J = 16.5, 7.6 Hz, 1 H), 2.89 (dd, J = 16.5, 9.5 Hz, 1 H),
5.53 (dd, J = 9.4, 7.5 Hz, 1 H), 7.03–7.56 (m, 8 H), 8.19 (s, 1
H) ppm; (CD3SOCD3): δ = 2.53 (dd, J = 15.9, 7.6 Hz, 1 H, part
overlapped with the signal of solvent), 2.90 (dd, J = 16.3, 9.5 Hz,
1 H), 5.74 (dd, J = 9.5, 8.0 Hz, 1 H), 7.28–7.70 (m, 8 H), 7.96 (s,
1 H) ppm. 13C NMR (CDCl3): δ = 34.51, 75.46, 113.03, 116.76,
Deuterated Compounds: Deuterated substrates 12,[4] 2c-d2
and
[17]
6c-d2,[6] are new compounds, prepared according to already re-
ported procedures.[18]
122.99, 123.02, 123.79, 124.29, 124.54, 124.58, 124.96, 125.19, (1E,3E)-1,4-Bis(diethylammino)-2,3-dinitro-1,3-butadiene-d2 (12):
129.28, 130.68, 131.70, 139.58, 144.33 ppm. HRMS: calcd. for Yellow solid, m.p. 147–148 °C (ethanol). 1H NMR (CDCl3): δ =
C17H12Cl2N2O4 378.0174; found 378.0180.
1.09 (t, J = 7.2 Hz, 6 H), 1.33 (t, J = 7.2 Hz, 6 H), 3.22 (dq, J =
14.3, 7.2 Hz, 2 H), 3.41 (dq, J = 14.3, 7.3 Hz, 2 H), 3.44 (dq, J =
14.4, 7.4 Hz, 4 H) ppm. 13C NMR (CDCl3): δ = 13.76, 14.92, 42.48,
52.17, 115.27, 149.49 (t, J = 24.7 Hz) ppm.
(E)-5-(4-Chlorophenyl)-3-[2-(4-chlorophenyl)-2-nitrovinyl]-4,5-di-
hydroisoxazole 2-Oxide (8f): Yellow solid, m.p. 178–179 °C (petro-
leum ether/dichloromethane). 1H NMR (CDCl3): δ = 2.48 (dd, J =
16.5, 7.7 Hz, 1 H), 2.86 (dd, J = 16.5, 9.3 Hz, 1 H), 5.53 (app. t, J
= 8.5 Hz, 1 H), 7.19 and 7.24 (AAЈBBЈ, J = 8.2 Hz, 2H each),
7.36 and 7.43 (AAЈBBЈ, J = 8.5 Hz, 2H each), 8.19 (s, 1 H) ppm;
(CD3SOCD3): δ = 2.52 (dd, J = 16.5, 8.0 Hz, 1 H, part overlapped
with the signal of solvent), 2.90 (dd, J = 16.4, 9.5 Hz, 1 H), 5.74
(dd, J = 9.4, 8.0 Hz, 1 H), 7.41 and 7.47 (AAЈBBЈ, J = 8.6 Hz, 2H
each), 7.51–7.56 (m, 4 H), 7.96 (s, 1 H) ppm (The peaks are broad;
GSD analysis shows the presence of a minor conformer with the
same pattern of signals almost completely overlap with the major
one). 13C NMR (CDCl3): δ = 38.01, 77.34, 112.98, 122.31, 127.29,
127.36, 129.04, 129.52, 132.34, 135.44, 135.59, 137.38, 148.98 ppm.
HRMS: calcd. for C17H12Cl2N2O4 378.0174; found 378.0175.
(1E,3E)-1,4-Bis(4-methylphenyl)-2,3-dinitro-1,3-butadiene-d2 (2c-
1
d2): Yellow solid, m.p. 143–144 °C (toluene/light petroleum). H
NMR (CDCl3): δ = 2.33 (s, 6 H), 7.15 and 7.35 (AAЈBBЈ, J =
8.2 Hz, 4H each) ppm.
1-Methyl-4-{(E)-2-[2-(4-methylphenyl)-1-nitrocyclopropyl]-2-
nitrovinyl}benzene-d2 (6c-d2): Yellow solid, m.p. 150–151 °C (eth-
1
anol). H NMR (CD3SOCD3): major conformer: δ = 1.77 (d, J =
7.2 Hz, 1 H), 2.23 (s, 3 H), 2.41 (s, 3 H), 2.73 (d, J = 7.0 Hz, 1 H),
6.88 and 7.04 (AAЈBBЈ, J = 7.8 Hz, 2 H each), 7.40 and 7.54
(AAЈBBЈ, J = 8.0 Hz, 2 H each) ppm; minor conformer: the only
distinguishable signals are: δ = 2.09 (s, 3 H), 2.30 (s, 3 H), 6.64 and
6.71 (AAЈBBЈ, J = 8.3 Hz, 2 H each) ppm.
(E)-5-(1-Naphthyl)-3-[2-(1-naphthyl)-1-nitrovinyl]-4,5-dihydro-
The study of the deuterium isotope effect in the 6Ǟ7Ǟ8 conver-
isoxazole 2-Oxide (8g): Yellow oil. 1H NMR (CDCl3): first con- sion rate was performed by means of both parallel and competitive
former: δ = 2.01 (dd, J = 16.6, 6.1 Hz, 1 H), 2.42 (dd, J = 16.6,
9.5 Hz, 1 H), 6.00 (app. t, J = 8.6 Hz, 1 H), 8.51 (s, 1 H) ppm;
second conformer: δ = 2.55 (dd, J = 16.5, 7.7 Hz, 1 H), 2.93 (dd,
tests. The parallel tests were performed by dissolving in two NMR
sample tubes 10.0 mg (0.03 mmol) of substrate (6c and 6c-d2,
respectively) in [D6]DMSO (1.0 mL) in the presence of NaI
J = 16.6, 9.7 Hz, 1 H), 6.09 (dd, J = 9.6, 6.1 Hz, 1 H), 8.48 (s, 1 (5.0 mg, 0.03 mmol). The tubes were kept at 60 °C as long as neces-
H); the signals of the 14 aromatic H of the two conformers overlap:
sary and checked by 1H NMR spectroscopy at scheduled times
7.18–7.38, 7.40–7.52, 7.55–7.71, 7.76–7.86 and 7.89–7.94 (5m, 14 (see Table 2). The competitive test was performed under the same
H in all) ppm; (CD3SOCD3): first conformer: δ = 1.78 (dd, J =
16.4, 5.9 Hz, 1 H), 2.47 (dd, J = 14.4, 9.6 Hz, 1 H, part overlapped
conditions described above, except for dissolving both substrates in
the same tube.
10
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1,2-Migration of a Nitro Group Within a β-Nitrostyryl Moiety
J.-M. Campagne, Chem. Eur. J. 2010, 16, 12207–12213; j) C.-
Y. Zhu, X.-L. Sun, X.-M. Deng, J.-C. Zheng, Y. Tang, Tetrahe-
dron 2008, 64, 5583–5589.
(E)-5-(4-Methylphenyl)-3-[2-(4-methylphenyl)-1-nitrovinyl]-4,5-dihy-
droisoxazole 2-Oxide-d2 (7c-d2 ): Yellow oil. 1 H NMR
(CD3SOCD3): δ = 2.36 (s, 3 H), 2.37 (s, 3 H), 3.31 (d, J = 17.1 Hz,
1 H), 3.82 (d, J = 17.1 Hz, 1 H), 7.29 (app. t, J = 8.5 Hz, 4 H),
7.41 and 7.44 (AAЈBBЈ, J = 8.2 Hz, 2H each) ppm.
[2]
[3]
For examples, see: a) T. Tsujihara, T. Shinohara, K. Takenaka,
S. Takizawa, K. Onitsuka, M. Hatanaka, H. Sasai, J. Org.
Chem. 2009, 74, 9274–9279; b) A. A. Fuller, B. Chen, A. R.
Minter, A. K. Mapp, J. Am. Chem. Soc. 2005, 127, 5376–5383;
c) D. Kim, J. Lee, P. J. Shim, J. I. Lim, H. Jo, S. Kim, J. Org.
Chem. 2002, 67, 764–771; d) J. W. Bode, E. M. Carreira, J. Org.
Chem. 2001, 66, 6410–6424.
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(E)-5-(4-Methylphenyl)-3-[2-(4-methylphenyl)-2-nitrovinyl]-4,5-dihy-
droisoxazole 2-Oxide-d2 (8c-d2): Yellow solid, m.p. 162–163 °C
(light petroleum/toluene); 1H NMR (CD3SOCD3): δ = 2.28 (s, 3
H), 2.32 (s, 3 H), 2.49 (d, J = 16.4 Hz, 1 H, part overlapped with
the signal of solvent), 2.79 (d, J = 16.4 Hz, 1 H), 7.15–7.28 (m, 4
H), 7.29–7.40 (m, 4 H) ppm.
Preparation of Pyrazolylisoxazole 11c: In a flask equipped with a
rubber septum and a magnetic stirring-bar, substrate 8c (1 mmol)
was dissolved in dry THF (40 mL), and the temperature kept at
0 °C. Diazomethane in ether was added in three portions
(0.5 mmol, 0.5 mol equiv. each). After the third portion, the reac-
tion mixture was left to gradually reach room temperature over-
night. The solution was then concentrated under vacuum at room
temperature and the crude mixture taken up with diethyl ether and
precipitated by adding petroleum ether.
[4]
[5]
5-(4-Methylphenyl)-3-[3(5)-(4-methylphenyl)-1H-pyrazol-4-yl]-4,5-di-
hydroisoxazole 2-Oxide (11c): White solid, m.p. 75–76 °C (taken up
with diethyl ether/petroleum ether). 1H NMR (CDCl3): δ = 2.35 (s,
3 H), 2.39 (s, 3 H), 2.97 (dd, J = 16.7, 8.2 Hz, 1 H), 3.25 (dd, J =
16.8, 9.1 Hz, 1 H), 5.52 (app. t, J = 8.6 Hz, 1 H), 7.13–7.30 (m, 8
H), 8.65 (s, 1 H) ppm (NH proton was not detected within the
spectral width –2–12 ppm); (CD3SOCD3): δ = 2.29 (s, 3 H), 2.32
(s, 3 H), 2.96 (dd, J = 16.5, 7.9 Hz, 1 H), 3.34 (dd, J = 16.4, 9.1 Hz,
1 H), 5.61 (app. t, J = 8.4 Hz, 1 H), 7.10–7.37 (m, 8 H), 8.26 and
8.51 (2 br. s, 1 H in all) ppm (NH proton was not detected within
the spectral width –2–12 ppm). 13C NMR (CDCl3): δ = 21.32,
21.51, 40.14, 107.58, 110.34, 126.12, 128.12, 129.36, 129.47, 129.63,
133.70, 135.26, 138.93, 139.48, 147.34 (one C overlapped with
CHCl3) ppm; (CD3SOCD3): δ = 20.74, 20.84, 76.08, 106.28, 109.72,
126.22, 128.60, 128.93, 129.18, 129.29, 135.62, 138.09, 138.80,
141.27, 149.62 ppm (one C overlapped with DMSO). HRMS:
calcd. for C20H19N3O2 333.1477; found 333.1477.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data and copies of the 1H and 13C NMR spectra
for all compounds. Diagnostic NOE interactions in compound 11c.
Acknowledgments
Financial support was provided by grants from Ministero dell’Is-
truzione, dell’Università
e
della Ricerca (MIUR) (PRIN
20085E2LXC and PRIN 2010FPTBSH).
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Maccagno et al.
FULL PAPER
[10]
[14] It should further be emphasized that the mechanistic hypothe-
sis of Scheme 5 is fully consistent with the lack of any signifi-
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bond.
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[13] See note 4 in ref.[8]
.
.
Received: June 12, 2013
Published Online: ᭿
12
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Pages: 13
1,2-Migration of a Nitro Group Within a β-Nitrostyryl Moiety
Nitro Group Migration
L. Bianchi, F. Ghelfi, G. Giorgi,
M. Maccagno,* G. Petrillo, D. Spinelli,
M. Stenta, C. Tavani ...................... 1–13
Uncommon 1,2-Migration of
Group Within a β-Nitrostyryl Moiety: Syn-
thetic Scope and Mechanistic Details
a Nitro
In spite of its infrequency, the migration of
a nitro group from the β- to the α-position
of a β-nitrostyryl moiety can be rational-
ized by stereo-electronic factors, as shown
here by means of computational and ex-
perimental studies. From the synthetic
point a view, two series of isomeric isoxazo-
line N-oxides can be obtained under con-
trolled conditions.
Keywords: Synthetic methods / Hetero-
cycles / Nitro group migration / Alkenes
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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13