Synthesis of 5-aminoisoxazolines from N-allyl compounds and nitrile oxides via tandem isomerization-1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tet.2010.06.040

A new strategy for the synthesis of derivatives of 5-aminoisoxazolines via tandem catalytic isomerization (of N-allyl systems to N-(1-propenyl) systems) - 1,3-dipolar cycloaddition (of a stable nitrile oxide to N-(1-propenyl) systems) is presented. Rhodiu

Full text of DOI:10.1016/j.tet.2010.06.040

Tetrahedron 66 (2010) 5972e5981
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Synthesis of 5-aminoisoxazolines from N-allyl compounds and nitrile oxides
via tandem isomerization-1,3-dipolar cycloaddition
,
a
a
a
a
Piotr Bujak a , Stanis1aw Krompiec , Joanna Malarz , Micha1 Krompiec , Micha1 Filapek ,
*
Witold Danikiewicz b, Magdalena Kania b, Katarzyna Ge˛barowska c, Iwona Grudzka a
a Institute of Chemistry, Faculty of Mathematics, Physics and Chemistry, University of Silesia ul. Szkolna 9, 40-007 Katowice, Poland
b Institute of Organic Chemistry, Polish Academy of Science, ul. Kasprzaka 44/52, 01-224 Warszawa 42, PO Box 58, Poland
c Centre of Polymer Chemistry, Polish Academy of Science, ul. Skłodowskiej-Curie 34, 41-819 Zabrze, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A new strategy for the synthesis of derivatives of 5-aminoisoxazolines via tandem catalytic isomerization
(of N-allyl systems to N-(1-propenyl) systems)d1,3-dipolar cycloaddition (of a stable nitrile oxide to
N-(1-propenyl) systems) is presented. Rhodium and ruthenium complexes, Verkade’s superbase, and
18-crown-6/KOH system were used for the syntheses of the N-(1-propenyl) systems. 4-P-substituted
isoxazoline was also synthesized via cycloaddition of diphenyl(1-propenyl)phosphine (prepared via
isomerization of allyldiphenylphosphine) to 2,6-dichlorobenzonitrile oxide. All cycloadditions were
regioselective but not stereoselective and not concerted. Cycloaddition to all N-(1-propenyl) systems
yielded 5-N-substituted isoxazolines, but cycloaddition to P-(1-propenyl) system lead to the formation of
a 4-P-regioisomer. This difference in regioselectivity is predicted by opposite FMO reactivity indices
calculated for model compounds: N-(1-propenyl)amine and N-(1-propenyl)phosphine.
Received 31 March 2010
Received in revised form 26 May 2010
Accepted 14 June 2010
Available online 18 June 2010
Keywords:
N-Allyl systems
Isomerization
1,3-Dipolar cycloaddition
Isoxazoline
Ó 2010 Elsevier Ltd. All rights reserved.
Verkade’s base
1. Introduction
N-substitutedunsaturatedcyclicsystems,15e17 butadienylamines,18 or
N-vinylimidazole8 served as dipolarophiles. Some 5-aminoisoxazo-
Substituted isoxazolines constitute an important class of com-
pounds having a well-known but still investigated biological activity.
Functionalized isoxazolines appear inpapers on neurotransmitters,1,2
and are used in the treatment of addictions, epilepsy, stroke, schizo-
phrenia, and Parkinson’s disease. Moreover, their activity as immu-
nosuppressants3 and blood coagulation factor Xa inhibitors,4 as well
as antibiotics of a broad antibacterial spectrum against both Gram-
positive and Gram-negative bacteria5 has been investigated. They are
being tested for their antiviral properties, including HIV inhibition.6
Isoxazoline rings are fundamental structural motifs of novel anti-
tuberculosis agents7 for the treatment of latent and drug-resistant
Mycobacterium tuberculosis infections. A 5-N-substituted isoxazoline
wasstudied asa protein tyrosine phosphatase 1Binhibitor, a potential
drug for type-2 diabetes.8 Isoxazolines are also used in the organic
lines were obtained in the reaction of N-cyclopropyl-N-alkylanilines
with HNO2.19
In the present work we demonstrated a new strategy for the
synthesis of derivatives of 5-aminoisoxazolines: the 1,3-dipolar
cycloaddition of nitrile oxides to N-(1-propenyl) systems, which are
obtained by isomerization of respective N-allyl systems. This tandem
reaction allows an easy preparation of many novel 5-N-substituted
isoxazolines unavailable by other routes. We have proved its utility
earlier, by showing new possibilities for the synthesis of 5-O- and 5-
S-substituted isoxazolines.20,21 In this paper we also analyze the
mechanism of cycloaddition and, its regioselectivity in particular.
2. Results and discussion
synthesisdas starting materials for syntheses of
-hydroxyketones,10 -hydroxyacids,11 and -aminoacids.12
Isoxazolines (including 5-N-substituted ones) are most often
b
-hydroxynitriles,9
The idea of a new strategy of the synthesis of 5-N-substituted
isoxazolines from N-allyl compounds and stable nitrile oxide is
shown in Scheme 1.
In the studied reactions, usually 2,6-dichloro-, 2,4,6-tri-
methyl-, and 2,4,6-trimethoxybenzonitrile oxide, which is one of
the most stable nitrile oxides,22 were used as the 1,3-dipoles.
They were generated in situ from the corresponding oximoyl
chlorides, in the reaction with triethylamine in methylene
b
b
b
obtained by 1,3-dipolar cycloaddition of nitrile oxides to functional-
ized alkenes.13,14 In the preparation of 5-N-substituted isoxazolines
* Corresponding author. Tel.: þ48 32 3591357; fax: þ48 32 2599978; e-mail
address: piotrbujakchem@poczta.onet.pl (P. Bujak).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.040

P. Bujak et al. / Tetrahedron 66 (2010) 5972e5981
5973
Cl
Cl
N
OH
N
OH
NCS
Cl
Cl
Cl
Cl
base
N
O
cat.
NXY
NXY
Cl
Me
NXY
Me
3a-l
1a-l
2a-l
Scheme 1. Tandem: Isomerization (of N-allyl systems to N-(1-propenyl) systems)dCycloaddition (of 2,6-dichlorobenzonitrile oxide to N-(1-propenyl) systems), for the synthesis of
5-aminoisoxazoline derivatives.
chloride13,23 (or with Verkade’s superbase, 2,8,9-triisopropyl-
2,5,8,9-tetraza-1-phosphabicyclo[3.3.3]undecane). The oximoyl
chlorides were, in turn, obtained in the reaction of appropriate
oximes with NCS, in the presence of a catalytic amount of HCl.14
The dipolarophiles, i.e., the N-(1-propenyl) systems (2ael), were
prepared via isomerization of the respective N-allyl systems
(1ael). All N-(1-propenyl) systems except 2i and 2j (see Table 1)
were synthesized as described in our earlier papers,24e32 via
isomerization of respective allyl systems in the presence of
[RuHCl(CO)(PPh3)3] or [RhH(CO)(PPh3)3]. On the other hand, the
dipolarophiles 2i and 2j were obtained by isomerization
reactions of the corresponding N-allyl compounds, catalysed by
18-crown-6/KOH or/and Verkade’s superbase, isomerization of 1i
being the first successful quantitative and stereoselective isom-
erization of N-allylazole (Table 1). Catalytic system consisting of
18-crown-6/KOH was particularly effective for the synthesis of
2i, but not for 2j, for which Verkade’s superbase was needed. It
is puzzling that the 18-crown-6/KOH system did not work in the
synthesis of 2j (it decomposed substrate 1j), despite the fact that
isomerization of 1k to 2k was quantitative in the presence of
this system (see Table 1). 18-Crown-6/KOH was used previously
for isomerization of a series of N-allylimines to 2-aza-1,3-di-
enes.33 Furthermore, rhodium and ruthenium complexes, which
are active isomerization catalysts for many N-allyl compounds,
were completely ineffective or hardly effective for the synthesis
of 2i and 2j. Moreover, t-BuOK (in DMSO) did not catalyze
isomerizations leading to 2i and 2j. The successful preparations
of 2i (only the Z isomer) and 2j are the first examples of
isomerization of N-allyl compounds catalyzed by Verkade’s
The results of the syntheses of 5-aminoisoxazolines 3ael
(Scheme 1) are collected in Table 2. Apparently, all reactions are
strictly regioselective. It is noteworthy that in the case of addition to
2-aza-1,3-dienes only 3,4-addition products (addition to C]C) are
observed.1,2-Adducts (to C]N) or 1,4-adducts are not formed at all.
An analogous regioselectivity has been observed by Caramella and
Bianchessi for the cycloaddition of benzonitrile oxide to 1-dime-
thylamino-1,3-butadiene.18 Both for 2-aza-1,3-dienes and 1-dia-
lkylamino-1,3-butadiene the addition is to the C]C bond
conjugated with the nitrogen atom lone pair.
In almost all (except one, 3l) the reactions studied, E/Z (in the
dipolarophile) and trans/cis (in the adduct) ratios were completely
different. This means that the investigated cycloadditions are not
concerted reactions, but consist of at least two steps. Also the result
received for 2a, in the case of which a cis-adduct is obtained from
a E-dipolarophile, confirms this conclusion: the rotation of the CeC
bond is required. These results are in full accord with our previous
research on the synthesis of 5-O-, 5-Si-, and 5-S-substituted iso-
xazolines.20,21 Generally, 1,3-dipolar cycloadditions of nitrile oxides
and related dipoles to the double bond can either be concerted (and
stereospecific) or stepwise (and nonstereospecific), depending on
the character and relative energies of FMOs of both reactants,
which also, together with partial charge distribution, determine the
regioselectivity.36 Therefore, the regioselectivity and non-
concertedness of the reactions studied here stem from the charge
distribution and FMOs of the nitrile oxide and N-(1-propenyl)
dipolarophiles. Partial charges and frontier MOs of nitrile oxides 37
and some enamines and enamides 38 have been discussed before. In
our opinion in the first step of the reaction the carbonecarbon bond
is formed and only in the second step the carboneoxygen is formed
(see Scheme 2) Moreover, when the CeC bond is formed first, the
transient product is formed, which is more stabilized. In the tran-
sient product [TP] (see Scheme 2) rotation of the CeC bond is
possible and therefore formation of both stereoisomeric dihy-
droisoxazoles is observed (even when the dipolarophile is a single
isomer). Another mechanism is also possible: the oxygen atom
(being more nucleophilic than nitrogen) attacks the carbon atom of
the double bond. An anion intermediate is formed, in which rota-
tion around the CeC bond is possible, as in the intermediate dis-
cussed previously. Such mechanism was suggested by Huisgen for
the regioselective but nonstereoselective cycloaddition of thio-
carbonyl ylides to dimethyl 3,4-dicyanofumarate.39
superbase
(2,8,9-triisopropyl-2,5,8,9-tetraza-1-phosphabicyclo
[3.3.3]undecane), which was used before for a transesterification
reaction.34,35 Verkade’s superbase was also applied in the syn-
thesis of 2i and the 2-aza-1,3-diene was obtained with the same
yield as with [RhH(CO)(PPh3)3], but with a different stereo-
selectivity (the Z isomer prevailed)dsee Table 1. It is interesting
to note that the superbase was used in a stoichiometric amount
for the isomerization of 1i, 1j, and 1k to, respectively, 2i, 2j, and
2k and then it served also as the base in the cycloaddition step,
generating the nitrile oxide. In these three cases the addition of
triethylamine (as in the rest of the cycloadditions) was
unnecessary.
We have started the studies on cycloaddition from checking if
the nitrile oxides we used are stable in the conditions of cycload-
dition reaction (in the presence of a base but in the absence of
a dipolarophile) and, in particular, if they undergo dimerization. It
was found that 2,4,6-trimethyl- and 2,4,6-trimethoxybenzonitrile
oxides do not undergo dimerization or any other transformation
during 24 h at room temperature in the CH2Cl2 solution. In turn,
only 5% of 2,6-dichlorobenzonitrile oxide dimerized while other
transformations were not observed, either.
We have also found that 2,4,6-trimethylbenzonitrile oxide and
2,4,6-trimethoxybenzonitrile oxide easily undergo cycloaddition to
2hdsee Scheme 3. This fact leads to the conclusion that our
method of the synthesis of 5-N-substituted isoxazolines is of gen-
eral applicability.
We have also found that the synthesis of 4-P-substituted iso-
xazolines from P-allyl compounds is also possibledsee Scheme 4.
Interestingly, the isomerization of diphenylallylphosphine to the

5974
P. Bujak et al. / Tetrahedron 66 (2010) 5972e5981
Table 1
The isomerization of N-allyl systems (CH2]CHCH2NXY) to N-(1-propenyl) systems (CH3CH]CHNXY)
N-allyl systems
Catalyst
t[ꢀC] (
s[h])
N-(1-propenyl) systems yield [%] (E/Z)
1a
1b
eNMe2
eN(i-Pr)2
[Rh]a
60 (2)
80 (2)
99 (only E)
99 (only E)
[Rh]a
O
1c
[Ru]b
[Ru]c
80 (3)
80 (2)
99 (1.00)
99 (1.40)
NH
NH
2
O
1d
Me
NH
Me
N
O
1e
1f
[Ru]c
[Ru]c
[Ru]c
80 (3)
80 (3)
70 (3)
99 (only E)
99 (only E)
99 (1.50)
Me
Me
N
O
O
1g
S
NH
O
1h
1i
[Ru]c
[Rh]a
60 (3)
80 (4)
99 (only E)
N
O
0 (d)
N
Verkade’s based
140 (24)
rt (24)
68 (only Z)
100 (only E)
N
18-crown-6/KOHe
Cl
[Rh]a
100 (4)
60 (4)
rt (24)
20 (0.20)
99 (1.30)
0 (d)f
1j
Verkade’s based
18-crown-6/KOHe
N
CH
Cl
1k
[Rh]a
100 (3)
99 (0.5)
N
CH
OMe
Verkade’s baseg
120 (4)
rt (24)
99 (2.00)
100 (1.20)
18-crown-6/KOHe
1l
[Rh]a
100 (3)
99 (0.60)
N
CH
O
a
[RhH(CO)(PPh3)3] (2 mol %) in C6D6 (1 mL/1 mmol substrate).
[RuClH(CO)(PPh3)3] (1 mol %) in THF (1 mL/1 mmol substrate).
[RuClH(CO)(PPh3)3] (1 mol %) in C6D6 (1 mL/1 mmol substrate).
DMSO (50 mol %, 1 mL/1 mmol substrate).
b
c
d
e
f
CH2]CHCH2NXY/KOH¼1:3 (1 mL C6D6/1 mmol substrate).
Decomposition of allyl substrate.
g
Without solvent (50 mol %).

P. Bujak et al. / Tetrahedron 66 (2010) 5972e5981
Table 2 (continued )
5975
Table 2
Synthesis of derivatives of 5-aminoisoxazolines via 1,3-dipolar cycloaddition of 2,
Isoxazolines
trans/cis (yield)b
6-Cl2C6H3CNO to CH3CH]CHNXYa
N
Ar
Isoxazolines
trans/cis (yield)b
Only cis (75)
O
Cl
N
Ar
3j
0.59 (80)
O
Me
N
CH
3a
Me
NMe
2
Cl
N
N
Ar
Ar
O
O
3b
3c
0.31 (70)
0.30 (70)
3k
0.90 (85)
0.12 (75)
Me
N
N
CH
OMe
Me
N(i-Pr)
2
N
Ar
O
Ar
NH
O
2
O
Me
NH
3l
0.62 (70)
Me
N
CH
N
Ar
O
O
a
Reaction conditions: rt, 24 h, 2,6-Cl2C6H3CNO/CH3CH]CHNXY/Et3N¼1:1:3;
3d
Me
O
0.71 (75)
conversion: 100% in all cases.
b
Isolated yield.
Me
N
NH
Ar
O
-
+
Ar
N
O
3e
0.20 (80)
N
Ar
N
Ar
Me
N
Me
-
O
O
O
Me
+
Me
Me
NXY
N
NXY
Me
Ar
NXY
O
[TP]
3f
0.19 (95)
Scheme 2. Proposed mechanism of the two-step cycloaddition of nitrile oxide to N-(1-
propenyl) compounds.
Me
N
O
Me
1-propenyl derivative in the presence of 18-crown-6/KOH system is
the first successful reaction of this type. Other catalysts we have
studied (superbase, [RuClH(CO)(PPh3)3], [RuCl2(PPh3)3], [RhH(CO)
(PPh3)3], [RuClH(CO)(PPh3)3], t-BuOK/DMSO), were completely
ineffective in this reaction.
N
Ar
O
3g
0.30 (80)
S
Me
NH
Isoxazoline obtained as shown in Scheme 4 (3m) is up till
now the first 4-P-substituted derivative of dihydroisoxazole. The
reaction was fully regioselective, as in the case of ArCNO cy-
cloaddition to enamines. However, the regioisomer was formed
(4-P-substituted) other than in the case of the addition to N-(1-
propenyl) compoundd5-N-substituted regioisomer was formed.
Interestingly, the regioselectivity of the addition of ArCNO to N-
and P-allyl compounds (1a, 1d, 1k, and 1m) was identical (see
Scheme 5) and similar to that reported earlier for C-, O-, and S-
allyl systems.20
O
N
Ar
O
O
Me
N
3h
0.18 (80)
O
In order to explain the observed differences in the regiose-
lectivity of addition to N-(1-propenyl) and P-(1-propenyl) com-
pounds (in contrast to the same direction of addition to N-allyl and
P-allyl compounds), theoretical calculations on model dipolar-
ophiles, (E)-H2ACH]CHCH3 and H2ACH2CH]CH2 (A¼N or P), have
been carried out using the DFT method with B3LYP functional (for
details see Experimental section). First of all, it is worth noting that
in (1-propenyl)amine the nitrogen lone pair is conjugated with the
N
Ar
O
3i
1.25 (75)
Me
N
N

5976
P. Bujak et al. / Tetrahedron 66 (2010) 5972e5981
O
N
Ar
O
Et N
3
N
OH
O
N
Ar
+
CH Cl , rt,
24h
Me
N
Me
2
2
Cl
O
O
Scheme 3. Cycloaddition of 2,4,6-trimethyl- and 2,4,6-trimethoxybenzonitrile oxide to (E)-N-(1-propenyl)phthalimide, for the synthesis of derivatives of 5-aminoisoxazolines.
Ar¼2,4,6-trimethylphenyl, 4h (70%; trans/cis¼0.10); 2,4,6-trimethoxyphenyl, 5h (70%; trans/cis¼0.12).
Cl
Cl
N
OH
NCS
N
OH
Cl
CH Cl
2
2
Cl
Et N
3
N
Cl
Cl
O
C H , rt,
6
6
Cl
24h
PPh
Ph P
2
Me
2
PPh
2
18-Crown-6/KOH
C H , rt, 24h
3m
6
6
(trans/cis = 0.14)
1m
2m
(E/Z = 0.52)
Scheme 4. Synthesis of 4-P-substituted isoxazoline 3m (76%; trans/cis¼0.14) from allyldiphenylphosphine 1m and 2,6-dichlorobenzaldoxime.
Cl
Cl
N
OH
+
Et N
3
N
O
Q
CH Cl , rt,
2
24h
2
Cl
Cl
Cl
Q
1a, 1d, 1k, 1m
6a, 6d, 6k, 6m (70-75%)
Q = -NXY (1a, 1d, 1k); -PPh2 (1m)
Scheme 5. Cycloaddition of 2,6-dichlorobenzonitrile oxide to selected N-allyl systems and allyldiphenylphosphine (1m). Q¼-NXY (1a, 1d, 1k); ePPh2 (1m).
double bond, while in (1-propenyl)phosphine the phosphorous
lone pair is orthogonal to the double bond. This has important
consequences for the charge (or rather frontier density) distribu-
tion in these molecules. In (1-propenyl)amine, the influence of the
nitrogen atom on the electronic structure of the double bond is
resonant, resulting in no (frontier) charge change near C1 and
(frontier) charge accumulation on C2, while in (1-propenyl)phos-
phine the heteroatom exerts only an inductive effect, which po-
vicinity of the double bond. For all the four studied compounds,
maps of electrostatic potential above the double bond are rather
symmetric, showing that the reaction is not charge-controlled, as
expected. Frontier molecular orbitals are expected to govern the
selectivity of this reaction and differences are found in the FMO
densities, indeed (see Table 3 for graphs of FMOs). In (1-propenyl)
amine, the HOMO (as well as
r
þ) is larger on C2, while LUMO (and
ꢁ) is larger on C1. On the other hand, in (1-propenyl)phosphine,
r
larizes the
p
cloud toward C1 (see Scheme 6).
HOMO-1 (and
r
þ) is greater on C1 (HOMO is essentially the lone
pair on phosphorous) and LUMO is larger on C2. Therefore, the FMO
reactivity indices in (1-propenyl)phosphine are opposite to those in
(1-propenyl)amine. This is the reason for opposite regioselectivity
of dipolar cycloaddition of nitrile oxides to (1-propenyl)diphenyl-
phosphine compared to enamines. It is noteworthy than in both 1-
propenyl compounds the FMO indices match the polarity predicted
by simple resonance/induction arguments (as in Scheme 6).
In the allyl systems, HOMO (or HOMO-1 in the case of allyl-
amine, where N lone pair is HOMO) is larger on C3, while LUMO is
either similar on C2 and C3 (allylphosphine) or slightly greater on C2
(allylamine). The FMO reactivity indices are therefore similar in
both allyl compounds, leading to same regioselectivity of the di-
polar addition.
H2N
δ+
H2P
δ−
+
-
H2N
Scheme 6. Effect of the heteroatom on the double bond on H2ACH]CHCH3, A¼N or P.
Standard reactivity indices (frontier molecular orbitals, Fukui
functions rþ and rꢁ, electrostatic potential) were analyzed in the

P. Bujak et al. / Tetrahedron 66 (2010) 5972e5981
5977
Table 3
Graphs of frontier MOs (on the plane perpendicular to the plane of the double bond) of model 1-propenyl dipolarophiles
3. Conclusions
4. Experimental
4.1. General
Results presented in this paper demonstrated that for all
studied N-(1-propenyl) systems (enamines, enamides, and 2-aza-
1,3-dienes) the 1,3-dipolar cycloaddition of 2,6-dichlorobenzoni-
trile oxide is a regioselective reaction. Also cycloadditions of two
other stable nitrile oxides (2,4,6-trimethyl- and 2,4,6-trimethox-
ybenzonitrile oxide) to (E)-N-(1-propenyl)phthalimide were
regioselectivedfor all N-(1-propenyl) systems exclusively 5-N-
substituted isoxazolines were obtained. Therefore this reaction can
be widely applied as a convenient method of the synthesis of 5-N-
substituted 4,5-dihydroisoxazoles. For the first time the product of
the cycloaddition of 2,6-dichlorobenzonitrile oxide to P-(1-pro-
penyl) system (diphenyl-(1-propenyl)phosphine) was also
obtained. However, the regioselectivity of this reaction was com-
pletely different from the regioselectivity of the cycloaddition of
ArCNO to N-(1-propenyl) systemsdwe have obtained 4-P-
substituted isoxazoline. Interestingly, the regioselectivity of the
cycloaddition of N-allyl system and P-allyl systems was the same
(5-substituted derivative was formed). This difference in regiose-
lectivity is predicted by opposite FMO reactivity indices calculated
for model compounds: N-(1-propenyl)amine and N-(1-propenyl)
phosphine. Furthermore, the reactivity indices for allylamine
and allylphosphine are similar, in accord with the experimental
results. Rhodium and ruthenium complexes, Verkade’s superbase
and 18-Crown-6/KOH system were used for syntheses of the N-(1-
propenyl) and P-(1-propenyl system) via isomerization of
appropriate allyl systems. Metals Scavenging agent (STREM):
phosphotungstic modified activated carbon (BASF MSA-FC) (1 g/
10 mg Ru) were used for removal of ruthenium and rhodium from
the products.
The solvents were purified and dried using standard methods.
The 1H, 13C, and 31P NMR spectra were recorded at 400, 100, and
162 MHz, respectively, on a Bruker AM 400. Low resolution mass
spectra were recorded in methanol on a Varian LC-920. HRMS
spectra were recorded in methanol on Mariner ESI-TOF (Applied
Biosystems) mass spectrometer using polyethylene glycol 400 (PEG
400) sodiated ions as internal standard. IR-spectra were recorded
on a Magna 500 Nicolet.
4.2. Allyl compounds, oximes, and isomerization catalysts
Allyl compounds 1a, 1d, and 1g and catalysts [RuCl(CO)(PPh3)3],
[Rh(CO(PPh)3]3, 2,8,9-triisopropyl-2,5,8,9-tetraza-1-phosphabicy-
clo[3.3.3]undecane, and 18-crown-6) were obtained from Aldrich.
N-allylamides (1e and 1f),40 N-allylamines (1b and 1c) 41,42 and N-
allylimines (1hem)43e45 were synthesized according to the litera-
ture. Oximes (from 2,6-dichlorobenzaldehyde, 2,4,6-trime-
thylbenzaldehyde and 2,4,6-trimethoxybenzaldehyde, Aldrich)
were prepared by methods from literature.14,22
4.3. N-(1-Propenyl) compounds
All 1-propenyl systems were prepared via isomerization of ap-
propriate allyl systems.
4.3.1. Isomerization of allyl systems 1i, 1j, and 1k to 2i, 2j, and 2k,
respectively, in the presence of [Rh] or superbase. Isomerization was

5978
P. Bujak et al. / Tetrahedron 66 (2010) 5972e5981
carried out in the screw-capped ampoules under an argon atmo-
sphere: allyl substrate, catalyst ([RhH(CO)(PPh3)3] or Verkade’s
superbase) and solvent (if necessary), were stirred for a given pe-
riod of time (reaction conditions see Table 1). After removal of the
solvent, the dipolarophile was used in the cycloaddition directly
(without removal of Rh or Verkade’s base).
CDCl3)
d
¼19.7 ppm (CH3CH), 24.1 (2ꢂ[(CH3)2CH]), 45.2 (2ꢂ
[(CH3)2CH]), 46.6 (CH3CH), 100.1 (OCHN), 157.0 (C]N), 128.2, 129.5,
132.0, 135.4 (CAr). IR (film) 3153, 2971, 2935, 2874, 2755, 2252, 1579,
1561, 1431, 1380, 1198, 1121, 909, 782, 734, 649, 542 cmꢁ1. MS (ESIþ)
m/z 329.1 [MþH]þ, HRMS (ESIþ): calcd for C16H22Cl2N2ONa
[MþNa]þ 351.1001 found 351.1017.
4.3.2. Isomerization of allyl systems 1i, 1j, 1k to 2i, 2j, 2k, re-
spectively, and diphenylallylphosphine 1m to (1-propenyl)diphenyl-
phosphine 2m in the presence of 18-crown-6/KOH. To a 1 mL 0.5 M
solution of 1i, 1j, 1k, or 1m in benzene 0.3 g of powdered KOH and
25 mg of 18-crown-6 were added. After stirring at room tempera-
ture for 24 h the mixture was washed with saturated NaCl solution.
Benzene layer was dried over anhydrous MgSO4, the solvent was
removed, and the dipolarophile was used in the cycloaddition.
Isomerization of 1aeh and 1l was reported in our previous
4.4.3. N-[3-(2,6-Dichlorophenyl)-4-methyl-4,5-dihydroisoxazol-5-yl]
urea (3c). Obtained as yellow solid (261 mg, 70%). Compound cis-
3c 1H NMR (400 MHz, CDCl3)
d
¼1.27 ppm (d, J¼7.0 Hz, 3H, CH3CH),
3.42 (q, J¼7.0 Hz, 1H, CH3CH), 5.91 (d, J¼6.0 Hz, 1H, OCHN),
7.08e7.66 (m, 3H, CAreH
13C NMR (100 MHz, CDCl3)
)
d
¼13.8 ppm
(CH3CH), 65.7 (CH3CH), 106.5 (OCHN), 152.7 (C]N), 154.2 (C]O),
126.9, 128.2, 132.8, 138.4 (CAr). Compound trans-3c 1H NMR
(400 MHz, CDCl3)
J¼7.30 Hz, 1H, CH3CH), 6.104 (d, J¼2.7 Hz, 1H, OCHN), 7.08e7.66 (m,
3H, CAreH). 13C NMR (100 MHz, CDCl3)
d
¼1.14 ppm (d, J¼7.3 Hz, 3H, CH3CH), 3.61 (q,
papers24e35
.
d¼12.4 ppm (CH3CH), 64.5
(CH3CH), 99.9 (OCHN), 153.1 (C]N), 155.4 (C]O), 124.8, 127.7,
132.4, 137.1 (CAr). IR (film) 3483, 3383, 3240, 2972, 2932, 2302, 1731,
1631, 1435, 1275, 1197, 1097, 783, 764, 699 cmꢁ1. MS (ESIþ) m/z
288.2 [MþH]þ, HRMS (ESIþ): calcd for C11H11Cl2N3O2Na [MþNa]þ
310.0126 found 310.0130.
4.4. Cycloadditions: synthesis and separation of isoxazolines
To a stirred solution of 1.3 mmol of 2,6-dichlorobenzaldoxime
in 10 mL of CH2Cl2 at room temperature was added 1.4 mmol of
solid NCS. The reaction was initiated by the addition of one drop of
concd hydrochloric acid. After stirring for 4 h, the obtained solu-
tion of 2,6-dichlorobenzohydroximoyl chloride in CH2Cl2 was
added to the isomerization product, at 0e5 ꢀC and then the solu-
tion of triethylamine (3.9 mmol) in CH2Cl2 (at 0e5 ꢀC) was added
dropwise. Triethylamine was not added only if the dipolarophile
was obtained in the presence of the superbase. The mixture was
stirred for 24 h at room temperature. The post-reaction mixture
was washed with water (3ꢂ10 ml), dried over Na2SO4, and dis-
solved in CH2Cl2 or hexane. The compounds in CH2Cl2 solutions
were separated using column chromatography on silica gel (elu-
ent: toluene or toluene/CH2Cl2). Pure and free from Ru and Rh
isoxazolines were obtained with yields given in the table. The
hexane solutions were mixed for 24 h with Metals Scavenging
agent (STREM): phosphotungstic modified activated carbon (BASF
MSA-FC) (1 g/10 mg Ru) and the ruthenium and rhodium com-
plexes were quantitatively adsorbed. After filtration the volatile
fractions were evaporated on a rotary evaporator and pure prod-
ucts were obtained.
4.4.4. N-[3-(2,6-Dichlorophenyl)-4-methyl-4,5-dihydroisoxazol-5-yl]
acetamide (3d). Obtained as yellow solid (279 mg, 75%). Compound
cis-3d 1H NMR (400 MHz, CDCl3)
d
¼1.08 ppm (d, J¼7.6 Hz, 3H,
CH3CH), 2.05 (s, 3H, CH3CO), 3.94 (dq, J¼8.2 Hz, J¼7.6 Hz,1H, CH3CH),
6.58 (d, J¼8.20 Hz, 1H, OCHN), 7.19e7.67 (m, 3H, CAreH). 13C NMR
(100 MHz, CDCl3)
d
¼8.6 ppm (CH3CH), 23.4 (CH3CO), 45.7 (CH3CH),
83.7 (OCHN), 127.8, 128.7, 132.8, 136.8, (CAr), 158.4 (C]N), 170.3 (C]
O). Compound trans-3d 1H NMR (400 MHz, CDCl3)
d¼1.26 ppm (d,
J¼7.4 Hz, 3H, CH3CH), 2.07 (s, 3H, CH3CO), 3.54 (dq, J¼4.2 Hz,
J¼7.4 Hz, 1H, CH3CH), 6.14 (d, J¼4.2 Hz, 1H, OCHN), 7.19e7.67 (m, 3H,
CAreH).13C NMR (100 MHz, CDCl3)
d
¼8.9 ppm (CH3CH), 23.3 (CH3CO),
50.6 (CH3CH), 88.2 (OCHN), 128.2, 128.9, 132.5, 136.1 (CAr), 158.7 (C]
N), 170.4 (C]O). IR (film) 3400, 3055, 2979, 2913, 2232, 1683, 1633,
1607, 1562, 1435, 1196, 1108, 912, 783, 743, 696, 543, 526 cmꢁ1. MS
(ESIþ) m/z 309.0 [MþNa]þ, HRMS (ESIþ): calcd for C12H12Cl2N2O2Na
[MþNa]þ 309.0168 found 309.0181.
4.4.5. N-[3-(2,6-Dichlorophenyl)-4-methyl-4,5-dihydroisoxazol-5-
yl]-N-(4-methylphenyl)acetamide (3e). Obtained as yellow solid
(390 mg, 80%). Compound cis-3e 1H NMR (400 MHz, CDCl3)
4.4.1. 3-(2,6-Dichlorophenyl)-N,N,4-methyl-4,5-dihydroisoxazol-5-
amine (3a). Obtained as yellow solid (266 mg, 75%). Compound cis-
d
¼1.25 ppm (d, J¼7.4 Hz, 3H, CH3CH),1.88 (s, 3H, CH3CO), 2.38 (s, 3H,
3a 1H NMR (400 MHz, CDCl3)
d
¼1.22 ppm (d, J¼7.3 Hz, 3H, CH3CH),
CH3eC6H4-), 3.53 (dq, J¼7.6 Hz, J¼7.4 Hz, 1H, CH3CH), 7.02 (d,
2.52 (s, 6H, (CH3)2N), 3.57 (dq, J¼5.8 Hz, J¼7.3 Hz, 1H, CH3CH), 5.176
J¼7.6 Hz, 1H, OCHN), 7.14e7.52 (m, 3Hþ4H, CAreH). 13C NMR
(d, J¼5.8 Hz, 1H, OCHN); 7.246e7.693 (m, 3H, CAreH). 13C NMR
(100 MHz, CDCl3)
d¼15.4 ppm (CH3CH), 21.0 (CH3eC6H4-), 23.4
(100 MHz, CDCl3)
d
¼16.2 ppm (CH3CH), 39.7 ((CH3)2N) 46.4
(CH3CO), 46.6 (CH3CH), 92.0 (OCHN), 157.20 (C]N), 168.4 (CH3CO),
(CH3CH), 106.0 (OCHN), 156.8 (C]N), 127.8, 128.2, 130.4, 135.6 (CAr).
IR (film) 3584, 3155, 2981, 2254, 1794, 1604, 1561, 1470, 1433, 1382,
1096 cmꢁ1. MS (ESIþ) m/z 273.9 [MþH]þ, HRMS (ESIþ): calcd for
C14H14Cl2N2ONa [MþNa]þ 295.0381 found 295.03459.
127.5, 128.1, 128.7, 129.3, 130.9, 135.3, 138.4, 139.1 (CAr). Compound
trans-3e 1H NMR (400 MHz, CDCl3)
d¼1.26 ppm (d, J¼7.1 Hz, 3H,
CH3CH),1.83(s, 3H,CH3CO), 2.39(s, 3H,CH3eC6H4-),3.43(q, J¼7.1 Hz,
1H, CH3CH), 7.17 (d, J¼3.6 Hz, 1H, OCHN), 7.14e7.52 (m, 3Hþ4H,
CAreH). 13C NMR (100 MHz, CDCl3)
d¼13.9 ppm (CH3CH), 20.8
4.4.2. 3-(2,6-Dichlorophenyl)-N,N-diisopropyl-4-methyl-4,5-dihy-
droisoxazol-5-amine (3b). Obtained as yellow solid (290 mg, 70%).
(CH3eC6H4-), 24.4 (CH3CO), 45.6 (CH3CH), 91.0 (OCHN),156.5 (C]N),
168.0 (CH3CO), 127.5, 128.18, 128.7, 129.75, 131.00, 135.5, 138.2, 139.2
(CAr). IR (film) 3302, 2982, 2303, 2254, 1667, 1605, 1515, 1434, 1265,
909, 735, 650 cmꢁ1. MS (ESIþ) m/z 399.0 [MþNa]þ, HRMS (ESIþ):
calcd for C19H18Cl2N2O2Na [MþNa]þ 399.0638 found 399.0634.
Compound cis-3b 1H NMR (400 MHz, CDCl3)
d¼1.07 ppm (d,
J¼6.7 Hz, 12H, 2ꢂ[(CH3)2CH]), 1.40 (d, J¼6.5 Hz, 3H, CH3CH), 3.32
(dq, J¼7.8, 6.5 Hz, 1H, CH3CH), 3.43 (septet, J¼6.7 Hz, 2H, 2ꢂ
[(CH3)2CH]), 5.42 (d, J¼7.8 Hz, 1H, OCHN); 7.208e7.690 (m, 3H,
CAreH), 13C NMR (100 MHz, CDCl3)
d
¼15.5 ppm (CH3CH), 22.62 (2ꢂ
4.4.6. N-[3-(2,6-Dichlorophenyl)-4-methyl-4,5-dihydroisoxazol-5-
[(CH3)2CH]), 45.05 (2ꢂ[(CH3)2CH]), 47.02 (CH3CH), 101.63 (OCHN),
yl]-N-1-naphthylacet-amide (3f). Obtained as red solid (501 mg,
157.551 (C]N), 127.9, 128.4, 130.6, 135.6 (CAr). Compound trans-3b
95%). Compound cis-3f 1H NMR (400 MHz, CDCl3)
d
¼1.22 ppm (d,
1H NMR (400 MHz, CDCl3)
d
¼1.15 ppm (d, J¼7.2 Hz, 12H, 2ꢂ
J¼7.4 Hz, 3H, CH3CH), 1.78 (s, 3H, CH3CO), 3.26 (dq, J¼7.1 Hz,
J¼7.4 Hz, 1H, CH3CH), 7.12 (d, J¼7.1 Hz, 1H, OCHN), 7.27e7.96 (m,
[(CH3)2CH]), 1.22 (d, J¼6.6 Hz, 3H, CH3CH); 3.44 (septet, J¼7.2 Hz,
2H, 2ꢂ[(CH3)2CH]), 3.60 (qd, J¼6.6, 2.3 Hz, 1H, CH3CH); 5.29 (d,
J¼2.3, 1H, OCHN), 7.21e7.69 (m, 3H, CAreH), 13C NMR (100 MHz,
3Hþ9H, CAreH). 13C NMR (100 MHz, CDCl3)
¼15.9 ppm (CH3CH),
d
23.0 (CH3CO), 45.7 (CH3CH), 92.5 (OCHN), 157.112 (C]N), 172.8

P. Bujak et al. / Tetrahedron 66 (2010) 5972e5981
5979
(CH3CO), 121.8, 126.6, 127.9, 128.0, 128.5, 128.6, 128.8, 129.2, 129.5,
130.9, 132.0, 134.2, 134.5 (CAr). Compound trans-3f 1H NMR
solid (360 mg, 70%). Compound cis-5h 1H NMR (400 MHz, CDCl3)
d
¼1.09 ppm (d, J¼7.3 Hz, 3H, CH3CH), 2.13 (s, 6H, 2ꢂCH3O), 2.23 (s,
(400 MHz, CDCl3)
d
¼1.55 (d, J¼6.7 Hz, 3H, CH3CH), 1.74 (s, 3H,
3H, CH3O); 3.98 (q, J¼7.3 Hz, 1H, CH3CH), 6.65 (d, J¼6.7 Hz, 1H,
CH3CO), 3.82 (dq, J¼3.20, 6.7 Hz, 1H, CH3CH); 7.215 (d, J¼3.2 Hz, 1H,
OCHN), 7.01e7.04 (m, 2Hþ4H, CAreH). 13C NMR (100 MHz, CDCl3)
OCHN), 7.27e7.96 (m, 3Hþ9H, CAreH). 13C NMR (100 MHz, CDCl3)
d
¼12.1 ppm (CH3CH), 47.6 (CH3CH), 52.1 (2ꢂCH3O), 52.9 (CH3O),
d
¼15.1 ppm (CH3CH), 22.7 (CH3CO), 41.8 (CH3CH), 93.5 (OCHN),
89.2 (OCHN), 159.8 (C]N), 162.3 (C]O), 110.2, 115.2, 122.0, 124.0,
159.1 (C]N), 168.9 (CH3CO), 122.6, 126.8, 127.1, 127.3, 128.1, 128.2,
129.5, 129.7, 130.3, 130.4, 132.9, 133.1, 134.9 (CAr). IR (film) 3018,
2952, 1674, 1431, 1381, 1306, 1284, 1216, 770, 754, 669 cmꢁ1. MS
(ESIþ) m/z 413.2 [MþH]þ, 435.1 [MþNa]þ, HRMS (ESIþ): calcd for
C22H18Cl2N2O2Na [MþNa]þ 435.0638 found 435.0648.
130.1, 131.8, 134.7 (CAr). Compound trans-5h 1H NMR (400 MHz,
CDCl3)
d
¼1.13 ppm (d, J¼7.2 Hz, 3H, CH3CH), 2.27 (s, 6H, 2ꢂCH3O),
2.31 (s, 6H, CH3O), 3.82 (qd, J¼7.2, 3.0 Hz, 1H, CH3CH), 6.37 (d,
J¼3.0 Hz, 1H, OCHN), 7.01e7.04 (m, 2Hþ4H, CAreH). 13C NMR
(100 MHz, CDCl3)
d
¼10.2 ppm (CH3CH), 48.2 (CH3CH), 51.8
(2ꢂCH3O), 52.0 (CH3O), 88.2 (OCHN), 157.6 (C]N), 163.4 (C]O),
112.1, 116.8, 123.0, 124.7, 129.8, 132.3, 135.3 (CAr). IR (film) 2987,
2856, 2281, 1772, 1698, 1489, 1387, 1367, 1137, 1054, 1025, 778,
716 cmꢁ1. MS (ESIþ) m/z 419.3 [MþNa]þ, HRMS (ESIþ): calcd for
C21H20N2O6Na [MþNa]þ 419.121190 found 419.12121.
4.4.7. N-[3-(2,6-Dichlorophenyl)-4-methyl-4,5-dihydroisoxazol-5-yl]
thiophene-2-carbox-amide (3g). Obtained as red solid (368 mg,
80%). Compound cis-3g 1H NMR (400 MHz, CDCl3)
d
¼1.29 ppm (d,
J¼7.3 Hz, 3H, CH3CH), 3.59 (q, J¼7.3 Hz, 1H, CH3CH), 6.57 (d,
J¼8.1 Hz, 1H, OCHN); 6.98e7.89 (m, 3Hþ3H, CAreH). 13C NMR
(100 MHz, CDCl3)
d
¼14.7 ppm (CH3CH), 45.7 (CH3CH), 88.7 (OCHN),
4.4.11. 3-(2,6-Dichlorophenyl)-5-(1H-imidazol-1-yl)-4-methyl-4,5-
dihydroisoxazole (3i). Obtained as yellow solid (287 mg, 75%).
158.8 (C]N), 161.5 (C]O), 128.2, 128.5, 128.6, 132.0, 132.1, 134.0,
135.3, 138.4 (CAr). Compound trans-3g 1H NMR (400 MHz, CDCl3)
Compound cis-3i 1H NMR (CDCl3)
d
¼1.25 ppm (d, J¼7.2 Hz, 3H,
d
¼1.14 ppm (d, J¼7.4 Hz, 3H, CH3CH), 3.66 (qd, J¼7.40, 3.5 Hz, 1H,
CH3CH), 6.29 (dd, J¼8.5, 3.5 Hz, 1H, OCHNH), 6.65 (d, J¼8.5 Hz, 1H,
OCHNH), 6.98e7.89 (m, 3Hþ3H, CAreH
13C NMR (100 MHz, CDCl3)
CH3CH), 5.51 (dq, J¼8.7, 7.20 Hz, 1H, CH3CH), 6.59 (dq, J¼8.7,
1.70 Hz,1H, OCHN), 7.13 (s, 1H, NCHCH), 7.29 (s, 1H, NCHCH), 7.39 (s,
)
1H, NCHN), 7.05e7.58 (m, 3H, CAr-H
¼12.5 ppm (CH3CH), 41.7 (CH3CH), 83.8 (OCHN), 154.2 (C]N),
123.5, 126.2, 127.9, 129.7, 131.0, 136.9, 137.1 (CAr). Compound trans-
3i 1H NMR (400 MHz, CDCl3)
)
13C NMR (100 MHz, CDCl3)
d
¼13.9 ppm (CH3CH), 46.4 (CH3CH), 84.2 (OCHN), 159.0 (C]N),
d
161.4 (C]O), 127.8, 128.0, 129.8, 131.6, 131.8, 135.2, 136.8, 137.64
(CAr). IR (film) 3407, 3292, 2973, 2250, 1643, 1532, 1499, 1433, 1291,
1196, 907, 731, 648 cmꢁ1. MS (ESIþ) m/z 357.2 [MþH]þ, HRMS (ESIþ):
calcd for C15H13Cl2N2O2Na [MþNa]þ 377.9972 found 377.9980.
d
¼1.37 ppm (d, J¼7.5 Hz, 3H, CH3CH),
3.92 (qd, J¼7.5, 3.7 Hz, 1H, CH3CH), 6.22 (d, J¼3.7 Hz, 1H, OCHN),
7.11 (s, 1H, NCHCH), 7.27 (s, 1H, NCHCH), 7.36 (s, 1H, NCHN),
7.05e7.58 (m, 3H, CAreH). 13C NMR (100 MHz, CDCl3)
d
¼14.8 ppm
4.4.8. 2-[3-(2,6-Dichlorophenyl)-4-methyl-4,5-dihydroisoxazol-5-
yl]-1H-isoindole-1,3(2H)-dione (3h). Obtained as yellow solid
(388 mg, 80%). Compound cis-3h 1H NMR (400 MHz, CDCl3)
(CH3CH), 52.9 (CH3CH), 92.8 (OCHN), 157.9 (C]N), 124.1, 127.7,
128.1, 129.5, 133.9, 135.6, 138.4 (CAr). IR (film) 3409, 2974, 2924,
2360, 2342, 2252, 1683, 1561, 1497, 1436, 1292, 1228, 912, 742,
649 cmꢁ1. MS (ESIþ) m/z 318.0 [MþNa]þ, HRMS (ESIþ): calcd for
C13H11Cl2N3ONa [MþNa]þ 318.0177 found 318.0178.
d
¼1.30 ppm (d, J¼7.4 Hz, 3H, CH3CH), 4.60 (dq, J¼7.8, 7.4 Hz, 1H,
CH3CH), 6.35 (d, J¼7.8 Hz, 1H, OCHN), 7.13e7.90 (m, 3Hþ4H, CAreH).
13C NMR (100 MHz, CDCl3)
d
¼15.2 ppm (CH3), 46.9 (CH3CH), 88.0
(OCHN), 158.13 (C]N), 188.7 (C]O), 123.8, 127.3, 128.4, 131.6, 134.6,
4.4.12. 3-(2,6-Dichlorophenyl)-N-[1-(2,6-dichlorophenyl)methy-
lene]-4-methyl-4,5-dihydro-isoxazol-5-amine (3j). Obtained as red
oil (417 mg, 80%). Compound cis-3j 1H NMR (400 MHz, CDCl3)
135.6, 138.2 (CAr). Compound trans-3h 1H NMR (400 MHz, CDCl3)
d
¼1.59 ppm (d, J¼6.5 Hz, 3H, CH3CH), 3.42 (q, J¼6.5 Hz, 1H, CH3CH),
5.84 (d, J¼4.7 Hz,1H, OCHN), 7.13e7.90 (m, 3Hþ4H, CAreH). 13C NMR
d
¼1.17 ppm (d, J¼7.6 Hz, 3H, CH3CH), 4.26 (dq, J¼8.6 Hz, J¼7.6 Hz,
(100 MHz, CDCl3)
d¼16.28 ppm (CH3), 41.8 (CH3CH), 79.1 (OCHN),
1H, CH3CH), 6.42 (dd, J¼8.6 Hz, J¼1.8 Hz, 1H, OCHN), 7.15e8.00 (m,
152.7 (C]N), 188.0 (C]O), 123.4, 128.0, 129.7, 131.2, 134.3, 136.0,
138.4 (CAr). IR (film) 3019, 1781, 1729, 1561, 1432, 1372, 1096, 1069,
1020, 881, 718 cmꢁ1. MS (ESIþ) m/z 376.9 [MþH]þ, HRMS (ESIþ):
calcd for C18H12Cl2N2O3Na [MþNa]þ 397.0123 found 397.0123.
3Hþ3H, CAreH), 9.11 (d, J¼1.8 Hz, 1H, CH]N). 13C NMR (100 MHz,
CDCl3)
d
¼16.2 ppm (CH3CH), 53.7 (CH3CH), 99.5 (OCHN), 156.21
(CH]N), 165.21 (C]N),128.3, 128.56, 129.2, 131.2, 131.9, 132.5,
133.4. 135.57 (CAr). Compound trans-3j 1H NMR (400 MHz, CDCl3)
d
¼1.45 ppm (d, J¼7.5 Hz, 3H, CH3CH), 3.74 (qd, J¼7.5, 2.5 Hz, 1H,
4.4.9. 2-(3-Mesityl-4-methyl-4,5-dihydroisoxazol-5-yl)-1H-iso-
indole-1,3(2H)-dione (4h). Obtained as yellow solid (316 mg, 70%).
CH3CH), 6.88 (dd, J¼2.5, 1.8 Hz, 1H, OCHN), 7.15e8.00 (m, 3Hþ7H,
CAreH). 9.16 (d, J¼1.8 Hz, 1H, CH]N). 13C NMR (100 MHz, CDCl3)
Compound cis-4h 1H NMR (400 MHz, CDCl3)
d¼1.13 ppm (d,
d
¼10.5 ppm (CH3CH), 49.2 (CH3CH), 94.5 (OCHN), 155.1 (CH]N),
J¼7.5 Hz, 3H, CH3CH), 2.27 (s, 6H, 2ꢂCH3eCAr), 2.36 (s, 3H, CH3eCAr),
4.16 (dq, J¼6.8 Hz, J¼7.5 Hz, 1H, CH3CH); 6.18 (d, J¼6.8 Hz, 1H,
OCHN), 7.59e7.79 (m, 2Hþ4H, CAreH). 13C NMR (100 MHz, CDCl3)
164.2 (C]N), 128.1, 128.8, 129.2, 131.6, 131.8, 132.4; 133.5, 135.3
(CAr). IR (film) 3286, 3082, 3015, 2982, 2885, 2226, 1653, 1581, 1560,
1431,1376,1324,1194, 1095, 924, 779, 742, 722, 645 cmꢁ1. MS (ESIþ)
m/z 403.0 [MþH]þ, 425.0 [MþNa]þ, HRMS (ESIþ): calcd for
C17H12Cl4N2ONa [MþNa]þ 422.9596 found 422.9600.
d
¼15.5 ppm (CH3CH), 19.9 (CH3eCAr), 20.3 (2ꢂCH3eCAr), 48.5
(CH3CH), 87.3 (OCHN),160.8 (C]N),166.5 (C]O),123.3,123.7,128.3,
128.8, 131.6, 134.2, 134.6 (CAr). Compound trans-4h 1H NMR
(400 MHz, CDCl3)
d
¼1.17 ppm (d, J¼7.1 Hz, 3H, CH3CH), 2.18 (s, 6H,
4.4.13. 3-(2,6-Dichlorophenyl)-N-[1-(4-methoxyphenyl)methylene]-
4-methyl-4,5-dihydro-isoxazol-5-amine (3k). Obtained as yellow
solid (400 mg, 85%). Compound cis-3k 1H NMR (400 MHz, CDCl3)
2ꢂCH3eCAr), 2.23 (s, 3H, CH3eCAr), 4.04 (qd, J¼7.1, 2.2 Hz, 1H,
CH3CH), 6.11 (d, J¼2.2 Hz, 1H, OCHN), 7.59e7.79 (m, 2Hþ4H, CAreH).
13C NMR (100 MHz, CDCl3)
d¼8.6 ppm (CH3CH), 20.6 (CH3eCAr), 20.7
d
¼1.08 ppm (d, J¼7.6 Hz, 3H, CH3CH), 3.83(CH3O), 4.16 (dq, J¼8.8,
(2ꢂCH3eCAr), 48.4 (CH3CH), 87.1 (OCHN), 161.1 (C]N),166.8 (C]O),
123.9,124.4,127.4,129.8,132.8,133.7,135.6 (CAr). IR (film) 3257, 2964,
2923, 2857, 2288, 1778, 1720, 1469, 1392, 1377, 1148, 1065, 1020, 872,
714, 628 cmꢁ1. MS (ESIþ) m/z 371.2 [MþNa]þ, HRMS (ESIþ): calcd for
C21H20N2O3Na [MþNa]þ 371.13716 found 371.13702.
7.6 Hz,1H, CH3CH), 6.28 (dd, J¼8.8,1.8 Hz,1H, OCHN), 6.92e7.83 (m,
3Hþ4H, CAreH), 8.43 (d, J¼1.8 Hz, 1H, CH]N). 13C NMR (100 MHz,
CDCl3)
d¼15.5 ppm (CH3CH), 52.7 (CH3CH), 55.6 (CH3O), 100.8
(OCHN), 158.3 (CH]N), 164.6 (C]N), 128.3, 128.6, 128.7, 130.3,
131.1, 131.9, 132.1, 135.5 (CAr). Compound trans-3k 1H NMR
(400 MHz, CDCl3)
J¼7.5, 2.8 Hz, 1H, CH3CH), 3.87 (CH3O), 5.89 (dd, J¼2.8, 1.8 Hz, 1H,
OCHN), 6.92e7.83 (m, 3Hþ4H, CAreH), 8.35 (d, J¼1.8 Hz,1H, CH]N).
d
¼1.38 ppm (d, J¼7.5 Hz, 3H, CH3CH), 3.62 (qd,
4.4.10. 2-[4-Methyl-3-(2,4,6-trimethoxyphenyl)-4,5-dihydroisox-
azol-5-yl]-1H-isoindole-1,3 (2H)-dione (5h). Obtained as yellow

5980
P. Bujak et al. / Tetrahedron 66 (2010) 5972e5981
13C NMR (100 MHz, CDCl3)
d
¼8.9 ppm (CH3CH), 48.9 (CH3CH), 55.4
found to be much more sensitive to small differences in orbital
shape than the usual isodensity surfaces.
(CH3O), 95.9 (OCHN), 157.4 (CH]N), 162.1 (C]N), 128.2, 128.4,
128.5, 130.3, 131.1, 131.9, 132.1, 135.5 (CAr). IR (film) 3348, 2945,
2832, 1685, 1606, 1450, 1431, 1030, 734, 659 cmꢁ1. MS (ESIþ) m/z
363.8 [MþH]þ, HRMS (ESIþ): calcd for C18H16Cl2N2O2Na [MþNa]þ
385.0486 found 385.0489.
Acknowledgements
This work was supported by The State Committee for Scientific
Research, Project No. N N204 272237. This work was partly sup-
ported by the Foundation for Polish Science (START scholarship for
Micha1 Krompiec). Micha1 Filapek and Micha1 Krompiec are grateful
for scholarships from the UPGOW project co-financed by the Eu-
ropean Social Fund.
4.4.14. 3-(2,6-Dichlorophenyl)-N-(2-furylmethylene)-4-methyl-4,5-
dihydroisoxazol-5-amine (3l). Obtained as yellow solid (293 mg,
70%). Compound cis-3l 1H NMR (400 MHz, CDCl3)
d¼1.10 ppm (d,
J¼7.7 Hz, 3H, CH3CH), 4.19 (dq, J¼7.7, 8.7 Hz, 1H, CH3CH), 6.35 (dd,
J¼8.7, 1.9 Hz, 1H, OCHN), 6.83e7.68 (m, 3Hþ3H, CAreH), 8.33 (d,
J¼1.9 Hz, 1H, CH]N). 13C NMR (100 MHz, CDCl3)
d¼12.5 ppm
Supplementary data
(CH3CH), 64.1 (CH3CH), 111.7 (OCHN), 154.1 (CH]N), 159.7 (C]N),
112.5, 115.0, 128.0, 128.4, 131.0, 135.0, 143.9, 144.7 (CAr). Compound
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.06.040. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
trans-3l 1H NMR (400 MHz, CDCl3)
d
¼1.38 ppm (d, J¼7.5 Hz, 3H,
CH3CH), 3.67 (qd, J¼7.5, 2.8 Hz, 1H, CH3CH), 5.93 (dd, J¼2.8, 1.8 Hz,
OCHN), 6.83e7.68 (m, 3Hþ3H, CAreH), 8.25 (d, J¼1.8 Hz,1H, CH]N).
13C NMR (100 MHz, CDCl3)
d
¼10.0 ppm (CH3CH), 63.5 (CH3CH),
111.62 (OCHN), 153.9 (CH]N), 157.7 (C]N), 113.9, 116.4, 128.0,
128.5, 131.9, 135.5, 144.9, 145.0 (CAr). IR (film) 3411, 3153, 3083,
References and notes
2886, 2252, 1650, 1561, 1432, 1195, 1018, 907, 781, 730, 649 cmꢁ1
,
1. Couti, P.; Amici, M.; Grazioso, G.; Roda, G.; Pinto, A.; Hausen, K.; Nielsen, B.;
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MS (ESIþ) m/z 323.1 [MþH]þ, HRMS (ESIþ): calcd for
D. E.; Sibille, P.; Acher, F. C.; Micheli, C. D. J. Med. Chem. 2005, 48, 6315.
C15H12Cl2N2O2Na [MþNa]þ 345.0173 found 345.0180.
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4.4.15. 3-(2,6-Dichlorophenyl)-4-(diphenylphosphino)-5-methyl-4,5-
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4. Pruitt, J. R.; Pinto, D. J.; Estrella, M. J.; Bostrom, L. L.; Knabb, R. M.; Wong, P. C.;
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Compound cis-3m 1H NMR (400 MHz, CDCl3)
d
¼1.98 ppm (ddd,
J¼6.6 Hz, JPH¼2.1 Hz, J¼1.7 Hz, 3H, CH3CHO), 6.27 (ddq,
JPH¼24.2 Hz, J¼16.8, 1.7 Hz, 1H, Ph2PCH), 6.70 (ddq, JPH¼19.2 Hz,
J¼16.8, 6.6 Hz, 1H, CH3CHO), 7.32e7.76 (m, 3Hþ10H, CAreH). 13C
NMR (100 MHz, CDCl3)
d
¼20.5 ppm (CH3CH), 45.5 (PCHCHCH3),
70.4 (PCHCHCH3), 147.9 (C]N), 128.2, 128.4, 128.5, 131.2, 131.3,
131.6, 133.9, 138.4 (CAr). 31P NMR (162 MHz, CDCl3)
¼23.3 ppm.
Compound trans-3m 1H NMR (400 MHz, CDCl3)
¼2.08 ppm (ddd,
d
10. Jiang, D.; Peng, J.; Chen, Y. Org. Lett. 2008, 10, 1695.
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11. Curran, D. P.; Scanga, S. A.; Fenk, C. J. J. Org. Chem. 1984, 49, 3474.
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19. Loeppky, R. N.; Elomari, S. J. Org. Chem. 2000, 65, 96.
J¼7.2 Hz, JPH¼3.1 Hz, J¼1.6 Hz, 3H, CH3CHO), 6.13 (ddq, JPH¼25.6 Hz,
12.8, 1.6 Hz, 1H, Ph2PCH), 6.80 (ddq, JPH¼40.3 Hz, J¼12.8, 7.2 Hz, 1H,
CH3CHO), 7.32e7.76 (m, 3Hþ10H, CAreH). 13C NMR (100 MHz,
CDCl3)
d
¼20.3 ppm (CH3CH), 52.8 (PCHCHCH3), 69.8 (PCHCHCH3),
149.6 (C]N), 128.2; 128.3, 128.5, 130.8, 131.9, 132.1, 133.6, 138.4
(CAr). 31P NMR (162 MHz, CDCl3)
d
¼38.6 ppm. IR (film) 3359, 3079,
3061, 2915, 2226, 1711, 1634, 1561, 1437, 1179, 1113, 964, 924, 912,
804, 784, 742, 696, 549 cmꢁ1. MS (ESIþ) m/z 414.1 [MþH]þ, HRMS
(ESIþ): calcd for C22H18Cl2NOPNa [MþNa]þ 436.0401 found
436.0402.
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ꢀ
25. Krompiec, S.; Suwinski, J. Pol. J. Chem. 1990, 64, 505.
NMR (400 MHz, CDCl3)
d
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26. Krompiec, S. Zesz. Nauk. Pol. Sl. s. Chem 1997, Z136.
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5.12e5.18 (m, 2H, CH2CH), 5.75e5.87 (m, 1H, CH2CH), 7.40e7.77 (m,
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d
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28. Krompiec, S.; Pigulla, M.; Bieg, T.; Szczepankiewicz, W.; Kuznik, N.; Krompiec,
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46
is partially based on GAMESS (US)
source code. Geometry opti-
mizations were done at B3LYP/6-31G(d) level. The results were
analyzed using MOLDEN.47 Orbital plots were constructed on
a plane containing the C]C bond, perpendicular to the plane de-
fined by C]CeN or C]CeP atoms, respectively. Such plots were
38. Krompiec, S.; Pigulla, M.; Krompiec, M.; Marciniec, B.; Chadyniak, J. J. Mol. Catal.
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5981
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