1,2,4-Oxadiazole 4-oxides as nitrones in 1,3-dipolar cycloaddition reactions to vinyl ethers

Article abstract of DOI:10.1002/ejoc.201101615

1,2,4-Oxadiazole 4-oxides display nitronic reactivity and selectivities identical to those of N-methyl-C-phenyl nitrone, which is a typical acyclic nitrone, affording comparable amounts of endo- and exo-5-alkoxyisoxazolidines. The exo stereoisomers undergo an easy rearrangement under the reaction conditions to yield oxadiazolinic esters. The structures of the adducts have been confirmed by X-ray structures and spectroscopic data. A donor p-methoxyphenyl at the nitronic carbon slows down the cycloaddition rate, while an acceptor p-nitrophenyl retards the rearrangement of the exo adduct. 1,2,4-Oxadiazole 4-oxides undergo 1,3-dipolar cycloaddition reactions with vinyl ethers to afford endo adducts and labile exo adducts that rearrange to oxadiazolinicesters. The structures of the isolated products were assigned on the basis of spectroscopic data and X-ray analyses. Copyright

Full text of DOI:10.1002/ejoc.201101615

FULL PAPER
DOI: 10.1002/ejoc.201101615
1,2,4-Oxadiazole 4-Oxides as Nitrones in 1,3-Dipolar Cycloaddition Reactions
to Vinyl Ethers
Paolo Quadrelli,*[a] Fabio Lunghi,[a] Bruna Bovio,[a] William Gautschi,[a] and
Pierluigi Caramella*[a]
Keywords: Heterocycles / Nitrones / Vinyl ethers / Cycloaddition / Synthesis design
1,2,4-Oxadiazole 4-oxides display nitronic reactivity and
selectivities identical to those of N-methyl-C-phenyl nitrone,
which is a typical acyclic nitrone, affording comparable
amounts of endo- and exo-5-alkoxyisoxazolidines. The exo
action conditions to yield oxadiazolinic esters. The structures
of the adducts have been confirmed by X-ray structures and
spectroscopic data. A donor p-methoxyphenyl at the nitronic
carbon slows down the cycloaddition rate, while an acceptor
stereoisomers undergo an easy rearrangement under the re- p-nitrophenyl retards the rearrangement of the exo adduct.
Introduction
1,2,4-Oxadiazole 4-oxides 1 are a family of heterocyclic
N-oxides that were prepared for the first time by Wieland
and Bauer in 1906.[1] These compounds remained largely a
chemical curiosity until very recently when further studies
on their synthesis and reactivity widened their applica-
tions.[2]
These heterocyclic N-oxides have properties that are
closely related to the chemistry of nitrile oxides 2, which
were actively studied in the past half century and provided
the first access to disubstituted 1,2,4-oxadiazole 4-oxides
carrying the same substituents (referred to herein as sym-
metrical).[3] The dimerization of 2 typically affords furoxans
3 in the absence of special additives. Under acid catalysis
[HCl in benzene or BF3 (0.5 equiv.) in hexane or benzene]
or basic catalysis (Me3N/EtOH), nitrile oxides 2 dimerize
into 1,2,4-oxadiazole 4-oxides 1. Alternatively, under
slightly different catalytic conditions (BF3 excess or pyr-
idine/EtOH), nitrile oxides 2 afford the six-membered di-
oxadiazines 4 (Scheme 1).[2] However, the more general
route to 1,2,4-oxadiazole 4-oxides 1 is based on the nitrile
oxide 2 cycloadditions to amidoximes 5, which afforded,
Scheme 1. R and RЈ stand for alkyl and/or aryl substituents. Label
A after the compound number specifies the diphenyl derivatives
described in the text; these were more extensively investigated.
(iA) BF3 (0.5 equiv.) in hexane or benzene. (iiA) Excess amount of
BF3 in hexane. (iB) Me3N in EtOH. (iiB) Pyridine (Py) in EtOH.
(iii) Benzene or methanol at room temp.
The chemistry of 1,2,4-oxadiazole 4-oxides 1 is related to
through the labile adducts 6, either the symmetrical or the the fragility of the heterocyclic ring, which undergoes a
asymmetrical (R ϶ RЈ) disubstituted 1,2,4-oxadiazole 4-ox- ready photochemical cycloreversion to nitriles and ni-
ides 1 by combining nitrile oxides 2 with amidoximes 5 car- trosocarbonyl intermediates (Scheme 2). Some authors no-
rying the same or different substituents in benzene or meth- ticed that the 1,2,4-oxadiazole 4-oxides 1 were light sensi-
anol.[4]
tive in solution, especially in the presence of triethylamine,
and had to be kept in the dark to prevent degradation to
the deoxygenated 1,2,4-oxadiazoles 7, which were always
found in old samples of 1.[5] The 1,2,4-oxadiazole 4-oxides
1 exhibit a low-frequency absorption in the UV spectra at
320–350 nm that is responsible of their photochemical be-
haviour. When degassed solutions of 1 in methanol were
exposed to sunlight or irradiated at 310 nm, smooth cleav-
[a] Dipartimento di Chimica, Università degli Studi di Pavia
Viale Taramelli 12, 27100 Pavia, Italy
Fax: +39-0382-987323
E-mail: paolo.quadrelli@unipv.it
pierluigi.caramella@unipv.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101615.
1418
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1418–1425

1,2,4-Oxadiazole 4-Oxides in 1,3-Dipolar Cycloaddition Reactions
age afforded nitriles 8 and the highly reactive nitrosocarb-
onyl intermediates 9, which could be easily and quantita-
tively trapped in situ with dienes and enes, affording a vari-
ety of hetero-Diels–Alder (HDA) adducts, such as 10, and
ene adducts, such as 11.[6] Nitrosocarbonyls are fleeting in-
termediates discovered by Kirby in the periodate oxidation
of hydroxamic acids and are very reactive dienophiles in
HDA cycloadditions.[7] They are also formed in the thermal
reversions of the HDA cycloadducts and under these non-
oxidative conditions easily enter ene reactions, too.[7b]
N-Oxide 1A behaves similarly to N-methyl-C-phenyl-
nitrone, but one of the stereoisomers undergoes an easy and
unexpected rearrangement under the reaction conditions.
Results and Discussion
Cycloadditions of 1A
N-Oxide 1A reacted smoothly with an excess (10 equiv.)
of vinyl ethers 14a,b under the same conditions as those
reported for the reaction of N-methyl-C-phenylnitrone with
ethyl vinyl ether (80 °C for 18 h in benzene). After 18 h, the
starting N-oxide 1A was fully consumed and chromato-
graphic separation afforded the cycloadducts 15a,b and the
esters 17a,b in comparable yields (Scheme 3) along with
minor amounts (10%) of 3,5-diphenyl-1,2,4-oxadiazole
(7A) derived from decomposition/deoxygenation of 1A.
Scheme 2.
The photochemical cleavage of 1,2,4-oxadiazole 4-oxides
1 represents the softest entry to the fleeting nitrosocarbonyl
intermediates and allows the study of their chemistry[8] and
the intriguing regio- and stereoselectivities of their ene reac-
tions under convenient and simple experimental condi-
tions.[9] Thermal cleavage also occurs, but requires harsher
conditions. The 1,2,4-oxadiazole 4-oxides 1 fragment neatly
in chlorobenzene (b.p. 132 °C) at reflux. In the presence of
Scheme 3.
Table 1 gives the relevant 1H and 13C NMR spectro-
an excess of cyclooctene, the ene adducts 12 were obtained scopic data that allowed structural assignments. The struc-
in excellent yields (73–87%).[10]
tures of the (6S,7aR)-6-alkoxy-3,7a-diphenyl-7,7a-dihydro-
The structure of the 1,2,4-oxadiazole 4-oxides 1 contains 6H-isoxazolo[2,3-d][1,2,4]oxadiazole cycloadducts (15a and
a fused nitrone moiety and suggests the possibility of a fur- 15b; Figure 1) were confirmed by single-crystal analyses,
ther reactivity channel of these heterocycles as nitrones. The which allowed regio- and stereochemical assignments. In
1,3-dipolar cycloadditions of nitrones have been extensively the cycloadducts, the alkoxy substituents are cis to the oxa-
investigated[11] and a few cases of nitronic reactivity of diazolinic rings and derive from endo cycloaddition of the
heteroaromatic nitrones (pyridine N-oxides and benzo de- heterocyclic nitrone. The bicyclic systems have boat-like
rivatives,[12] furoxans[13]) were reported.
shapes with the isoxazolidinic ring adopting an envelope
Herein, we report evidence of the nitronic reactivity of conformation with the flap on the side of the oxadiazolinic
3,5-diphenyl-1,2,4-oxadiazole 4-oxide (1A) and a few sym- ring. In the envelope conformation, the acetalic methine
metrically or unsymmetrically substituted derivatives in the proton is orthogonal to the adjacent trans-methylene pro-
1,3-dipolar cycloaddition to ethyl and n-butyl vinyl ethers. ton and synperiplanar to the cis one (see below). The spec-
Somewhat surprisingly, these heterocyclic N-oxides display troscopic data of 15a,b are fully consistent with this picture;
reactivity and selectivities almost identical to those of N- the acetalic methine is a doublet (J = 5 Hz) because of cou-
methyl-C-phenylnitrone, a typical, well-investigated acyclic pling with the adjacent cis protons and no coupling to the
nitrone, which affords only 5-alkoxy-substituted isoxazolid- adjacent orthogonal trans protons is observed.
ines because of the dominating influence of the
The spectroscopic data of the (R)-alkyl 2-(3,5-diphenyl-
HOMO(enol ether)–LUMO(nitrone) interaction and compar- 4,5-dihydro-1,2,4-oxadiazol-5-yl)acetate adducts 17a,b are
able amounts of the two possible stereoisomers, 13N and not consistent with the structure of a primary cycloadduct.
1
13X, derived from the endo and exo approaches.[14]
The methine proton is missing in the H and 13C NMR
Eur. J. Org. Chem. 2012, 1418–1425
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1419

P. Quadrelli, F. Lunghi, B. Bovio, W. Gautschi, P. Caramella
Table 1. Yields, physical constants and relevant NMR spectroscopic data[a] of cycloadducts 15a,b and 16a,b along with the esters 17a,b.
FULL PAPER
Yield
[%][b]
M.p. [°C]
Solvent
NMR[b]
Atom label
A
B
C
D[c]
R = OEt
15a
38 [28]
0 [15]
90–92 ethanol
80 (dec.) ethanol
97–102 ethanol
1H
13C
1H
2.95 (dd, 14; 5)
51.9
2.94 (dd, 14; 3)
51.3
3.25 (d, 15)
43.4
3.19 (d, 14)
51.9
3.34 (dd, 14; 5)
51.3
3.25 (d, 15)
43.4
5.38 (d, 5)
104.4
5.47 (dd, 5; 3)
108.0
6.32 (br. s)
/
3.31 (m)
63.7
3.62, 3.96 (m)
64.1
4.09 (q)
61.0
16a
17a
13C
1H
33 [22]
13C
R = OnBu
15b
38 [28]
0 [17]
88–90 ethanol
82 (dec.) ethanol
82–85 ethanol
1H
13C
1H
2.94 (dd, 14; 5)
51.5
2.92 (dd, 14; 3)
51.4
3.33 (d, 15)
43.4
3.18 (d, 14)
51.5
3.24 (dd, 14; 5)
51.4
3.33 (d, 15)
43.4
5.36 (d, 5)
104.3
5.45 (dd, 5; 3)
102.7
6.42 (br. s)
/
3.23 (m)
67.9
3.49, 3.58 (m)
64.9
4.12 (q)
69.4
16b
17b
13C
1H
38 [22]
13C
[a] δ, CDCl3; multiplicities and coupling constants (J in Hz) are given in parentheses. [b] The yields after 10 h at 80 °C are given in square
brackets. [c] OCH2 moiety of OR substituent.
The Labile exo Cycloadducts
Because the cis endo adducts 15a are thermally stable un-
der the reaction conditions, the likely origin of the re-
arranged adducts 17a,b is their formation from the labile
and missing (6R,7aR)-6-alkoxy-3,7a-diphenyl-7,7a-dihydro-
6H-isoxazolo[2,3-d][1,2,4]oxadiazole adducts (16a,b). Con-
trol experiments on samples withdrawn from the reaction
mixture of 1A and 14a at the beginning of the experiment
(Δ, 1 h) showed the doublet for the acetalic proton of 15a
at δ = 5.38 ppm along with a dd of comparable intensity at
δ = 5.47 ppm that was attributed to the acetalic proton of
the missing primary cycloadduct 16a. The ratio 15/16 stead-
ily increases with time and reaches 1.7:1 after heating for
10 h. By interrupting the reaction after heating for 10 h,
chromatographic separation afforded a sample of 16a in a
Figure 1. ORTEP plots of cycloadducts 15a and 15b with atom
15% yield along with unreacted 1A (20%), 15a (28%) and
17a (22%). Operating in the same way for the reaction of
1A with 14b, the primary adduct 16b could be similarly iso-
lated. Control experiments showed that the primary ad-
labelling (ellipsoids at the 25% probability level). Hydrogen atoms
are omitted for clarity, except for those of the isoxazolidinic ring.
spectra and the methylene protons appear as an AB system ducts 16a,b rearranged quantitatively to 17a,b under these
with no coupling to adjacent protons. Moreover, a broad reaction conditions (benzene, Δ, 18 h).
1
NH signal at δ = 6.3–6.4 ppm is present in the H NMR
The spectroscopic data for the labile cycloadducts 16a,b
spectra, while the OCH2 protons of the ethyl and n-butyl are similar to those of 15a,b. The only noteworthy differ-
substituents are deshielded by 0.8 ppm and fall in the typi- ence is the multiplicity of the methine protons, which ap-
cal region of ester derivatives. Accordingly, the IR spectra pear as doublets in 15a,b and double doublets in 16a,b.
of 17a show an ester absorption at 1734 cm–1 and an NH B3LYP/6-31G* calculations[15] on the model methyl deriva-
absorption at 3212 cm–1. Isomer 17b gives similar absorp- tives 15c and 16c (R = OMe) show a change in the confor-
tions. The spectroscopic data are consistent with the re- mations of the adducts, which account for the observed
arranged structures given for 17a,b.
trend (Figure 2).
1420
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1418–1425

1,2,4-Oxadiazole 4-Oxides in 1,3-Dipolar Cycloaddition Reactions
Figure 2. The lowest energy conformers of methoxy derivatives 15c (a) and 16c (b). Bold symbols indicate the atoms residing on the flap
of the isoxazolidinic envelope. Curved arrows specify the dihedral angles in degrees between the acetalic methine and the adjacent
methylene protons. The inset shows the almost parallel alignments (arrows) of the π-type pz lone pairs with the adjacent C–O bond of
15c involved in the anomeric and exo anomeric effects.
Figure 2a shows the boat-like conformer of the lowest former 5E lies at slightly higher energy. The free energy dif-
energy endo adduct 15c and labelled 5E to indicate the enve- ference is 1.1 kcalmol–1 and corresponds to a 86:14 ratio
lope conformation of the isoxazolidinic ring with the isox- of the conformers. The boat-like conformation is usually
azolidinic C-5 on the flap above the envelope plane; con- preferred in similar bicyclic systems. Fusion of cyclopen-
5
former E is essentially identical to the X-ray structures of tane to an isoxazolinic ring[17] or similar rings[18] favour
15a,b and the dihedral angles between the methine and boat-like conformations because of the relief of non-bonded
methylene protons are specified beside the curved arrows. interactions between the heterocyclic ring and the substitu-
This conformation lies in a deep minimum and other con- ents on the adjacent cyclopentane carbon atoms. In the case
formers are too high in energy (by more than 3 kcalmol–1) of 15c, the conformational preference for the boat is re-
to contribute to the coupling constants. The remarkable sta- lieved by anomeric and exo anomeric effects, which ef-
5
1
bility of the lowest energy conformer E can be ascribed ficiently stabilize conformer E, whereas the boat-like con-
to anomeric and exo anomeric effects,[16] which involve the former 5E maintains only the exo anomeric stabilization. In
stabilizing interactions of the π-type pz lone pairs of the the more abundant conformer 1E, the methine and adjacent
ring and chain oxygen atoms with the neighbouring σ* C– trans-methylene proton are still almost orthogonal, whereas
5
O bonds, as depicted in the inset of Figure 2. The almost in the minor conformer E they are in an antiperiplanar
parallel alignments of the pz lone pairs with the adjacent arrangement and contribute to the larger trans coupling
σ* C–O bonds constrain the exocyclic methoxy group in an constants of 16a,b as a weighted average of the couplings
axial position and the O–R bond in a gauche relationship of the two conformers.
to the C–O bond of the envelope.
In the labile exo cycloadducts 16a,b, the methine protons
Figure 2b shows the two lowest energy conformers of the face the –O–N=C(Ph) moiety of the oxadiazolinic ring and
exo adduct 16c. The preferred conformer is 1E, in which the this proximity could induce easy thermal rearrangements.
flap of the isoxazolidinic envelope involves the ring oxygen A likely mechanism for the rearrangement is the retro-ene
atom and the bicyclic system is twisted, and a boat-like con- reaction depicted in Scheme 4 to yield the tautomers 18a,b
Eur. J. Org. Chem. 2012, 1418–1425
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1421

P. Quadrelli, F. Lunghi, B. Bovio, W. Gautschi, P. Caramella
FULL PAPER
of the ester 17a,b. The driving force of the reaction can be Table 2. Yields of products in the cycloadditions of 19a–f to vinyl
ethyl ether.
attributed to the cleavage of a weak N–O bond and the
formation of a strong C=O bond.
3-Ar
5-ArЈ
Yield [%]
20 21 22
7
20/21 + 22
19a p-MeOC6H4 p-MeOC6H4
6
–
10 60
0.6
1.15
2
1.5
1.2
1.93
19b p-NO2C6H4 p-NO2C6H4 39 10 24 15
19c p-MeOC6H4
19d p-NO2C6H4
Ph
Ph
28
36
–
–
–
8
14 20
24 15
10 65
19e
19f
Ph
Ph
p-MeOC6H4 12
p-NO2C6H4 29
7
20
Scheme 4.
The most striking features of Table 2 are the low yields
of adducts 20 and 22 in the reactions of the 5-(p-meth-
oxyphenyl) derivatives 19a,e, which afford mainly the oxadi-
azoles 7a,e, and the presence of significant amounts of the
unrearranged adducts 21 in the case of the 5-(p-nitrophenyl)
derivatives 19b,f. The low yields of adducts in the reactions
of 19a,e, in which the donor aryl group is attached to the
nitronic carbon atom, can be attributed to a decrease
of the cycloaddition rate with respect to deoxygenation be-
cause the 5-donor aryl should decrease the electro-
philicity of the nitronic carbon atom and then influence the
HOMO(enol ether)–LUMO(nitrone) interaction. The effect of
the 5-acceptor aryl in the case of 19b,f instead indicates a
decrease in the rearrangement rate of adducts 21b,f; this is
presumably of inductive origin.
The stereoselectivity of the cycloadditions is also affected
by the aryl substituents, as shown by the last column of
Table 2, which gives the endo/exo ratios as 20/(21 + 22). In
all cases, comparable amounts of endo and exo products are
formed and the stereoselectivity ranges from 2:1 to 1:2.
In summary, 1,2,4-oxadiazole 4-oxides (1) easily enter
1,3-dipolar cycloadditions with enol ethers under condi-
tions similar to those of N-methyl-C-phenylnitrone. Various
furoxans 3 similarly enter cycloaddition reactions under
slightly more forcing conditions (boiling toluene).[13] This
stands in marked contrast to heteroaromatic N-oxides de-
rived from pyridine N-oxides. In cycloadditions with ethyl
crotonate, isoquinoline N-oxide and phenanthridine N-ox-
ide are less reactive than N-methyl-C-phenylnitrone by 820-
and 420-fold, respectively, and the reduced reactivity may
be in part attributed to the loss of aromaticity in the cyclo-
addition transition state.[12c] The 1,2,4- and 1,2,5-oxadi-
azoles display, however, reduced aromaticity[20] and the loss
of aromaticity in the cycloadditions should become less de-
manding.
Retro-ene reactions have broad applications in synthe-
sis.[19] The best-known retro-ene reaction is perhaps the
ready thermal decarboxylation of β-keto acids, which af-
fords CO2 and the enol tautomer of the ketone. Other use-
ful retro-ene reactions are known and include various re-
lated elimination reactions, such as the Cope elimination of
N-oxides and sulfoxide and selenoxide eliminations.
Other Cycloadditions
To ascertain the possible role of the substituents of 1,2,4-
oxadiazole 4-oxides on the reaction outcome in cycload-
ditions to vinyl ethyl ether, we have briefly examined the
reactions of the symmetrical 1,2,4-oxadiazole 4-oxides
19a,b with p-methoxyphenyl and p-nitrophenyl groups as
donor and acceptor aryls, respectively. We have also tested
the reactions of a few unsymmetrical 1,2,4-oxadiazole-4-
oxides 19c,d and 19e,f, in which donor and acceptor aryls
replace the phenyls in the 3- and 5-positions, respectively
(Scheme 5).
Scheme 5.
Conclusions
The cycloadditions were performed under the same con-
Symmetrical 1,2,4-oxadiazole 4-oxide 1A underwent
ditions already described and the reaction mixtures were smooth 1,3-dipolar cycloaddition reactions with vinyl
submitted to chromatographic separation to afford prod- ethers at 80 °C in benzene to afford endo adducts and oxa-
ucts 20–22 in variable amounts along with the deoxy- diazolinic esters, which derived from an easy rearrangement
genated oxadiazoles 7a–f. The structures of the isolated ad- of the exo adducts. The labile exo cycloadducts could be
ducts were determined by spectroscopic characterization isolated and the structures of the products were assigned on
and were similar to those of adducts 15–18 already de- the basis of the spectroscopic data as well as X-ray analyses.
scribed; Table 2 reports the product distributions.
Sizeable substituent effects on the reaction outcome derived
1422
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1418–1425

1,2,4-Oxadiazole 4-Oxides in 1,3-Dipolar Cycloaddition Reactions
(t, J = 7 Hz, 3 H, CH3), 1.17 (m, 2 H, CH2), 1.32 (m, 2 H, CH2),
2.94 (dd, J = 14, 5 Hz, 1 H, CH-H), 3.18 (d, J = 14 Hz, 1 H, HC-
H), 3.23 (m, 2 H, O-CH2), 5.36 (d, J = 5 Hz, 1 H, O-CH-O), 7.41
(m, 6 H, arom.), 7.71 (m, 2 H, arom.), 8.01 (m, 2 H, arom.) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 13.3, 18.5, 30.7, 51.5, 67.9,
104.3, 106.3, 125.0, 125.3, 127.1, 128.0, 128.1, 128.2, 130.2, 139.2,
158.4 ppm. C20H22N2O3 (338.39): calcd. C 70.99, H 6.55, N 8.28;
found C 71.0, H 7.0, N 8.1.
mainly from substitutions at the nitronic carbon atom. Re-
placement of the phenyl group at the nitronic carbon atom
with a p-methoxyphenyl group slowed down the cycload-
dition rate, whereas an acceptor p-nitrophenyl group re-
tarded the rearrangement of the exo adducts.
Experimental Section
Compound 17b: 0.27 g (38%). M.p. 82–85 °C from ethanol. IR: ν
˜
= 3209 (NH), 1736 (C=O) cm–1. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 0.96 (t, J = 7 Hz, 3 H, CH3), 1.35 (m, 2 H, CH2), 1.59
(m, 2 H, CH2), 3.33 (AB syst., JAB = 15 Hz, 2 H, CH2), 4.12 (m,
2 H, O-CH2), 6.42 (s, 1 H, NH), 7.59 (m, 6 H, arom.), 7.74 (m, 2
H, arom.), 7.88 (m, 2 H, arom.) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 13.5, 18.8, 30.2, 43.4, 64.9, 98.1, 125.4, 125.5, 126.4,
128.3, 128.6, 128.7, 130.9, 140.3, 155.6, 170.4 ppm. C20H22N2O3
(338.39): calcd. C 70.99, H 6.55, N 8.28; found C 70.9, H 6.7, N
8.2.
General: Elemental analyses were performed on a C. Erba 1106
elemental analyzer. IR spectra (Nujol mulls) were recorded on an
1
FTIR Perkin–Elmer RX-1 instrument. H and 13C NMR spectra
were recorded on a Bruker AVANCE 300 spectrometer in the speci-
fied deuterated solvents. Chemical shifts are expressed in ppm from
internal tetramethylsilane (δ). Column chromatography and TLC
were performed on silica gel 60 (0.063–0.200 mm) (Merck) with
cyclohexane/ethyl acetate from 9:1 to 5:5 as the eluant. The identifi-
cation of samples from different experiments was secured by mixed
melting points and superimposable IR spectra.
Upon reducing the reaction time to 10 h, in addition to unreacted
1A (18%) and the adducts 15b (30%) and 17b (20%) previously
described, the exo adduct 16b (17%) was isolated and charac-
Materials: 3,5-Diphenyl-1,2,4-oxadiazole 4-oxide (1A) and the
1,2,4-oxadiazole 4-oxides 19a–f were prepared according to pub-
lished procedures.[4b]
terized. 0.12 g (17%). IR: ν = 1652 (C=N) cm–1. 1H NMR
˜
(300 MHz, CDCl3, 25 °C): δ = 1.01 (t, J = 7 Hz, 3 H, CH3), 2.92
(dd, J = 14, 3 Hz, 1 H, CH-H), 3.24 (dd, J = 14, 5 Hz, 1 H, HC-
H), 3.49 and 3.58 (m, 1 H, 1 H, O-CH2), 5.45 (dd, J = 5, 3 Hz, 1
H, O-CH-O), 7.42 (m, 6 H, arom.), 7.70 (m, 2 H, arom.), 8.03 (m,
2 H, arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 19.4,
51.4, 64.9, 102.7, 125.8, 126.1, 128.1, 128.3, 128.6, 128.7, 129.0,
131.1, 158.5 ppm. C20H22N2O3 (338.39): calcd. C 70.99, H 6.55, N
8.28; found C 71.0, H 6.6, N 8.3.
Cycloadditions of 1A with Vinyl Ethers 14a,b: N-Oxide 1A (500 mg,
2.1 mmol) was heated along with the vinyl ethers 14a,b (10 equiv.)
in closed vessels kept at 80 °C over a 18 h period in stirred solutions
in benzene (15 mL), up to complete disappearance of the starting
heterocycle. After evaporation of the solvent and excess vinyl ether
under reduced pressure, the residues were submitted to column
chromatography to isolate the products.
Cycloadduct 15a: 0.25 g (38%). M.p. 90–92 °C from ethanol. IR: ν
˜
= 1654 (C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.99
(t, J = 7 Hz, 3 H, CH3), 2.95 (dd, J = 14, 5 Hz, 1 H, CH-H), 3.19
(d, J = 14 Hz, 1 H, HC-H), 3.31 (m, 2 H, O-CH2), 5.38 (d, J =
5 Hz, 1 H, O-CH-O), 7.49 (m, 6 H, arom.), 7.71 (m, 2 H, arom.),
8.02 (m, 2 H, arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 14.4, 51.9, 63.7, 104.4, 106.7, 125.4, 125.7, 127.4, 128.4, 128.5,
128.6, 130.7, 139.6, 159.1 ppm. C18H18N2O3 (310.13): calcd. C
69.66, H 5.85, N 9.03; found C 69.6, H 5.9, N 9.1.
Cycloadditions of 19a–f with Ethyl Vinyl Ether: 3,5-Aryl-1,2,4-oxa-
diazole 4-oxides 19a–f (500 mg) were heated with ethyl vinyl ether
(10 equiv.) in closed vessels kept at 80 °C over a 18 h period in
stirred solutions in benzene (15 mL). After evaporation of the sol-
vent and excess vinyl ether under reduced pressure, the residues
were submitted to column chromatography to isolate the products.
Cycloadduct 20a: 0.04 g (6%). Thick oil. IR: ν = 1660 (C=N) cm–1.
˜
1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.99 (t, J = 7 Hz, 3 H,
CH3), 2.93 (dd, J = 14, 5 Hz, 1 H, CH-H), 3.13 (d, J = 14 Hz, 1
H, HC-H), 3.30 (q, 2 H, O-CH2), 3.83 (s, 3 H, OCH3), 3.88 (s, 3
H, OCH3), 5.35 (d, J = 5 Hz, 1 H, O-CH-O), 6.99 (m, 4 H, arom.),
7.58 (m, 2 H, arom.), 7.94 (m, 2 H, arom.) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 14.4, 51.7, 55.2, 63.7, 104.4, 106.2,
113.5, 113.7, 113.9, 118.2, 126.8, 129.0, 131.8, 159.7, 161.4 ppm.
C20H22N2O5 (370.40): calcd. C 64.85, H 5.99, N 7.56; found C 64.8,
H 6.0, N 7.5.
Compound 17a: 0.21 g (33%). M.p. 97–102 °C from ethanol. IR: ν
˜
= 3212 (NH), 1734 (C=O) cm–1. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 1.14 (t, J = 7 Hz, 3 H, CH3), 3.25 (AB syst., JAB
=
15 Hz, 2 H, CH2), 4.09 (q, 2 H, O-CH2), 6.32 (s, 1 H, NH), 7.46
(m, 6 H, arom.), 7.65 (m, 2 H, arom.), 7.79 (m, 2 H, arom.) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 13.8, 43.4, 61.0, 98.1,
125.4, 125.6, 126.4, 128.3, 128.6, 128.7, 130.9, 140.3, 155.6,
170.3 ppm. C18H18N2O3 (310.13): calcd. C 69.66, H 5.85, N 9.03;
found C 69.7, H 5.8, N 9.0.
Compound 22a: 0.06 g (10%). oil. IR: ν = 3329 (NH), 1731 (C=O),
˜
1686 (C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.14 (t,
J = 7 Hz, 3 H, CH3), 3.19 (AB syst., J = 16 Hz, 1 H, CH2), 3.80
(s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.06 (q, 2 H, O-CH2), 6.28
(s, 1 H, NH), 6.93 (m, 2 H, arom.), 6.99 (m, 2 H, arom.), 7.56 (m, 2
H, arom.), 7.69 (m, 2 H, arom.) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 13.9, 43.2, 55.2, 55.3, 60.9, 97.7, 107.7, 113.5, 113.7,
114.0, 117.7, 127.1, 127.9, 132.6, 159.8, 161.5, 170.4 ppm.
C20H22N2O5 (370.40): calcd. C 64.85, H 5.99, N 7.56; found C 65.0,
H 6.0, N 7.6.
Upon reducing the reaction time to 10 h, in addition to unreacted
1A (20%) and the adducts 15a (28%) and 17a (22%) previously
described, the exo adduct 16a (15%) was isolated and fully charac-
terized. 0.10 g (15%). IR: ν = 1653 (C=N) cm–1. 1H NMR
˜
(300 MHz, CDCl3, 25 °C): δ = 1.33 (t, J = 7 Hz, 3 H, CH3), 2.94
(dd, J = 14, 3 Hz, 1 H, CH-H), 3.34 (dd, J = 14, 5 Hz, 1 H, HC-
H), 3.62 and 3.96 (m, 1 H, 1 H, O-CH2), 5.47 (dd, J = 5, 3 Hz, 1
H, O-CH-O), 7.45 (m, 6 H, arom.), 7.56 (m, 2 H, arom.), 8.25 (m,
2 H, arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 15.1,
51.3, 64.1, 108.0, 126.1, 127.5, 128.1, 128.3, 128.6, 128.7, 129.0,
130.9, 158.3 ppm. C18H18N2O3 (310.13): calcd. C 69.66, H 5.85, N
9.03; found C 69.6, H 5.7, N 9.1.
Cycloadduct 20b: 0.24 g (39%). Thick oil. IR:
ν = 1605
˜
1
(C=N) cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 0.97 (t, J =
7 Hz, 3 H, CH3), 2.91 (dd, J = 14, 5 Hz, 1 H, CH-H), 3.30 (m, 2
H, O-CH2), 3.22 (d, J = 14 Hz, 1 H, HC-H), 5.44 (d, J = 5 Hz, 1
H, O-CH-O), 7.87 (m, 2 H, arom.), 8.18 (m, 2 H, arom.), 8.31 (m,
Cycloadduct 15b: 0.27 g (38%). M.p. 88–90 °C from ethanol. IR: ν
˜
= 1688 (C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.77
Eur. J. Org. Chem. 2012, 1418–1425
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1423

P. Quadrelli, F. Lunghi, B. Bovio, W. Gautschi, P. Caramella
FULL PAPER
4 H, arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 14.3,
52.0, 64.2, 104.6, 107.2, 123.9, 124.0, 126.5, 128.2, 131.1, 145.7,
148.1, 149.0, 157.8 ppm. C18H16N4O7 (400.34): calcd. C 54.00, H
4.03, N 13.99; found C 54.1, H 4.0, N 13.5.
(t, J = 7 Hz, 3 H, CH3), 2.95 (dd, J = 14, 5 Hz, 1 H, CH-H), 3.15
(d, J = 14 Hz, 1 H, HC-H), 3.29 (m, 2 H, O-CH2), 3.84 (m, 3 H,
OCH3), 5.36 (d, J = 5 Hz, 1 H, O-CH-O), 6.95 (m, 2 H, arom.),
7.47 (m, 3 H, arom.), 7.60 (m, 2 H, arom.), 7.99 (m, 2 H,
arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 14.3, 51.6,
55.2, 63.7, 104.4, 107.9, 113.5, 113.8, 114.4, 126.8, 127.4, 128.1,
128.4, 128.7, 128.8, 129.2, 130.0, 130.6, 132.8, 159.1 ppm.
C19H20N2O4 (340.37): calcd. C 67.04, H 5.92, N 8.23; found C 67.1,
H 5.9, N 8.4.
Cycloadduct 21b: 0.06 g (10%). M.p. 115–117 °C from ethanol. IR:
ν = 1609 (C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
˜
1.35 (t, J = 7 Hz, 3 H, CH3), 2.94 (dd, J = 14, 2 Hz, 1 H, CH-H),
3.38 (dd, J = 14, 5 Hz, 1 H, HC-H), 3.65 and 3.98 (m, 2 H, O-
CH2), 5.49 (dd, J = 5, 2 Hz, 1 H, O-CH-O), 8.00 (m, 2 H, arom.),
8.12 (m, 2 H, arom.), 8.30 (m, 4 H, arom.) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 15.0, 51.6, 64.2, 102.4, 108.4, 123.7,
123.9, 127.3, 128.3, 131.1, 144.5, 148.3, 149.1, 156.9 ppm.
C18H16N4O7 (400.34): calcd. C 54.00, H 4.03, N 13.99; found C
54.0, H 4.1, N 13.8.
Compound 22e: 0.06 g (10%). M.p. 165–168 °C from ethanol. IR:
1
ν = 1613 (C=N), 1739 (C=O) cm–1. H NMR (300 MHz, CDCl ,
˜
3
25 °C): δ = 1.17 (t, J = 7 Hz, 3 H, CH3), 3.23 (AB syst., 1 H, CH2),
3.83 (s, 3 H, OCH3), 4.08 (q, 2 H, O-CH2), 6.29 (s, 1 H, NH), 6.93
(m, 2 H, arom.), 7.47 (m, 3 H, arom.), 7.58 (m, 2 H, arom.), 7.78
(m, 2 H, arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 13.9,
43.0, 55.2, 61.0, 113.6, 114.4, 125.4, 126.3, 127.1, 127.4, 128.7,
130.0, 130.8 155.6, 159.9, 170.4 ppm. C19H20N2O4 (340.37): calcd.
C 67.04, H 5.92, N 8.23; found C 67.0, H 6.0, N 8.2.
Compound 22b: 0.15 g (24%). oil. IR: ν = 1654 (C=N) cm–1. 1H
˜
NMR (300 MHz, CDCl3, 25 °C): δ = 1.19 (t, J = 7 Hz, 3 H, CH3),
3.25 (AB syst., J = 16 Hz, 1 H, CH2), 4.12 (q, 2 H, O-CH2), 6.52
(s, 1 H, NH), 7.84 (m, 2 H, arom.), 7.94 (m, 2 H, arom.), 8.32 (m,
4 H, arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 13.8,
43.4, 61.7, 98.2, 123.7, 124.0, 126.7, 127.4, 130.8, 147.2, 148.1,
149.1, 154.1, 169.7 ppm. C18H16N4O7 (400.34): calcd. C 54.00, H
4.03, N 13.99; found C 54.1, H 4.2, N 13.9.
Cycloadduct 20f: 0.18 g (29%). M.p. 113–116 °C from ethanol. IR:
ν = 1601 (C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
˜
0.98 (t, J = 7 Hz, 3 H, CH3), 2.87 (dd, J = 14, 5 Hz, 1 H, CH-H),
3.21 (d, J = 14 Hz, 1 H, HC-H), 3.29 (m, 2 H, O-CH2), 5.41 (d, J
= 5 Hz, 1 H, O-CH-O), 7.50 (m, 3 H, arom.), 7.88 (m, 2 H, arom.),
7.99 (m, 2 H, arom.), 8.30 (m, 2 H, arom.) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 14.3, 52.1, 64.0, 104.4, 105.9, 123.8,
125.0, 126.5, 127.5, 128.6, 131.0, 146.5, 148.0, 159.2 ppm.
C18H17N3O5 (355.34): calcd. C 60.84, H 4.82, N 11.83; found C
60.7, H 4.7, N 11.9.
Cycloadduct 20c: 0.18 g (28%). M.p. 88–90 °C from ethanol. IR: ν
˜
= 1610 (C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.00
(t, J = 7 Hz, 3 H, CH3), 2.93 (dd, J = 14, 5 Hz, 1 H, CH-H), 3.16
(d, J = 14 Hz, 1 H, HC-H), 3.30 (m, 2 H, O-CH2), 3.88 (m, 3 H,
OCH3), 5.36 (d, J = 5 Hz, 1 H, O-CH-O), 6.98 (m, 2 H, arom.),
7.41 (m, 3 H, arom.), 7.68 (m, 2 H, arom.), 7.94 (m, 2 H,
arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 14.4, 52.0,
55.3, 63.7, 104.3, 106.3, 113.9, 118.1, 125.4, 128.5, 128.6, 129.1,
139.7, 158.8, 161.4 ppm. C19H20N2O4 (340.37): calcd. C 67.04, H
5.92, N 8.23; found C 67.0, H 6.0, N 8.2.
Cycloadduct 21f: 0.05 g (8%). M.p. 82–85 °C from ethanol. IR: ν
˜
= 1608 (C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.34
(t, J = 7 Hz, 3 H, CH3), 2.89 (dd, J = 14, 2 Hz, 1 H, CH-H), 3.20
(d, J = 14 Hz, 1 H, HC-H), 3.63 and 3.98 (m, 2 H, O-CH2), 5.49
(dd, J = 5, 2 Hz, 1 H, O-CH-O), 7.50 (m, 3 H, arom.), 7.94 (m, 2
H, arom.), 7.98 (m, 2 H, arom.), 8.25 (m, 2 H, arom.) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 15.0, 51.5, 64.0, 102.4, 104.4,
123.5, 123.8, 126.5, 127.4, 127.5, 128.6, 128.7, 128.9, 129.1, 131.0,
131.2, 145.3, 146.5, 158.2 ppm. C18H17N3O5 (355.34): calcd. C
60.84, H 4.82, N 11.83; found C 60.8, H 4.8, N 11.7.
Compound 22c: 0.09 g (14%). M.p. 98–102 °C from ethanol. IR: ν
˜
= 3252 (NH), 1732 (C=O), 1614 (C=N) cm–1. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 1.12 (t, J = 7 Hz, 3 H, CH3), 3.21 (AB syst., J
= 17 Hz, 1 H, CH2), 3.83 (s, 3 H, O-CH3), 4.05 (q, 2 H, O-CH2),
6.33 (s, 1 H, NH), 6.93 (m, 2 H, arom.), 7.38 (m, 3 H, arom.), 7.66
(m, 4 H, arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 13.8,
43.5, 55.3, 61.0, 97.8, 108.3, 113.8, 117.7, 125.5, 127.3, 128.0, 128.3,
128.6, 130.2, 140.6, 155.4, 170.2 ppm. C19H20N2O4 (340.37): calcd.
C 67.04, H 5.92, N 8.23; found C 67.1, H 5.9, N 8.3.
Compound 22f: 0.04 g (7%). Thick oil. IR: ν = 3338 (NH), 1730
˜
1
(C=O), 1602 (C=N) cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ
= 1.16 (t, J = 7 Hz, 3 H, CH3), 3.24 (AB syst., 1 H, CH2), 4.09 (q,
2 H, O-CH2), 6.45 (s, 1 H, NH), 7.49 (m, 3 H, arom.), 7.84 (m, 2
H, arom.), 7.93 (m, 2 H, arom.), 8.26 (m, 2 H, arom.) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 13.8, 43.5, 61.5, 97.2, 109.1,
123.3, 123.5, 128.5, 129.0, 131.2, 133.3, 147.7, 148.0, 155.6,
169.8 ppm. C18H17N3O5 (355.34): calcd. C 60.84, H 4.82, N 11.83;
found C 60.9, H 4.8, N 11.8.
Cycloadduct 20d: 0.23 g (36%). M.p. 97–99 °C from ethanol. IR: ν
˜
= 1654 (C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.98
(t, J = 7 Hz, 3 H, CH3), 2.97 (dd, J = 14, 5 Hz, 1 H, CH-H), 3.21
(d, J = 14 Hz, 1 H, HC-H), 3.31 (m, 2 H, O-CH2), 5.40 (d, J =
5 Hz, 1 H, O-CH-O), 7.41 (m, 3 H, arom.), 7.68 (m, 2 H, arom.),
8.19 (m, 2 H, arom.), 8.33 (m, 2 H, arom.) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 14.4, 51.9, 63.9, 104.6, 108.0, 123.8,
125.2, 128.1, 128.6, 128.9, 131.8, 138.8, 148.8, 157.7 ppm.
C18H17N3O5 (355.34): calcd. C 60.84, H 4.82, N 11.83; found C
60.8, H 4.8, N 11.5.
CCDC-764733 (for 15a) and -764734 (for 15b) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Compound 22d: 0.15 g (24%). M.p. 203–205 °C from ethanol. IR:
Supporting Information (see footnote on the first page of this arti-
cle): Crystallographic data and bond lengths, angles and torsion
angles of cycloadducts 15a and 15b. Cartesian coordinates of com-
pounds 15c and 16c reported in Figure 2.
1
ν = 1611 (C=N), 1736 (C=O) cm–1. H NMR (300 MHz, CDCl ,
˜
3
25 °C): δ = 1.16 (t, J = 7 Hz, 3 H, CH3), 3.24 (AB syst., 1 H, CH2),
4.09 (q, 2 H, O-CH2), 6.43 (s, 1 H, NH), 7.40 (m, 3 H, arom.), 7.64
(m, 2 H, arom.), 7.95 (m, 2 H, arom.), 8.31 (m, 2 H, arom.) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 13.8, 43.5, 61.3, 99.1,
125.4, 127.3, 128.5, 129.0, 131.4, 133.1, 140.1, 149.0, 154.1,
170.1 ppm. C18H17N3O5 (355.34): calcd. C 60.84, H 4.82, N 11.83;
found C 60.7, H 4.7, N 11.8.
Acknowledgments
Financial support by the University of Pavia (Fondo d’Ateneo per
Cycloadduct 20e: 0.08 g (12%). M.p. 96–99 °C from ethanol. IR: ν
la Ricerca, FAR), Ministero dell’Università
(MIUR) (PRIN 2008, CUP F11J10000010001) and EUTICALS
e della Ricerca
˜
= 1609 (C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.98
1424
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1418–1425

1,2,4-Oxadiazole 4-Oxides in 1,3-Dipolar Cycloaddition Reactions
915–925; c) H. Seidl, R. Huisgen, R. Grashey, Chem. Ber. 1969,
102, 926–930.
[13] a) T. Shimizu, Y. Hayashi, K. Teramura, J. Org. Chem. 1983,
48, 3053–3058; b) T. Shimizu, Y. Hayashi, T. Taniguchi, K.
Teramura, Tetrahedron 1985, 41, 727–738.
[14] P. DeShong, C. M. Dicken, R. R. Staib, A. J. Freyer, S. M.
Weinreb, J. Org. Chem. 1982, 47, 4397–4403.
S.p.a. (V. le Milano, 86/88, 26900 Lodi, Italy) is gratefully acknowl-
edged. Thanks are due to Dr. Massimo Boiocchi (Centro Grandi
Strumenti, CGS) for X-ray data collection. Allocation of computer
time by CINECA (Centro Interuniversitario Nord-Est di Calcolo
Automatico) Casalecchio di Reno (Bologna) is also gratefully ac-
knowledged.
[15] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr., T.
Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pom-
elli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P.
Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich,
A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D.
Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui,
A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu,
A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J.
Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara,
M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W.
Wong, C. Gonzalez, J. A. Pople, Gaussian 03, Revision B.02,
Gaussian, Inc., Pittsburgh, PA, 2003.
[1] H. Wieland, H. Bauer, Ber. Dtsch. Chem. Ges. 1906, 39, 1480–
1488.
[2] P. Quadrelli, P. Caramella, Curr. Org. Chem. 2007, 11, 959–986.
[3] P. Caramella, P. Grünanger in 1,3-Dipolar Cycloaddition Chem-
istry (Eds.: A. Padwa), Wiley, New York, 1984, vol. 1, pp. 291–
392.
[4] a) P. Caramella, E. Cereda, Synthesis 1971, 433–434; b) P.
Quadrelli, A. Gamba Invernizzi, M. Falzoni, P. Caramella, Tet-
rahedron 1997, 53, 1787–1796.
[5] a) F. De Sarlo, A. Guarna, J. Chem. Soc. Perkin Trans. 1 1976,
1825–1827; b) P. Quadrelli, M. Mella, P. Caramella, Tetrahe-
dron Lett. 1999, 40, 797–800.
[6] P. Quadrelli, M. Mella, A. Gamba Invernizzi, P. Caramella,
Tetrahedron 1999, 55, 10497–10510.
[7] a) G. W. Kirby, Chem. Soc. Rev. 1977, 6, 1–24; b) G. E. Keck,
R. R. Webb, J. B. Yates, Tetrahedron 1981, 37, 4007–4016; c)
L. H. Dao, J. M. Dust, D. Mackay, K. N. Watson, Can. J.
Chem. 1979, 57, 1712–1719; d) S. M. Weinreb, R. R. Staib, Tet-
rahedron 1982, 38, 3087–3128; e) D. L. Boger, S. M. Weinreb,
Hetero Diels–Alder Methodology in Organic Chemistry, Aca-
demic Press, San Diego, 1987; f) W. Carruthers, Cycloaddition
Reactions in Organic Synthesis, Pergamon Press, Oxford, 1990;
[16] a) W. L. Jorgensen, L. Salem, The Organic Chemist’s Book of
Orbitals, Academic Press, New York, 1973, pp. 42–43; b) E.
Juaristi, G. Cuevas, Tetrahedron 1992, 48, 5019–5087; c)
G. R. J. Tatcher, The Anomeric Effect and Related Stereoelec-
tronic Effects, ACS Symposium Series, Washington (DC), 1993.
g) J. Streith, A. Defoin, Synthesis 1994, 1107–1117; h) P. F. [17] P. Quadrelli, R. Scrocchi, P. Caramella, A. Rescifina, A. Pip-
Vogt, M. J. Miller, Tetrahedron 1998, 54, 1317–1348.
[8] a) A. D. Cohen, B.-B. Zeng, S. B. King, J. P. Toscano, J. Am.
Chem. Soc. 2003, 125, 1444–1445; b) P. Quadrelli, R. Scrocchi,
A. Piccanello, P. Caramella, J. Comb. Chem. 2005, 7, 887–892.
[9] a) P. Quadrelli, M. Mella, A. Piccanello, S. Romano, P. Cara-
mella, J. Org. Chem. 2007, 72, 1807–1810; b) P. Quadrelli, S.
Romano, A. Piccanello, P. Caramella, J. Org. Chem. 2009, 74,
2301–2310.
erno, Tetrahedron 2004, 60, 3643–3651.
[18] a) F. G. Cocu, G. Wolczunowicz, L. Bors, T. Posternak, Helv.
Chim. Acta 1970, 53, 739–749; b) R. Steyn, H. Z. Sable, Tetra-
hedron 1971, 27, 4429–4447; c) E. L. Eliel, S. H. Wilen, Stereo-
chemistry of Organic Compounds, Wiley, New York, 1994.
[19] a) G. V. Boyd, The Chemistry of Double Bonded Functional
Groups (Ed.: S. Patai), Wiley, New York, 1989, pp. 477–525; b)
B. B. Snider, Comprehensive Organic Synthesis (Eds.: B. M.
Trost, I. Fleming), Pergamon Press, Oxford, 1991, vol. 2, pp.
527–561 and vol. 5. pp. 1–27; c) P. C. Astles, S. V. Mortlock,
E. J. Thomas, Comprehensive Organic Synthesis (Eds.: B. M.
Trost, I. Fleming), Pergamon Press, Oxford, 1991; d) for a con-
cise summary, see: I. Fleming, Pericyclic Reactions, Oxford
University Press, Oxford, 1999, pp. 84–87.
[10] P. Quadrelli, G. Campari, M. Mella, P. Caramella, Tetrahedron
Lett. 2000, 41, 2019–2022.
[11] a) J. J. Tufariello in 1,3-Dipolar Cycloaddition Chemistry (Eds.:
A. Padwa), Wiley, New York, 1984, vol. 2, pp. 83–168; b)
K. B. G. Torsell, Nitrile Oxides, Nitrones and Nitronates in Or-
ganic Synthesis, VCH, Weinheim, 1988; c) P. Grünanger, P.
Vita-Finzi, Isoxazoles, Wiley, New York, 1991, vol. 49, part 2,
pp. 649–778.
[20] A. R. Katritzky, K. Jug, D. C. Onicin, Chem. Rev. 2011, 101,
1421–1449.
[12] a) H. Seidl, R. Huisgen, R. Knorr, Chem. Ber. 1969, 102, 904–
Received: November 8, 2011
Published Online: January 20, 2012
914; b) R. Huisgen, H. Seidl, J. Wulff, Chem. Ber. 1969, 102,
Eur. J. Org. Chem. 2012, 1418–1425
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1425