Synthesis of isoxazoline derivatives through boulton-katritzky rearrangement of 1,2,4-oxadiazoles

Article abstract of DOI:10.1002/ejoc.201201308

The base-induced rearrangement of 1,2,4-oxadiazoles into isoxazoline derivatives is reported. This represents the first example of a three-atom side-chain rearrangement that involves a saturated CCO side chain at C-3 of the oxadiazole. Nonaromatic 3-amino-isoxazoline derivatives are obtained in good yields. Interestingly, this reaction occurs through the rearrangement of aromatic oxadiazoles to form less stable bonds than those that are broken. The first example of a Boulton-Katritzky Rearrangement that involves an oxadiazole ring with a saturated CCO side chain is reported. From a mechanistic point of view, the results present a new and interesting feature of this reaction. Because of the presence of a stable intermediate, this rearrangement affords nonaromatic isoxazolines.

Full text of DOI:10.1002/ejoc.201201308

FULL PAPER
DOI: 10.1002/ejoc.201201308
Synthesis of Isoxazoline Derivatives through Boulton–Katritzky Rearrangement
of 1,2,4-Oxadiazoles
Antonio Palumbo Piccionello,*[a] Annalisa Guarcello,[a] Andrea Pace,[a] and
Silvestre Buscemi[a]
Keywords: Synthetic methods / Rearrangement / Heterocycles / Aromaticity
The base-induced rearrangement of 1,2,4-oxadiazoles into
isoxazoline derivatives is reported. This represents the first
example of a three-atom side-chain rearrangement that in-
volves a saturated CCO side chain at C-3 of the oxadiazole.
Nonaromatic 3-amino-isoxazoline derivatives are obtained in
good yields. Interestingly, this reaction occurs through the
rearrangement of aromatic oxadiazoles to form less stable
bonds than those that are broken.
When Z = O, the driving force of the reaction is ascribed
to the higher stability of the heterocycle that is formed.[1]
The only reported example of a BKR that allows the forma-
tion of nonaromatic heterocycles (i.e., pyrazolines) was ac-
complished by the rearrangement of 1,2,4-oxadiazole deriv-
atives that contain a saturated CCN side chain.[5] Therefore,
in the context of our research on heterocyclic rearrange-
ments[3,4,6] and on applications of 1,2,4-oxadiazole deriva-
tives,[7] we investigated the occurrence of a BKR of oxadi-
azole 3, which contains a saturated CCO side chain at C-
3 of a 1,2,4-oxadiazole ring, to produce the nonaromatic
isoxazoline derivative 4 (see Scheme 1).
Introduction
Heterocyclic ring rearrangements have been well-docu-
mented in the literature. Among these, the Boulton–
Katritzky rearrangement (BKR) is one of the most investi-
gated ring transformation reactions because of its synthetic
applications and intriguing mechanistic features.[1,2] It con-
sists of an interconversion between two five-membered
heterocycles that involves a pivotal annular nitrogen (see
Figure 1).
Figure 1. General scheme of the BKR.
This rearrangement typically occurs with 1-oxa-2-azoles
(see Figure 1, D = O), such as isoxazoles[3] and 1,2,4-oxa-
diazoles.[4] When the nucleophilic Z atom (e.g., Z = N, S,
or C) in the side chain attacks the electrophilic N-2, the
O-1 in the ring acts as an internal leaving group, which
results in the cleavage of the O–N bond. This process is
irreversible, and the driving force is due to the “leaving
group ability” of the ABD sequence and the formation of
the more stable N–N, S–N, or C–N bond that replaces the
less stable O–N bond.
Scheme 1. CCO side-chain rearrangement of 1,2,4-oxadiazole.
Results and Discussion
The selected starting oxadiazoles 3a–3j were obtained
through two different synthetic pathways (see Scheme 2).
Compounds 3a–3g were synthesized by the conventional
amidoxime route,[1b,8] which started from readily available
β-hydroxynitriles 5a–5e that were converted into the corre-
sponding amidoximes 6. The target oxadiazoles 3 were ob-
tained through a one-pot cyclization/hydrolysis process.
Notably, the pair of diastereomers syn-3e and anti-3f was
obtained by applying this procedure. However, oxadiazoles
3h–3j were easily obtained by using another synthetic route,
that is, the reduction of the corresponding ketones 7a–7c.[4a]
[a] Dipartimento di Scienze e Tecnologie Molecolari e
Biomolecolari (STEMBIO), Università degli Studi di Palermo,
Viale delle Scienze, Parco d’Orleans II, Ed. 17, 90128 Palermo,
Italy
Fax: +39-091592568
E-mail: antonio.palumbopiccionello@unipa.it
Homepage: www.unipa.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201308
1986
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1986–1992

Isoxazoline Derivatives through Boulton–Katritzky Rearrangement
Table 1. Products distribution for the reaction of oxadiazole 3a in
the presence of different solvents and amounts of base.
Entry Solvent Base (equiv.)
Conversion
4a
8a
1
2
3
4
5
6
EtOH
EtOH
EtOH
DMF
DMF
DMF
DMSO tBuOK (0.1)
DMSO tBuOK (0.1)
DMSO tBuOK (1)
DMSO tBuOK (5)
tBuOK (0.1)
tBuOK (1)
tBuOK (5)
tBuOK (0.1)
tBuOK (1)
tBuOK (5)
–
–
–
–
–
–
–
–
–
–
–
–
53
85
–
8
87
100
22
35
–
5
68
34
18
20
–
7
8[a]
9
–
[b]
–
10
18
[a] Reaction time is 72 h. [b] Trace amount identified by GC–MS.
From the data, the best reaction conditions were iden-
tified as 1 equiv. of tBuOK as the base and DMSO as the
solvent (see Table 1, Entry 8). Even if the total conversion
of the starting material was not accomplished, these were
considered the best conditions to prevent the formation of
decomposition products and minimize the competitive for-
mation of the elimination byproduct 8a.
By using these optimal conditions, we explored the gen-
erality and scope of the reaction with regard to the forma-
tion of various substituted isoxazolines 4 (see Table 2). In
all cases, the target isoxazolines 4 were obtained in good to
high yields, with the one exception of the reaction of 5-
methyl-substituted oxadiazole 3g. In this case, only the for-
mation of (E)-cinnamonitrile (75% yield) was observed.
Interestingly, in the case of the diastereomers syn-3e and
anti-3f, the rearrangement reaction occurred with the reten-
tion of configuration (syn Ǟ cis and anti Ǟ trans).
Scheme 2. Synthesis of oxadiazoles 3 (Py = pyridine).
With oxadiazoles 3 in hand, a preliminary optimization
of the reaction conditions for the BKR was performed on
representative compound 3a (see Table 1). All of the reac-
tions were performed at room temp. for 24 h, but the condi-
tions were varied by changing the solvent and base. When
the reaction was performed in EtOH, compound 3a was
unreactive, even in the presence of an excess amount of the
base (see Table 1, Entries 1–3).[9] Interestingly, when tBuOK
was used as the base and the reaction was performed in
aprotic polar solvents [i.e., N,N-dimethylformamide (DMF)
and dimethyl sulfoxide (DMSO)], isoxazoline 4a was
formed along with the elimination product 8a, but this oc-
curred only in the presence of at least a stoichiometric
amount of base (see Table 1). There was a partial conver-
sion of oxadiazole 3a into 4a with substoichiometric
amounts of base, but after a longer reaction time of 72 h
(see Table 1, Entry 8). The reactions that were performed in
apolar solvents [i.e., dichloromethane (DCM) and tetra-
hydrofuran (THF)] and other polar protic solvents (i.e.,
MeOH and iPrOH) gave the same results as those obtained
with EtOH. Using other bases such as NEt3 or K2CO3 left
the reactant unchanged. Furthermore, the reaction per-
formed in DMSO with bases stronger than tBuOK [such as
NaNH2, BuLi, and lithium diisopropylamide (LDA)] re-
Table 2. Products distribution for the reaction of oxadiazoles 3.
Reactant
R
RЈ RЈЈ
4
8
[b]
3a (17%)[a]
3b (11%)[a]
3c (9%)[a]
3d (13%)[a]
3e (12%)[a]
3f (8%)[a]
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
H
H
H
H
Et Ph
Et Ph
H
H
H
H
H
Ph
68
54
63
58
74
80
–
66
57
86
–
23
18
19
–
4-ClC6H4
4-MeOC6H4
–
3g (14%)[a]
3h (6%)[a]
3i (18%)[a]
3j (12%)[a]
Ph
–
[b]
Me
Me
Me
–
[b]
[b]
4-ClC6H4
4-MeOC6H4
–
–
[a] Recovered substrate. [b] Trace amount identified by GC–MS.
The stereochemistry of cis-4e and trans-4f isoxazolines
1
sulted in the formation of complex mixtures of decomposi- was assigned by means of H NMR experiments. We com-
tion products.
pared the coupling constant values between the H-4 and H-
Eur. J. Org. Chem. 2013, 1986–1992
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1987

A. Palumbo Piccionello, A. Guarcello, A. Pace, S. Buscemi
FULL PAPER
5 methine protons (J4,5trans Ͻ J4,5cis
)
[8] as well as their chem- Table 3. Optimized geometries and energy values (ΔE, kcal/mol)
relative to neutral species 3a[a] and to anionic species 3a–[a], calcu-
ical shifts, which are deshielded more in the cis isomer than
lated in vacuo.
in the trans isomer (see Exp. Sect.).[10]
Only in the case of oxadiazoles 3b–3d, which contain an
aryl-substituted side chain, was there formation of the eli-
mination byproducts in moderate yields. This was presum-
ably because of the formation of a conjugated styryl moiety.
However, in the case of compounds 3e and 3f, the forma-
tion of the corresponding byproducts 8 was not observed.
Probably, this was due to the steric hindrance of the side
chain. All of the isoxazolines 4 were stable under the reac-
tion conditions, which configures this BK rearrangement as
irreversible.
According to the general scheme of the BK rearrange-
ment, the base is involved in the formation of isoxazolines 4
through the initial formation of alcoholate anion 3–, which
undergoes an internal nucleophilic substitution at the piv-
otal N-2 atom of the oxadiazole ring (see Scheme 3). Pro-
tonation of intermediate 4– produces the final isoxazolines
4. From a mechanistic point of view, the formation of a
nonaromatic heterocycle through the breaking and refor-
mation of the O–N bond is unusual. The driving force of
the reaction should be ascribed to the higher stabilization
of anion 4– with respect to anion 3–, which suggests the
essential role of the stability of the involved intermediates,
instead of the nonaromaticity of the final product.[1]
[a] The energy values calculated at the B3LYP/6-311++G(d,p) level
for compounds 3a and for 3a– are –647.18163 and –646.57978 au,
respectively.
viously observed reactivity of 3-aryl-5-methyl-1,2,4-oxadi-
azole derivatives (see Scheme 4).[11] Under the same reac-
tion conditions, nitrile 5b gave cinnamonitrile (10), which
was also demonstrated by a separate experiment with 5b
(see Scheme 4).
Scheme 3. Proposed mechanism for rearrangement of compounds
3.
Scheme 4. Proposed mechanism for the reaction of compound 3g.
To address this point, we performed a computational
study at the hybrid DFT B3LYP level (see Computational
Details in the Exp. Sect.) on representative compounds 3a,
4a, and their corresponding anionic species. The results
were obtained in vacuo and are reported in Table 3. The
obtained results confirm that the formation of nonaromatic
Conclusions
In summary, we have reported the first example of a
isoxazoline 4a, which is 6.4 kcal/mol less stable with respect BKR of 1,2,4-oxadiazole derivatives 3, which contain a sat-
to the corresponding oxadiazole, is driven by the formation urated CCO side chain, to produce the 3-acylamino-isox-
of anion 4a–, which is 26.8 kcal/mol more stable than the azoline derivatives 4. This reaction is an unusual example
oxadiazolyl alcoholate 3a–.
of an irreversible rearrangement that allows the formation
A speculative mechanistic hypothesis could explain the of nonaromatic heterocycles. Considering the biological ac-
peculiar reactivity of the 5-methyl-substituted oxadiazole 3g tivity of isoxazolines[12] and the renewed interest in the syn-
on the basis of a base-induced ring opening of the oxadiaz- theses of 3-aminoisoxazolines,[13] the reported rearrange-
ole ring to occur through the fragmentation intermediate 9 ment represents a valid approach toward the synthesis of
to give β-hydroxynitrile 5b. This is analogous to the pre- highly substituted compounds. The accessibility of the pre-
1988
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Isoxazoline Derivatives through Boulton–Katritzky Rearrangement
7.31 (m, 5 H), 8.65 (s, 1 H, exch. with D2O) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 12.0, 20.3, 51.0, 73.9, 126.6, 126.8,
127.7, 144.7, 153.7 ppm. GC–MS: m/z (%) = 208 (100) [M]+.
C11H16N2O2 (208): calcd. C 63.44, H 7.74, N 13.45; found C 63.40,
H 7.75, N 13.40.
cursor, the ease of workup, and the good product yields
encourage further use of this synthetic methodology. These
results confirm the versatility of the 1,2,4-oxadiazole ring
in the preparation of new heterocyclic structures.
anti-(Z)-NЈ-Hydroxy-2-[hydroxy(phenyl)methyl]butanamidine (6f):
Oil (458 mg, 44% yield). 1H NMR (300 MHz, [D6]DMSO): δ =
0.78 (t, J = 8.1 Hz, 3 H), 1.28–1.30 (m, 1 H), 1.47–1.57 (m, 1 H),
2.07–2.15 (m, 1 H), 4.66 (d, J = 6.0 Hz, 1 H), 5.24 (s, 2 H, exch.
with D2O), 5.36 (s, 1 H, exch. with D2O), 7.16–7.31 (m, 5 H), 8.68
(s, 1 H, exch. with D2O) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 11.9, 23.1, 50.7, 74.0, 126.5, 126.8, 127.9, 144.8, 153.8 ppm. GC–
MS: m/z (%) = 208 (100) [M]+. C11H16N2O2 (208): calcd. C 63.44,
H 7.74, N 13.45; found C 63.55, H 7.60, N 13.50.
Experimental Section
General Methods: Melting points were determined with a hot-stage
apparatus. FTIR spectra were recorded with the samples as a Nujol
mull. 1H and 13C NMR spectroscopic data were recorded at the
indicated frequencies, and the residual solvent peak was used as a
reference. The peaks from the minor tautomer are given in paren-
theses. Flash chromatography was performed by using silica gel
(Merck, 0.040–0.063 mm) and mixtures of ethyl acetate and petro-
leum ether (b.p. in the range of 40–60 °C) in various ratios. All
reagents were commercially available. Compounds 5e,[14] 6a,[15] and
7a–7c[3a] were obtained as previously reported. Compounds 3a,[16]
8a,[5b] and 8b[17] were obtained by methods different from those
previously reported, and their data are consistent with the literature
data.
General Procedure for the Synthesis of Oxadiazoles 3a–3g: To a
dispersion of amidoxime 6 (2 mmol) in toluene (30 mL) were added
the appropriate acyl chloride (4 mmol) and pyridine (4 mmol,
0.32 mL), and the mixture was heated at reflux for 1 h. The solvent
was removed under reduced pressure, and to a solution of the re-
sulting residue in THF/EtOH (10:1, 20 mL) was added NaOH (1 m
solution, 5 mL). The mixture was stirred at room temperature over-
night. The solvent was then removed, and the residue was treated
with water (50 mL). The solution was neutralized with dilute HCl,
and the resulting solution was extracted with ethyl acetate (50 mL).
The organic layer was dried with Na2SO4 and filtered, and the sol-
vent was removed under reduced pressure. The obtained residue
was chromatographed to give oxadiazoles 3a–3g.
Synthesis of Amidoximes 6: To a solution of hydroxynitrile 5
(5 mmol) in EtOH (40 mL) was added a mixture of hydroxylamine
hydrochloride (10 mmol) and NaOH (8 mmol) in water (10 mL).
The mixture was heated at reflux for 1 h. The solvent was then
removed under vacuum, and the residue was treated with ethyl
acetate (100 mL). The resulting mixture was filtered, and the fil-
trate was concentrated under reduced pressure to give amidoximes
6.
2-(5-Phenyl-1,2,4-oxadiazol-3-yl)ethanol (3a): 258 mg, 68% yield;
m.p. 58–59 °C (petroleum ether); ref.[16] m.p. 58–59 °C.
(Z)-NЈ,3-Dihydroxy-3-phenylpropanimidine (6b): 738 mg, 82%
yield; m.p. 60–61 °C (petroleum ether). H NMR (300 MHz, [D6]-
1-Phenyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethanol (3b): 383 mg,
72% yield; m.p. 66–67 °C (petroleum ether). H NMR (300 MHz,
1
1
DMSO): δ = 2.25–2.29 (m, 2 H), 4.84 (br. s, 1 H), 5.50 (d, J =
3.6 Hz, 1 H, exch. with D2O), 5.38 (s, 2 H, exch. with D2O), 7.18–
7.39 (m, 5 H), 8.57 (s, 1 H, exch. with D2O) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 41.9, 71.4, 126.9, 127.9, 129.0, 146.5,
152.2 ppm. GC-MS: m/z (%) = 180 (100) [M]+. C9H12N2O2 (180):
calcd. C 59.99, H 6.71, N 15.55; found C 59.95, H 6.65, N 15.50.
CDCl3): δ = 3.30 (d, J = 6.3 Hz, 2 H), 3.58 (s, 1 H, exch. with
D2O), 5.32 (t, J = 6.3 Hz, 1 H), 7.33–7.63 (m, 8 H), 8.19–8.22 (m,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 36.1, 72.1, 124.3,
126.1, 128.3, 128.6, 129.0, 129.5, 133.4, 143.1, 169.2, 176.0 ppm.
GC–MS: m/z (%) = 266 (100) [M]+. FTIR (Nujol): ν = 3379,
˜
1608 cm–1. C16H14N2O2 (266): calcd. C 72.16, H 5.30, N 10.52;
found C 72.10, H 5.35, N 10.40.
(Z)-3-(4-Chlorophenyl)-NЈ,3-dihydroxypropanamidine (6c): 963 mg,
90% yield; m.p. 114–116 °C (petroleum ether). 1H NMR(300 MHz,
[D6]DMSO): δ = 2.25–2.41 (m, 2 H), 4.90–4.95 (m, 1 H), 5.45–5.48
(m, 3 H, exch. with D2O), 7.38–7.48 (m, 4 H), 8.83 (s, 1 H, exch.
with D2O) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 40.8, 69.7,
127.9, 128.0, 131.4, 144.5, 150.9 ppm. GC–MS: m/z (%) = 214 (100)
[M]+, 216 (32) [M + 2]+. C9H11ClN2O2 (214): calcd. C 50.36, H
5.17, N 13.05; found C 50.30, H 5.25, N 13.10.
1-(4-Chlorophenyl)-2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethanol
(3c):
1
426 mg, 71% yield; m.p. 103–105 °C (petroleum ether). H NMR
(300 MHz, CDCl3): δ = 3.19–3.22 (m, 2 H), 5.22 (dd, J1 = 7.2 Hz,
J2 = 5.4 Hz, 1 H), 7.32–7.41 (m, 4 H), 7.48–7.65 (m, 3 H), 8.09–
8.15 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 36.3, 71.6,
127.8, 128.8, 129.1, 129.4, 129.8, 130.8, 133.7, 134.2, 141.8,
169.1 ppm. GC–MS: m/z (%) = 300 (100) [M]+, 302 (34) [M + 2]+.
C16H13ClN2O2 (300): calcd. C 63.90, H 4.36, N 9.31; found C
63.85, H 4.35, N 9.40.
(Z)-3-(4-Methoxyphenyl)-NЈ,3-dihydroxypropanamidine
(6d):
1
788 mg, 75% yield; m.p. 100–102 °C (petroleum ether). H NMR
(300 MHz, [D6]DMSO): δ = 2.26–2.40 (m, 2 H), 3.78 (s, 3 H), 4.89
(br. s, 1 H), 5.29 (d, J = 3.3 Hz, 1 H, exch. with D2O), 5.44 (s, 2
H, exch. with D2O), 6.92 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.4 Hz,
2 H), 8.84 (s,1 H, exch. with D2O) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 41.0, 55.2, 70.1, 113.5, 127.2, 137.6, 151.4, 158.4,
162.1 ppm. GC–MS: m/z (%) = 210 (100) [M]+. C10H14N2O3 (210):
calcd. C 57.13, H 6.71, N 13.33; found C 57.10, H 6.70, N 13.35.
1-(4-Methoxyphenyl)-2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethanol (3d):
345 mg, 65% yield; m.p. 72–74 °C (petroleum ether). 1H NMR
(300 MHz, CDCl3): δ = 3.13–3.17 (m, 2 H), 3.74 (s, 3 H), 5.3 (t, J
= 6.4 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 2 H), 7.32 (d, J = 8.6 Hz, 2 H),
7.46–7.52 (m, 3 H), 8.05–8.10 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 29.7, 55.3, 71.4, 114.0, 123.9, 127.0, 128.2, 129.2,
132.9, 134.8, 159.3, 168.8, 175.6 ppm. GC–MS: m/z (%) = 296 (100)
[M]+. C17H16N2O3 (296): calcd. C 68.91, H 5.44, N 9.45; found C
68.85, H 5.40, N 9.60.
(Z)-NЈ-Hydroxy-2-[hydroxy(phenyl)methyl]butanamidine 6e and 6f:
The obtained residue was chromatographed to give diastereomeric
amidoximes 6e and 6f.
syn-1-Phenyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)butan-1-ol
(3e):
syn-(Z)-NЈ-Hydroxy-2-[hydroxy(phenyl)methyl]butanamidine (6e): 429 mg, 73% yield; m.p. 86–88 °C (petroleum ether). 1H NMR
Oil (416 mg, 40% yield). 1H NMR (300 MHz, [D6]DMSO): δ =
0.80 (t, 3 H, J = 8.1 Hz), 1.53–1.61 (m, 2 H), 4.68 (dd, 1 H, J1 =
6.6 Hz, J2 = 3.6 Hz), 5.24–5.28 (m, 3 H, exch. with D2O), 7.14–
(300 MHz, CDCl3): δ = 0.84 (t, J = 7.5 Hz, 3 H), 1.68–1.92 (m, 2
H), 3.21–3.27 (m, 1 H), 4.02 (br. s, 1 H, exch. with D2O), 5.15 (d,
J = 4.5 Hz, 2 H), 7.25–7.42 (m, 5 H), 7.48–7.62 (m, 3 H), 8.11–
Eur. J. Org. Chem. 2013, 1986–1992
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1989

A. Palumbo Piccionello, A. Guarcello, A. Pace, S. Buscemi
8.16 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.5, 20.7, vent was removed under reduced pressure, and the residue was
FULL PAPER
46.9, 75.5, 126.8, 128.2, 128.8, 128.9, 129.8, 130.8, 133.6, 142.2,
172.4, 176.5 ppm. GC–MS: m/z (%) = 294 (100) [M]+. C18H18N2O2
(294): calcd. C 73.45, H 6.16, N 9.52; found C 73.40, H 6.20, N
9.45.
chromatographed to give isoxazolines 4 and oxadiazoles 8.
3-(Benzoylamino)-4,5-dihydroisoxazoline (4a): 1.29 mg, 68% yield;
m.p. 165–166 °C (ethyl acetate). 1H NMR (300 MHz, [D6]DMSO):
δ = 3.54 (t, J = 9.9 Hz, 2 H), 4.35 (t, J = 9.9 Hz, 2 H), 7.54–7.67
(m, 3 H), 7.99–8.02 (m, 2 H), 11.14 (s, 1 H, exch. with D2O) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 34.8, 68.6, 128.2, 128.6,
132.4, 133.3, 155.2, 165.5 ppm. GC–MS: m/z (%) = 190 (100)
anti-1-Phenyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)butan-1-ol
(3f):
423 mg, 72% yield; m.p. 72–73 °C (petroleum ether). 1H NMR
(300 MHz, CDCl3): δ = 0.87 (t, J = 7.4 Hz, 3 H), 1.61–1.84 (m, 2
H), 3.25–3.36 (m, 1 H), 3.99 (br. s, 1 H, exch. with D2O), 5.05 (d,
J = 7.6 Hz, 2 H), 7.27–7.45 (m, 5 H), 7.47–7.63 (m, 3 H), 8.10–
[M]+. FTIR (Nujol): ν = 3255, 1683, 1624, 1583 cm–1. C H N O
˜
10 10
2
2
(190): calcd. C 63.15, H 5.30, N 14.73; found C 63.10, H 5.35, N
8.19 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.3, 24.4, 14.60.
47.2, 76.3, 127.0, 128.6, 128.9, 129.2, 129.8, 130.8, 133.5, 142.7,
3-(Benzoylamino)-5-phenyl-4,5-dihydroisoxazoline (4b): 144 mg,
171.6, 176.4 ppm. GC–MS: m/z (%) = 294 (100) [M]+. C18H18N2O2
(294): calcd. C 73.45, H 6.16, N 9.52; found C 73.55, H 6.10, N
9.35.
54% yield; m.p. 133–134 °C (ethyl acetate). 1H NMR (300 MHz,
CDCl3): δ = 3.82 (dd, J1 = 18.0 Hz, J2 = 8.7 Hz, 1 H), 4.23 (dd, J1
= 18.0 Hz, J2 = 10.5 Hz, 1 H), 5.78 (dd, J1 = 10.5 Hz, J2 = 8.7 Hz,
1 H), 7.41–7.68 (m, 8 H), 7.98–8.01 (m, 2 H), 9.51 (s, 1 H, exch.
2-(5-Methyl-1,2,4-oxadiazol-3-yl)-1-phenylethanol (3g): 229 mg,
1
56% yield; m.p. 97–98 °C (petroleum ether). H NMR (300 MHz, with D2O) ppm. 13C NMR (75 MHz, CDCl3): δ = 42.6, 82.9, 126.3,
CDCl3): δ = 2.16 (s, 3 H), 2.90 (d, J = 6.0 Hz, 2 H), 5.98 (t, J =
128.1, 128.7, 129.1, 129.3, 133.0, 133.2, 140.6, 155.0, 165.7 ppm.
6.0 Hz, 1 H), 7.40 (br. s, 5 H) ppm. 13C NMR (75 MHz, CDCl3): GC–MS: m/z (%) = 266 (100) [M]+. C16H14N2O2 (266): calcd. C
δ = 21.3, 25.9, 70.9, 126.5, 129.4, 129.6, 137.6, 170.0, 172.2 ppm.
GC–MS: m/z (%) = 294 (100) [M]+. C11H12N2O2 (204.23): calcd.
C 64.69, H 5.92, N 13.72; found C 64.60, H 5.90, N 13.95.
72.16, H 5.30, N 10.52; found C 72.25, H 5.15, N 10.50.
3-(Benzoylamino)-5-(4-chlorophenyl)-4,5-dihydroisoxazoline
(4c):
189 mg, 63% yield; m.p. 145–147 °C (ethyl acetate). 1H NMR
General Procedure for the Synthesis of Oxadiazoles 3h–3j: To a
solution of oxadiazole 7 (2 mmol) in CH3OH (20 mL) was added
NaBH4 (152 mg, 4 mmol), and the mixture was heated at reflux for
2 h. The solution was concentrated under reduced pressure, and the
residue was chromatographed to give oxadiazoles 3h–3j.
(300 MHz, [D6]DMSO): δ = 3.70 (dd, J1 = 17.7 Hz, J2 = 8.4 Hz, 1
H), 4.15 (dd, J1 = 17.7 Hz, J2 = 10.5 Hz, 1 H), 5.65 (dd, J1
=
10.5 Hz, J2 = 8.4 Hz, 1 H), 7.27–7.55 (m, 7 H), 7.93–7.98 (m, 2
H), 10.08 (s, 1 H, exch. with D2O) ppm. 13C NMR (75 MHz, [D6]
DMSO): δ = 43.1, 81.5, 129.1, 129.2, 129.5, 129.7, 133.5, 133.7,
134.1, 141.0, 155.3, 166.5 ppm. GC–MS: m/z (%) = 300 (100)
[M]+, 302 (34) [M + 2]+. C16H13ClN2O2 (300): calcd. C 63.90, H
4.36, N 9.31; found C 63.90, H 4.35, N 9.35.
1-(5-Phenyl-1,2,4-oxadiazol-3-yl)propan-2-ol (3h): 335 mg, 82%
1
yield; m.p. 53–55 °C (petroleum ether). H NMR (300 MHz, [D6]-
DMSO): δ = 1.24 (d, J = 6.0 Hz, 3 H), 2.81–2.88 (m, 2 H), 4.12–
4.24 (m, 1 H), 4.90 (d, J = 5.4 Hz, 1 H, exch. with D2O), 7.66–7.79
3-(Benzoylamino)-5-(4-methoxyphenyl)-4,5-dihydroisoxazoline (4d):
(m, 3 H), 8.13–8.16 (m, 2 H) ppm. 13C NMR (75 MHz, [D6] 172 mg, 58% yield; m.p. 126–127 °C (ethyl acetate). 1H NMR
DMSO): δ = 23.5, 35.6, 64.5, 123.7, 127.9, 129.7, 133.2, 169.2,
(300 MHz, [D6]DMSO): δ = 3.65 (dd, J1 = 18.0 Hz, J2 = 9.0 Hz, 1
H), 3.75 (s, 3 H), 4.03 (dd, J1 = 18.0 Hz, J2 = 10.5 Hz, 1 H), 5.57
(t, J = 9.9 Hz, 1 H), 6.84 (d, J = 8.7 Hz, 2 H), 7.26 (d, J = 8.7 Hz,
2 H), 7.33–7.79 (m, 3 H), 7.82–7.87 (m, 2 H), 9.37 (s, 1 H, exch.
with D2O) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.8, 55.3, 81.3,
114.1, 127.8, 128.2, 128.6, 129.7, 132.5, 133.2, 154.4, 159.3,
165.6 ppm. GC–MS: m/z (%) = 296 (100) [M]+. C17H16N2O3 (296):
calcd. C 68.91, H 5.44, N 9.45; found C 68.90, H 5.50, N 9.45.
174.7 ppm. GC–MS: m/z (%) = 204 (100) [M]+. FTIR (Nujol): ν =
˜
3251, 1608 cm–1. C11H12N2O2 (204): calcd. C 64.67, H 5.90, N
13.75; found C 64.70, H 5.95, N 13.65.
1-[5-(4-Chlorophenyl)-1,2,4-oxadiazol-3-yl]propan-2-ol (3i): 357 mg,
1
75% yield; m.p. 89–90 °C (petroleum ether). H NMR (300 MHz,
CDCl3): δ = 1.41 (d, J = 6.3 Hz, 3 H), 2.93–3.10 (m, 3 H), 4.38
(br. s, 1 H), 7.57 (d, J = 8.7 Hz, 2 H), 8.11 (d, J = 8.7 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 23.3, 35.5, 66.1, 122.8, 129.8, cis-3-(Benzoylamino)-4-ethyl-5-phenyl-4,5-dihydroisoxazoline (4e):
130.0, 139.8, 169.5, 175.0 ppm. GC–MS: m/z (%) = 238 (100)
218 mg, 74% yield; m.p. 142–143 °C (ethyl acetate). 1H NMR
(300 MHz, [D6]DMSO): δ = 0.51 (t, J = 7.5 Hz, 3 H), 1.27–1.36
(m, 2 H), 4.16–4.19 (m, 1 H), 5.72 (d, J = 9.3 Hz, 1 H), 7.40–7.67
(m, 8 H), 8.01–8.04 (m, 2 H), 11.10 (s, 1 H, exch. with D2O) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 11.4, 20.2, 50.5, 85.2, 127.2,
128.3, 128.5, 128.7, 128.9, 132.8, 133.5, 136.3, 158.6, 166.0 ppm.
GC–MS: m/z (%) = 294 (100) [M]+. C18H18N2O2 (294): calcd. C
73.45, H 6.16, N 9.52; found C 73.40, H 6.20, N 9.65.
[M]+, 240 (33) [M + 2]+. FTIR (Nujol): ν = 3100, 1606 cm–1.
˜
C11H11ClN2O2 (238): calcd. C 55.36, H 4.65, N 11.74; found C
55.30, H 4.60, N 11.55.
1-[5-(4-Methoxyphenyl)-1,2,4-oxadiazol-3-yl]propan-2-ol
(3j):
426 mg, 91% yield; m.p. 57–58 °C (petroleum ether). 1H NMR
(300 MHz, CDCl3): δ = 1.37 (d, J = 6.0 Hz, 3 H), 2.87–3.04 (m, 2
H), 3.55 (br. s, 1 H, exch. with D2O), 3.90 (s, 3 H), 4.34 (br. s, 1
H), 7.02 (d, J = 8.7 Hz, 2 H), 8.05 (d, J = 8.7 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 22.7, 35.0, 55.3, 65.5, 114.3, 116.2,
129.9, 163.1, 168.6, 175.2 ppm. GC–MS: m/z (%) = 234 (100)
trans-3-(Benzoylamino)-4-ethyl-5-phenyl-4,5-dihydroisoxazoline (4f):
235 mg, 80% yield; m.p. 135–137 °C (ethyl acetate). 1H NMR
(300 MHz, [D6]DMSO): δ = 1.05 (t, J = 7.2 Hz, 3 H), 1.65–1.72
(m, 1 H), 1.81–1.86 (m, 1 H), 3.95–4.00 (m, 1 H), 5.50 (d, J =
4.5 Hz, 1 H), 7.36–7.68 (m, 8 H), 7.98–8.01 (m, 2 H), 11.05 (s, 1
H, exch. with D2O) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
11.8, 24.6, 56.5, 86.3, 126.5, 128.9, 129.2, 129.6, 129.8, 133.5, 134.1,
[M]+. FTIR (Nujol): ν = 3323, 1614 cm–1. C H N O (234):
˜
12 14
2
3
calcd. C 61.53, H 6.02, N 11.96; found C 61.50, H 6.05, N 11.90.
General Procedure for the Rearrangement of Oxadiazoles 3: To a
solution of oxadiazole 3 (1 mmol) in DMSO (5 mL) was added
tBuOK (112 mg, 1 mmol), and the mixture was stirred at room
temperature for 24 h. The reaction mixture was treated with water
(50 mL), and the resulting solution was neutralized with HCl (1 m
solution). The solution was extracted with ethyl acetate (50 mL),
and the organic layer was dried with Na2SO4 and filtered. The sol-
143.0, 156.8, 166.4 ppm. GC–MS: m/z (%)
= 294 (100).
C18H18N2O2 (294): calcd. C 73.45, H 6.16, N 9.52; found C 73.55,
H 6.25, N 9.50.
3-(Benzoylamino)-5-methyl-4,5-dihydroisoxazoline (4h): 135 mg,
66% yield; m.p. 131–132 °C (ethyl acetate). 1H NMR (300 MHz,
1990
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1986–1992

Isoxazoline Derivatives through Boulton–Katritzky Rearrangement
[D6]DMSO): δ = 1.35 (d, J = 6.0 Hz, 3 H), 3.6 (dd, J1 = 17.4 Hz,
J2 = 8.7 Hz, 1 H), 3.62–3.71 (dd, J1 = 17.4 Hz, J2 = 9.6 Hz, 1 H),
4.67–4.79 (m, 1 H), 7.53–7.68 (m, 3 H), 7.96–8.01 (m, 2 H), 11.10
(s, 1 H, exch. with D2O) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 20.5, 41.2, 76.6, 128.2, 128.6, 132.4, 133.3, 154.6, 165.5 ppm.
Computational Details: The molecular and anionic species are
shown in Table 3. Their geometry was fully optimized in vacuo by
using the hybrid DFT B3LYP method[18] and the 6-311++G(d,p)
basis set.[19] Their Cartesian coordinates are available in the Sup-
porting Information. All calculations were performed by using the
GC–MS: m/z (%) = 204 (100) [M]+. FTIR (Nujol): ν = 3280, 1675, Gaussian 03 program package.[20]
˜
1624, 1506 cm–1. C11H12N2O2 (204): calcd. C 64.69, H 5.92, N
Supporting Information (see footnote on the first page of this arti-
13.72; found C 64.65, H 5.90, N 13.80.
1
cle): H and 13C NMR spectra of new compounds, energy values,
3-[(4-Chlorobenzoyl)amino]-5-methyl-4,5-dihydroisoxazoline
(4i):
and Cartesian coordinates of all computed species.
136 mg, 57% yield; m.p. 177–179 °C (ethyl acetate). 1H NMR
(300 MHz, [D6]DMSO): δ = 1.34 (d, J = 6.3 Hz, 3 H), 3.15 (dd, J1
= 17.4 Hz, J2 = 8.7 Hz, 1 H), 3.66 (dd, J1 = 17.4 Hz, J2 = 9.6 Hz,
1 H), 4.67–4.77 (m, 1 H), 7.64 (d, J = 8.7 Hz, 2 H), 8.02 (d, J1 =
8.7 Hz, 2 H), 11.20 (s, 1 H, exch. with D2O) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 20.7, 41.3, 76.9, 128.9, 130.4, 132.2,
137.5, 154.7, 164.7 ppm. GC–MS: m/z (%) = 238 (100) [M]+, 240
Acknowledgments
Dr. Giampaolo Barone (University of Palermo) is deeply acknowl-
edged for the helpful discussion about the DFT calculations. Fin-
ancial support by the University of Palermo is gratefully acknowl-
edged.
(33) [M + 2]+. FTIR (Nujol): ν = 3240, 1733, 1594 cm–1.
˜
C11H11ClN2O2 (238): calcd. C 55.36, H 4.65, N 11.74; found C
55.35, H 4.60, N 11.70.
[1] a) A. J. Boulton, A. R. Katritzky, A. M. Hamid, J. Chem. Soc.
C 1967, 2005–2007; b) N. Vivona, G. Cusmano, M. Ruccia, D.
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3-[(4-Methoxybenzoyl)amino]-5-methyl-4,5-dihydroisoxazoline (4j):
201 mg, 86% yield; m.p. 122–124 °C (ethyl acetate). 1H NMR
(300 MHz, [D6]DMSO): δ = 1.34 (d, J = 6.0 Hz, 3 H), 3.15 (dd, J1
= 17.4 Hz, J2 = 8.7 Hz, 1 H), 3.65 (dd, J1 = 17.4 Hz, J2 = 9.6 Hz,
1 H), 3.88 (s, 3 H), 4.67–4.75 (m, 1 H), 7.08 (d, J = 8,7 Hz, 2 H),
8.01 (d, J1 = 8.7 Hz, 2 H), 10.94 (s, 1 H, exch. with D2O) ppm. 13
C
NMR (75 MHz, [D6]DMSO): δ = 20.7, 41.4, 55.8, 76.7, 114.0,
125.5, 130.5, 155.0, 162.8, 165.0 ppm. GC–MS: m/z (%) = 234 (100)
[M]+. FTIR (Nujol): ν = 3220, 1652, 1606 cm–1. C H N O (234):
˜
12 14
2
3
calcd. C 61.53, H 6.02, N 11.96; found C 61.55, H 6.10, N 11.90.
[2] For recent mechanistic studies of azole-to-azole interconver-
sion reactions of the Boulton–Katritzky-type, see: a) B. Cosi-
melli, V. Frenna, S. Guernelli, C. Z. Lanza, G. Macaluso, G.
Petrillo, D. Spinelli, J. Org. Chem. 2002, 67, 8010–8018; b) F.
DЈAnna, V. Frenna, G. Macaluso, S. Morganti, P. Nitti, V.
Pace, D. Spinelli, R. Spisani, J. Org. Chem. 2004, 69, 8718–
8722; c) F. DЈAnna, V. Frenna, G. Macaluso, S. Marullo, S.
Morganti, V. Pace, D. Spinelli, R. Spisani, C. Tavani, J. Org.
Chem. 2006, 71, 5616–5624.
[3] a) A. Pace, P. Pierro, S. Buscemi, N. Vivona, G. Barone, J. Org.
Chem. 2009, 74, 351–358; b) A. Martorana, P. Piccionello, S.
Buscemi, G. Giorgi, A. Pace, Org. Biomol. Chem. 2011, 9, 491–
496; c) A. Martorana, A. Pace, S. Buscemi, A. P. Piccionello,
Org. Lett. 2012, 14, 3240–3243.
[4] a) A. Pace, I. Pibiri, A. P. Piccionello, S. Buscemi, N. Vivona,
G. Barone, J. Org. Chem. 2007, 72, 7656–7666; b) A. P. Pic-
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2008, 64, 4004–4010; c) A. P. Piccionello, A. Pace, S. Buscemi,
N. Vivona, Org. Lett. 2009, 11, 4018–4020; d) A. P. Piccionello,
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3493.
[5] a) D. Korbonits, I. Kanzel-Szvoboda, K. Horvath, J. Chem.
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Bakò, K. Horvath, J. Chem. Res. Synop. 1979, 64, (M) 02801.
[6] a) A. Pace, I. Pibiri, S. Buscemi, N. Vivona, Heterocycles 2004,
63, 2627–2648; b) A. Pace, I. Pibiri, S. Buscemi, N. Vivona, L.
Malpezzi, J. Org. Chem. 2004, 69, 4108–4115; c) S. Buscemi,
A. Pace, I. Pibiri, N. Vivona, T. Caronna, J. Fluorine Chem.
2004, 125, 165–173; d) A. P. Piccionello, A. Pace, I. Pibiri, S.
Buscemi, N. Vivona, Tetrahedron 2006, 62, 8792–8797; e) A. P.
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5-Phenyl-3-vinyl-1,2,4-oxadiazole (8a): Oil; ref.[5b] oil. 1H NMR
(300 MHz, CDCl3): δ = 5.83 (dd, J1 = 10.8 Hz, J2 = 1.5 Hz, 1 H),
6.52 (dd, J1 = 17.4 Hz, J2 = 1.5 Hz, 1 H), 6.81 (dd, J1 = 17.4 Hz,
J2 = 10.8 Hz, 1 H), 7.52–7.62 (m, 3 H), 8.16–8.22 (m, 2 H) ppm.
(E)-5-Phenyl-3-styryl-1,2,4-oxadiazole (8b): 57 mg, 23% yield; m.p.
102–103 °C (petroleum ether); ref.[17] m.p. 102 °C.
(E)-3-(4-Chlorostyryl)-5-phenyl-1,2,4-oxadiazole (8c): 51 mg, 18%;
1
m.p. 119–121 °C (petroleum ether). H NMR (300 MHz, CDCl3):
δ = 7.10 (d, J = 16.2 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 2 H), 7.52–7.63
(m, 5 H), 7.77 (d, J = 16.2 Hz, 1 H), 8.18–8.22 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 114.3, 124.9, 128.9, 129.3, 129.8
(overlapped signals), 133.5, 134.6, 135.9, 138.5, 168.9, 175.8 ppm.
GC-MS: m/z (%)
= +
282 (100) [M]+, 284 (33) [M 2]+.
C16H11ClN2O (282): calcd. C 67.97, H 3.92, N 9.91; found C 67.95,
H 3.85, N 9.90.
(E)-5-(4-Methoxystyryl)-5-phenyl-1,2,4-oxadiazole (8d): 53 mg,
19% yield; m.p. 135–136 °C. 1H NMR (300 MHz, CDCl3): δ = 3.87
(s, 3 H), 6.96 (d, J = 8.8 Hz, 1 H) 7.01 (d, J = 16.2 Hz, 1 H), 7.55–
7.63 (m, 5 H), 7.79 (d, J = 16.2 Hz, 1 H), 8.19–8.24 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 55.4, 110.6, 114.3, 124.3, 128.1,
128.2, 128.9, 129.1, 132.7, 138.8, 160.7, 168.7, 174.9 ppm. GC–MS:
m/z (%) = 278 (100) [M]+. C17H14N2O2 (278): calcd. C 73.37, H
5.07, N 10.07; found C 73.30, H 5.10, N 10.15.
Reaction of Nitrile 5b with tBuOK: To a solution of β-hydroxynitrile
5b (1 mmol) in DMSO (5 mL) was added tBuOK (112 mg,
1 mmol), and the mixture was stirred at room temperature for 6 h.
The mixture was treated with water (50 mL), and the resulting solu-
tion was neutralized with HCl (1 m solution). The solution was
extracted with ethyl acetate (50 mL), and the organic layer was
dried with Na2SO4 and filtered. The solvent was removed under
reduced pressure, and the resulting residue was chromatographed
to give (E)-cinnamonitrile (10, 109 mg, 84% yield).
[7] a) I. Pibiri, A. P. Piccionello, A. Calabrese, S. Buscemi, N. Vi-
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Eur. J. Org. Chem. 2013, 1986–1992
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1991

A. Palumbo Piccionello, A. Guarcello, A. Pace, S. Buscemi
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Received: October 4, 2012
Published Online: February 7, 2013
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