Synthesis of stable isoxazolines by [3+2] cycloaddition of oxaziridines with alkynes

Article abstract of DOI:10.1016/j.tet.2008.03.092

N-Alkyl substituted oxaziridines undergo a [3+2] cycloaddition reaction with a variety of terminal alkynes to give the product isoxazolines, whose stability appears to depend on the electronic properties of the groups on the C-3 and C-5 positions. The presence of an electron withdrawing group on C-5 and/or an electron donating group on C-3 causes isomerization of the isoxazolines to β-amino enones.

Full text of DOI:10.1016/j.tet.2008.03.092

Tetrahedron 64 (2008) 4979–4984
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of stable isoxazolines by [3þ2] cycloaddition
of oxaziridines with alkynes
*
Marilena Fabio, Ludovico Ronzini, Luigino Troisi
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Salento, via Prov.le Lecce-Monteroni, 73100 Lecce, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Alkyl substituted oxaziridines undergo a [3þ2] cycloaddition reaction with a variety of terminal
alkynes to give the product isoxazolines, whose stability appears to depend on the electronic properties
of the groups on the C-3 and C-5 positions. The presence of an electron withdrawing group on C-5 and/or
an electron donating group on C-3 causes isomerization of the isoxazolines to b-amino enones.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 28 November 2007
Received in revised form 13 March 2008
Accepted 27 March 2008
Available online 1 April 2008
1. Introduction
The reactivity involving the oxaziridine C–O bond cleavage has
been studied much less. In fact, only reactions of oxaziridines with
The biological properties of oxaziridines have not been in-
vestigated very much; only recently, their potential as antifungal1
and antitumor agents2 has been reported. In contrast, their re-
activity, stereochemistry, and usefulness in organic chemistry have
been the object of several studies.3–20 A number of methods of
preparation have been reported including oxidation of imines with
a peracid,3 with cobalt-mediated molecular oxygen4 or with urea–
hydrogen peroxide,5 amination of ketenes,6 addition of hydroxamic
acid to propiolates,7 and photolysis of nitrones.8
heterocumulenes to afford five-membered heterocycles have been
reported.16
Indeed, our previous results about the synthesis of isox-
azolidines by a [3þ2] cycloaddition of oxaziridines and alkenes via
cleavage of the C–O bond, were considered as novel and interesting
aspects (Scheme 1).21
Ar'
O
O
The strained oxaziridine ring promises an unusually high re-
activity due to an inherently weak N–O bond and has received
considerable attention mainly due to the chirality of the nitrogen
atom showing an inversion barrier of 25–32 kcal/mol in N-alkyl
substituted oxaziridines.9
R
Ar'
R
N
N
Ar
toluene, reflux
Ar
Ar = Ph, 2-Pyridinyl, 3-Pyridinyl, 4-Pyridinyl, 2-Thiazolyl, 2-Benzothiazolyl
Ar' = P-MeC6H4, 2-Pyridinyl
R = H, Me
The oxaziridines can be used as both oxygenating and aminating
agents in reactions with a wide variety of nucleophiles. The general
mechanism, as oxygenating agent, involves nucleophilic attack on
the oxaziridine oxygen with simultaneous C–O bond cleavage.
Oxaziridines have been used in the direct oxygenation of enolates,10
epoxidation of alkenes,11 oxidation of nitrogen nucleophiles,12 and
oxidation of C–H bonds.13 Thioethers,14 enamines,15 organometallic
reagents,16 and tertiary Si–H bonds17 can be oxygenated as well.
Oxaziridines can also be used as a source of electrophilic nitrogen
in many transformations. Alcohols can be converted into O-alkyl
oximes,18 thioethers into sulfimides,19 enolates into a-amino
carbonyl compounds,20 and C–H into amines.6,20b The general
mechanism involves, in this case, nucleophilic attack on the oxa-
ziridine nitrogen with simultaneous N–O bond cleavage.
Scheme 1.
The possibility that D4-isoxazolines could be obtained via
a [3þ2] cycloaddition reaction between alkynes and oxaziridines
has been evaluated by us and the results of our study in this context
are reported here.
Although the potential of D4-isoxazolines as synthons for cyclic
or acyclic nitrogen compounds22 and their biological activity,23
only a few synthetic methods of these compounds have been
reported. More often than not, isoxazolines have not been isolated
and characterized because of their instability under the conditions
at which they are formed, due to their bias to undergo rearrange-
ment reactions.22 There are only two significant routes to D4-
isoxazolines. The most general and widely used one is due to
Huisgen and co-workers and is based on the cycloaddition of
nitrones with alkynes.24 However, investigators are urged to be
wary of early reports of isoxazolines formed by cycloadditions that
are not supported by spectral characterization.
* Corresponding author.
E-mail address: luigino.troisi@unile.it (L. Troisi).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.092

4980
M. Fabio et al. / Tetrahedron 64 (2008) 4979–4984
R1
Ar1
R2
Ar2
R1
O
N
Ar1
NH
R2
Ar2
m-CPBA
Ar2
R2
N
Ar1
+
CH2Cl2
Ar1
toluene, reflux 6-16h
N
R1
O
R1
O
1-9
10-21
22-27
Scheme 2.
Another route to D4-isoxazolines is based on the addition of
Grignard reagents to isoxazolium salts25 or their reduction with
sodium borohydride.26
It seems to be also noteworthy the [3þ2] cycloaddition reaction
between unsaturated ketones and hydroxylamines (RNHOH)
followed by dehydration.27
An EWG such as an a-aza-heterocycle (2-pyridine, 2-benzo-
thiazole) on the carbon atom of the oxaziridine makes the oxygen
atom more electrophilic and increases the cyclization rate (entries 5
and 7, Table 1) according the approach A.
However, an alternative mechanism via a nitrone can also be
considered.
A two-step mechanism could be proposed: the
Herein, we describe a new and highly efficient methodology of
synthesis of 3,5-di-aryl-4-isoxazolines based on the cycloaddition
of a variety of aryl alkynes with 2-alkyl-3-aryloxaziridines.
oxaziridine rearranges to the isomeric nitrone, which then reacts
with the alkyne to give the isoxazoline. This hypothesis is not in
accordance with the electrophilic trend of the oxygen atom in the
cycloaddition reaction; moreover, the reaction of N-alkyl-nitrones
with alkynes was reported not to be regioselective giving mixtures
of 5- and 4-substituted isoxazolines.29
2. Results and discussion
Known oxaziridines 1, 2, 4–6, and 828,21 and novel oxaziridines
3, 7, and 9 were prepared via oxidation of the corresponding imines
with m-chloroperbenzoic acid (m-CPBA). The oxaziridines 1–5
were isolated exclusively in the trans isomeric form, while the
oxaziridines 6–9 were obtained in a diastereomeric mixture
(Scheme 2).28
A solution of oxaziridine (1.0 mmol) and alkyne (1.5 mmol) was
refluxed in toluene for 6–16 h, until TLC showed that the reaction
was complete. After solvent evaporation, the yellow crude material
was flash chromatographed on a silica gel column.
3. Conclusion
In conclusion, we have reported a new reaction of oxaziridines,
which is useful in organic synthesis: the [3þ2] cycloaddition
reaction with alkynes. By this reaction, it is possible to synthesize
isoxazolines, which are not easy to obtain by other methods.
4. Experimental
4.1. General
The main reaction products were the isoxazolidines 10–21. Only
a small amount of by-products, such as arylaldehydes and aryl-
imines, were observed and identified by GC–MS.
All reactions were performed under N2 using oven-dried glass-
ware. Et2O and THF were distilled from sodium/benzophenone
ketyl before use. CH2Cl2 was distilled from calcium hydride before
use. Column chromatography was performed using 100–200 times
excess 32–64 mm grade silica gel. TLC analysis was performed on
glass TLC plates (0.25 mm 60 F-254 silica gel). Gas chromatography
(GC) was conducted on an Rtx-5 30-m fused silica capillary column
(split ratiow100:1). The following program was used: method
A¼initial temperature of 100 ꢀC for 0.0 min, ramp 10 ꢀC/min to
280 ꢀC, and hold for 15 min; the standard operating conditions
were 300 ꢀC injector temperature and 290 ꢀC detector temperature.
GC–MS was conducted using method A temperature program.
NMR spectroscopy data were collected at 400 MHz or 500 MHz.
The following solvent and reference values (ppm) were used: CDCl3
(1H: 7.26, 13C: 77.0). The purity of all products was determined to be
>95% by NMR and/or GC analyses unless specified otherwise.
Samples for IR analysis were prepared as dilute solutions in CHCl3,
and data are reported as wave numbers (cmꢁ1). Melting points
were determined in open capillary tubes. Low-resolution and
high-resolution electron impact (EI) mass spectra were obtained
with a typical ionization voltage of 70 eV. The electrospray ioni-
zation (HR-ESI-MS) experiments were carried out on a hybrid
QqTOF mass spectrometer (PE SCIEX-QSTAR) fitted with an ion
spray ionization source.
Many isoxazolidines proved to be unstable under the experi-
mental conditions: at 110 ꢀC they converted into the rearranged
b-amino enones 22–27 following the N–O bond cleavage. The
analysis of the data in Table 1 suggests that the N–O bond cleavage
is facilitated when an electron withdrawing group (EWG), such as
an a-aza-heterocycle, is on the C-3 (entries 4, 6, 9, 11, and 14, Table
1) or an electron donating group (ERG), as a p-MeO-C6H4, is on C-5
(entry 12, Table 1) of the isoxazoline moiety.
The isoxazolines and the corresponding opened compounds
were isolated pure and identified by 1H and 13C NMR spectroscopy.
Chemical shifts of the C-3 and C-4 protons are consistent with those
reported for similar compounds.25,26
The rate of the cycloaddition reaction seems to depend on the
electronic properties of groups on the carbon atom of the oxazir-
idine. An EWG, such as an a-aza-heterocycle, increases the cycli-
zation rate, so that the reaction was complete within 6 h (entries 5
and 7, Table 1). For reaction times longer than 6 h, isoxazolines 13
and 14 isomerize to the opened compounds 22 and 23, respectively
(entries 4 and 6, Table 1). Accordingly, refluxing of isoxazoline 14
overnight in toluene gave 23 as the sole product, while compounds
24, 26, and 27 were formed even at lower temperature and using
shorter reaction times. Spectroscopic data of products 22–27
showed in the 1H NMR spectrum a chemical shift of the N–H proton
at y11.6 ppm and a value of infrared absorbance of the C]O at
y1590 cmꢁ1, in accordance with a hydrogen-bridged cyclic struc-
ture (Scheme 2).
4.2. General procedure for the preparation of imines
The high regioselectivity observed in the cycloaddition reaction
could be the result of steric interactions: approach A should be
favored (Scheme 3).
Accordingly, there was no [3þ2] cycloaddition reaction when an
internal alkyne such as 1-phenyl-propyne was refluxed with
oxaziridine 1.
The appropriate amine (1 mmol) and the corresponding alde-
hyde (1 mmol) were dissolved in anhydrous Et2O (20 mL) in the
presence of 7 g of molecular sieves (4 Å, 1.6 mm pellets), according
to Tagushi’s method.30 The formation of imine was monitored by
GC. After 1 h the molecular sieves were filtered and the solvent
evaporated to obtain the pure imine.

M. Fabio et al. / Tetrahedron 64 (2008) 4979–4984
4981
Table 1
Synthesis of 3,5-diaryl-isoxazolines 10–21
Entry
1
Oxaziridine
Ar1
R1
Ar2
R2
H
t (h)
Total yielda (%)
90
Product distributionb
1
t-Bu
16
10(100)
2
2
3
4
4
5
5
6
7
1
5
1
8
9
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
16
16
16
6
93
91
81
92
98
82
50
80
90
90
60
60
70
11(100)
H3CO
H3C
3
12(100)
4
13(45), 22(55)
13(100), 22(0)
14(2), 23(98)
14(95), 23(5)
15(100)
N
5
N
S
N
S
N
6
16
6
7
8
16
8
S
N
9
Et
16(0), 24(100)
17(100)
10
11
12
13
14
15
t-Bu
t-Bu
t-Bu
i-Pr
i-Pr
10
6
N
S
N
18(90), 25(10)
19(0), 26(100)
20(100)
N
16
16
8
H3CO
S
N
21(0), 27(100)
1
5
t-Bu
t-Bu
Me
Me
48
48
d
d
d
d
S
N
16
a
Yields based on chromatographically isolated, pure products.
Product distributions evaluated by GC and 1H NMR spectroscopy.
b
4.2.1. tert-Butyl-(4-methyl-benzilidene)-amine
4.2.2. tert-Butyl-(4-methoxy-benzilidene)-amine
Yield 173 mg; 99%; oil; 1H NMR (400 MHz, CDCl3) d 1.28 (s, 9H),
2.36 (s, 3H), 7.19 (d, 2H, J¼7.9 Hz), 7.63 (d, 2H, J¼7.9 Hz), 8.23 (s,1H);
13C NMR (100.62 MHz, CDCl3) d 21.4, 29.7, 57.0, 127.8, 129.2, 134.5,
140.2, 155.0; GC–MS (70 eV) m/z 175 (9) [Mþ], 160 (100), 135 (13),
118 (54), 91 (33), 57 (26); FTIR (CHCl3) cmꢁ1 3024, 2968, 1641, 1575,
1458, 1370, 1202, 1106. HRMS: calcd for C12H17N: 175.1362; found:
175.1365.
Yield 189 mg; 99%; oil; 1H NMR (400 MHz, CDCl3) d 1.28 (s, 9H),
3.81 (s, 3H), 6.90 (d, 2H, J¼8.7 Hz), 7.68 (d, 2H, J¼8.7 Hz), 8.20 (s,
1H); 13C NMR (100.62 MHz, CDCl3) d 29.7, 55.2, 56.8, 113.8, 129.3,
130.1, 154.4, 162.2; GC–MS (70 eV) m/z 191 (12) [Mþ], 176 (100), 134
(45), 77 (23), 57 (24); FTIR (CHCl3) cmꢁ1 3024, 2967, 1641, 1579,
1512, 1308, 1251, 1165. HRMS: calcd for C12H17NO: 191.1311; found:
191.1308.

4982
M. Fabio et al. / Tetrahedron 64 (2008) 4979–4984
Ar1
H
2.40–2.50 (m, 1H), 5.05 (s, 1H), 7.40 (t, 1H, J¼7.9 Hz), 7.48 (t, 1H,
Ar
R
J¼7.9 Hz), 7.88 (d, 1H, J¼8.2 Hz), 8.06 (d, 1H, J¼8.2 Hz); 13C NMR
(100.62 MHz, CDCl3) d 18.6, 21.2, 62.8, 77.0, 122.0, 123.5, 126.0,
126.2, 135.5, 153.0, 167.1; GC–MS (70 eV) m/z 220 (31) [Mþ], 205
(58), 162 (100), 135 (80), 108 (28), 58 (75); FTIR (CHCl3) cmꢁ1 3067,
3029, 2986, 2941, 2876, 1605, 1524, 1455, 1319, 1241, 1158. HRMS:
calcd for C11H12N2SO: 220.0671; found: 220.0671.
Ar
O
N
Ar1
Ar1
N
O
R
approach A
Ar
Ar1
Ar
H
N
Minor diastereomer (cis): 1H NMR (400 MHz, CDCl3) d 0.94 (d,
3H, J¼6.5 Hz), 1.32 (d, 3H, J¼6.2 Hz), 2.79–2.82 (m, 1H), 5.30 (s, 1H),
7.40 (t, 1H, J¼7.9 Hz), 7.48 (t, 1H, J¼7.9 Hz), 7.88 (d, 1H, J¼8.2 Hz),
8.06 (d, 1H, J¼8.2 Hz); 13C NMR (100.62 MHz, CDCl3) d 18.0, 21.8,
54.1, 76.8, 121.6, 125.4, 123.4, 126.6, 135.3, 153.8, 163.4; GC–MS
(70 eV) m/z 220 (41) [Mþ], 205 (60), 162 (100), 135 (75), 108 (32), 58
(70); FTIR (CHCl3) cmꢁ1 3067, 3030, 2986, 2939, 2877, 1601, 1524,
1458, 1316, 1243, 1158. HRMS: calcd for C11H12N2SO: 220.0671;
found: 220.0671.
R
O
O
approach B
N
R
Scheme 3.
4.2.3. Ethyl-benzothiazol-2-ylmethylene-amine
Yield 188 mg; 99%; oil; 1H NMR (400 MHz, CDCl3) d 1.30 (t, 3H,
J¼7.3 Hz), 3.62–3.68 (m, 2H), 7.42 (t, 1H, J¼7.9 Hz), 7.48 (t, 1H,
J¼8.1 Hz), 7.90 (d, 1H, J¼7.9 Hz), 8.05 (d, 1H, J¼8.1 Hz), 8.62 (s, 1H);
13C NMR (100.62 MHz, CDCl3) d 16.3, 55.8, 121.9, 123.8, 126.2, 126.3,
135.0, 150.5, 153.6, 169.0; GC–MS (70 eV) m/z 190 (22) [Mþ], 175
(100), 148 (50), 135 (18); FTIR (CHCl3) cmꢁ1 3069, 3030, 2982, 1630,
1511, 1459, 1434, 1367, 1316, 1221. HRMS: calcd for C10H10N2S:
190.0566; found: 190.0567.
4.4. General procedure for the cycloaddition reaction
A solution of the alkyne (1.5 mmol) and oxaziridines 1–9
(1.0 mmol) in toluene (10 mL) was refluxed under magnetic stirring
for 6–16 h (Table 1). Afterthis time, TLC wasused tomonitor reaction
progress. The solution was cooled to rt and evaporated to dryness to
give a yellow crude material. The reaction mixture was purified by
flash chromatography (silica gel, petroleum ether/ethyl ether¼95:5
for entries 1, 2, 3, 8, 12, and 13 of Table 1; petroleum ether/ethyl
ether¼85:15 for entries 4, 5, 6, 7, 9, 10, 11, and 14 of Table 1).
4.2.4. iso-Propyl-benzothiazol-2-ylmethylene-amine
Yield 202 mg; 99%; oil; 1H NMR (400 MHz, CDCl3) d 1.31 (d, 6H,
J¼6.3 Hz), 3.72–3.75 (heptet, 1H, J¼6.3 Hz), 7.42 (t, 1H, J¼7.9 Hz),
7.48 (t, 1H, J¼8.1 Hz), 7.91 (d, 1H, J¼7.8 Hz), 8.07 (d, 1H, J¼7.7 Hz),
8.55 (s, 1H); 13C NMR (100.62 MHz, CDCl3) d 23.6, 61.3, 121.9, 123.9,
126.3, 126.4, 135.0, 153.1, 153.6, 167.7; GC–MS (70 eV) m/z 204 (20)
[Mþ], 189 (100), 148 (45), 135 (16); FTIR (CHCl3) cmꢁ1 3065, 3030,
2987, 1630, 1509, 1456, 1433, 1364, 1321, 1218. HRMS: calcd for
4.4.1. 2-tert-Butyl-3,5-diphenyl-isoxazoline (10)
Yield 251 mg; 90%; oil; 1H NMR (400 MHz, CDCl3) d 1.22 (s, 9H),
5.27 (d, 1H, J¼2.8 Hz), 5.28 (d, 1H, J¼2.8 Hz), 7.24 (t, 1H, J¼7.7 Hz),
7.30–7.38 (m, 5H), 7.43 (d, 2H, J¼7.3 Hz), 7.57 (dd, 2H, J¼1.3 Hz,
J¼8.0 Hz); 13C NMR (100.62 MHz, CDCl3) d 25.1, 60.9, 68.6, 97.1,125.6,
127.2,128.3,128.5,128.6,128.8,144.5,152.8; GC–MS (70 eV) m/z 279
(42) [Mþ], 222 (51), 206 (62), 105 (100), 77 (40), 57 (12); FTIR
(CHCl3) cmꢁ1 3065, 3031, 2977, 2937, 2874, 1658, 1600, 1493, 1365,
1051, 1025. HRMS: calcd for C19H21NO: 279.1624; found: 279.1620.
C
11H12N2S: 204.0723; found: 204.0726.
4.3. General procedure for the preparation of oxaziridines 1–9
A small excess of m-chloroperbenzoic acid (1.1 mmol) in 3 mL of
methylene chloride was added with stirring and cooling (0–5 ꢀC) to
asolutionofimine(1 mmol)in5 mLofmethylenechloride. Whenthe
reaction was complete, the formed m-chlorobenzoic acid was re-
moved by filtration. The filtrate was washed two times with a dilute
solution of Na2SO3 (5%), then with a solution of Na2CO3, and finally
with water. After drying over MgSO4, the solvent was evaporated and
the residue purified by a column chromatography (silica gel partly
deactivated with triethylamine, petroleum ether/ethyl ether¼95:5
for 1, 2, 3, 6, and 8; petroleum ether/ethyl ether¼8:2 for 4, 5, 7, and 9).
4.4.2. 2-tert-Butyl-3-(4-methoxy-phenyl)-5-phenyl-
isoxazoline (11)
Yield 287 mg; 93%; oil; 1H NMR (400 MHz, CDCl3) d 1.21 (s, 9H),
3.80 (s, 3H), 5.24 (s, 2H), 6.87 (d, 2H, J¼7.1 Hz), 7.30–7.38 (m, 5H),
7.57 (d, 2H, J¼7.1 Hz); 13C NMR (100.62 MHz, CDCl3) d 25.1, 55.3,
60.8, 68.1, 97.2, 113.9, 125.5, 128.4, 128.7, 136.8, 152.7, 158.8; GC–MS
(70 eV) m/z 309 (30) [Mþ], 252 (68), 251 (100), 236 (40), 105 (80),
77 (66), 57 (15); FTIR (CHCl3) cmꢁ1 3063, 3030, 2975, 2935, 2840,
1660, 1607, 1510, 1248, 1173, 1034. HRMS: calcd for C20H23NO2:
309.1730; found: 309.1733.
4.3.1. 2-tert-Butyl-3-(4-methyl-phenyl)-oxaziridine (3)
1
Yield 172 mg; 90%; oil; H NMR (400 MHz, CDCl3) d 1.17 (s, 9H),
2.34 (s, 3H), 4.65 (s, 1H), 7.17 (d, 2H, J¼7.9 Hz), 7.33 (d, 2H, J¼7.9 Hz);
13CNMR(100.62 MHz,CDCl3)d21.3, 25.2, 58.3,73.6,127.5,129.1,132.6,
139.7; GC–MS (70 eV) m/z191 (19) [Mþ],160(75),135(33),119(40), 91
(29), 57 (100); FTIR (CHCl3) cmꢁ1 2974, 1617, 1529, 1475, 1388, 1363,
1309, 1260. HRMS: calcd for C12H17NO: 191.1311; found: 191.1314.
4.4.3. 2-tert-Butyl-5-phenyl-3-p-tolyl-isoxazoline (12)
Yield 266 mg; 91%; oil; 1H NMR (400 MHz, CDCl3) d 1.21 (s, 9H),
2.33 (s, 3H), 5.24 (s, 2H), 7.14 (d, 2H, J¼7.9 Hz), 7.30–7.38 (m, 5H),
7.56 (d, 2H, J¼7.9 Hz); 13C NMR (100.62 MHz, CDCl3) d 21.1, 25.1,
60.8, 68.4, 97.2, 125.5, 127.1, 128.3, 128.7, 129.2, 136.8, 141.6, 152.7;
GC–MS (70 eV) m/z 293 (29) [Mþ], 236 (43), 235 (28), 105 (100), 77
(35), 57 (10); FTIR (CHCl3) cmꢁ1 3060, 3030, 2977, 2932, 2872, 1660,
1599, 1230, 1178, 1024. HRMS: calcd for C20H23NO2: 293.1781;
found: 293.1782.
4.3.2. 2-Ethyl-3-benzothiazol-2yl-oxaziridine (7)
Yield 165 mg; 80%; oil; 1H NMR (400 MHz, CDCl3) d 1.33 (t, 3H,
J¼7.3 Hz), 2.79–2.88 (m, 1H), 3.07–3.15 (m, 1H), 5.05 (s, 1H), 7.40 (t,
1H, J¼7.9 Hz), 7.48 (t, 1H, J¼7.9 Hz), 7.88 (d, 1H, J¼8.2 Hz), 8.06 (d,
1H, J¼8.2 Hz); 13C NMR (100.62 MHz, CDCl3) d 12.3, 56.7, 77.4,122.0,
123.4, 126.0, 126.2, 135.3, 153.7, 166.8; GC–MS (70 eV) m/z 206 (34)
[Mþ], 162 (64), 135 (100), 108 (28); FTIR (CHCl3) cmꢁ1 3064, 3031,
2987, 2939, 2878, 1601, 1523, 1458, 1317, 1241, 1158, 1084. HRMS:
calcd for C10H10N2SO: 206.0515; found: 206.0512.
4.4.4. 2-tert-Butyl-5-phenyl-3-(pyridin-2-yl)-isoxazoline (13)
Yield 257 mg; 92% (entry 5); oil; 1H NMR (400 MHz, CDCl3)
d 1.22 (s, 9H), 5.40 (d, 1H, J¼2.9 Hz), 5.46 (d, 1H, J¼2.9 Hz), 7.16 (t,
1H, J¼6.5 Hz), 7.31–7.37 (m, 3H), 7.56 (dd, 2H, J¼1.3 Hz, J¼7.4 Hz),
7.68–7.75 (m, 2H), 8.51 (d, 1H, J¼5.0 Hz); 13C NMR (100.62 MHz,
CDCl3) d 24.9, 60.8, 70.5, 96.3, 122.06, 122.12, 125.5, 128.3, 128.4,
128.9, 137.2, 148.2, 152.9, 163.6; GC–MS (70 eV) m/z 280 (8) [Mþ],
4.3.3. 2-iso-Propyl-3-benzothiazol-2yl-oxaziridine (9)
Yield 187 mg; 85%; oil. Major diastereomer (trans): 1H NMR
(400 MHz, CDCl3) d 1.24 (d, 3H, J¼6.6 Hz), 1.35 (d, 3H, J¼6.4 Hz),

M. Fabio et al. / Tetrahedron 64 (2008) 4979–4984
4983
236 (43), 235 (28), 105 (100), 77 (35), 57 (10); FTIR (CHCl3) cmꢁ1
3060, 3030, 2977, 2932, 2872, 1660, 1599, 1230, 1178, 1024. HRMS:
calcd for C18H20N2O: 280.1577; found: 280.1572.
147.9, 149.6, 152.5; GC–MS (70 eV) m/z 280 (73) [Mþ], 223 (100),
207 (40), 195 (10), 169 (45), 147 (16), 120 (90), 106 (35), 78 (60), 57
(13); FTIR (CHCl3) cmꢁ1 3060, 3030, 2986, 2929, 2856, 1675, 1585,
1365, 1211. HRMS: calcd for C18H20N2O: 280.1577; found: 280.1579.
4.4.5. 3-tert-Butyl-amino-1-phenyl-3-pyridin-2-yl-propenone (22)
Yield 125 mg; 44% (entry 4); oil; 1H NMR (400 MHz, CDCl3)
d 1.24 (s, 9H), 5.64 (s, 1H), 7.30–7.46 (m, 5H), 7.77 (t, 1H, J¼7.6 Hz),
7.86 (d, 2H, J¼6.6 Hz), 6.68 (d, 1H, J¼5.0 Hz), 11.72 (br s, 1H); 13C
NMR (100.62 MHz, CDCl3) d 31.4, 54.2, 94.3, 123.7, 127.0, 128.1,
128.2, 130.7, 136.4, 140.3, 148.8, 156.0, 164.2, 188.4; GC–MS (70 eV)
m/z 280 (15) [Mþ], 237 (46), 147 (22), 105 (100), 77 (45), 57 (18);
FTIR (CHCl3) cmꢁ1 3064, 3035, 2998, 2929, 2855, 1678, 1583, 1464,
1341, 1230, 1200. HRMS: calcd for C18H20N2O: 280.1577; found:
280.1575.
4.4.11. 2-tert-Butyl-5-(pyridin-2-yl)-3-benzothiazolyl-
isoxazoline (18)
Yield 273 mg; 81%; oil; 1H NMR (400 MHz, CDCl3) d 1.29 (s,
9H), 5.86 (d, 1H, J¼3.0 Hz), 5.94 (d, 1H, J¼3.0 Hz), 7.24 (dd, 1H,
J¼4.6 Hz, J¼7.4 Hz), 7.34 (t, 1H, J¼7.5 Hz), 7.45 (t, 1H, J¼7.5 Hz),
7.55 (d, 1H, J¼8.0 Hz), 7.71 (t, 1H, J¼7.8 Hz), 7.87 (d, 1H, J¼7.8 Hz),
7.97 (d, 1H, J¼8.0 Hz), 8.59 (d, 1H, J¼4.6 Hz); 13C NMR
(100.62 MHz, CDCl3) d 25.1, 61.2, 67.6, 98.5, 120.5, 121.6, 122.9,
123.7, 124.7, 125.8, 135.6, 136.6, 147.2, 149.7, 153.6, 153.9, 175.5;
GC–MS (70 eV) m/z 337 (7) [Mþ], 279 (18), 231 (55), 175 (100), 148
(12), 78 (20), 57 (6); FTIR (CHCl3) cmꢁ1 3030, 2975, 1585, 1475,
1431, 1363, 1197. HRMS: calcd for C19H19N3OS: 337.1251; found:
337.1247.
4.4.6. 2-tert-Butyl-5-phenyl-3-benzothiazolyl-isoxazoline (14)
Yield 262 mg; 78% (entry 7); oil; 1H NMR (400 MHz, CDCl3)
d 1.26 (s, 9H), 5.49 (d, 1H, J¼2.9 Hz), 5.79 (d, 1H, J¼2.9 Hz), 7.33–7.37
(m, 5H), 7.45 (t, 1H, J¼8.0 Hz), 7.54 (t, 1H, J¼1.3 Hz, J¼7.9 Hz), 7.87
(d, 1H, J¼7.9 Hz), 7.97 (d, 1H, J¼8.0 Hz); 13C NMR (100.62 MHz,
CDCl3) d 25.0, 61.2, 67.5, 94.4, 121.9, 122.7, 124.5, 125.7, 128.4, 128.7,
128.9, 129.5, 135.5, 153.9, 154.1, 179.3; GC–MS (70 eV) m/z 336 (0)
[Mþ], 278 (100), 250 (22), 223 (19), 105 (20), 77 (49); FTIR
(CHCl3) cmꢁ1 3068, 3034, 2957, 2927, 1673, 1599, 1367, 1218. HRMS:
calcd for C20H20N2OS: 336.1298; found: 336.1293.
4.4.12. 3-tert-Butyl-amino-1-(pyridin-2-yl)-3-
benzothiazolyl-propenone (25)
Yield 30 mg; 9%; oil; 1H NMR (400 MHz, CDCl3) d 1.26 (s, 9H),
6.79 (s, 1H), 7.34 (dd, 1H, J¼4.6 Hz, J¼7.8 Hz), 7.49 (t, 1H,
J¼8.0 Hz), 7.56 (t, 1H, J¼8.1 Hz), 7.81 (td, 1H, J¼1.7 Hz, J¼7.8 Hz),
7.95 (d, 1H, J¼7.8 Hz), 8.13 (d, 2H, J¼8.0 Hz), 8.60 (d, 1H, J¼4.6 Hz),
11.66 (br s, 1H); 13C NMR (100.62 MHz, CDCl3) d 31.2, 54.9, 95.5,
121.5, 121.6, 124.1, 125.4, 126.3, 126.6, 135.5, 136.8, 148.6, 153.1,
155.6, 157.3, 164.0, 186.7; GC–MS (70 eV) m/z 337 (80) [Mþ], 322
(10), 305 (55), 294 (60), 203 (100), 161 (80), 78 (79), 57 (15); FTIR
(CHCl3) cmꢁ1 3068, 3030, 3011, 2968, 2931, 2870, 1677, 1593, 1531,
1327, 1230, 1192. HRMS: calcd for C19H19N3OS: 337.1251; found:
337.1248.
4.4.7. 3-tert-Butyl-amino-1-phenyl-3-benzothiazolyl-
propenone (23)
Yield 323 mg; 96% (entry 6); oil; 1H NMR (400 MHz, CDCl3)
d 1.39 (s, 9H), 6.00 (s, 1H), 7.38–7.57 (m, 5H), 7.90 (d, 2H, J¼8.2 Hz),
7.95 (d, 1H, J¼8.0 Hz), 8.14 (d, 1H, J¼8.1 Hz), 11.62 (br s, 1H); 13C
NMR (100.62 MHz, CDCl3) d 31.1, 54.6, 95.9,121.6,122.3,124.1,126.3,
126.7, 127.1, 128.2, 131.1, 135.0, 139.5, 152.8, 156.3, 188.7; GC–MS
(70 eV) m/z 336 (35) [Mþ], 279 (100), 251 (38), 105 (88), 77 (58), 57
(20); FTIR (CHCl3) cmꢁ1 3392, 3068, 3030, 3006, 2968, 2933, 2872,
1675, 1588, 1531, 1329, 1231, 1192. HRMS: calcd for C20H20N2OS:
336.1298; found: 336.1295.
4.4.13. 3-tert-Butyl-amino-1-(4-methoxy-phenyl)-3-
phenyl-propenone (26)
Yield 185 mg; 60%; oil; 1H NMR (400 MHz, CDCl3) d 1.22 (s, 9H),
3.83 (s, 3H), 6.87 (d, 2H, J¼8.9 Hz), 7.26 (s, 1H), 7.38–7.42 (m, 5H),
7.84 (d, 2H, J¼8.9 Hz),11.73 (br s,1H); 13C NMR (100.62 MHz, CDCl3)
d 31.8, 53.9, 55.3, 94.8, 113.4, 127.8, 128.3, 128.8, 128.9, 133.0, 137.8,
161.7, 166.5, 186.9; GC–MS (70 eV) m/z 309 (45) [Mþ], 294 (25), 252
(100), 135 (35), 77 (10), 57 (5); FTIR (CHCl3) cmꢁ1 3063, 3030, 3012,
2975, 2935, 1680, 1597, 1310, 1238, 1193. HRMS: calcd for
4.4.8. 2-Ethyl-3,5-diphenyl-isoxazoline (15)
1
Yield 125 mg; 50%; oil; H NMR (400 MHz, CDCl3) d 1.30 (t, 3H,
J¼7.1 Hz), 2.96–3.05 (m, 1H), 3.25–3.32 (m, 1H), 4.95 (d, 1H, J¼
2.6 Hz), 5.38 (d, 1H, J¼2.6 Hz), 7.25–7.38 (m, 8H), 7.59 (dd, 2H,
J¼1.7 Hz, J¼7.3 Hz); 13C NMR (100.62 MHz, CDCl3) d 12.5, 54.4, 75.1,
96.1, 125.7, 127.1, 127.6, 128.4, 128.6, 128.9, 129.1, 142.4, 152.5; GC–
MS (70 eV) m/z 251 (50) [Mþ], 234 (100), 174 (20), 105 (26), 77 (28);
FTIR (CHCl3) cmꢁ1 3063, 3030, 2928, 2854, 1656, 1601, 1494, 1449,
1274. HRMS: calcd for C17H17NO: 251.1311; found: 251.1310.
C20H23NO2: 309.1730; found: 309.1727.
4.4.14. 2-iso-Propyl-3,5-diphenyl-isoxazoline (20)
Yield 159 mg; 60%; oil; 1H NMR (400 MHz, CDCl3) d 1.20 (d, 3H,
J¼6.5 Hz), 1.27 (d, 3H, J¼6.4 Hz), 3.27–3.36 (m, 1H), 5.14 (d, 1H, J¼
2.6 Hz), 5.33 (d, 1H, J¼2.5 Hz), 7.32–7.40 (m, 8H), 7.58 (dd, 2H,
J¼1.7 Hz, J¼7.3 Hz); 13C NMR (100.62 MHz, CDCl3) d 18.7, 21.0, 62.3,
74.1, 96.3, 125.6, 127.1, 127.5, 128.3, 128.6, 129.0, 129.2, 142.4, 152.8;
GC–MS (70 eV) m/z 265 (50) [Mþ], 222 (25), 188 (18), 167 (25), 118
(23), 105 (100), 91 (30), 77 (40); FTIR (CHCl3) cmꢁ1 3066, 3030,
2978, 2935, 2875, 1661, 1602, 1493, 1365, 1051, 1025. HRMS: calcd
for C18H19NO: 265.1468; found: 265.1471.
4.4.9. 3-Ethyl-amino-1-phenyl-3-benzothiazolyl-propenone (24)
Yield 246 mg; 80%; oil; 1H NMR (400 MHz, CDCl3) d 1.33 (t, 3H,
J¼7.3 Hz), 3.69–3.76 (m, 2H), 6.23 (s, 1H), 7.38–7.59 (m, 5H), 7.92
(dd, 2H, J¼1.3 Hz, J¼7.9 Hz), 7.97 (d, 1H, J¼7.8 Hz), 8.14 (d, 1H,
J¼7.8 Hz),11.24 (br s,1H); 13C NMR (100.62 MHz, CDCl3) d 16.0, 39.9,
94.4, 121.6, 124.2, 126.5, 126.8, 127.1, 128.3, 131.2, 134.9, 139.8, 153.3,
155.7,161.8,189.2; GC–MS (70 eV) m/z 308 (100) [Mþ], 293 (74), 236
(26), 203 (66), 160 (52), 136 (15), 105 (30), 77 (35); FTIR
(CHCl3) cmꢁ1 3395, 3069, 3031, 3008, 2973, 2936, 2872, 1685, 1589,
1531, 1329, 1231, 1192. HRMS: calcd for C18H16N2OS: 308.0985;
found: 308.0981.
4.4.15. 3-iso-Propyl-amino-1-phenyl-3-benzothiazolyl-
propenone (27)
Yield 225 mg; 70%; oil; 1H NMR (400 MHz, CDCl3) d 1.33 (d, 6H,
J¼6.3 Hz), 4.29–4.48 (m, 1H), 6.19 (s, 1H), 7.40–7.69 (m, 5H), 7.88–
8.07 (m, 3H), 8.14 (d, 1H, J¼8.1 Hz), 11.19 (br d, 1H, J¼6.8 Hz); 13C
NMR (100.62 MHz, CDCl3) d 24.2, 46.4, 94.4, 121.6, 124.3, 126.5,
126.8, 127.1, 128.3, 131.2, 135.0, 139.8, 153.4, 155.1, 162.0, 189.2; GC–
MS (70 eV) m/z 322 (100) [Mþ], 307 (95), 217 (80), 160 (56), 105
(70), 77 (45); FTIR (CHCl3) cmꢁ1 3352, 3069, 3032, 3012, 2969,
2935, 2875, 1685, 1592, 1531, 1329, 1231, 1190. HRMS: calcd for
4.4.10. 2-tert-Butyl-5-(pyridin-2-yl)-3-phenyl-isoxazoline (17)
Yield 252 mg; 90%; oil; 1H NMR (400 MHz, CDCl3) d 1.16 (s, 9H),
5.27 (d, 1H, J¼2.7 Hz), 5.70 (d, 1H, J¼2.7 Hz), 7.14–7.18 (m, 2H), 7.25
(t, 2H, J¼7.4 Hz), 7.37 (d, 2H, J¼7.8 Hz), 7.48 (d, 1H, J¼7.8 Hz), 7.65 (t,
1H, J¼7.8 Hz), 8.51 (d, 1H, J¼4.3 Hz); 13C NMR (100.62 MHz, CDCl3)
d 25.2, 60.9, 68.6, 101.1, 120.2, 123.3, 127.2, 127.3, 128.5, 136.6, 143.9,
C22H18N2OS: 322.1141; found: 322.1144.

4984
M. Fabio et al. / Tetrahedron 64 (2008) 4979–4984
13. (a) Arnone, A.; Caviccholi, M.; Montanari, V.; Resnati, G. J. Org. Chem. 1994, 59,
Acknowledgements
5511; (b) Arnone, A.; Foletto, S.; Metrangolo, P.; Pregnolato, M.; Resnati, G. Org.
Lett. 1999, 1, 281.
We are grateful to Prof. Saverio Florio from the University of Bari,
Dipartimento Farmaco-Chimico for kindly editing this manuscript.
We also thank the University of Lecce and the Italian Consorzio
Interuniversitario Nazionale ‘Metodologie e Processi Innovativi di
Sintesi’ (CINMPIS) for financial support.
14. (a) Betchell, D.; Page, P. C. B.; Vahedi, H. J. Org. Chem. 2000, 65, 6756; (b)
Sandrinelli, F.; Perrio, S.; Averbuch-Pouchot, M. T. Org. Lett. 2002, 4, 3619.
15. Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703.
16. Davis, F. A.; Wei, J.; Sheppard, A. C.; Guberwick, S. Tetrahedron Lett. 1987, 28,
5115.
17. Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919.
18. Choong, I. C.; Ellman, J. A. J. Org. Chem. 1999, 64, 6528.
19. Armstrong, A.; Cooker, R. S. Chem. Commun. 2002, 904.
20. (a) Vidal, J.; Guy, L.; Steriv, S.; Collet, A. J. Org. Chem. 1993, 58, 4791; (b) Enders,
D.; Poisez, C.; Joseph, R. Tetrahedron: Asymmetry 1998, 9, 3704.
21. Fabio, M.; Ronzini, L.; Troisi, L. Tetrahedron 2007, 63, 12896.
22. Freeman, J. P. Chem. Rev. 1983, 83, 241.
23. (a) Lukevics, E.; Arsnyan, P,; Germane, S.; Shestakova, I. Appl. Organomet. Chem.
1999, 13, 795; (b) Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. J. Med. Chem. 2001, 44,
2921.
References and notes
1. Peng, L.; Chen, C.; Gonzales, C. R.; Balog-Nair, V. Int. J. Mol. Sci. 2002, 3, 1145.
2. Mlochowski, J.; Kubicz, E.; Kloc, K.; Mordaski, M.; Peczynska, W.; Syper, L.
Liebigs Ann. Chem. 1988, 455.
3. (a) Wider, J.; Keller-Schierlein, W. Helv. Chim. Acta 1974, 57, 657; (b) Emmons,
W. D. J. Am. Chem. Soc. 1956, 78, 6208.
24. (a) Huisgen, R.; Grashey, R.; Hauck, H.; Seidl, H. Chem. Ber. 1968, 101, 2043; (b)
Houk, K. N. Pericyclic Reactions; Marchand, A. P., Lehr, R. E., Eds.; Academic: New
York, NY, 1977; Vol. II, p 181; (c) Sasaki, T.; Ando, M. Bull. Chem. Soc. Jpn. 1968,
41, 2960; (d) Noland, W. E.; Modier, R. F. J. Am. Chem. Soc. 1964, 86, 2086; (e)
Bond, C. C.; Hooper, M. J. Chem. Soc. C 1969, 2453.
4. Lin, Y.; Miller, M. J. J. Org. Chem. 2001, 66, 8282.
5. Damavaudi, J. A.; Karami, B.; Zolfigol. Synlett 2002, 933.
6. Andrae, S.; Schimtz, E. Synthesis 1991, 327.
7. Zong, K.; Shin, S. I.; Ryu, E. K. Tetrahedron Lett. 1998, 39, 6227.
8. Toda, F.; Tauaka, K. Chem. Lett. 1987, 2283.
25. Adachi, I.; Harada, K.; Miyazaki, R.; Kano, H. Chem. Pharm. Bull. 1974, 22, 61.
26. (a) Adachi, I.; Miyazaki, R.; Kano, H. Chem. Pharm. Bull. 1974, 22, 70; (b) Alberola,
A.; Gonzales, A. M.; Laguna, M. A.; Pulido, F. J. Synthesis 1982, 1067.
27. (a) Harries, C.; Jablonaski, L. Chem. Ber. 1898, 31, 1371; (b) Ishikawa, T.; Kudoh,
T.; Yoshida, J.; Yasuhara, A.; Manabe, S.; Saito, S. Org. Lett. 2002, 11, 1907.
28. (a) Mohajer, D.; Iranpoor, N.; Rezaeir, A. Tetrahedron Lett. 2004, 45, 631; (b)
Pews, R. G. J. Org. Chem. 1967, 32, 1628.
9. Bjorgo, J.; Boyd, D. R. J. Chem. Soc., Perkin Trans. 2 1973, 1575.
10. Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem. Soc. 1985, 107, 4346.
11. (a) Davis, F. A.; Adul-Malik, N. F.; Awad, S. B.; Harakal, M. E. Tetrahedron Lett.
1981, 22, 917; (b) Anderson, D. R.; Woods, K. W.; Beak, P. Org. Lett. 1999, 1, 1415;
(c) Houk, K. H.; Liu, J.; Demello, N. C.; Condroski, K. R. J. Am. Chem. Soc. 1997, 119,
10147; (d) Bohe, L.; Hanquet, G.; Lusinghi, M.; Lusinghi, X. Tetrahedron Lett.
1993, 34, 7271; (e) Aggarwal, V. K.; Wong, M. F. Chem. Commun. 1996, 161; (f)
Page, P. C.; Rassias, G. A.; Bethell, D.; Schilling, M. B. J. Org. Chem. 1998, 63, 2774.
12. Paleo, M. R.; Aurrecoecea, N.; Jung, K. J.; Rapoport, H. J. Org. Chem. 2003, 68, 130.
29. Sims, J.; Houk, K. N. J. Am. Chem. Soc. 1973, 22, 5798.
30. Taguchi, K.; Westheimer, F. H. J. Org. Chem. 1971, 36, 1570.