[3+2]-cycloaddition reaction between chiral oxaziridines and nitriles: Enantioselective synthesis of 2,3-dihydro-1,2,4-oxadiazoles

Article abstract of DOI:10.1055/s-0030-1258175

Enantiomerically pure 2,3-dihydro-1,2,4-oxadiazoles were synthesized by a cycloaddition reaction between chiral oxaziridines and nitriles. Assignment of absolute configurations was made by X-ray diffraction analysis, NOESY spectra, and theoretical calculations. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258175

PAPER
3211
[3+2]-Cycloaddition Reaction between Chiral Oxaziridines and Nitriles:
Enantioselective Synthesis of 2,3-Dihydro-1,2,4-oxadiazoles
E
nantioselective
u
Synthesis
o
i
f
2, 3-D
g
ihydro-1,2, 4
i
-oxadia
n
zoles o Troisi,*a Salvatore Caccamese,b Tullio Pilati,c Valeria Videtta,a Francesca Rosatoa
a
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Salento, via prov. Lecce-Monteroni, 73100 Lecce, Italy
Fax +39(832)298732; E-mail: luigino.troisi@unisalento.it
b
c
University of Catania, Dipartimento di Scienze Chimiche, viale A. Doria 6, 95125 Catania, Italy
C.N.R. Institute of Molecular Science and Technology, via G. Golgi 19, 20133 Milan, Italy
Received 14 May 2010; revised 21 May 2010
The valuable and diverse biological activity of molecules
containing isoxazoline and/or isoxazolidine,24 and 1,2,4-
oxadiazoline25 rings, in addition to the high level of asym-
metric induction observed in the heteroatom transfer to
alkenes26 and sulfides27,28 by N-protected oxaziridines,
suggest that chiral oxaziridines could be employed in the
[3+2]-cycloaddition reaction with alkenes, alkynes, and
nitriles with a good level of stereocontrol.
Abstract: Enantiomerically pure 2,3-dihydro-1,2,4-oxadiazoles
were synthesized by a cycloaddition reaction between chiral oxazir-
idines and nitriles. Assignment of absolute configurations was made
by X-ray diffraction analysis, NOESY spectra, and theoretical cal-
culations.
Key words: oxaziridines, oxadiazolines, stereoselectivity, cycload-
dition, nitriles
Herein we report the results on the [3+2]-cycloaddition re-
action of chiral oxaziridines with nitriles in order to obtain
chiral 2,3-dihydro-1,2,4-oxadiazoles.
The oxaziridine ring has received considerable attention
mainly due to the chirality of the nitrogen atom, which has
an inversion barrier of 25–32 kcal/mol in N-alkyl-substi-
tuted oxaziridines.1 Owing to the presence of an inherent-
ly weak N–O bond, due to the strained ring, oxaziridines
can be used as oxygenating agents toward enolates,2 alk-
enes,3–8 thioethers,9,10 enamines,11 organometallic re-
agents,12 and C–H13,14 and Si–H15 bonds. Moreover,
oxaziridines can be used as aminating agents in the con-
version of alcohols into O-alkyl oximes,16 thioethers into
sulfimides,17 enolates into a-aminocarbonyl compounds
and structures with C–H bonds into amines.18,19
The enantiomerically pure imines 1–329–34 were prepared
by reacting (R)- or (S)-1-phenylethylamine (1.0 mmol)
with the corresponding arylaldehyde (1.0 mmol) in anhy-
drous diethyl ether in the presence of molecular sieves for
2–3 hours.35 After completion of the reaction (yield
>95%), the solvent was removed under reduced pressure
to yield the pure imines. The oxidation of the obtained
imines 1–3 was performed according to previously report-
ed methodology (Scheme 2).36
The addition of m-chloroperoxybenzoic acid (1.1 mmol)
to imines 1–3 (1.0 mmol) in dichloromethane at 0 °C af-
forded oxaziridines 4–6 in high overall yields (85–95%)
(Table 1). All the reactions proceeded with fairly good
stereoselectivity. From each imine, two diastereomeric
oxaziridines were generated, both in a trans configura-
tion, in which the nitrogen atoms have become stereo-
centers because of the high interconversion barrier.1 The
oxaziridines were isolated in enantiomerically pure form
after column chromatography on silica gel.
Recently, we identified a novel reactivity of oxaziridines;
a [3+2]-cycloaddition reaction performed with alk-
enes,20,21 alkynes,22 and nitriles23 by selective cleavage of
the C–O bond to afford stable isoxazolidines, isoxazo-
lines, and 2,3-dihydro-1,2,4-oxadiazoles (or 1,2,4-oxadia-
zolines), respectively (Scheme 1).
O
Ar2
Ar2
R
N
Ar1
The observed trans stereoselectivity (trans/cis, 100:0)
may be due to synchronous oxygen transfer from the m-
chloroperoxybenzoic acid to the imine, which in solution
assumes the more stable trans structure, while the stereo-
chemistry of the new stereogenic centers (C3 and N2) of
the oxaziridine ring is the outcome of asymmetric induc-
tion exerted by the pre-existing closest stereocenter.21
Ar2
O
Ar2
R
R
O
N
N
Ar1
Ar1
Ar2
N
O
Ar2
R
N
Subsequently, these oxaziridines were used in their enan-
tiomerically pure form for the [3+2]-cycloaddition reac-
tion with nitriles. In detail, the oxaziridine (–)-(1¢S,2S,3S)-
4 (1.0 mmol) was reacted in refluxing benzonitrile (5.0
mL) and the reaction was followed by TLC. After 15
hours, when the oxaziridine was completely consumed,
the reaction mixture was cooled to room temperature and
concentrated to remove the solvent under reduced pres-
N
Ar1
Scheme 1 [3+2] Cycloaddition with alkenes, alkynes, and nitriles
SYNTHESIS 2010, No. 18, pp 3211–3216
Advanced online publication: 12.06.2010
DOI: 10.1055/s-0030-1258175; Art ID: Z12610SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

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L. Troisi et al.
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molecular
sieves
Ar1
O
*
Ar1CHO
MCPBA
CH2Cl2
H2N
Ph
N
N
Ar1
*
Ph
Et2O
Ph
*
1–3
4–6
Scheme 2 Synthesis of the chiral oxaziridines 4–6
Table 1 Yield and Isomeric Distribution of Chiral Oxaziridines 4–6
Entry
Ar1
1-Phenylethylamine
Total yield (%)
Isomeric distribution (%)
1
2
3
4
5
6
Ph
(S)
(R)
(S)
(R)
(S)
(R)
95
95
85
85
90
90
(–)-(1¢S,2S,3S)-4 (23); (+)-(1¢S,2R,3R)-4 (77)
(+)-(1¢R,2R,3R)-4 (25); (–)-(1¢R,2S,3S)-4 (75)
(–)-(1¢S,2S,3S)-5 (19); (+)-(1¢S,2R,3R)-5 (81)
(+)-(1¢R,2R,3R)-5 (20); (–)-(1¢R,2S,3S)-5 (80)
(–)-(1¢S,2S,3S)-6 (18); (+)-(1¢S,2R,3R)-6 (82)
(–)-(1¢R,2R,3R)-6 (18); (+)-(1¢R,2S,3S)-6 (82)
Ph
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
sure. The reaction time was considerably longer (96 h), obtained in entry 2, (+)-(1¢S,3S)-7 and (–)-(1¢S,3R)-7,
when the oxaziridines (1.0 mmol) and the benzonitrile were isolated in a similar ratio (Table 2, entry 1), as con-
(2.0 mmol) were reacted in refluxing toluene. The crude firmed by 1H and 13C NMR analysis and by specific rota-
mixture was purified by column chromatography on silica tion measurements.
gel. The oxadiazolines (+)-(1¢S,3S)-7 and (–)-(1¢S,3R)-7
However, when the oxaziridines (+)-(1¢R,2R,3R)-4 and
were isolated in a diastereomeric ratio of 81:19 (Table 2,
(–)-(1¢R,2S,3S)-4 were used in the [3+2]-cycloaddition re-
entry 2).
action, the oxadiazolines (–)-(1¢R,3R)-7 and (+)-(1¢R,3S)-
The reaction was also monitored by 1H NMR spectrosco- 7 were formed in a ratio of ~82:18. In both cases (entries
py, which showed the progressive decrease of the oxazir- 3 and 4), H and 13C NMR spectra and specific rotation
1
idine and the formation of the two oxadiazolines 7, with values confirmed that the oxadiazolines are enantiomers
the same diastereomeric ratio of 81:19.
of the products formed from (+)-(1¢S,2R,3R)-4 and (–)-
(1¢S,2S,3S)-4 (cf. entries 1 and 2 with entries 3 and 4).
When the oxaziridine (+)-(1¢S,2R,3R)-4 was reacted un-
der the usual conditions, the same diastereomers that were
Table 2 Synthesis of 2,3-Dihydro-1,2,4-oxadiazoles 7–10
O
O
*
Ar2
140 °C
*
Ph
N
Ar2
N
Ph
N
Ar1
15–20 h
N
*
Ar1
4–6
7–10
Entry
Oxaziridine
Ar1
Ar2
Ph
Ph
Ph
Ph
Total yield (%) Isomeric distribution (%)a and specific rotation [a]b
1
2
3
4
5
6
7
8
(+)-(1¢S,2R,3R)-4
(–)-(1¢S,2S,3S)-4
(–)-(1¢R,2S,3S)-4
(+)-(1¢R,2R,3R)-4
(+)-(1¢S,2R,3R)-5
(+)-(1¢R,2R,3R)-5
(–)-(1¢R,2R,3R)-6
(–)-(1¢R,2R,3R)-4
Ph
Ph
Ph
Ph
75
73
70
69
57
62
79
81
(1¢S,3S)-7 (80) [a] +59.2; (1¢S,3R)-7 (20) [a] –60.6
(1¢S,3S)-7 (81) [a] +58.5; (1¢S,3R)-7 (19) [a] –60.0
(1¢R,3R)-7 (82) [a] –61.4; (1¢R,3S)-7 (18) [a] +62.8
(1¢R,3R)-7 (80) [a] –60.8; (1¢R,3S)-7 (20) [a] +62.0
(1¢S,3S)-8 (71) [a] +77.5; (1¢S,3R)-8 (29) [a] –72.1
(1¢R,3R)-8 (76) [a] –78.0; (1¢R,3S)-8 (24) [a] +71.3
(1¢R,3R)-9 (74) [a] –38.5; (1¢R,3S)-9 (26) [a] +27.0
(1¢R,3R)-10 (70) [a] –34.9; (1¢R,3S)-10 (30) [a] +38.7
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
BTzc
4-MeC6H4
Ph
a Isomeric distribution was calculated by 1H NMR spectroscopy on the crude product.
b For specific details see the experimental section.
c BTz = benzothiazol-2-yl.
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Enantioselective Synthesis of 2,3-Dihydro-1,2,4-oxadiazoles
3213
A similar pathway was observed with the oxaziridine 5. In
detail, from reaction of oxaziridine (+)-(1¢S,2R,3R)-5 with
the benzonitrile gave the oxadiazolines (+)-(1¢S,3S)-8
(71%) and (–)-(1¢S,3R)-8 (29%), while the oxaziridine
(+)-(1¢R,2R,3R)-5 gave the oxadiazolines (–)-(1¢R,3R)-8
(76%) and (+)-(1¢R,3S)-8 (24%). The results were con-
firmed again by 1H and 13C NMR spectra and specific ro-
tation values.
Ar
Ar
N
Ar
N
N
O
O
Ph
O
N
∗
N
∗
Ph
N
Ph
∗
Ph
Ph
∗
Ph
∗
Ar
N
The same pathway was observed in the cycloaddition re-
action either between oxaziridine 6 and benzonitrile (en-
try 7) or between oxaziridine 4 and benzothiazole-2-
carbonitrile (entry 8).
O
Ph
*
N
Ph
*
The structure of one of the less abundant diastereomers,
specifically the compound (+)-(1¢R,3S)-10, was obtained
by X-ray diffraction analysis (Figure 1).37
Scheme 3 Mechanism for 2,3-dihydro-1,2,4-oxadiazoles synthesis
formations of these configurations are shown in Figure 2,
structures 2A and 2B, respectively. The difference in the
total energy (DE) of these diastereomers is 2.27 kcal/mol;
the configuration (–)-(1¢R,3R)-7 is at lower relative ener-
gy (0 kcal/mol). In these cases the trans relationship be-
tween the substituent at C3 and the substituent at N2 was
chosen. If we suppose, instead, that there is a cis relation-
ship between these substituents in the (–)-(1¢R,3R)-7 and
(+)-(1¢R,3S)-7 diastereomers, as shown in Figure 2, struc-
tures 2C and 2D, respectively, DE values obtained by cal-
culation were 4.13 and 2.65 kcal/mol, respectively. Thus,
the most probable configuration, justified also by the cy-
cloaddition stereoselectivity, is the trans (1¢R,3R) config-
uration.
The conformational search for each diastereomer was per-
formed by molecular mechanics calculation through an
iterative process using the MM2 force field by the Chem-
Bio 3D Ultra package and a molecular dynamic program
with 10000 steps and a target temperature of 300 K was
applied to obtain the minimum energy conformation for
the configurations shown in Figure 2. The bond lengths
and bond angles of the heterocyclic ring used were identi-
cal for all diastereomers.
Figure 1 Plot of compound (+)-(1¢R,3S)-10 with partial numbering
scheme; ellipsoids at 50% probability level, H atoms not to scale
The stereoselectivity in the formation of the 2,3-dihydro-
1,2,4-oxadiazoles was attributed to the stereocontrol ex-
erted by the stereocenter external to the oxaziridine ring
bonded to the nitrogen. In fact, the analysis of the results
reported in Table 2 indicates that diastereomeric oxadia-
zolines (1¢R,3R) were predominantly formed from all ox-
aziridines that contained the (1¢R)-stereocenter (entries 3,
4, and 6–8), while diastereomeric oxadiazolines (1¢S,3S)
were generated in a greater amount from oxaziridines that
contained the (1¢S)-stereocenter (entries 1, 2, and 5).
Therefore, C3 in the 1,2,4-oxadiazolines did not necessar-
ily retain the starting absolute configuration of the oxazir-
idine. This suggests that the [3+2] cycloaddition occur
according to the mechanism reported in Scheme 3. In de-
tail, initially the oxaziridine oxygen attacks the carbon on
the nitrile and then the nitrogen of the nitrile attacks the
oxaziridine C3, which, influenced by the pre-existing ste-
reocenters, rotates giving the more stable diastereomer.
Moreover, NOESY measurements on the diastereomer
(+)-(1¢R,3S)-10 showed that the substituents on N2 and
C3 adopt and strongly maintain a stable trans configura-
tion at room temperature and also in deuterochloroform
solution. As consequence, N2 of the oxadiazoline became
a stable stereocenter with known configuration always op-
posite to that of C3, i.e. (S)-N2 vs (R)-C3 and vice versa.
In conclusion, the described methodology afforded chiral
2,3-dihydro-1,2,4-oxadiazoles with good yield, regio- and
stereoselectivity. In detail: (a) the oxaziridine rings were
opened along the C–O bond and the addition to –CN was
regiocontrolled, specifically the oxygen attacks the nitrile
carbon and the carbon bonds to the nitrile nitrogen; (b)
only trans-oxadiazolines were isolated and the absolute
configuration of the various chiral centers was assigned
by X-ray diffraction analysis, NOESY measurements, and
theoretical calculations.
The configurational assignment was also based on com-
putational methods of the relative energy of diastereomers
(–)-(1¢R,3R)-7 and (+)-(1¢R,3S)-7. The most stable con-
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L. Troisi et al.
PAPER
Figure 2 The most stable conformations of compound 7
All reactions were performed under an atmosphere of N2 in oven-
dried glassware, using syringe/septum cap techniques. Reagents
were generally the best quality commercial grade and used without
further purification unless otherwise indicated. Et2O and THF were
purified by distillation from Na before use. CH2Cl2 was distilled
from CaH2 before use. Petroleum ether (PE) refers to the fraction
to Taguchi’s protocol35 (GC monitoring). After 1–3 h, the molecular
sieves were filtered and the mixture was concentrated under vacu-
um to obtain the pure imine. The spectroscopic data observed were
in agreement with those reported in the literature for the same imi-
nes.29–34
1
with bp 40–60 °C. H and 13C NMR spectra were recorded on a
Oxaziridines 4–6; General Procedure
Bruker Avance 400 apparatus (400.13 and 100.62 MHz, for 1H and
13C, respectively) with CDCl3 as solvent and TMS as internal stan-
dard [d = 7.26 (1H); d = 77.0 (13C)]. IR spectra were recorded with
an FT-IR spectrophotometer Digilab Scimitar Series FTS 2000. Po-
larimetric measurements were performed by a Jasco P-120 polarim-
eter. GC-MS analyses were performed with an Agilent
Technologies 6850 series II gas chromatograph (5% phenyl-poly-
methylsiloxane capillary column, 30 m, 0.25 mm i.d.), equipped
with a 5973 Network mass-selective detector operating at 70 eV.
The electrospray ionization [HRMS (ESI)] experiments were car-
ried out in a hybrid QqTOF mass spectrometer (PE SCIEX–
QSTAR) equipped with a ion spray ionization source. MS (+) spec-
tra were acquired by direct infusion (5 mL/min) of a soln containing
the appropriate sample (10 pmol/mL), dissolved in 0.1% AcOH in
MeOH–H2O (50:50) soln at the optimum ion voltage of 4800 V.
The N2 gas flow was set at 2.07 bar and the potentials of the orifice,
the focusing ring, and the skimmer were kept at 30 V, 50 V, and 25
V relative to ground, respectively. Melting points were determined
using an Electrothermal melting point apparatus and are uncorrect-
ed. TLC was performed on Merck silica gel plates with F-254 indi-
cator; viewing was by UV light (254 nm). Column chromatography
was performed on silica gel (63–200 mm) using PE–Et2O or PE–
EtOAc mixtures.
A small excess of mCPBA (1.1 mmol) in CH2Cl2 (3 mL) was added
to a soln of imine (1.0 mmol) dissolved in CH2Cl2 (5 mL) that was
stirred and cooled (0–5 °C). When the reaction was complete, the
organic mixture was washed with 5% Na2SO3 soln (2 × 5 mL) and
5% Na2CO3 soln (5 mL), dried (anhyd Na2SO4), and concentrated
in vacuo; the crude product was purified by column chromatogra-
phy [silica gel partly deactivated with Et3N, PE–Et2O, 95:5 (phenyl-
oxaziridines) and PE–Et2O, 8:2 (all other oxaziridines)]. The
spectroscopic data observed were in agreement with those reported
in the literature for the same imines.21
Oxadiazoles 7–9; General Procedure
A soln of oxaziridine 4–6 (1.0 mmol) in PhCN (3 mL) was heated
at 140 °C under magnetic stirring. When TLC showed the reaction
to be complete, the soln was cooled to r.t. and then the PhCN was
distilled off under reduced pressure to give a yellow crude material.
The products were isolated by flash chromatography (silica gel,
PE–Et2O, 95:5) and identified by spectroscopic analysis; GC-MS:
all compounds were unstable on the chromatography column.
3,5-Diphenyl-2-(1-phenylethyl)-2,3-dihydro-1,2,4-oxadiazole
(7)
(+)-(1¢S,3S)-7
Yellow oil; [a]D24.0 +59.2 (c 0.02, CHCl3).
Imines 1–3; General Procedure
IR (CHCl3): 3030, 2989, 2926, 1664, 1493, 1452, 1322, 1220 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.67 (d, J = 6.4 Hz, 3 H, CH3),
4.11 (q, J = 6.4 Hz, 1 H, CH3CHPh), 5.90 (s, 1 H, NCHN), 7.08–
The appropriate 1-phenylethylamine (1 mmol) and the correspond-
ing aldehyde (1 mmol) were dissolved in anhyd Et2O (20 mL) in the
presence of molecular sieves (4 Å, 1.6 mm pellets, 7.0 g), according
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Enantioselective Synthesis of 2,3-Dihydro-1,2,4-oxadiazoles
3215
7.10 (m, 2 H, HPh), 7.22–7.58 (m, 11 H, HPh), 8.05 (d, J = 7.5 Hz, 2
HRMS (ESI): m/z [M + H]+ calcd for C23H23N2O: 343.1732; found:
H, HPh).
343.1734.
13C NMR (100.62 MHz, CDCl3): d = 21.7, 67.2, 89.3, 125.6, 126.0,
126.4, 128.0, 128.1, 128.3, 128.6, 126.8, 129.1, 132.1, 139.9, 140.9,
161.2.
HRMS (ESI): m/z [M + H]+ calcd for C22H21N2O: 329.1576; found:
329.1578.
(+)-(1¢R,3S)-9
Yellow oil; [a]D24.0 +27.0 (c 0.02, CHCl3).
IR (CHCl3): 3020, 2928, 2857, 1657, 1452, 1375, 1090 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.52 (d, J = 6.7 Hz, 3 H, CH3CH),
2.33 (s, 3 H, PhCH3), 4.20 (q, J = 6.7 Hz, 1 H, CH3CHPh), 6.09 (s,
1 H, NCHN), 7.16 (d, J = 8.0 Hz, 2 H, HPh), 7.28–7.49 (m, 10 H,
HPh), 7.77 (d, J = 8.0 Hz, 2 H, HPh).
(–)-(1¢S,3R)-7
Yellow oil; [a]D24.0 –60.0 (c 0.02, CHCl3).
IR (CHCl3): 3030, 2988, 2927, 1655, 1495, 1452, 1322, 1220 cm–1.
13C NMR (100.62 MHz, CDCl3): d = 19.4, 21.2, 66.2, 88.9, 125.5,
126.6, 127.6, 127.9, 128.4, 128.5, 129.2, 130.9, 131.8, 137.7, 137.9,
141.3, 160.9.
1H NMR (400 MHz, CDCl3): d = 1.54 (d, J = 6.6 Hz, 3 H, CH3),
4.22 (q, J = 6.6 Hz, 1 H, CH3CHPh), 6.13 (s, 1 H, NCHN), 7.22–
7.52 (m, 13 H, HPh), 7.78(d, J = 7.0 Hz, 2 H, HPh).
HRMS (ESI): m/z [M + H]+ calcd for C23H23N2O: 343.1732; found:
343.1731.
13C NMR (100.62 MHz, CDCl3): d = 19.3, 66.2, 88.9, 125.5, 126.7,
127.1, 127.6, 127.9, 128.2, 128.4, 128.5, 129.1, 131.8, 140.6, 141.2,
161.0.
HRMS (ESI): m/z [M + H]+ calcd for C22H21N2O: 329.1576; found:
329.1577.
5-(Benzothiazol-2-yl)-3-phenyl-2-(1-phenylethyl)-2,3-dihydro-
1,2,4-oxadiazole (10)
A soln of benzothiazole-2-carbonitrile (BTCN, 1.5 mmol) and ox-
aziridine 4 (1.0 mmol) in toluene (10 mL) was refluxed under mag-
netic stirring (TLC monitoring). When the reaction was complete,
the soln was cooled to r.t. and the solvent was evaporated under re-
duced pressure giving a yellow crude material. The products were
isolated by flash chromatography (silica gel, PE–Et2O, 9:1) and
identified by spectroscopic analysis; GC-MS: both compounds
were unstable on the chromatography column.
3-(4-Chlorophenyl)-5-phenyl-2-(1-phenylethyl)-2,3-dihydro-
1,2,4-oxadiazole (8)
(+)-(1¢S,3S)-8
Yellow solid; mp 61.5–63.0 °C; [a]D24.0 +77.5 (c 0.02, CHCl3).
IR (CHCl3): 3030, 2987, 2927, 2855, 1654, 1492, 1452, 1322, 1090
cm–1.
(–)-(1¢R,3R)-10
1H NMR (400 MHz, CDCl3): d = 1.66 (d, J = 6.3 Hz, 3 H, CH3),
4.10 (q, J = 6.3 Hz, 1 H, CH3CHPh), 5.85 (s, 1 H, NCHN), 7.02 (d,
J = 8.3 Hz, 2 H, HPh), 7.19 (d, J = 8.3 Hz, 2 H, HPh), 7.31–7.36 (m,
5 H, HPh), 7.48 (t, J = 7.7 Hz, 2 H, HPh), 7.55 (d, J = 7.3 Hz, 1 H,
HPh), 8.02 (d, J = 8.3 Hz, 2 H, HPh).
13C NMR (100.62 MHz, CDCl3): d = 21.7, 67.3, 88.8, 125.4, 127.9,
128.3, 128.4, 128.6, 128.8, 128.9, 132.2, 133.8, 138.6, 140.7, 161.4.
Yellow solid; mp 90–92 °C; [a]D24.0 –34.9 (c 0.02, CHCl3).
IR (CHCl3): 3030, 3007, 2927, 2854, 1655, 1495, 1454, 1376, 1310,
1080 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.73 (d, J = 6.4 Hz, 3 H, CH3CH),
4.23 (q, J = 6.4 Hz, 1 H, CH3CHPh), 6.00 (s, 1 H, NCHN), 7.18–
7.40 (m, 10 H, HPh), 7.50–7.60 (m, 2 H, HBTz), 7.97 (d, J = 7.8 Hz,
1 H, HBTz), 8.24 (d, J = 8.2 Hz, 1 H, HBTz).
13C NMR (100.62 MHz, CDCl3): d = 21.7, 67.6, 89.5, 121.8, 124.9,
125.0, 126.6, 127.0, 127.2, 127.9, 128.3, 128.8, 131.3, 136.0, 137.1,
140.3, 153.4, 156.4.
HRMS (ESI): m/z [M + H]+ calcd for C22H20ClN2O: 363.1186;
found: 363.1187.
(–)-(1¢S,3R)-8
Yellow oil; [a]D24.0 –72.1 (c 0.02, CHCl3).
HRMS (ESI): m/z [M + H]+ calcd for C23H20N3OS: 386.1249;
found: 386.1751.
IR (CHCl3): 3030, 2926, 2855, 1656, 1490, 1457, 1375, 1091 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.53 (d, J = 6.6 Hz, 3 H, CH3),
4.23 (q, J = 6.6 Hz, 1 H, CH3CHPh), 6.08 (s, 1 H, NCHN), 7.30–
7.42 (m, 10 H, HPh), 7.48 (t, J = 7.4 Hz, 2 H, HPh), 7.77 (d, J = 8.4
Hz, 2 H, HPh).
13C NMR (100.62 MHz, CDCl3): d = 22.7, 66.1, 88.1, 125.2, 127.8,
128.1, 128.2, 128.3, 128.4, 128.5, 132.0, 134.0, 139.2, 140.8, 161.3.
(+)-(1¢R,3S)-10
Colorless crystal; mp 78–80 °C; [a]D24.0 +38.7 (c 0.02, CHCl3).
IR (CHCl3): 3030, 3008, 2927, 2856, 1661, 1496, 1455, 1377, 1311,
1080 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.63 (d, J = 6.7 Hz, 3 H, CH3CH),
4.33 (q, J = 6.7 Hz, 1 H, CH3CHPh), 6.16 (s, 1 H, NCHN), 7.27–
7.63 (m, 12 H, HPh, HBTz), 7.91 (d, J = 7.8 Hz, 1 H, HBTz), 8.19 (d,
J = 8.2 Hz, 1 H, HBTz).
HRMS (ESI): m/z [M + H]+ calcd for C22H20ClN2O: 363.1186;
found: 363.1185.
13C NMR (100.62 MHz, CDCl3): d = 18.5, 66.5, 88.8, 121.8, 124.9,
125.3, 126.8, 127.0, 127.7, 128.0, 128.5, 129.1, 131.8, 135.9, 139.3,
139.5, 153.1, 156.2.
HRMS (ESI): m/z [M + H]+ calcd for C23H20N3OS: 386.1249;
found: 386.1750.
5-Phenyl-2-(1-phenylethyl)-3-(4-tolyl)-2,3-dihydro-1,2,4-oxadi-
azole (9)
(–)-(1¢R,3R)-9
Yellow oil; [a]D24.0 –38.5 (c 0.02, CHCl3).
IR (CHCl3): 3020, 2927, 2858, 1657, 1453, 1375, 1090 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.65 (d, J = 6.4 Hz, 3 H, CH3CH),
2.27 (s, 3 H, PhCH3), 4.09 (q, J = 6.4 Hz, 1 H, CH3CHPh), 5.86 (s,
1 H, NCHN), 6.97 (d, J = 8.1 Hz, 2 H, HPh), 7.04 (d, J = 8.1 Hz, 2
H, HPh), 7.28–7.38 (m, 5 H, HPh), 7.47 (t, J = 7.2 Hz, 2 H, HPh), 7.54
(d, J = 7.3 Hz, 1 H, HPh), 8.03 (d, J = 8.3 Hz, 2 H, HPh).
13C NMR (CDCl3): d = 21.1, 22.8, 67.2, 89.3, 126.3, 128.1, 128.4,
128.6, 128.7, 128.8, 129.0, 129.1, 132.0, 137.1, 137.7, 141.1, 161.1.
Acknowledgment
This work was carried out under the framework of the University of
Salento and the C.I.N.M.P.I.S. (Consorzio Interuniversitario Nazio-
nale Metodologie e Processi Innovativi di Sintesi) for the financial
support.
Synthesis 2010, No. 18, 3211–3216 © Thieme Stuttgart · New York

3216
L. Troisi et al.
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(37) X-ray crystallographic data for 10: C23H19N3OS, Mr =
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space group P21, a = 11.6205(12), b = 6.2907(5),
c = 13.6858(15) Å, b = 96.168(10)°, V = 994.66(17) Å3,
Z = 2, Dc = 1.287 g cm–3, l(Mo-Ka) = 0.71073 Å, m(Mo-
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data collection below 2q = 55°, 4024 data collected, 3153
independent, 2804 observed [I > 2s(I)]. The structure was
solved by SIR200238a, and refined on F2 by SHELX9738b
.
Final R = 0.0369, wR = 0.0944, on observed data, goodness-
of-fit = 1.033; Flack parameters –0.03 (8); –0.21 < Dr < 0.25
eÅ–3. Crystallographic data, excluding structure factors,
have been deposited with the Cambridge Crystallographic
Data Centre as Supplementary Publication Number CCDC
767590. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44(1223)336033 or e-mail:
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Synthesis 2010, No. 18, 3211–3216 © Thieme Stuttgart · New York