Poly(ethylene glycol) supported liquid-phase synthesis of 1,2,4-oxadiazolines

Article abstract of DOI:10.1055/s-2003-40511

The liquid-phase synthesis of oxadiazolines via 1,3-dipolar cycloaddition reaction on poly(ethylene glycol) support (PEG) is described. 1,3-Dipolar cycloadditions of nitrile oxide generated in situ on soluble polymer with a variety of imines provided a li

Full text of DOI:10.1055/s-2003-40511

PAPER
1569
Poly(ethylene glycol) Supported Liquid-Phase Synthesis of 1,2,4-
Oxadiazolines
S
ynthesis of 1,2,4-
u
O
xadiazoline
-
s
Feng Lin, Jian Zhang, Sun-Liang Cui, Yan-Guang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
Fax +86(571)87951512; E-mail: orgwyg@css.zju.edu.cn
Received 24 March 2003
itoring the reactions. Liquid-phase synthesis profits from
both the advantageous features of homogeneous solution
chemistry (high reactivity, lack of diffusion phenomena
and ease of analysis without following the cleavage-and-
Abstract: The liquid-phase synthesis of oxadiazolines via 1,3-di-
polar cycloaddition reaction on poly(ethylene glycol) support
(PEG) is described. 1,3-Dipolar cycloadditions of nitrile oxide gen-
erated in situ on soluble polymer with a variety of imines provided
a library of 1,2,4-oxadiazolines in good yields and purity. The reac- check technique) and of solid-phase methods (use of ex-
tions were run in the homogeneous phase and the synthetic sequen-
cess reagents and easy isolation and purification of prod-
ucts).3 Moreover, owing to the homogeneity of liquid-
ces were performed in parallel one-pot fashion. Quantitative
conversion in the 1,3-dipolar cycloaddition reaction was verified by
phase reactions, the reaction conditions can be readily
1H NMR analysis. The polymer bound products were isolated in ex-
shifted from solution-phase systems without large chang-
cellent yields by simple precipitation of the soluble support.
es, and the amount of the excessive regents is less than
Key words: 1,3-dipolar cycloaddition, soluble polymer, liquid-
that in solid-phase reactions. Among the various soluble
phase synthesis, oxadiazolines, poly(ethylene glycol)
polymers, (polyethylene glycol) (PEG) is the most useful
and promising.4 PEG is soluble in most common solvents
and has a strong propensity to crystallize. The recent in-
The polymer-supported synthesis of small heterocyclic
terest in PEG-supported synthesis, including liquid-phase
molecules is the subject of intense research activity,1 since
combinatorial strategies, prompts us to report our results.
it represents one of the most promising ways to generate
Substituted 1,2,4-oxadiazolines offer a high degree of
small molecular libraries in the field of combinatorial
chemistry.2 The availability of general reaction protocols
for organic molecule libraries which lead to high yields of
pure products is essential for the success of combinatorial
chemistry. Solid-phase synthesis can be complicated by
heterogeneous reaction conditions, the requirement for
large quantities of solid support and the difficulty in mon-
structure diversity and have proven to be very important
in medicinal chemistry.5 Solution methods for their prep-
aration via 1,3-dipolar cycloaddition of imines with nitrile
oxides are well documented.6 In connection with our re-
search on the PEG-supported liquid-phase synthesis,7 we
have synthesized a small library of 1,2,4-oxadiazolines
HOOC
CHO
O
1
OH
dihydroxy-PEG
MW=4000
NH2OH HCl
CHO
trioctylamine
r.t.
O
DCC , DMAP, r.t.
2
Cl
O
O
O
5
NCS
O
r.t.
trioctylamine
r.t.
N OH
N OH
3
4
N
O
O
CH3ONa
N
O
R1
H3CO
O
R1
O
N
R3
CH3OH r.t.
R2
N
6
R2
R3
7
R3
R1
R2
R3 NH2
N
O
molecular sieves
r.t.
R1
R2
5
Scheme 1
Synthesis 2003, No. 10, Print: 21 07 2003.
Art Id.1437-210X,E;2003,0,10,1569,1573,ftx,en;F02303SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1570
X.-F. Lin et al.
PAPER
which exploits three sites of chemical diversity through a
1,3-dipolar cycloaddition of imines with nitrile oxide on
PEG support. Commercially available difunctional PEG
4000 was chosen as soluble polymer support. Our efforts
at obtaining a representative library of 1,2,4-oxadiazo-
lines are presented below.
Table 1 Liquid-Phase Synthesis of 4,5-Dihydro-1,2,4-oxadiazoles
7a–m
Prod- R1
uct
R2
R3
Yield Purity
(%)a (%)b
7a
7b
H
H
91
93
96
89
As show in Scheme 1, the aldehyde was attached to the
PEG 4000 support by esterification of PEG with 4-car-
boxybenzaldehyde (1) in the presence of 1,3-dicyclohex-
ylcarbodiimide (DCC) and 4-(dimethylamino)pyridine
(DMAP) in anhydrous CH2Cl2 at room temperature for 24
hours. The conversion of terminal hydroxyl groups on
PEG was determined by 1H NMR analysis to be quantita-
tive. The PEG-bound aldehyde 2 was converted to oxime
3 by treating with hydroxylamine hydrochloride in the
presence of trioctylamine in CH2Cl2 at room temperature.8
The reaction went to completion over 24 hours and gave a
high yield of the corresponding PEG-bound aldoxime 3.
Reaction of the aldoxime 3 with N-chlorosuccinimide
(NCS) in CH2Cl2 afforded the PEG-bound chlorooxime 4,
which is a precursor to the nitrile oxide. To this was added
excess imines 5 as a dichloromethane solution before gen-
erating the nitrile oxide by slow addition of trioctylamine
over a period of two hours. The resulting mixture was
shaken at room temperature overnight. The PEG-bound
1,2,4-oxadiazolines 6 were obtained by precipitation.
Quantitative conversion in the 1,3-dipolar cycloaddition
F
7c
7d
7e
7f
H
H
H
H
H
86
88
79
84
82
95
93
91
97
96
CH3
F
F
CH3
OCH3
7g
NO2
7h
7i
H
H
90
86
98
91
O
O
O
O
F
F
7j
Me
H
83
87
90
94
1
reaction was verified by H NMR analysis. The target
compounds 7 were released from the PEG by treatment of
the polymer bound products 6 with 0.1 N NaOMe in
methanol at room temperature. Normally, cleavage was
completed after stirring in 0.1N NaOMe/MeOH for 6
hours.
7k
O
O
O
O
7l
H
H
Bu
89
91
95
93
A variety of imines (prepared by incubating the aldehyde
and the amine in dichloromethane overnight at room tem-
perature in the presence of activated 4 Å molecular sieves)
reacted well with the soluble polymer-supported chlo-
rooxime under similar reaction conditions to afford the
corresponding 1,2,4-oxadiazolines in good yields and pu-
rity. Both aromatic and aliphatic aldimines produced good
yields of products. Table 1 summarizes some of the initial
results we have obtained by application of the above
methodology.
7m
F
F
a Yields refer to products cleaved from PEG.
b Purities were determined by HPLC analysis.
Ph
molecular sieves
H2N
Ph
N
+
PhCHO
Ph
Me
8
Me
In the next stage of our work we developed the first exam-
ple of stereoselective cycloaddition between PEG-sup-
ported nitrile oxide and enantiopure imine 8. As shown in
Scheme 2, the latter compound was synthesised starting
from benzaldehyde and (S)-1-phenylethylamine as the
chiral building block. Clean PEG-supported nitrile oxide
cycloaddition to enantiopure 8 was performed by treat-
ment with PEG-bound chlorooxime 4 in the presence of
trioctylamine. The usual reaction workup gave a mixture
of inseparable PEG-supported 1,2,4-oxadiazoline 9 and
cleavage from the support afforded 1,2,4-oxadiazoline 10.
It can be noted that, although the 1,2,4-oxadiazolines 10
were obtained with satisfactory overall yield (92%) and
purity (95%), the stereoselectivity of cycloaddition was
disappointing, the ratio of the mixtrure of 10 being 11:9.
N
N
1) NCS
O
O
O
3
2) 8, trioctylamine
Ph
Me
Ph
9
N
N
CH3ONa
CH3OH
O
MeO2C
Ph
Me
Ph
10 (11:9 mixture)
Scheme 2
Synthesis 2003, No. 10, 1569–1573 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,2,4-Oxadiazolines
1571
6a
In summary, we have demonstrated that liquid-phase
methodology can be applied efficiently in parallel one-pot
synthesis of 1,2,4-oxadiazoline library. All reactions in-
volved here are highly efficient in giving the desired com-
pounds at room temperature. Crude products are usually
obtained in high purity and high yield just by simple pre-
cipitation and washing, providing their direct use in pri-
mary biological assays without further purification.
1H NMR (500 MHz, CDCl3): = 3.50–3.83 (m, PEG backbone,
OCH2CH2O), 4.46 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 6.54 (s, 1
H), 6.78 (d, J = 8 Hz, 2 H), 7.12–7.18 (m, 3 H), 7.46 (m, 3 H), 7.60
(m, 2 H), 7.68 (d, J = 8 Hz, 2 H), 8.01 (d, J = 8 Hz, 2 H).
6b
1H NMR (500 MHz, CDCl3): = 3.47–3.85 (m, PEG backbone,
OCH2CH2O), 4.46 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 6.46 (s, 1
H), 6.79–6.88 (m, 4 H), 7.45 (m, 3 H), 7.58 (m, 2 H), 7.64 (d, J = 8
Hz, 2 H), 8.01 (d, J = 8 Hz, 2 H).
1H NMR spectra were obtained on a Bruker Avance DMX 500 MHz
instrument. FT-IR spectra were recorded on Perkin-Elmer 298 spec-
trophotometer. MS data were recorded on HP5989B instrument. El-
emental analyses were carried out on a EA-1110 elemental
analyzer. HPLC analysis was carried out on Agilent 1100
(250 × 4.6mm C18 Column, gradient elution 80% MeOH and 20%
H2O, 0.8 mL/min, UV detection at = 254 nm). Mps were deter-
mined on X4 mp apparatus and are uncorrected. All the chemicals
were used without further purification.
6c
1H NMR (500 MHz, CDCl3): = 3.50–3.85 (m, PEG backbone,
OCH2CH2O), 4.46 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 6.48 (s, 1
H), 6.68 (d, J = 8 Hz, 2 H), 6.97 (d, J = 8 Hz, 2 H), 7.45 (m, 3 H),
7.58 (m, 2 H), 7.65 (d, J = 8 Hz, 2 H), 8.00 (d, J = 8 Hz, 2 H).
6d
1H NMR (500 MHz, CDCl3): = 3.50–3.85 (m, PEG backbone,
OCH2CH2O), 4.46 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 6.53 (s, 1
H), 6.78 (d, J = 8 Hz, 2 H), 7.13–7.21 (m, 5 H), 7.58 (m, 2 H), 7.66
(d, J = 8 Hz, 2 H), 8.00 (d, J = 8 Hz, 2 H).
The PEG-Bound Aldehyde 2; General Procedure
4-Carboxybenzaldehyde (1.5 g, 10 mmol), DCC (2.06 g, 10 mmol)
and DMAP (305 mg, 2.5 mmol) were added to PEG (5 g, 2.5 mmol)
in CH2Cl2 (40 mL) and the mixture was stirred at r.t. for 24 h. The
precipitate was removed by filtration and the filtrate was diluted
with i-PrOH (200 mL). CH2Cl2 was removed under reduced pres-
sure and the residue was cooled to –20 °C. The white precipitate
was collected and washed several times with i-PrOH and Et2O. Af-
ter drying in vacuum, the PEG-bound aldehyde 2 was obtained as a
white powder.
6e
1H NMR (500 MHz, CDCl3): = 2.26 (s, 3 H), 3.50–3.85 (m, PEG
backbone, OCH2CH2O), 4.46 (t, J = 5 Hz, 2 H, PEG–OCH2OCO),
6.45 (s, 1 H), 6.67 (d, J = 8 Hz, 2 H), 6.98 (d, J = 8 Hz, 2 H), 7.14
(t, J = 8.5 Hz, 2 H), 7.57 (dd, J = 5.5 Hz, 5.4 Hz, 2 H), 7.63 (d, J = 8
Hz, 2 H), 7.98 (d, J = 8 Hz, 2 H).
1H NMR (500 MHz, CDCl3): = 3.50–3.86 (m, PEG backbone,
OCH2CH2O), 4.51 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 7.96 (d,
J = 8 Hz, 2 H), 8.22 (d, J = 8 Hz, 2 H), 10.11 (s, 1 H).
6f
1H NMR (500M Hz, CDCl3): = 3.50–3.83 (m, PEG backbone,
OCH2CH2O), 3.85 (s, 3 H), 4.46 (t, J = 5 Hz, 2 H, PEG–
OCH2OCO), 6.50 (s, 1 H), 6.76 (d, J = 7.6 Hz, 2 H), 6.97 (d, J = 8.6
Hz, 2 H), 7.11–7.17 (m, 3 H), 7.51 (d, J = 8.6 Hz, 2 H), 7.65 (d,
J = 8 Hz, 2 H), 8.00 (d, J = 8 Hz, 2 H).
The PEG-Bound Adoxime 3; General Procedure
PEG-bound aldehyde 2 (2.5 mmol), NH2OH·HCl (15 mmol) and
trioctylamine (20 mmol) were added to CH2Cl2 (40 mL) at r.t. and
the mixture was stirred for 24 h. i-PrOH (200 mL) was added to the
reaction mixture and the CH2Cl2 was removed under reduced pres-
sure. The residue was cooled to –20 °C and the white precipitate
was collected. The solid was washed with i-PrOH and Et2O several
times. After drying in vacuum, the solid was stored to be used in the
next step of the synthesis.
6g
1H NMR (500 MHz, CDCl3): = 3.49–3.83 (m, PEG backbone,
OCH2CH2O), 4.46 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 6.63 (s, 1
H), 6.83 (d, J = 7.6 Hz, 2 H), 7.18–7.25 (m, 3 H), 7.66–7.69 (m, 3
H), 7.96 (d, J = 7.7 Hz, 2 H), 8.02 (d, J = 8.4 Hz, 2 H), 8.33 (d,
J = 7.7 Hz, 2 H), 8.47 (s, 1 H).
1H NMR (500 MHz, CDCl3): = 3.50–3.85 (m, PEG backbone,
OCH2CH2O), 4.48 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 7.64 (d,
J = 8 Hz, 2 H), 8.05 (d, J = 8 Hz, 2 H), 8.13 (s, 1 H), 8.7–9.4 (br, 1
H).
6h
1H NMR (500 MHz, CDCl3): = 3.49–3.83 (m, PEG backbone,
OCH2CH2O), 4.46 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 6.02 (d,
J = 5 Hz, 2 H), 6.44 (s, 1 H), 6.78 (d, J = 7.5 Hz, 2 H), 6.84 (d,
J = 7.9 Hz, 1 H), 7.00 (d, J = 7.9 Hz, 1 H), 7.12–7.18 (m, 4 H), 7.64
(d, J = 8 Hz, 2 H), 8.00 (d, J = 8 Hz, 2 H).
The PEG-Bound 1,2,4-oxadiazolines 6 and 9; General Proce-
dure
Solutions of imines were prepared by incubating the aldehyde (2
mmol) and the amine (2 mmol) in CH2Cl2 (4 mL) overnight at r.t. in
the presence of activated 4 Å molecular sieves and were used direct-
ly in the next reaction without further purification. To a solution of
PEG-bound aldoxime 3 (0.5 mmol) in anhyd CH2Cl2 (5 mL) was
added NCS (134 mg, 1 mmol). After stirring the mixture at r.t. for
2 h, the above prepared solution of the corresponding imine 5 (2
mmol) in CH2Cl2 (4 mL) was added in one portion followed by
dropwise addition of trioctylamine (0.5 mL) in CH2Cl2 (1 mL) over
2 h. The mixture was stirred overnight at r.t. Then, addition of cold
Et2O (70 mL) to the reaction mixture precipitated the solid, which
was then filtered and washed with Et2O to afford the PEG-bound
1,2,4-oxadiazoline 6 or 9.
6i
1H NMR (500 MHz, CDCl3): = 3.50–-3.83 (m, PEG backbone,
OCH2CH2O), 4.46 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 6.02 (d,
J = 5 Hz, 2 H), 6.36 (s, 1 H), 6.79 (m, 2 H), 6.83 (d, J = 8 Hz, 1 H),
6.88 (t, J = 8.7 Hz, 2 H), 6.97 (d, J = 6.3 Hz, 1 H), 7.12 (s, 1 H), 7.61
(d, J = 8 Hz, 2 H), 7.99 (d, J = 8 Hz, 2 H).
6j
1H NMR (500 MHz, CDCl3): = 1.80 (s, 3 H), 3.50–3.84 (m, PEG
backbone, OCH2CH2O), 4.44 (t, J = 5 Hz, 2 H, PEG–OCH2OCO),
6.48 (s, 1 H), 6.81 (m, 2 H), 6.88 (t, J = 8.8 Hz, 2 H), 7.37 (m, 3 H),
7.57 (d, J = 7 Hz, 2 H), 7.63 (d, J = 5.6 Hz, 2 H), 7.96 (d, J = 5.6 Hz,
2 H).
Synthesis 2003, No. 10, 1569–1573 © Thieme Stuttgart · New York

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X.-F. Lin et al.
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IR (KBr): 1724 (C=O), 1612 cm–1 (C=N).
1H NMR (500 MHz, CDCl3): = 3.50–3.84 (m, PEG backbone,
OCH2CH2O), 4.08 (d, J = 15.9 Hz, 1 H), 4.43 (d, J = 15.9 Hz, 1 H),
4.46 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 5.98 (d, J = 5 Hz, 2 H),
6.17 (s, 1 H), 6.76 (d, J = 8 Hz, 2 H), 6.83 (d, J = 8 Hz, 1 H), 7.02
(s, 1 H), 7.04 (d, J = 7.2 Hz, 2 H), 7.26 (m, 3 H), 7.76 (d, J = 8 Hz,
2 H), 8.12 (d, J = 8 Hz, 2 H).
1H NMR (500 MHz, CDCl3): = 2.25 (s, 3 H), 3.91 (s, 3 H), 6.45
(s, 1 H), 6.69 (d, J = 8 Hz, 2 H), 6.97 (d, J = 8 Hz, 2 H), 7.46 (m, 3
H), 7.59 (m, 2 H), 7.66 (d, J = 8 Hz, 2 H), 7.99 (d, J = 8 Hz, 2 H).
MS: m/z (%) = 372 (M+, 57.66), 266 (100), 235 (71.14), 195
(46.08), 105 (59.55), 91 (66.91), 77 (67.90), 65 (45.85), 51 (41.65),
Anal. Calcd for C23H20N2O3: C, 74.16; H, 5.42; N, 7.53. Found: C,
74.02; H, 5.68; N, 7.32.
6l
1H NMR (500 MHz,CDCl3): = 0.75 (t, J = 7.3 Hz, 3 H), 1.18 (m,
2 H), 1.43 (m, 2 H), 3.04 (m, 2 H), 3.50–3.84 (m, PEG backbone,
OCH2CH2O), 4.50 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 6.01 (d,
J = 5 Hz, 2 H), 6.22 (s, 1 H), 6.83 (d, J = 7.9 Hz, 2 H), 7.01 (d,
J = 7.9 Hz, 1 H), 7.09 (s, 1 H), 7.70 (d, J = 8 Hz, 2 H), 8.15 (d, J = 8
Hz, 2 H).
7d
Pale yellow, solid; mp 131–133 °C.
IR (KBr): 1727 (C=O), 1604 cm–1 (C=N).
1H NMR (500 MHz, CDCl3): = 3.91 (s, 3 H), 6.52 (s, 1 H), 6.77
(d, J = 8 Hz, 2 H), 7.12–7.20 (m, 5 H), 7.57 (m, 2 H), 7.65 (d, J = 8
Hz, 2 H), 8.00 (d, J = 8 Hz, 2 H).
6m
1H NMR (500 MHz, CDCl3): = 3.50–3.84 (m, PEG backbone,
OCH2CH2O), 4.46 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 6.44 (s, 1
H), 6.78 (q, J = 5.0 Hz, 2 H), 6.89 (q, J = 8.6 Hz, 2 H), 7.14 (t,
J = 8.6 Hz, 2 H), 7.57 (q, J = 5.0 Hz, 2 H), 7.63 (d, J = 8.5 Hz, 2 H),
7.99 (d, J = 8.5 Hz, 2 H).
MS: m/z (%) = 376 (M+, 42.02), 252 (90.26), 221 (100), 199
(54.71), 123 (38.63), 77 (87.86), 51 (41.83).
Anal. Calcd for C22H17FN2O3: C, 70.19; H, 4.56; N, 7.45. Found: C,
70.32; H, 4.46; N, 7.29.
7e
9
1H NMR (500 MHz, CDCl3): = 1.43 (d, J = 7.2 Hz, 1.35 H), 1.55
(d, J = 6.9 Hz, 1.65 H), 3.50–3.84 (m, PEG backbone, OCH2CH2O),
4.46 (t, J = 5 Hz, 2 H, PEG–OCH2OCO), 4.80 (q, J = 6.9 Hz, 0.55
H), 4.87 (q, J = 7.2 Hz, 0.45 H), 6.24 (s, 0.45 H), 6.36 (s, 0.55 H),
7.08–7.42 (m, 10 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.92 (d, J = 8.1 Hz,
1 H), 8.18 (m, 2 H).
White solid; mp 105–107 °C.
IR (KBr): 1720 (C=O), 1607 cm–1 (C=N).
1H NMR (500 MHz, CDCl3): = 2.25 (s, 3 H), 3.91 (s, 3 H), 6.46
(s, 1 H), 6.67 (d, J = 8 Hz, 2 H), 6.98 (d, J = 8 Hz, 2 H), 7.14 (t,
J = 8.5 Hz, 2 H), 7.57 (dd, J = 5.5, 5.4 Hz, 2 H), 7.64 (d, J = 8 Hz,
2 H), 7.99 (d, J = 8 Hz, 2 H).
MS: m/z (%) = 390 (M+, 10.96), 266 (41.22), 254 (47.50), 163
(54.41), 91 (41.93), 71 (35.25), 57 (74.64), 43 (100).
1,2,4-Oxadiazolines 7a–j and 10; General Procedure
The cleavage of the PEG support was accomplished by treating 6
(0.5 mmol) with 0.1 N NaOMe in MeOH (10 mL) at r.t. for 6 h.
Et2O and water were added to the reaction mixture and the organic
phase was separated. After drying (Na2SO4), the solvent was re-
moved under reduced pressure to afford the desired 1,2,4-oxadiazo-
line 7. Analytical samples were prepared by column chromatogra-
phy on silica gel (EtOAc–hexane, 1:3), if necessary.
Anal. Calcd for C23H19FN2O3: C, 70.74; H, 4.91; N, 7.18. Found: C,
70.51; H, 4.73; N, 7.36.
7f
White solid; mp 140–142 °C.
IR (KBr): 1717 (C=O), 1611 cm–1 (C=N).
1H NMR (500 MHz, CDCl3): = 3.85 (s, 3 H), 3.91 (s, 3 H), 6.50
(s, 1 H), 6.77 (d, J = 7.6 Hz, 2 H), 6.97 (d, J = 8.6 Hz, 2 H), 7.11–
7.18 (m, 3 H), 7.51 (d, J = 8.6 Hz, 2 H), 7.66 (d, J = 8 Hz, 2 H), 7.99
(d, J = 8 Hz, 2 H).
MS: m/z (%) = 388 (M+, 19.46), 252 (72.64), 238 (62.30), 221
(100), 211 (42.22), 135 (31.80), 90 (27.40), 77 (76.76), 51 (29.03).
7a
Pale yellow solid; mp 127–129 °C.
IR (KBr): 1720 (C=O), 1610 cm–1 (C=N).
1H NMR (500 MHz, CDCl3): = 3.91 (s, 3 H), 6.55 (s, 1 H), 6.79
(d, J = 8 Hz, 2 H), 7.11–7.19 (m, 3 H), 7.46 (m, 3 H), 7.60 (m, 2 H),
7.68 (d, J = 8 Hz, 2 H), 8.00 (d, J = 8 Hz, 2 H).
Anal. Calcd for C23H20N2O4: C, 71.11; H, 5.19; N, 7.22. Found: C,
70.88; H, 5.14; N, 7.05.
MS: m/z (%) = 358 (M+, 29.13), 252 (56.29), 221 (63.55), 181
(46.53), 105 (38.07), 77 (100), 51 (49.34).
Anal. Calcd for C22H18N2O3: C, 73.72; H, 5.07; N, 7.82. Found: C,
73.56; H, 4.91; N, 7.64.
7g
White solid; mp 138–140 °C.
IR (KBr): 1716 (C=O), 1513 cm–1 (C=N).
7b
1H NMR (500 MHz, CDCl3): = 3.91 (s, 3 H), 6.63 (s, 1 H), 6.83
(d, J = 7.6 Hz, 2 H), 7.18–7.23 (m, 3 H), 7.67–7.70 (m, 3 H), 7.96
(d, J = 7.7 Hz, 2 H), 8.0 (d, J = 8.4 Hz, 2 H), 8.32 (d, J = 7.7 Hz, 2
H), 8.47 (s, 1 H).
MS: m/z (%) = 403 (M+, 19.74), 281 (13.66), 252 (66.69), 221
(75.29), 104 (42.23), 77 (100), 51 (53.18).
White solid; mp 135–136 °C.
IR (KBr): 1723 (C=O), 1612 cm–1 (C=N).
1H NMR (500 MHz, CDCl3): = 3.90 (s, 3 H), 6.46 (s, 1 H), 6.77–
6.90 (m, 4 H), 7.45 (m, 3 H), 7.58 (m, 2 H), 7.64 (d, J = 8 Hz, 2 H),
8.00 (d, J = 8 Hz, 2 H).
MS: m/z (%) = 376 (M+, 63.59), 270 (96.42), 239 (100), 198
(56.56), 105 (51.89), 77 (66.49), 51 (45.71).
Anal. Calcd for C22H17N3O5: C, 65.49; H, 4.25; N, 10.42. Found: C,
65.27; H, 4.30; N, 10.29.
Anal. Calcd for C22H17FN2O3: C, 70.19; H, 4.56; N, 7.45. Found: C,
70.21; H, 4.48; N, 7.11.
7h
Pale yellow solid; mp 118–120 °C.
IR (KBr): 1713 (C=O), 1611 cm–1 (C=N).
7c
White solid; mp 141–143 °C.
Synthesis 2003, No. 10, 1569–1573 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,2,4-Oxadiazolines
IR (KBr): 1724 (C=O), 1606 cm–1 (C=N).
1H NMR (500 MHz, CDCl3): = 3.91 (s, 3 H), 6.44 (s, 1 H), 6.78
(q, J = 5.0 Hz, 2 H), 6.89 (q, J = 8.6 Hz, 2 H), 7.14 (t, J = 8.6 Hz, 2
H), 7.57 (q, J = 5.0 Hz, 2 H), 7.63 (d, J = 8.5 Hz, 2 H), 7.99 (d,
J = 8.5 Hz, 2 H).
1573
1H NMR (500 MHz, CDCl3): = 3.91 (s, 3 H), 6.01 (d, J = 5 Hz, 2
H), 6.45 (s, 1 H), 6.78 (d, J = 7.5 Hz, 2 H), 6.84 (d, J = 7.9 Hz, 1 H),
7.00 (d, J = 7.9 Hz, 1 H), 7.10–7.19 (m, 4 H), 7.64 (d, J = 8 Hz, 2
H), 7.99 (d, J = 8 Hz, 2 H).
MS: m/z (%) = 402 (M+, 28.02), 252 (78.46), 238 (60.63), 221
(100), 149 (43.60), 77 (91.51), 51 (43.16).
MS: m/z (%) = 394 (M+, 52.27), 270 (78.01), 239 (100), 216
Anal. Calcd for C23H18N2O5: C, 68.64; H, 4.51; N, 6.96. Found: C,
68.31; H, 4.67; N, 6.78.
(47.20), 95 (64.46), 75 (47.11).
Anal. Calcd for C22H16F2N2O3: C, 66.99; H, 4.09; N, 7.11. Found:
C, 66.81; H, 4.05; N, 7.21.
7i
White solid; mp 150–152 °C.
IR (KBr): 1728 (C=O), 1608 cm–1 (C=N).
10
Pale yellow solid; mp 131–133 °C.
1H NMR (500 MHz, CDCl3): = 3.91 (s, 3 H), 6.02 (d, J = 5 Hz, 2
H), 6.36 (s, 1 H), 6.78 (m, 2 H), 6.84 (d, J = 8 Hz, 1 H), 6.89 (t,
J = 8.7 Hz, 2 H), 6.96 (d, J = 6.3 Hz, 4 H), 7.11 (s, 1 H), 7.64 (d,
J = 8 Hz, 2 H), 7.98 (d, J = 8 Hz, 2 H).
MS: m/z (%) = 420 (M+, 37.56), 270 (95.84), 239 (100), 149
(54.50), 95 (45.03), 57 (68.97), 43 (69.13).
IR (KBr): 1724 (C=O), 1612 cm–1 (C=N).
1H NMR (500 MHz, CDCl3):
diastereomers) = 1.43 (d, J = 7.2 Hz, 1.35 H), 1.55 (d, J = 6.9 Hz,
1.65 H), 3.95 (s, 3 H), 4.80 (q, J = 6.9 Hz, 0.55 H), 4.87 (q, J = 7.2
Hz, 0.45 H), 6.24 (s, 0.45 H), 6.36 (s, 0.55 H), 7.08–7.42 (m, 10 H),
7.83 (d, J = 8.1 Hz, 1 H), 7.92 (d, J = 8.1 Hz, 1 H), 8.18 (m, 2 H).
= (11:9 mixture of
Anal. Calcd for C23H17FN2O5: C, 65.70; H, 4.08; N, 6.67. Found: C,
65.47; H, 4.27; N, 6.71.
MS: m/z (%) = 387 (M+ + 1, 3.13), 105 (100), 77 (15.18).
Anal. Calcd for C24H22N2O3: C, 74.58; H, 5.74; N, 7.25. Found: C,
74.51; H, 5.75; N, 7.21.
7j
Pale yellow, solid; mp 110–112 °C.
IR (KBr): 1727 (C=O), 1612 cm–1 (C=N).
Acknowledgements
1H NMR (500 MHz, CDCl3): = 1.80 (s, 3 H), 3.89 (s, 3 H), 6.48
(s, 1 H), 6.80–6.83 (m, 2 H), 6.87 (t, J = 8.8 Hz, 2 H), 7.36–7.42 (m,
3 H), 7.57 (d, J = 7 Hz, 2 H), 7.63 (d, J = 5.6 Hz, 2 H), 7.94 (d,
J = 5.6 Hz, 2 H).
This work was financially supported by the National Natural Sci-
ence Foundation of China (No. 20272051) as well as by the
Teaching and Research Award Program for Outstanding Young
Teachers in Higher Education Institutions of MOE, P.R.C.
MS: m/z (%) = 390 (M+, 7.86), 375 (39.96), 270 (39.48), 239
(63.98), 198 (26.45), 105 (100), 77 (49.80), 43 (35.30).
References
Anal. Calcd for C23H19FN2O3: C, 70.74; H, 4.91; N, 7.18. Found: C,
70.38; H, 4.73; N, 7.23.
(1) (a) Früchtel, J. S.; Jung, G. Angew. Chem., Int. Ed Engl..
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1999, 307. (d) Luisa, G.; Giorgio, M.; Pietro, C. J. Chem.
Soc., Perkin Trans. 1 2002, 2504. (e) Racker, R.; Doring,
K.; Reiser, O. J. Org. Chem. 2000, 65, 6932.
7k
Pale yellow solid; mp 112–113 °C.
IR (KBr): 1717 (C=O), 1610 cm–1 (C=N).
1H NMR (500 MHz, CDCl3): = 3.94 (s, 3 H), 4.08 (d, J = 15.9 Hz,
1 H), 4.44 (d, J = 15.9 Hz, 1 H), 5.99 (d, J = 5 Hz, 2 H), 6.17 (s, 1
H), 6.76 (d, J = 8 Hz, 2 H), 6.83 (d, J = 8 Hz, 1 H), 7.01 (s, 1 H),
7.04 (d, J = 7.2 Hz, 2 H), 7.26 (m, 3 H), 7.76 (d, J = 8 Hz, 2 H), 8.13
(d, J = 8 Hz, 2 H).
MS: m/z (%) = 417 (M+ + 1, 14.55), 295 (8.12), 149 (10.13), 91
(100), 76 (12.08), 65 (20.72).
Anal. Calcd for C24H20N2O5: C, 68.21; H, 4.84; N, 6.73. Found: C,
68.21; H, 4.67; N, 6.79.
7l
(f) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.
Chem.–Eur. J. 2000, 6, 133.
White solid; mp 114–115 °C.
IR (KBr): 1723 (C=O), 1613 cm–1 (C=N).
(5) Chimirri, A.; Grasso, S.; Monforte, A. M.; Monforte, P.;
Zappala, M.; Carotti, A. Chem. Pharm. Bull. 1980, 28, 3296.
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(b) Morocchi, S.; Ricca, A.; Velo, L. Chim. Ind. 1967, 49,
168. (c) Enders, D.; Meyer, I.; Runsink, J.; Raabe, G.
Heterocycles 1999, 50, 995.
(7) (a) Shang, Y. J.; Wang, Y. G. Tetrahedron Lett. 2002, 43,
2247. (b) Xia, M.; Wang, Y. G. Tetrahedron Lett. 2002, 43,
7703. (c) Shang, Y. J.; Wang, Y. G. Synthesis 2002, 1663.
(d) Lin, X. F.; Ma, C.; Yang, Y. W.; Wang, Y. G. Chin.
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1H NMR (500 MHz, CDCl3): = 0.75 (t, J = 7.3 Hz, 3 H), 1.18 (m,
2 H), 1.43 (m, 2 H), 3.04 (m, 2 H), 3.97 (s, 3 H), 6.01 (d, J = 5 Hz,
2 H), 6.22 (s, 1 H), 6.83 (d, J = 7.9 Hz, 2 H), 7.01 (d, J = 7.9 Hz, 1
H), 7.09 (s, 1 H), 7.71 (d, J = 8 Hz, 2 H), 8.12 (d, J = 8 Hz, 2 H).
MS: m/z (%) = 382 (M+, 46.70), 261 (24.70), 218 (48.04), 162
(98.33), 149 (68.21), 76 (47.20), 57 (60.92), 41 (100).
Anal. Calcd for C21H22N2O5: C, 65.94; H, 5.80; N, 7.33. Found: C,
66.01; H, 5.67; N, 7.31.
7m
White solid; mp 150–152 °C.
Synthesis 2003, No. 10, 1569–1573 © Thieme Stuttgart · New York