Synthesis of novel 1,3,4-oxadiazin-5(6H)-ones and 2-hydroxymethyl-1,3,4-oxadiazoles

Article abstract of DOI:10.3987/COM-06-10842

Reactions of α-hydroxyacid hydrazides (benzilic, R- and S-mandelic) and triethyl orthoesters (orthoformate, orthoacetate, orthopropionate, orthobenzoate) in glacial acetic acid resulted in two groups of heterocyclic compounds, derivatives of 6-phenyl- 1,3

Full text of DOI:10.3987/COM-06-10842

HETEROCYCLES, Vol. 68, No. 11, 2006
2269
HETEROCYCLES, Vol. 68, No. 11, 2006, pp. 2269 - 2283. © The Japan Institute of Heterocyclic Chemistry
Received, 14th July, 2006, Accepted, 19th September, 2006, Published online, 22nd September, 2006. COM-06-10842
SYNTHESIS OF NOVEL 1,3,4-OXADIAZIN-5(6H)-ONES AND
2-HYDROXYMETHYL-1,3,4-OXADIAZOLES
Agnieszka Kudelko* and Wojciech Zieliński
Department of Organic Technology and Petrochemistry, Silesian University of
Technology, Ul. Krzywoustego 4, PL-44101 Gliwice, Poland
E-mail: Agnieszka.Kudelko@polsl.pl
Abstract – Reactions of α-hydroxyacid hydrazides (benzilic, R- and S-mandelic)
and triethyl
orthobenzoate) in glacial acetic acid resulted in two groups of heterocyclic
compounds, derivatives of 6-phenyl-1,3,4-oxadiazin-5-(6H)-one
orthoesters
(orthoformate,
orthoacetate,
orthopropionate,
and 2-hydroxymethyl-1,3,4-oxadiazole. Their structures were confirmed by
typical spectroscopic methods and X-Ray analysis. Spectral characteristic of the
compounds and attempts to elucidate the mechanism are discussed.
INTRODUCTION
1,3,4-Oxadiazines belong to a group of heterocyclic compounds that exhibit a wide range of biological
activities.1 A lot of compounds containing a fused 1,3,4-oxadiazine arrangement demonstrate strong
antiviral and antibacterial activities.2-5 They also inhibit some metabolic processes proceeding in the
presence of enzyms such as: monoamine oxidaze, lipoxygenaze or cycloxygenaze.6,7 Cardiotonic and
antihypertensive activities have been reported for 2-substituted-1,3,4-oxadiazin-5(6H)-ones.8,9 They are
also applied in agriculture as pesticides, acaricides and nematocides.10,11 Working earlier on the synthesis of
4-acylamino-1,2,4-triazoles in the reactions of α-hydroxycarboxylic acid hydrazides and orthoesters some
single 1,3,4-oxadiazin-5(6H)-one derivatives have been obtained.12 Inspired by the biological activity of
such compounds, we have attempted to modify conditions properly in order to produce them. This area
seemed to be also very interesting due to the fact that 1,3,4-oxadiazin-5(6H)-ones have not been
synthesized this way so far. The most popular method to synthesize 1,3,4-oxadiazine arrangement uses
N-substituted alkyl- or arylcarboxylic acid hydrazides as substrates that undergo cyclization in acidic or

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HETEROCYCLES, Vol. 68, No. 11, 2006
basic medium.13-15 The others involve azodicarbonyl compounds and methoxyethylene derivatives in
Diels-Alder reactions.16,17 Few cases of four-18 and five-membered ring19 expansions yielding such
1,3,4-oxadiazines have been also reported. The aim of our study was to synthesize some novel
1,3,4-oxadiazin-5(6H)-one derivatives starting from α-hydroxycarboxylic acid hydrazides and orthoesters.
RESULTS AND DISCUSSION
Our earlier research12 on the reactions of α-hydroxycarboxylic acid hydrazides with the excess of
orthoesters revealed that 1-(alkanecarbonyl)-2-ethoxymethylenehydrazines (2, Scheme 1) were the main
products. The introduction of ethanol and acetic acid changed the course of the reaction and more extended
N,N’-bis(alkanecarbonylamino)formamidines (4) were produced. They underwent the further cyclization to
the final heterocyclic compounds, the derivatives of 4-acylamino-1,2,4-triazoles (5, Scheme 1). Those
reactions where triethyl ortoformate were applied in, we separated two different products: acyclic
intermediate (2) and 1,3,4-oxadiazin-5(6H)-ones (3).
H
OH
Ph C C
R1
OH
O
O
N
O
OC2H5
R2-C(OC2H5)3
reflux, 72 h
O
R2 = H
N
Ph C C
R1
N C
R2
Ph
R1
NH-NH2
N
H
R2
1
2
3
AcOH, EtOH
reflux, 3 h
+ 1
O
C
H
N
O
C
OH
C Ph
R1
N
N
N
HO
N
OH
Ph
C
N
C
R2
N
C
R2
AcOH, EtOH
reflux, 3 h
Ph
R1
R1
H
H
NH
O
5
4
C
R1
R1 = H, Ph
R2 = H, Me, Et
C
HO
Ph
Scheme 1
Considering this fact we came to the conclusion that it was the acidic hydrogen atom in triethyl ortoformate
molecule responsible for the cyclization of the intermediate (2) to 1,3,4-oxadiazin-5(6H)–one (3). If such
foundation holds, the introduction of acidic solvent to the reactions of the rest of orthoesters (R2 = Me, Et,
Ph) should lead to the same group compounds (3). Following this idea, α-hydroxyacid hydrazies (1) were
subjected to heating with the excess of orthoesters in the acetic acid medium (Scheme 2). The first series
concerned the reactions of benzilic acid hydrazide with orthoesters (R2 = H, Me, Et, Ph). This time no

HETEROCYCLES, Vol. 68, No. 11, 2006
2271
acyclic intermediates (2) were isolated. The reactions held in the presence of glacial acetic acid afforded a
mixture of two cyclic compounds: 1,3,4-oxadiazin-5(6H)-one (3) and 1,3,4-oxadiazole (6).
OH
OH
O
OC2H5
R2
O
R2-C(OC2H5)3
C C
R1
Ph
C C
R1
N C
Ph
hydrazide-orthoester = 1 : 5
AcOH, reflux, 3 h
3: 10-65%
NH-NH2
N
H
1
2
6: 25-85%
R1 = H, Ph
R2 = H, Me, Et, Ph
H
R2
O
N
O
N
OH
+
C
Ph
R1
N
N
R2
Ph
O
R1
6
3
Scheme 2
The yields of 1,3,4-oxadiazin-5(6H)-ones (3a-c) fairly vary from 10-65% (Table 1) and depend on the kind
of substituent R2 contributed by orthoester.
Table
1.
Characteristics
of
6,6-diphenyl-1,3,4-oxadiazin-5(6H)-ones
(3a-c)
and
2-(1,1-diphenyl-1-hydroxymethyl)-1,3,4-oxadiazoles (6a-d) derived from benzilic acid hydrazide.
Product
3a
R1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R2
H
Yielda) [%]
mp [oC]
212-214
208-210
185-187
191-193
125-127
121-123
151-153
Rf
65
25
21
68
15
78
85
0.62
0.34
0.55
0.42
0.48
0.52
0.60
6a
H
3b
Me
Me
Et
6b
3c
6c
Et
6d
Ph
a) Yield in respect to the original hydrazide.
The more bulky the substituent R2 is, the lower 1,3,4-oxadiazin-5(6H)-one yield is resulted and finally in
the case of triethyl orthobenzoate (R2 = Ph) we did not obtained any six-membered derivative but only the
five-membered one. Four derivatives of 2-(1,1-diphenyl-1-hydroxymethyl)-1,3,4-oxadiazole (6a-d) were
simultaneously obtained with much better yields (68-85%, Table 1). Contrary to the six-membered
derivatives of 3, we observed the reversed trend in the case of 6a-d. The yields of 1,3,4-oxadiazoles depend
on electronic effects of the substituents R2 attached to the ethoxymethylene carbon atom. The highest yield

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HETEROCYCLES, Vol. 68, No. 11, 2006
was obtained in the case of 6d (R2 = Ph) due to the fact that phenyl group is the electron withdrawing one
and it stabilizes the tautomeric structure 2b (Scheme 3) responsible for the formation of 1,3,4-oxadiazoles.
We have also prepared two enantiomeric S- and R- hydrazides of mandelic acid and subjected them to the
heating with the excess of orthoesters in the conditions mentioned above. The reactions have again resulted
in two products but this time the yields of 1,3,4-oxadiazin-5(6H)-ones (3e-h, 3i-l) increased a little at the
cost of 1,3,4-oxadiazoles (6e-h, 6i-l) comparing to the series based on benzilic acid hydrazide (Tables 2, 3).
The structures of products were confirmed by means of elemental analyses, typical spectroscopic methods
(UV, MS, 1H- and 13C-NMR) and X-Ray analysis. Optical rotations [α] were also determined for products
(3e-l) and (6e-l) obtained from optically active S- and R-mandelic acid hydrazides.
Table
2.
Characteristics
of
6-phenyl-1,3,4-oxadiazin-5(6H)-ones
(3e-h)
and
2-(1-hydroxy-1-phenylmethyl)-1,3,4-oxadiazoles (6e-h) derived from S(+)-mandelic acid hydrazide.
R1
R2
Yielda) [%]
mp [oC]
Rf
20
Product
[α]D
(MeOH, C=1.0)
3e
6e
3f
H
H
H
H
H
H
H
H
H
H
50
45
45
50
24
64
12
85
129-132
-
0.54
0.40
0.40
0.32
0.50
0.32
0.12
0.45
- 203.9
+ 4.2
- 117.8
+ 5.7
Me
Me
Et
106-108
126-128
-
6f
3g
6g
3h
6h
- 50.5
+ 18.5
+ 15.7
+ 60.2
Et
69-71
84-85
148-149
Ph
Ph
a) Yield in respect to the original hydrazide.
Considering the optical rotations in two series of 2-(1-hydroxy-1-phenylmethyl)-1,3,4-oxadiazoles (6e-h,
6i-l) one should noticed that four pair of enantiomers were obtained. The absolute configuration at the
asymmetric carbon atom is hold because such atom is not involved in the formation of 6. We assumed,
that the intermediate 1-(alkanecarbonyl)-2-ethoxymethylenehydrazine (2) played the essential role in the
formation of both heterocyclic products. The hydrazide (2a) may occur in another tautomeric form -
hydroxyhydrazone (2b), where the second methylene carbon atom appears (Scheme 3). It is substituted
with the hydroxy group that attacks N-ethoxymethylene carbon atom yielding 1,3,4-oxadiazole
arrangement.

HETEROCYCLES, Vol. 68, No. 11, 2006
2273
H
R2
O
N
O
OC2H5
R2
O
OC2H5
R2
H
H
H
C C
N C
C C
N C
Ph C
N
Ph
Ph
- C2H5OH
N
H
N
HO
HO
HO
6
2a
2b
Scheme 3
Table
3.
Characteristics
of
6-phenyl-1,3,4-oxadiazin-5(6H)-ones
(3i-l)
and
2-(1-hydroxy-1-phenylmethyl)-1,3,4-oxadiazoles (6i-l) derived from R(-)-mandelic acid hydrazide.
R1
R2
Yielda) [%]
mp [oC]
Rf
20
Product
[α]D
(MeOH, C=1.0)
3i
6i
H
H
H
H
H
H
H
H
H
H
60
32
50
45
30
65
10
84
129-131
-
0.54
0.40
0.40
0.32
0.50
0.32
0.12
0.45
+ 97.4
- 4.3
+ 119.3b)
- 5.7
3j
6j
3k
6k
3l
Me
Me
Et
103-105
126-127
-
+ 48.4
- 18.6
- 28.1
- 60.4
Et
68-70
83-84
148-149
Ph
Ph
6l
a) Yield in respect to the original hydrazide.
b) 6R absolute configuration according to X-Ray analysis.
The measurements of the optical rotation for 1,3,4-oxadiazin-5(6H)-ones (3e-h, 3i-l) derived from two
enantiomeric S- and R-mandelic acid hydrazides showed that the mixtures of enantiomers are formed. In
contrast to 1,3,4-oxadiazoles, the asymmetric carbon atom in the intermediate (2) is directly involved in
the formation of 1,3,4-oxadiazin-5(6H)-one (3). If such a product arised from the attack of the α-hydroxy
group at the ethoxymethylene carbon atom in the intermediate (2a), the absolute cofiguration would be
hold and one would obtained pure enantiomers (Scheme 4, path A). The X-Ray investigation of
2-methyl-5-phenyl-1,3,4-oxadiazin-5(6H)-one (3j) obtained in the reaction of R-mandelic acid
hydrazide and triethyl ortoacetate revealed that the molecule has the same absolute R configuration at C6
like starting hydrazide. It proves that the product is really resulted in this way. However, the differences
in measured values (R2 = H, Ph) suggest that the formation of 3 could partly proceed another path through
the stable benzyl cation (Scheme 4, path B). The asymmetry at carbon in hydrazide (2) is lost and after
the substitution with the water molecule and further cyclization two optical isomers are formed.

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HETEROCYCLES, Vol. 68, No. 11, 2006
O
OC2H5
O
OC2H5
H
O
H
OC2H5
R2
+
H
H
+
C C
N C
C C
N C
C C
N C
Ph
R2
Ph
H2O
R2
N
H
-H2O
path B
N
H
N
H
HO
Ph
+
2
+
H
H2O
path A
O
- EtOH
H
C C
H
Ph
N
N
HO
R2
O
O H
R2
H
C
+
C C
N C
O
+
N
H
Ph
H
C2H5
- EtOH
- H
+
+
- H
O
R2
R2
Ph
H
H
O
O
H
C
H
N
N
Ph
Ph
N
N
N
O
O
O
N
H
3
3
H
R2
Scheme 4
As mentioned before, the structure of 2-methyl-6-phenyl-1,3,4-oxadiazin-5(6H)-one (3j) was confirmed
by X-Ray analysis. ORTEP20 drawing of 3j is shown in Figure 1. There are two independent molecules A
and B in asymmetric part of the unit cell of 3j.
Figure 1. ORTEP drawing of 3j showing 30 % probability displacement ellipsoids.

HETEROCYCLES, Vol. 68, No. 11, 2006
2275
These molecules, having the same absolute configuration of C6 identified as R and very similar geometry
(Table 4), differ in conformation described by torsion angle O1–C6–C11–C12 of -34.6(2)o and 92.5(2)o
for A and B, respectively. The oxadiazine rings both adopt diplanar conformation, with asymmetry
N3A,N4A
N3B,N4B
parameters ∆C2
= 2.2(3)o and ∆C2
= 0.8(3)o,21 and two torsion angles close to 0o
[O1–C2–N3–N4 of -0.3(3)o and 0.0(3)o and N3–N4–C5–C6 of 1.1(2)o and -0.2(3)o] in molecules A and B,
respectively.
Table 4. Selected bond distances [Å] and angles [o] for 3j in molecules A and B.
Bond [Å]
O1-C2
A
B
Angle [o]
C2-O1-C6
A
B
1.347(3)
1.348(3)
118.79(14)
116.67(18)
125.40(15)
126.34(18)
121.1(2)
118.74(15)
116.56(19)
125.43(17)
126.30(18)
120.7(3)
O1-C6
O8-C5
N3-C2
N3-N4
N4-C5
C2-C7
C5-C6
C6-C11
1.439(2)
1.215(2)
1.261(2)
1.392(2)
1.330(3)
1.489(3)
1.519(3)
1.512(2)
1.440(3)
1.220(2)
1.260(3)
1.395(2)
1.324(3)
1.490(3)
1.512(3)
1.508(3)
C2-N3-N4
C5-N4-N3
N3-C2-O1
N3-C2-C7
O1-C2-C7
O8-C5-N4
O8-C5-C6
N4-C5-C6
O1-C6-C11
O1-C6-C5
C11-C6-C5
112.6(2)
112.9(2)
123.73(18)
120.06(19)
116.21(15)
111.84(15)
113.05(16)
110.01(14)
123.52(18)
120.06(19)
116.42(16)
111.34(16)
112.97(17)
111.89(15)
In the crystal structure of 3j (Figure 2), the molecules
related by 21 axes are joined in molecular chains
parallel to Y crystallographic axis via N4–H4...O8
classical intermolecular hydrogen bonds. Additionally,
the molecular packing in the crystal is influenced by
the presence of the three-dimensional network of the
weak intermolecular C–H...X ( X = N, O ) hydrogen
bonds. The geometry and symmetry codes of all
intermolecular interactions are presented in Table 5.
Figure 2. Packing diagram of the molecule (3j).
The hydrogen bonds are indicated by broken lines.

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HETEROCYCLES, Vol. 68, No. 11, 2006
Table 5. The geometry of the intermolecular hydrogen bonds in 3j.
Type
Symmetry
code
D-H
H…A
[Å]
D…A
[Å]
D-H…A
[o]
[Å]
N4A-H4A...O8A
N4B-H4B...O8B
2655
0.84(3)
0.78(3)
0.97(3)
1.05(3)
1.03(3)
0.97(4)
2.00(3)
2.07(3)
2.46(3)
2.44(3)
2.59(3)
2.59(4)
2.826(2)
2.850(2)
3.412(3)
3.478(3)
3.542(3)
3.521(3)
169(3)
173(3)
168(2)
169(2)
153(3)
162(3)
2656
C6A-H6A...N3A
C6B-H6B...N3B
1545
1545
C14B-H14B...O8B
C15B-H15B...O8B
2655 = 1-x, ½+y, -z;
1455 = -1+x, y, z;
1455
2556
1545 = x, -1+y, z;
2656 = 1-x, ½+y, 1-z;
2556 = -x, ½+y, 1-z
CONCLUSIONS
Investigation studies on the reactions of α-hydroxycarboxylic acid hydrazides and orthoesters in different
conditions revealed the possibility to synthesize both acyclic and heterocyclic compounds. Hydrazides
heated in the excess of orthoesters gave acyclic 1-(alkanecarbonyl)-2-ethoxymethylenehydrazines (2)
while in the presence of ethanol and acetic acid the more extended N,N’-bis-
(alkanecarbonylamino)formamidines (4) were formed. The lasts underwent cyclization to
4-acylamino-1,2,4-triazoles (5). Those cases where reactions were carried only in acetic acid medium and
without the presence of alcohol, two different heterocyclic products were formed, the derivatives of
6-phenyl-1,3,4-oxadiazin-5(6H)-one (3) and 2-hydroxymethyl-1,3,4-oxadiazole (6). Concluding,
α-hydroxyacid hydrazides can constitute potential precursors for the synthesis of nitrogen- and
nitrogen-oxygen-containing heterocyclic systems.
EXPERIMENTAL
UV spectra were recorded on a Shimadzu UV-2102 spectrophotometer. Elemental analyses were carried
1
out with a VarioEL analyser. The H- and 13C-NMR spectra were recorded on a Varian Inova 300
spectrometer in DMSO solution using TMS as internal standard. Thin layer chromatography was carried
out on silica gel 60 F254 (Merck) thin layer chromatography plates using a benzene-ethyl acetate (1:3 v/v) as
the mobile phase. Optical rotations were measured on Perkin Elmer Polarymeter 141 in methanol solution
at the concentration of approx. 1 % (D line of sodium light, room temperature). Orthoesters were purchased
from Fluka Chemie GmbH and methyl esters of benzilic, S- and R-mandelic acids from Alfa Aesar
Gmbh&Co KG.

HETEROCYCLES, Vol. 68, No. 11, 2006
2277
Synthesis of α-hydroxyacids hydrazides (1a-c).
The hydrazides of α-hydroxyacids were obtained according to a standard procedure in the reaction of
methyl esters of α-hydroxyacids with hydrazine hydrate.
The hydrazide of S-mandelic acid (1a)22 : mp 151-153oC; [α]D20 +38.2 (MeOH, C=1.0).
The hydrazide of R-mandelic acid (1b)22 : mp 152-153oC; [α]D20 –38.1 (MeOH, C=1.0).
The hydrazide of benzilic acid (1c)23 : mp 167-169oC.
General procedure for the preparation of substituted of 1,3,4-oxadiazin-5(6H)-ones (3) and
2-(1-hydroxy-1-phenylmethyl)-1,3,4-oxadiazoles (6).
The starting hydrazide (0.01 mole) of benzilic (1a) or mandelic acids (1b, 1c) was added to the mixture of
the appropriate triethyl orthoester (0.05 mole) and 1 mL (0.018 mole) of glacial AcOH. It was kept under
reflux for about 3 h. After cooling the excessive orthoester and AcOH were evaporated under reduced
pressure. The crude yellow oil was washed with 50 mL of hot water, dissolved in 50 mL of Et2O and
dried over anhydrous CaCl2. The solvent was evaporated and the oily residue was subjected to the column
chromatography (silica gel, eluent: benzene-AcOEt 1:3 mixture). Products (3, 6) were crystallized from
benzene-hexane mixtures.
Products obtained from benzilic acid hydrazide:
6,6-Diphenyl-1,3,4-oxadiazin-5(6H)-one (3a).
1
This compound was obtained as a white solid in 65% yield; mp 212-214°C; Rf: 0.62; H-NMR
13
(DMSO-d6, Me4Si): δ 7.29-7.43 (m, 11H, 2 Ph, CH), 11.24 (s, 1H, NH) ppm; C-NMR: δ 83.74 (C6),
127.02, 128.33, 128.74, 138.24 (Ph), 141.54 (C2), 162.68 (C5) ppm; MS: m/z (int %) 51 (14), 63 (17), 77
(34), 78 (12), 82 (12), 103 (22), 105 (37), 164 (10), 165 (80), 166 (51), 167 (15), 193 (18), 194 (100), 195
(15), 252 (M+, 11); UV: λmax (ε·10-3) MeOH 244.0 (3.40), 208.2 (17.25). Anal. Calcd for C15H12N2O2: C,
71.41; H, 4.80; N, 11.10. Found: C, 71.45; H, 4.83; N, 11.11.
2-(1,1-Diphenyl-1-hydroxymethyl)-1,3,4-oxadiazole (6a).
1
This compound was obtained as a white solid in 25% yield; mp 208-210°C; Rf: 0.34; H-NMR
(DMSO-d6, Me4Si): δ 7.05 (s, 1H, OH), 7.30-7.44 (m, 10H, 2 Ph), 10.07 (s, 1H, H-C5) ppm; 13C-NMR: δ
80.42 (COH), 127.36, 127.62, 143.69 (Ph), 157.70 (C5), 167.98 (C2) ppm; MS: m/z (int %) 51 (12), 77
(15), 105 (100), 165 (62), 181 (18), 181 (72), 183 (15), 194 (85), 252 (M+, 24); UV: λmax (ε·10-3) MeOH
255.0 (0.54), 206.0 (21.60). Anal. Calcd for C15H12N2O2: C, 71.41; H, 4.80; N, 11.10. Found: C, 71.42;
H, 4.79; N, 11.08.
6,6-Diphenyl-2-methyl-1,3,4-oxadiazin-5(6H)-one (3b).
1
This compound was obtained as a white solid in 21% yield; mp 185-187°C; Rf: 0.55; H-NMR
(DMSO-d6, Me4Si): δ 2.01 (s, 1H, CH3), 7.29-7.45 (m, 10H, 2 Ph), 11.09 (s, 1H, NH) ppm; 13C-NMR: δ

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HETEROCYCLES, Vol. 68, No. 11, 2006
18.15 (CH3), 83.64 (C6), 126.88, 128.35, 128.65, 138.64 (Ph), 149.98 (C2), 162.40 (C5) ppm; MS: m/z
(int %) 77 (10), 165 (64), 166 (66), 167 (12), 194 (100), 195 (16), 266 (M+, 14); UV: λmax (ε·10-3) MeOH
243.6 (4.15), 206.4 (20.71). Anal. Calcd for C16H14N2O2: C, 71.16; H, 5.31; N, 10.53. Found: C, 72.20; H,
5.30; N, 10.53.
2-(1,1-Diphenyl-1-hydroxymethyl)-5-methyl-1,3,4-oxadiazole (6b).
1
This compound was obtained as a white solid in 68% yield; mp 191-193°C22; Rf: 0.42; H-NMR
13
(DMSO-d6, Me4Si): δ 2.50 (s, 3H, CH3), 7.29-7.37 (m, 11H, 2 Ph, OH) ppm; C-NMR: δ 10.59 (CH3),
75.95 (COH), 126.64, 127.66, 127.98, 143.60 (Ph), 164.36 (C5), 169.10 (C2) ppm; MS: m/z (int %) 51
(22), 77 (46), 105 (100), 181 (15), 182 (60), 183 (11), 189 (10), 266 (M+, 28); UV: λmax (ε·10-3) MeOH
258.0 (0.52), 206.2 (22.54). Anal. Calcd for C16H14N2O2: C, 71.16; H, 5.31; N, 10.53. Found: C, 72.18; H,
5.35; N, 10.50.
6,6-Diphenyl-2-ethyl-1,3,4-oxadiazin-5(6H)-one (3c).
1
This compound was obtained as a white solid in 15% yield; mp 125-127°C; Rf: 0.48; H-NMR
(DMSO-d6, Me4Si): 0.98 (t, J=7.5 Hz, 3H, CH3), 2.31 (q, J=7.5 Hz, 2H, CH2), 7.28-7.42 (m, 10H, 2 Ph),
11.12 (s, 1H, NH) ppm; 13C-NMR: δ 10.52 (CH3), 18.47 (CH2), 83.56 (C6), 126.78, 128.45, 128.71,
138.77 (Ph), 153.12 (C2), 162.45 (C5) ppm; MS: m/z (int %) 77 (15), 165 (49), 166 (56), 194 (100), 195
(13), 280 (M+, 27); UV: λmax (ε·10-3) MeOH 252.0 (5.06), 202.8 (24.56). Anal. Calcd for C17H16N2O2: C,
72.83; H, 5.76; N, 9.99. Found: C, 72.82; H, 5.80; N, 10.01.
2-(1,1-Diphenyl-1-hydroxymethyl)-5-ethyl-1,3,4-oxadiazole (6c).
1
This compound was obtained as a white solid in 78% yield; mp 121-123°C; Rf: 0.52; H-NMR
(DMSO-d6, Me4Si): 1.24 (t, J=7.5 Hz, 3H, CH3), 2.84 (q, J=7.5 Hz, 2H, CH2), 7.27-7.36 (m, 11H, Ph,
13
OH) ppm; C-NMR: δ 10.44 (CH3), 18.35 (CH2), 75.98 (COH), 126.60, 127.63, 127.95, 143.58 (Ph),
168.15 (C5), 168.95 (C2) ppm; MS: m/z (int %) 51 (18), 54 (10), 77 (45), 105 (100), 165 (15), 181 (16),
182 (53), 183 (15), 193 (16), 280 (M+, 49); UV: λmax (ε·10-3) MeOH 259.0 (0.51), 206.0 (24.20). Anal.
Calcd for C17H16N2O2: C, 72.83; H, 5.76; N, 9.99. Found: C, 72.85; H, 5.71; N, 9.96.
2-(1,1-Diphenyl-1-hydroxymethyl)-5-phenyl-1,3,4-oxadiazole (6d).
1
This compound was obtained as a white solid in 85% yield; mp 151-153°C; Rf: 0.60; H-NMR
(DMSO-d6, Me4Si): 7.29-7.46 (m, 10H, 2 Ph), 7.53 (s, 1H, OH), 7.59-7.64 (m, 3H, Ph-C5), 7.99 (d, 2H,
Ph-C5) ppm; 13C-NMR: δ 76.15 (COH), 123.18, 126.58, 126.64, 127.73, 128.03, 129.49, 132.15, 143.46
(Ph), 164.49 (C5), 169.18 (C2) ppm; MS: m/z (int %) 77 (56), 103 (17), 105 (100), 182 (18), 223 (14),
251 (11), 311 (18), 328 (M+, 12); UV: λmax (ε·10-3) MeOH 252.8 (25.57), 207.0 (44.00). Anal. Calcd for
C21H16N2O2: C, 76.80; H, 4.92; N, 8.52. Found: C, 76.83; H, 4.94; N, 8.50.
Products obtained from (S)-mandelic acid hydrazide:
6-Phenyl-1,3,4-oxadiazin-5(6H)-one (3e).

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2279
This compound was obtained as a white solid in 50% yield; mp 129-132°C; Rf: 0.54; [α]D20 –203.9
1
(MeOH, C=1.0); H-NMR (DMSO-d6, Me4Si): δ 5.79 (s, 1H, H-C6), 7.25 (s, 1H, H-C2), 7.35-7.44 (m,
5H, Ph), 11.00 (s, 1H, H-N4) ppm; 13C-NMR: δ 75.63 (C6), 126.42, 127.11, 128.80, 135.93 (Ph), 140.40
(C2), 161.21 (C5) ppm; MS: m/z (int %) 63 (10), 77 (14), 79 (10), 89 (17), 90 (45), 118 (100), 119 (10),
176 (M+, 11); UV: λmax (ε·10-3) MeOH 247.2 (2.88), 207.8 (7.78). Anal. Calcd for C9H8N2O2: C, 61.35;
H, 4.58; N, 15.89. Found: C, 61.30; H, 4.65; N, 15.82.
(2S)-(1-Hydroxy-1-phenylmethyl)-1,3,4-oxadiazole (6e).
This compound was obtained as a colourless oil in 45% yield; Rf: 0.40; [α]D20 +4.2 (MeOH, C=1.0);
1H-NMR (DMSO-d6, Me4Si): δ 6.08 (d, 1H, J=4.5 Hz, H-C2), 6.76 (d, 1H, J=4.5 Hz, OH), 7.32-7.46 (m,
13
5H, Ph), 9.17 (s, 1H, H-C5) ppm; C-NMR: δ 66.08 (HCOHPh), 126.41, 127.29, 128.42, 139.51 (Ph),
154.73 (C5), 167.02 (C2) ppm; MS: m/z (int %) 71 (28), 77 (68), 78 (21), 79 (48), 90 (12), 105 (100), 106
(34), 107 (20), 118 (10), 132 (11), 176 (M+, 44); UV: λmax (ε·10-3) MeOH 257.4 (0.26), 210.2 (8.39).
Anal. Calcd for C9H8N2O2: C, 61.35; H, 4.58; N, 15.89. Found: C, 61.34; H, 4.60; N, 15.86.
2-Methyl-(6S)-phenyl-1,3,4-oxadiazin-5(6H)-one (3f).
This compound was obtained as a white solid in 45% yield; mp 106-108°C; Rf: 0.40; [α]D20 - 117.8
(MeOH, C=1.0); 1H-NMR (DMSO-d6, Me4Si): 1.95 (s, 3H, CH3), 5.75 (s, 1H, H-C6), 7.35-7.46 (m, 5H,
Ph), 10.89 (s, 1H, H-N4) ppm; 13C-NMR: δ 17.84 (CH3), 75.73 (C6), 126.94, 127.40, 128.65, 135.98 (Ph),
148.69 (C2), 160.87 (C5) ppm; MS: m/z (int %) 63 (10), 77 (11), 89 (13), 90 (39), 105 (10), 118 (100),
119 (10), 190 (M+, 11); UV: λmax (ε·10-3) MeOH 245.0 (4.30), 207.8 (9.87). Anal. Calcd for C10H10N2O2:
C, 63.14; H, 5.31; N, 14.72. Found: C, 63.19; H, 5.37; N, 14.70.
(2S)-(1-Hydroxy-1-phenylmethyl)-5-methyl-1,3,4-oxadiazole (6f).
This compound was obtained as a white solid in 50% yield; mp 126-128°C; Rf: 0.32; [α]D20 +5.7 (MeOH,
1
C=1.0); H-NMR (DMSO-d6, Me4Si): δ 2.45 (s, 3H, CH3), 5.96 (d, J=4.8 Hz, 1H, HCOHPh), 6.67 (d,
J=4.8 Hz, 1H, HCOHPh), 7.29-7.47 (m, 5H, Ph) ppm; 13C-NMR: δ 10.46 (CH3), 66.26 (HCOHPh),
126.40, 128.08, 128.40, 139.52 (Ph), 164.05 (C5), 167.23 (C2) ppm; MS: m/z (int %) 77 (66), 78 (17), 79
(50), 85 (15), 91 (11), 105 (100), 106 (22), 107 (16), 132 (10), 190 (M+, 36); UV: λmax (ε·10-3) MeOH
257.2 (0.18), 207.8 (10.34). Anal. Calcd for C10H10N2O2: C, 63.14; H, 5.31; N, 14.72. Found: C, 63.16; H,
5.35; N, 14.76.
2-Ethyl-(6S)-phenyl-1,3,4-oxadiazin-5(6H)-one (3g).
This compound was obtained as a colourless oil in 24% yield; Rf: 0.50; [α]D20 -50.5 (MeOH, C=1.0);
1H-NMR (DMSO-d6, Me4Si): δ 0.96 (t, J=7.5 Hz, 3H, CH3), 2.23 (q, J=7.5 Hz, 2H, CH2), 5.73 (s, 1H,
H-C6), 7.24-7.42 (m, 5H, Ph), 10.98 (s, 1H, NH) ppm; 13C-NMR: δ 9.82 (CH3), 18.20 (CH2), 75.63 (C6),
127.05, 128.22, 128.72, 135.92 (Ph), 151.95 (C2), 161.00 (C5) ppm; MS: m/z (int %) 77 (24), 79 (11), 89

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HETEROCYCLES, Vol. 68, No. 11, 2006
(17), 90 (40), 91 (21), 105 (29), 117 (13), 118 )100), 119 (12), 131 (12), 132 (19), 204 (M+, 19); UV: λ
max (ε·10-3) MeOH 257.4 (0.18), 209.4 (10.62). Anal. Calcd for C11H12N2O2: C, 64.68; H, 5.93; N, 13.71.
Found: C, 64.62; H, 5.92; N, 13.73.
(2S)-(1-Hydroxy-1-phenylmethyl)-5-ethyl-1,3,4-oxadiazole (6g).
This compound was obtained as a white solid in 64% yield; mp 69-71°C; Rf: 0.32; [α]D20 +18.5 (MeOH,
C=1.0); 1H-NMR (DMSO-d6, Me4Si): δ 1.21 (t, J=7.5 Hz, 3H, CH3), 2.81 (q, J=7.5 Hz, 2H, CH2), 5.98 (d,
13
J=5.1 Hz, 1H, HCOHPh), 6.60 (d, J=5.1 Hz, 1H, HCOHPh), 7.25-7.46 (m, 5H, Ph) ppm; C-NMR: δ
10.37 (CH3), 18.27 (CH2), 66.35 (HCOHPh), 126.43, 128.05, 128.38, 139.58 (Ph), 167.14 (C5), 167.87
(C2) ppm; MS: m/z (int %) 71 (12), 77 (70), 78 (16), 79 (55), 91 (11), 97 (22), 99 (13), 105 (100), 106
(20), 107 (24), 118 (10), 132 (12), 204 (M+, 28); UV: λmax (ε·10-3) MeOH 251.4 (0.23), 207.4 (9.68).
Anal. Calcd for C11H12N2O2: C, 64.68; H, 5.93; N, 13.71. Found: C, 64.65; H, 5.98; N, 13.75.
(2S)-(1-Hydroxy-1-phenylmethyl)-5-phenyl-1,3,4-oxadiazole (6h).
This compound was obtained as a white solid in 85% yield; mp 148-149°C; Rf: 0.45; [α]D20 +60.2 (MeOH,
1
C=1.0); H-NMR (DMSO-d6, Me4Si): δ 6.13 (d, J=4.8 Hz, 1H, HCOHPh), 6.90 (d, J=4.8 Hz, 1H,
13
HCOHPh), 7.32-7.46 (m, 3H, Ph), 7.56-7.64 (m, 5H, Ph), 7.98 (d, J=6.6 Hz, 2H, Ph) ppm; C-NMR: δ
66.44 (HCOHPh), 123.16, 126.51, 126.58, 128.19, 128.47, 129.48, 132.10, 139.43 (2 Ph), 164.23 (C5),
167.46 (C2) ppm; MS: m/z (int %) 63 (11), 76 (11), 77 (100), 78 (11), 79 (38), 103 (24), 104 (17), 105
(96), 106 (17), 107 (37), 145 (15), 252 (M+, 41); UV: λmax (ε·10-3) MeOH 252.0 (19.26), 204.6 (25.04).
Anal. Calcd for C15H12N2O2: C, 71.41; H, 4.80; N, 11.10. Found: C, 71.45; H, 4.83; N, 11.13.
Products obtained from (R)-mandelic acid hydrazide:
(2R)-(1-Hydroxy-1-phenylmethyl)-1,3,4-oxadiazole (6i).
This compound was obtained as a colourless oil in 32% yield; Rf: 0.40; [α]D20 -4.3 (MeOH, C=1.0);
1H-NMR (DMSO-d6, Me4Si): δ 6.08 (d, 1H, J=4.5 Hz, H-C2), 6.78 (d, 1H, J=4.5 Hz, OH), 7.30-7.50 (m,
5H, Ph), 9.19 (s, 1H, H-C5) ppm; 13C-NMR: 66.31 (HCOHPh), 126.49, 127.84, 128.36, 139.50 (Ph),
154.75 (C5), 167.10 (C2) ppm; MS: m/z (int %) 71 (18), 77 (60), 78 (11), 79 (40), 90 (22), 105 (100), 106
(24), 107 (12), 118 (11), 132 (18), 176 (M+, 40); UV: λmax (ε·10-3) MeOH 241.2 (0.49), 209.4 (8.29).
Anal. Calcd for C9H8N2O2: C, 61.35; H, 4.58; N, 15.89. Found: C, 61.32; H, 4.62; N, 15.90.
2-Methyl-(6R)-phenyl-1,3,4-oxadiazin-5(6H)-one (3j).
This compound was obtained as a white solid in 50% yield; mp 103-105°C; Rf: 0.40; [α]D20 + 119.3
(MeOH, C=1.0); 1H-NMR (DMSO-d6, Me4Si): 1.96 (s, 3H, CH3), 5.73 (s, 1H, H-C6), 7.35-7.40 (m, 5H,
Ph), 10.90 (s, 1H, H-N4) ppm; 13C-NMR: δ 17.68 (CH3), 75.70 (C6), 126.64, 127.26, 128.58, 135.90 (Ph),
148.71 (C2), 160.85 (C5) ppm; MS: m/z (int %) 77 (12), 89 (13), 90 (39), 105 (11), 118 (100), 119 (10),
190 (M+, 11); UV: λmax (ε·10-3) MeOH 245.8 (4.25), 210.4 (9.62). Anal. Calcd for C10H10N2O2: C, 63.14;

HETEROCYCLES, Vol. 68, No. 11, 2006
2281
H, 5.31; N, 14.72. Found: C, 63.20; H, 5.35; N, 14.68.
(2R)-(1-Hydroxy-1-phenylmethyl)-5-methyl-1,3,4-oxadiazole (6j).
This compound was obtained as a white solid in 45% yield; mp 126-127°C; Rf: 0.32; [α]D20 –5.7 (MeOH,
1
C=1.0); H-NMR (DMSO-d6, Me4Si): δ 2.44 (s, 3H, CH3), 5.94 (d, J=4.8 Hz, 1H, HCOHPh), 6.63 (d,
J=4.8 Hz, 1H, HCOHPh), 7.33-7.44 (m, 5H, Ph) ppm; 13C-NMR: δ 10.46 (CH3), 66.94 (HCOHPh),
127.08, 128.75, 129.07, 139.64 (Ph), 163.50 (C5), 167.81 (C2) ppm; MS: m/z (int %) 77 (45), 78 (14), 79
(51), 85 (10), 91 (17), 105 (100), 106 (21), 107 (19), 190 (M+, 42); UV: λmax (ε·10-3) MeOH 257.2 (0.20),
209.0 (7.76). Anal. Calcd for C10H10N2O2: C, 63.14; H, 5.31; N, 14.72. Found: C, 63.17; H, 5.33; N,
14.70.
2-Ethyl-(6R)-phenyl-1,3,4-oxadiazin-5(6H)-one (3k).
This compound was obtained as a colourless oil in 30% yield; Rf: 0.50; [α]D20 +48.4 (MeOH, C=1.0);
1H-NMR (DMSO-d6, Me4Si): δ 0.96 (t, J=7.5 Hz, 3H, CH3), 2.23 (q, J=7.5 Hz, 2H, CH2), 5.72 (s, 1H,
H-C6), 7.31-7.42 (m, 5H, Ph) ppm; 10.96 (s, 1H, NH) ppm; 13C-NMR: δ 9.84 (CH3), 18.27 (CH2), 75.73
(C6), 127.09, 128.26, 128.73, 135.99 (Ph), 151.98 (C2), 161.06 (C5) ppm; MS: m/z (int %) 77 (20), 89
(11), 90 (30), 91 (13), 105 (19), 118 (100), 119 (15), 132 (24), 204 (M+, 29); UV: λmax (ε·10-3) MeOH
248.2 (2.74), 209.4 (9.39). Anal. Calcd for C11H12N2O2: C, 64.68; H, 5.93; N, 13.71. Found: C, 64.64; H,
5.90; N, 13.75.
(2R)-(1-Hydroxy-1-phenylmethyl)-5-ethyl-1,3,4-oxadiazole (6k).
This compound was obtained as a white solid in 65% yield; mp 68-70°C; Rf: 0.32; [α]D20 -18.6 (MeOH,
C=1.0); 1H-NMR (DMSO-d6, Me4Si): δ 1.20 (t, J=7.5 Hz, 3H, CH3), 2.81 (q, J=7.5 Hz, 2H, CH2), 5.96 (d,
13
J=5.1 Hz, 1H, HCOHPh), 6.58 (d, J=5.1 Hz, 1H, HCOHPh), 7.27-7.46 (m, 5H, Ph) ppm; C-NMR: δ
11.06 (CH3), 18.94 (CH2), 66.92 (HCOHPh), 127.08, 128.70, 129.04, 140.29 (Ph), 167.83 (C5), 166.52
(C2) ppm; MS: m/z (int %) 77 (57), 78 (11), 79 (34), 91 (19), 97 (16), 99 (12), 105 (100), 106 (12), 107
(34), 132 (15), 204 (M+, 38); UV: λmax (ε·10-3) MeOH 257.4 (0.26), 210.8 (9.89). Anal. Calcd for
C11H12N2O2: C, 64.68; H, 5.93; N, 13.71. Found: C, 64.70; H, 5.95; N, 13.70.
(2,6R)-Diphenyl-1,3,4-oxadiazin-5(6H)-one (3l).
This compound was obtained as a white solid in 10% yield; mp 83-84°C; Rf: 0.12; [α]D20 –28.1 (MeOH,
1
C=1.0); H-NMR (DMSO-d6, Me4Si): 6.04 (s, 1H, H-C6), 7.28-7.70 (m, 8H, Ph-C6, Ph-C2), 7.79 (d,
13
J=8.1 Hz, 2H, Ph-C2), 11.44 (s, 1H, NH) ppm; C-NMR: δ 75.95 (C6), 125.97, 126.62, 127.63, 128.21,
128.70, 128.89, 135.39, 136.76 (2 Ph), 147.00 (C2), 161.50 (C5) ppm; MS: m/z (int %) 77 (49), 90 (18),
91 (11), 105 (100), 118 (53), 252 (M+, 14); UV: λmax (ε·10-3) MeOH 276.8 (10.78), 203.2 (23.51). Anal.
Calcd for C15H12N2O2: C, 71.41; H, 4.80; N, 11.10. Found: C, 71.38; H, 4.85; N, 11.15.

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(2R)-(1-Hydroxy-1-phenylmethyl)-5-phenyl-1,3,4-oxadiazole (6l).
This compound was obtained as a white solid in 84% yield; mp 148-149°C; Rf: 0.45; [α]D20 -60.4 (MeOH,
1
C=1.0); H-NMR (DMSO-d6, Me4Si): δ 6.15 (d, J=4.8 Hz, 1H, HCOHPh), 6.89 (d, J=4.8 Hz, 1H,
13
HCOHPh), 7.32-7.44 (m, 3H, Ph), 7.53-7.62 (m, 5H, Ph), 7.99 (d, J=6.6 Hz, 2H, Ph) ppm; C-NMR: δ
66.40 (HCOHPh), 123.26, 126.58, 126.70, 128.98, 129.45, 129.98, 132.95, 139.98 (2 Ph), 164.43 (C5),
167.62 (C2) ppm; MS: m/z (int %) 77 (100), 78 (16), 79 (45), 103 (14), 105 (66), 106 (21), 107 (38),
145 (11), 252 (M+, 26); UV: λmax (ε·10-3) MeOH 254.4 (20.02), 204.2 (26.05). Anal. Calcd for
C15H12N2O2: C, 71.41; H, 4.80; N, 11.10. Found: C, 71.46; H, 4.82; N, 11.15.
X-Ray structure determination for 3j: C10H10N2O2, M = 190.20, monoclinic, space group P21, a =
8.4439(17) Å, b = 5.8484(12) Å, c = 19.938(4) Å, β = 95.07(3)o, V = 980.7(3) Å3, Z = 4, Dx = 1.288
gcm-3, F(000) = 400, µ(CuKα) = 0.758 mm-1, crystal size 0.50 x 0.05 x 0.05 mm. Colorless needle
crystals were obtained by slow evaporation of a methanol solution. X-Ray data were collected on a
Bruker SMART APEX CCD diffractometer at rt. Lattice parameters were obtained from least-squares
refinement of setting angles of 48 reflections (θ range 10.1 – 39.2o). Intensity data were collected using
CuKα radiation (λ = 1.54178 Å), ω-scan technique, multi-scan absorption correction24 (Tmin/Tmax
=
0.8081); no. of measured reflection 11173 (θ range 2.22 – 70.05o, index ranges -10 ≤ h ≤ 10, -6 ≤ k ≤ 6,
-24 ≤ l ≤ 24), no. of independent reflections 3412 (Rint = 0.0158). The structure was solved by direct
methods using SIR9225 and refined by full-matrix least-squares with SHELXL97.26 All hydrogen atoms
were located from ∆ρ map and their coordinates were refined with isotropic displacement parameters
taken as 1.5 times those of the respective parent atoms. The assumed absolute stereochemistry of the 3j
was confirmed by refinement of the Flack parameter 26 x = -0.3(2) with 1359 Bijvoet pairs. The final R =
0.0420, wR = 0.1251 for 1251 reflections [I > 2σ(I)] and 314 parameters, S = 0.944, extinction coefficient
g = 0.0068(12), (∆/σ)max = 0.000,(∆ρ)max = 0.257 and (∆ρ)min = -0.194 eÅ-3.
ACKNOWLEDGEMENTS
The authors wish to thank crystallographers: Andrzej Fruziński, Ph.D. from Technical University of Lodz
and Zbigniew Karczmarzyk, Ph.D. from University of Podlasie for X-Ray analysis.
This work was supported by the State Committee of Scientific Research, Grant No 3T09B01929.
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