Synthesis, oxidation and dehydrogenation of cyclic N,O- and N,S-acetals. Part III. [1,2] Transformation of N,O-acetals: 3-Acyl-1,3,4-oxadiazolines

Article abstract of DOI:10.1002/jhet.5570440603

(Chemical Equation Presented) Various aldehyde and ketone acylhydrazones are synthesized and, under acylating conditions, cyclized into 3-acyl-1,3,4-oxadiazolines. The scope and limitations of these cyclizations and the possible side reactions (e.g. formation of the open-chain N,O-acylhydrazinocarbinols) are dissected. For the first time, simple, convenient and efficient dehydrogenations of 3-acyl-1,3,4-oxadiazolines to oxadiazoles by treatment with potassium permanganate, or more conveniently, with ammonium cerium(IV) nitrate (CAN) are presented. CAN oxidation of 2,2-disubstituted 3-acyl-1,3,4-oxadiazolines, as well as that of aldehyde diacylhydrazones (open-chain isomers of 2,5-disubstituted 3-acyl-1,3,4- oxadiazolines) regenerates the parent carbonyl compounds.

Full text of DOI:10.1002/jhet.5570440603

Nov-Dec 2007
1235
Synthesis, Oxidation and Dehydrogenation of Cyclic N,O- and N,S-
Acetals. Part III. [1,2] Transformation of N,O-Acetals:
3-Acyl-1,3,4-Oxadiazolines
László Somogyi
Department of Organic Chemistry, University of Debrecen, P.O. Box 20, H–4010 Debrecen, Hungary
(Fax: + 36 (52) 453-836), somoladeszerv@freemail.hu.
Received June 5, 2006
R3
O
R3
O
N
N
N
O
NAc
R2
R1
R1 = H
R2 R1
R2
KMnO4
CAN
Various aldehyde and ketone acylhydrazones are synthesized and, under acylating conditions, cyclized
into 3-acyl-1,3,4-oxadiazolines. The scope and limitations of these cyclizations and the possible side
reactions (e.g. formation of the open-chain N,O-acylhydrazinocarbinols) are dissected. For the first time,
simple, convenient and efficient dehydrogenations of 3-acyl-1,3,4-oxadiazolines to oxadiazoles by
treatment with potassium permanganate, or more conveniently, with ammonium cerium(IV) nitrate (CAN)
are presented. CAN oxidation of 2,2-disubstituted 3-acyl-1,3,4-oxadiazolines, as well as that of aldehyde
diacylhydrazones (open-chain isomers of 2,5-disubstituted 3-acyl-1,3,4-oxadiazolines) regenerates the
parent carbonyl compounds.
J. Heterocyclic Chem., 44, 1235 (2007).
cally valuable 3-acyl-1,3,4-oxadiazolines will be
considered. It should also be noted that due to the dimin-
ished nucleophilicity of oxygen, in comparison to that of
sulfur, acylhydrazones do not cyclize spontaneously into
the isomeric 2,3-dihydro-1,3,4-oxadiazoles.
Moreover, upon chemical or enzymatic [19] deacyl-
ation 3-acyl-1,3,4-oxadiazolines cleave into acylhydra-
zones, and even the “heteroaromatic” 1,3,4-oxadiazole
ring system can be opened [8] by intra- or intermolecular
nucleophilic functionalities.
INTRODUCTION
Numerous representatives of the 1,3,4-oxadiazol(in)e
ring system exhibit remarkable physical [3], chemical or
biological [4] properties (recently some 1,3,4-oxadiazoles,
carbocyclic acid hydrazides and semicarbazides have been
prepared [5] as peptidomimetics).
Cyclocondensation of N,N'-diacyl- or N-acyl-N'-thio-
acylhydrazines via elimination of the elements of water or
hydrogen sulfide, as well as transformation of 5-
substituted tetrazoles with acid chlorides or anhydrides,
moreover, syntheses starting from trichloromethylarenes
are convenient methods for the synthesis of 2,5-disubst-
ituted 1,3,4-oxadiazoles. As a valuable and versatile
alternative, dehydrocyclization of aldehyde acylhydra-
zones has been effected by treatment with a variety of
oxidants such as chlorine–carbon tetrachloride [6], potas-
sium hexacyanoferrate(III)–aq. sodium hydroxide [7], 3-
methylbutylnitrite–diethyl ether [7], iodine–mercury(II)
oxide [8a,b,9], lead(IV) acetate [10,12d], lead(IV) oxide–
acetic acid [11], nickel(II) peroxide [10e], bromine–
sodium acetate [12a-i], iodine–aq. sodium carbonate [12j],
iron(III) chloride–acetic acid [13], potassium perman-
ganate–acetone [10d], Chloramine T [14], (diacetoxy-
iodo)benzene [15] which transforms also N,N'-diacyl-
hydrazines into oxadiazoles[16], and zinc chloride–acetic
acid [17]. – Also, dehydrogenation of 2,5-disubstituted 3-
acetyl-2,3-dihydro-1,3,4-oxadiazoles by treatment with
lead(IV) acetate has been performed [18].
RESULTS AND DISCUSSION
In order to explore the scope and limitations of the
aimed synthesis steps, a variety of substituted benzalde-
hyde acylhydrazones (1, see Table 3) was prepared and,
under acetylating conditions, cyclized into 3-acetyl-1,3,4-
oxadiazolines (2, Table 4). The products (2) were
subjected to treatment with various oxidants and dehydro-
genating agents of diverse mechanism of action (CAN,
(diacetoxyiodo)benzene, potassium permanganate; see
Table 5).
Scheme 1
acetylation
KMnO4
CAN
1
3
2
The structure of the products, (di)acylhydrazones (1,6),
oxadiazolines (2) and oxadiazoles (3), was supported by
1H and 13C nmr spectral data (see Tables 1 and 2).
Of the various 1,3,4-oxadiazole syntheses, for this once,
dehydrogenation reactions of the chemically or biologi-

1236
L. Somogyi
Vol 44
Table 1
Characteristic 1H nmr spectral data [a] of (di)acylhydrazones (1,6), oxadiazolines (2) and oxadiazoles (3).
ꢀ(ppm)
CH=N
ꢀ (ppm)
Compound O-CH(Ar)-N
Compound
NH/OH
CH3
CH3
1b
11.43[b]
11.31[c]
[e]10.12
11.94
8.13[b]
7.97[c]
7.80
2.20[d]
1.95[f]
2.39
2a
2c
2d
[e]6.94
[e]7.05
[e]6.97
2.17
2.35
2.26
2.15
1c
1d
8.46
11.68[b]
11.55[c]
12.18
8.23[b]
8.06[c]
8.55
2.23[d]
1.98[f]
2e
2f
[e]7.16
[e]7.35
2.37
2.42
1e
1f
2g
[e]7.28[u]
2.37
2.32
12.35
8.83
1g
12.13
8.82
2h
7.52
2.20
2.11
11.74
1h
11.66[g]
11.52[h]
12.17[k]
11.07[l]
8.32[g]
8.21[h]
8.68[k]
7.98[l]
2.16[i]
1.97[j]
2i
2k
7.70
7.01
2.32
2.95[q,r]
2.35
2.34
1i
1j
2.96[n,r]
2o
[e]7.01
10.97[m] 7.84[m] 2.95[n,r]
2.29
2.16[o]
1.90[p]
3d
3g
3h
3o
[e]2.68[v]
[e]2.46
[e]2.66
[e]2.47
1k
1l
11.57
10.79
8.31
7.87
2.98[q,r]
2.95[q,r]
1.22[s]
1m
1o
6a
6b
[e]8.56
7.99
8.47
1.36[s]
11.86[t]
[e]8.52
[e]8.50
2.52[q]
2.56[w]
2.25
6c
[e]9.67[b]
9.34[c]
8.20
2.35[d]
2.17[x]
2.14[x]
2.58[w]
2.25
6d
[e]8.94
[a] 200 MHz, for solutions in [dimethylsulfoxide-d6] if not otherwise stated before the first column. [b] 1/3 H. [c] 2/3 H. [d] 2 H, 2/3 Ac. [e] For
solutions in deuteriochloroform. [f] 1 H, 1/3 Ac. [g] 1/4H. [h] 3/4H. [i] 3/4Ac. [j] 1/4Ac; ref. 66: ꢀ 10.8 (NH) and 10.4 (CH=N, improbably
downfield shifted value!). [k] Ref. 66: ꢀ 10.6 (NH) and 10.4 (CH=N, improbably downfield shifted value!). [l] 0.4 H. [m] 0.6 H. [n] Together 6 H.
[o] 1.8 H (0.6 Ac). [p] 1.2 H (0.4 Ac). [q] 6 H. [r] NMe2. [s] t, J 7 Hz (CH2CH3). [t] 2 H (!), deuterium oxide - exchangeable (in the 500 MHz
spectrum this 2 H0 singlet signal is somewhat broadened. The single crystal X-ray0 analysis supported the hydrazone structure with
intramolecularly0 proximal OH and NH groups.); 13C nmr (dimethylsulfoxide-d6): ꢀ 164.780 (C=O), 159.03 (=C–OH), 148.72 (CH=N), no upfield
signals from0 117.27 (aromatic C). [u] Dubious; beside the signal of solvent (ꢀ 7.26) it is superimposed on the signals of aromatic hydrogens. [v]
360 MHz. [w] Presumably the N–Ac. [x] In total 1 H, 1/3 Ac.
For the cyclization of acylhydrazones under
acylating conditions among others hot acetic
anhydride or, at lower temperatures, the acetic
anhydride–sulfuric acid, 4-toluenesulfonic acid,
trifluoroacetic acid, zinc chloride or acetic
anhydride–sodium acetate, triethylamine, pyridine
couples or acetic chloride and acetic chloride–
dimethylanilin, respectively, were successfully
applied. It should be noted, however, that similar
agents are reported also to transform acylhydrazones
and, as a result of degradation, semicarbazones
[20,21] into acylhydrazones and diacylhydrazones. In
turn, upon treatment with acetic anhydride–zinc
chloride at room temperature [20], upon thermolysis
in neat form [22], or in hot propionic anhydride [20]
aldehyde and ketone diacylhydrazones were
transformed, via N,N' acetyl migration, into the
corresponding 3-acetyl-5-methyl-1,3,4-oxadiazolines.
On the other hand, thermolysis of oxadiazolines (8a)
has been reported [22] to give, likewise with N,N' acetyl
migration in an intermediary azomethine imine species,
the isomeric benzophenone diacetylhydrazone.
Thus, while in the case of the N,S-acetals,
unacylated benzothiazolines and 1,3,4-thiadiazolines,
a ring–chain tautomerism can occur, a somewhat
similar isomer transformation is potential for the
acylated oxygen analogs 3-acyl-1,3,4-oxadiazolines
and diacylhydrazones.
Certain aldehyde acylhydrazones (e.g. 1b,g,o), some of
them exhibiting also a peculiar reaction mechanism of
formation [23], resisted cyclization under the given
acetylating conditions (or underwent only under special

Nov-Dec 2007
Synthesis, Oxidation and Dehydrogenation of Cyclic N,O- and N,S-Acetals. Part III
1237
requirements) but transformed into diacylhydrazones (6a-
d, see EXPERIMENTAL). On this subject, particularly
the acetic anhydride–zinc chloride couple is capable of
producing transformations of various types. This agent is
due to the competition of the acetylating agent with the
carbonyl or acetoximino azomethine moiety of the
substrate via addition of acetic anhydride onto the C=N
bond [28] into acetylated hydrazinocarbinols (e.g. 7c [29])
Table 2
Characteristic 13C nmr spectral data [a] of oxadiazolines (2) and oxadiazoles (3).
ꢂ[ppm]
Compound
C=O7
O–C(R7)=N
O–C(Ar)H–N7
CH3[b]b
7
2co
[c]174.89
[c,d]168.07
155.67o
156.18o
91.48o
90.26o
21.38o
21.26o
2do
oo
11.30[e]
21.35o
2eo
2fo
2ho
[c,d]168.21
[c]167.84
[c]166.83
155.77o
153.56o
155.57o
90.69o
90.61o
88.63o
21.18o
20.93o
10.95[e]
21.18o
2io
[c,d]167.41
[c]167.43
155.33o
155.57o
89.29o
92.86o
2ko
40.23[f]
21.43o
2oo
[c]169.17
167.467
152.81o
91.46o
21.53o
20.95o
3do
3ho
[g]
[g]
[c,d]11.15[e]
[c]11.00[e]
[a] 50.3 MHz, for solutions in dimethyl sulfoxide-d6 if not stated otherwise before the first column. [b] CH3–C=O if not stated otherwise. [c] For
solutions in deuterio-chloroform. [d]90 MHz. [e] 5-Me. [f] 2C, NMe2. [g] C-2 and C-5 of the heterocycle cannot be unequivocally distinguished.
R6
C
R7
R7
R1
H
H
H
H
H
Cl
Cl
Cl
Cl
H
H
H
H
H
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
R3
H
Cl
Cl
NO2
NO2
Cl
Cl
H
R4
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
R5
H
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
H
R6
Ph
R7
Ph
Me
Ph
Meo
Pho
N
N
O
H
NH
N
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
O
NAc
R1
R2
O
N
H
O
Me
Ph
C
C
R5
R4
R1
R2
R5
R4
R1
R5
R4
R5
R4
R1
R2
Meo
Pho
R2
4-pyridylo
2-(HO)C6H4
Me
4-pyridylo
2-(AcO)C6H4
Me
R3
R3
R3
R3
H
Ph
Meo
Ph
Meo
Pho
1
2
3
4
NMe2
NMe2
NMe2
NO2
OH
H
Pho
OEto
OEto
OEt
H
2-(HO)C6H4
2-(AcO)C6H4
or geminal diacetates (for the preparation of 7a,b,d,e and
4-nitrobenzylidene diacetate see EXPERIMENTAL).
Potassium permanganate oxidation, which has been
successfully used previously [30,31] and also most
recently [1] for transforming 3-acetyl-1,3,4-thiadiazolines
into 1,3,4-thiadiazoles, was applied efficiently for the
dehydrogenation of the oxygen analogs 3-acetyl-1,3,4-
oxadiazolines (2) to oxadiazoles (3) now for the first time
(see Table 5). However, for the (2ꢀ3) transformation
CAN oxidation now turned out to be a novel and more
advantageous way, as this method is more ready and, with
more simple processing, often affords almost pure crude
products and in better yields in comparison to the
potassium permanganate oxidation (see Table 5). Upon
treatment with CAN, similarly to 3-acetyl-2,5-diphenyl-
known not only to effect cyclizations accompanied by
acetylation [24] (2ꢀ3) but also to transform, with partial
deacetylation (!), 3-acetyl-5-methyl-1,3,4-oxadiazolines
[25] or diacetylhydrazones [21d] into acetylhydrazones.
Moreover, acylhydrazones of type A (Scheme 2) have
been reported [20,24b] to cleave, with acetolysis of the
CꢁN acetal bond, into acetylated aldopyranoses and 5-
substituted 2-methyl-1,3,4-oxadiazoles. Treatment of
some (di)acylhydrazones with the acetic anhydride–zinc
chloride and acetic anhydride–sulfuric acid couples or hot
acetic anhydride leads to the formation of transacylated
products [21e,26] or to the regeneration of the parent
carbonyl compound [21e,27]. Under acylating conditions,
some acylhydrazones carrying electron-withdrawing
groups do not cyclize into oxadiazolines but transform

1238
L. Somogyi
Vol 44
1,3,4-oxadiazoline (2a), benzaldehyde benzoylhydrazone
(1a) also transformed into 2,5-diphenyl-1,3,4-oxadiazole
(3a), however, in poor yield. On the other hand, under the
same conditions CAN failed to dehydrogenate 3-acetyl-2-
(2,4-dichlorophenyl)-5-(4-pyridyl)-1,3,4-oxadiazoline (2f)
to oxadiazole (3f), probably due to a significant tendency
of pyridyl moiety to form strong cerium complexes.
CꢁN [38] or NꢁN [39] bond formation, degradation of
carboxylic acid hydrazides [40] to parent acids, Hofmann-
type rearrangement [41] or conversion of carboxamides to
hydrazines with NꢁN bond formation [42], regeneration
of the carbonyl from (acyl)hydrazones [43], from oximes
[44], and from dithianes [45] have also been described.
R1
H
R2
Cl
H
R3
Ac
Ac
H
R4
Me
R3
6a
6b
6c
6d
R4
R
R'
Me
Ph
2-(HO)C6H4
4-pyridyl
OEt
N
H
2-(AcO)C6H4
2-(AcO)C6H4
2-(AcO)C6H4
5a
5b
5c
5d
5e
5f
H
H
H
H
H
Ac
H
N
O
R
H
H
R2
R1
R'
N
Cl
Cl
Ac
R
O
6
5
Ph
For comparsion also some related oxadiazolines (8)
disubstituted at position 2 were synthesized and subjected
to react with CAN (see Table 6, EXPERIMENTAL). In
these reactions the parent ketones were formed and
isolated, except the well-soluble and volatile acetone from
8e, in good yields.
Besides potassium permanganate and CAN, in a single
case, also 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
dehydrogenation was tested and found to be entirely
inadequate for the transformation of oxadiazoline (2i)
after boiling in benzene even for 25 hours. Moreover,
treatment with (diacetoxyiodo)benzene in methanol at
room temperature for 19 hours failed to transform oxadia-
zolines (2f) or 5-(2-acetoxyphenyl)-3-acetyl-2-(2,4-
dichlorophenyl)-1,3,4-oxadiazoline (2g) into the corre-
sponding oxadiazoles (3f and 3g, respectively), the
reaction 2gꢀ3g, however, was complete in 2.5 hours by
CAN dehydrogenation at room temperature (see Table 5).
On the other hand, treatment with CAN under similar
conditions degraded 2,4-dichlorobenzaldehyde N-(2-
acetoxybenzoyl)-N-acetylhydrazone (6d), the open-chain
isomer of oxadiazoline (2g), to the parent aldehyde (4g),
as well as 2,3,4,5,6-penta-O-acetyl-D-galactose diacety-
lhydrazone (10) to 2,3,4,5,6-penta-O-acetyl-D-galactose
R2
R1
R2
Ac
Ac
Ac
Ac
H
R3
OAc
N
N
O
7a
7b
7c
7d
7e
4-chlorophenyl
4-nitrophenyl
5-nitro-2-furyl
4-nitrophenyl
4-nitrophenyl
Me
Me
Me
OEt
OEt
R1
R3
Ac
7
CAN oxidation of bioxadiazoline (9), standing for both an
aldehyde and ketone derivative, led to the formation of N,N-
diacetyl-N'-benzoylhydrazine (5f, see EXPERIMENTAL)
and not methyl 5-phenyl-1,3,4-oxadiazol-2-yl ketone, as
expected.
R4
R1
Ph
Ph
Ph
R2
Ph
Ph
Ph
Me
Me
R3
Me
Me
Ph
Me
Me
R4
Me
Ph
Ph
Ph
Ph
N
isolated
as
its
ethyl
hemiacetal
(11,
see
8a
8b
8c
8d
8e
O
N
R3
EXPERIMENTAL).
R1 R2
O
4-BrC6H4
Me
Scheme 2
8
HX
R
HX
R
X
R
C
Y
NH
C
N
C
CAN-mediated transformations of nitrogen and/or
oxygen containing related compounds of various types are
known. Treatment with ceric salts transforms carboxylic
acid hydrazides into the parent acids [46] or their esters
[47], substituted hydrazones, semicarbazones, oximes or
oxime ethers [48], as well as azines [49] or acetals [50]
YH NH
YH
A
B
C
Y= O
X = O, S
As mentioned, (diacetoxyiodo)benzene is known to
dehydrocyclize [15] aldehyde acylhydrazones into 2,5-
disubstituted 1,3,4-oxadiazoles in 24-68% yield. Some
related compounds transform, however, differently.
Hypervalent iodine oxidation [32] has been reported to
transform alkoxycarbonyl (ald)imines into oxazoles with
CꢁO bond formation [33], but to rearrange ꢀ2-oxazolines
with CꢁO bond cleavage [34]. Transformation of
arylhydrazines [35] and hydrazones [36] into ethers, as
well as carboxylic acid hydrazides into N,N-diacyl-
hydrazines [37], heterocyclization of hydrazones with
N
EtO
OH
HC
NAc2
OAc
Ac
Ac
OAc
H
N
O
N
O
AcO
AcO
N
AcO
AcO
N
Ph
Me
Ph
OAc
OAc
OAc
OAc
9
10
11

Nov-Dec 2007
Synthesis, Oxidation and Dehydrogenation of Cyclic N,O- and N,S-Acetals. Part III
1239
General Procedure for the Preparation of Acylhydrazones
(1) and Oxadiazolines (2) (see Tables 3 and 4). A mixture of
the reaction components (and the solvent if used) was made to
react if possible with stirring as stated in Table 3 and Table 4.
General Procedure for Potassium permanganate
Oxidation (see Table 3). With slight modification of the
literature method [30] to a stirred and cooled suspension of the
finely powdered substrate in 99% acetic acid were added finely
powdered potassium permanganate in small portions, and water
in 3-4 portions. For processing the reaction mixtures see the
into the parent carbonyl compounds (regeneration of
carbonyl compounds by treating dioxolanes with
cerium(III) chloride has also been reported) [51], aryl-
substituted carbazides into bisarylcarbodiazones [52],
while some ketone phenylhydrazones into the 4- and 2-
nitrophenyl derivatives [53].
EXPERIMENTAL
indications in Table
EXPERIMENTAL).
5
and General Operations (see
Melting points (uncorrected): Kofler block. Solutions were
concentrated under reduced pressure in a rotary evaporator (< 50
°C, bath). tlc: Kieselgel 60 F254 (Merck, Alurolle). Ir
(potassium bromide disks): Perkin-Elmer 16 PC-FT spectro-
photometer. 200 MHz 1H- and 50 MHz 13C nmr: Bruker WP 200
General Procedure for Ammonium cerium(IV) nitrate
Oxidation (see Table 5). To a stirred suspension/solution of the
powdered substrate in acetonitrile was added CAN in small
portions (the proper time intervals being indicated by the change
of color) and water in 3-4 portions. For processing the reaction
mixtures see the indications in Table 5 and the General
Operations (EXPERIMENTAL).
1
SY, 360 MHz H- and 90 MHz 13C nmr: Bruker AM 360, and
500 MHz 1H nmr: Bruker DRX 500 spectrometers; for recording
the 13C spectra, J-echo techniques were used. X-ray diffraction
analysis for compound 1o: Enraf Nonius MACH3
diffractometer.
General Operations of Processing the Reaction Mixtures
(see Tables 3-6). (A) The product was filtered off in the cold.
Table 3
Preparation and properties of acylhydrazones (1)
Product
Reactiono
componentso
(mmol) o
Solvento
(mL) o
Reactiono
temp. (°C)[a]
(time, h) o
Workup[b]
Yield[c]
%
Mp (°C)
(solvent)
Lit. mp (°C)
(solvent)
Formula[d]
(mol. mass)
1a
1b
1c
4a
(50)
4b
(30)
4c
(60)
4d
(60)
4e
(60)
4f
(30)
4g
(40)
4h
(30)
4i
(30)
4j
(50)
4k
(50)
4l
(40) (40.7)
4m
(40) (40.7)
4n
5b EtOAco
(50) (50)
5a EtOAc[h]
(35) (30)
5b EtOAc[h]
(60) (50)
5a EtOAc[h]
(70) (80)
bpo
(3.5)
bpo
(4)[i]
bpo
(4)
bpo
A
99
70
80
78
85
93
94
91
94
97
97
95
75
96
94
212[e]
206 (EtOH)[f]
209 (EtOH)[g]
151-153
(EtOH)[k]
175[l]
(MeOH)
202[m]
(EtOH)
C14H12N2O
(224.3)
C9H9N2OCl
(196.6)
C14H11N2OCl
(258.7)
C9H9N3O3
(207.2) o
C14H11N3O3
(269.3) o
C13H9N3OCl2
(294.1)
C14H10N2O2Cl2
(309.1) o
C9H8N2OCl2
(231.1) o
C14H10N2OCl2
(293.2) o
C11H15N3O
(205.3)
C16H17N3O
(267.3)
C12H17N3O2
(235.3) o
C10H11N3O4
(237.2) o
C11H13N2O4Br
(317.1)
A[j]
A
154
(50% 2-PrOH)
176[e]
178 (CHCl3)
188[e]
201 (2-PrOH)
246[e]
242 (ME–H2O)[n] (EtOH)
228[e]
228 (EtOH)
240[e]
241 (EtOAc)
199–200[e]
199 (2-PrOH)[r]
232[e]
1d
1e
A
(4.5)
bpo
(4)
5b EtOAc[h]
(60) (80)
A
240[o]
o
1f
5d EtOAco
(30) (60)
bp
A
228–229o
(aq. EtOH)[p]
(2.5)
bpo
(2.5)
bpo
(3.5)
bpo
(2.5)
bpo
(2)
o
1g
1h[q]
1i
5c EtOAco
(40) (80)
A
ꢀ
200–201o
(EtOH)[s]
231[t]
(EtOH)
173–174[v]
o
5a EtOAc[h]
(35) (30)
5b EtOAco
A
A
(30)
(30)
1j
5a EtOAco
(60) (30)
A[u]
A
175–176[e]
177 (EtOAc)
190[e]
188 (EtOAc)
155[e]
156 (EtOAc)
146[e]
147 (EtOAc)
210[e]
1k
1l
5b EtOAco
(50) (15)
5e EtOAco
bpo
(2)
191–192o
(EtOH)[w]
154–155[y]
(aq. EtOH)
147–148o
bpo
(2)
A[x]
A
(10)
EtOAco
(40)
1m
1n
1o
5e
bpo
(4)
(EtOAc)[z]
5e EtOAco
(5)
EtOAco
(50)
bpo
(1)
A
ꢀ
(5)
4o
(20)
(5.1)
5c
(20)
211 (ME–H2O)[n]
254[e]
bpo
(3)
A[bb]
250–252[cc]
(EtOH)
C14H12N2O2
(240.3) o
250 (EtOH)
[a] Bath if not bp. [b] For general operations of processing the reaction mixtures see EXPERIMENTAL. [c] Without workup of the mother liquors.
[d] The C, H, N, as well as Br or Cl analyses data for the products are agreeing with the theoretical values within ±0.3–0.4% limit. [e] Crude product.
[f] Ref. 59. [g] Ref. 60. [h] In the presence of a catalytic amount of 4-toluenesulfonic acid. [i] The formed water was removed azeotropically. [j] The
mother liquor was concentrated. [k] Ref. 23. [l] Ref. 61. [m] Ref. 62. [n] 2-Methoxyethanol with addition of water. [o] Ref. 63. [p] Ref. 64. [q] For
the preparation by acetylating 2,6-dichlorobenzaldehyde hydrazone see EXPERIMENTAL. [r] With addition of water to the hot solution. [s] Ref. 65;
ref. 66: 105 °C (sic!; ethanol). [t] Ref. 66. [u] Previously hexane (30 mL) was added. [v] Ref. 67. [w] Ref. 68. [x] Previously hexane (20 mL) was
added. [y] Ref. 69. [z] Ref. 70. [bb] Previously hexane (40 mL) was added to the warm mixture. [cc] Ref. 71a; ref. 71b: 249-250 °C (from ethanol);
ref. 71c: 230 °C (from ethanol); ref. 71d: 208 °C (sic!; from ethanol).

1240
L. Somogyi
Vol 44
(B) The cold reaction mixture was poured into ice and water. (C)
The reaction mixture was concentrated. (D) The cold residue
was triturated with a small amount of anhydrous ethanol and
kept at room temperature for 0.5–1 hour then hexane was added.
(E) The cold residue was triturated with ice–water. (F) The cold
residue was triturated with ethyl acetate–hexane. (G) The
solution of the product in chloroform was washed with aq.
sodium hydrogen carbonate and water, dried (magnesium
sulfate), and then concentrated. (H) The residue was crystallized
from methanol and then from hexane. (I) sodium hydrogen
carbonate was added in excess to the mixture, which was then
extracted with chloroform. The chloroform solution was washed
with water, dried (magnesium sulfate) and concentrated. The
residue was triturated with ether. (J) Under ice–water cooling, to
the stirred reaction mixture was added 30% hydrogen peroxide
in small portions until discoloration was complete. (K) The
mixture was diluted with 2–3-fold volume of water. (L) The
mixture was extracted with ether, the organic phase was washed
with aq. sodium hydrogencarbonate and water, dried
(magnesium sulfate), and then concentrated.
2,6-Dichlorobenzaldehyde acetylhydrazone (1h). To
a
suspension of 2,6-dichlorobenzaldehyde hydrazone (14.18 g, 75
mmol) in anhyd. pyridine (50 mL) was added acetic anhydride
(25 mL, 265 mmol). The mixture was kept at room temperature
for 4 hours and then poured into ice–water to give crude 1h
(17.17 g, 99%), mp 197-198 °C. For the preparation of 1h from
2,6-dichlorobenzaldehyde with acethydrazide (5a) see Table 3.
Ammonium cerium(IV) nitrate Oxidation of Bioxadiazoline
(9), Preparation of N,N-Diacetyl-N'-benzoylhydrazine (5f).
Procedure A. To a stirred solution of 9 (the higher-melting
isomer [24d,f], mp 155 °C; 1.962 g, 5 mmol) in acetonitrile (25
mL) were added water (0.5 ml) and in small portions CAN
(5.613 g, 10.2 mmol) during 4 hours at room temperature. The
mixture was stirred more for 1 hour, then filtered and the filtrate
concentrated. The residue was partitioned in chloroform–water,
the chloroform solution was washed with water, aq. sodium
hydrogencarbonate and water, dried (magnesium sulfate),
treated with charcoal, and then concentrated. The residue was
triturated with diethyl ether (3 mL) and hexane (15 mL) was
added to give crude (1.008 g, 91.5%) or recrystallized 5f (0.572
g, 52%), mp 150 °C (from water). Ir: 3216, 3014, 1734, 1716,
1664, 1602, 1578 cm-1. 1H nmr (200 MHz, deuteriochloroform):
ꢀ 8.40 (br s, 1H, deuterium oxide - exchangeable, NH), 7.87-
7.83 (m, 2H) and 7.59-7.42 (m, 3H, Ph), 2.49, 2.47, 2.44, and
2.43 (superimposed, 6H, 2Ac); 13C nmr (50.3 MHz,
deuteriochloroform): ꢀ 171.82 (2C=O), 167.71 (C=O), 132.90
(aromatic CH), 131.08 (quat. aromatic C), 128.83 (2 aromatic
2,6-Dichlorobenzaldehyde hydrazone. To a solution of
hydrazine hydrate (2 mL, 98%, 40 mmol) in isopropyl alcohol
(50 mL) was added 2,6-dichlorobenzaldehyde (5.00 g, 28.6
mmol) with stirring. The mixture was boiled for 2.5 hours then
concentrated to give crude (5.03 g, 93%, mp 136-137 °C) or
recrystallized hydrazone, mp 138 °C (from ethanol). Anal.
Calcd. for C7H6N2Cl2: C, 44.47; H, 3.20; N, 14.82; Cl, 37.51.
Found: C, 44.56; H, 3.19; N, 14.55; Cl, 38.03.
Table 4
Preparation and properties of 1,3,4-oxadiazolines (2)
Product Substrateo
o (mmol) o
Agentso
(mmol) o
Reactiono
temp. (°C)[a]
(time, h) o
bp o
Workup[b]
Yield[c]
%
Mp (°C) o
(solvent)o
Formula[d]
(mol. mass)
2a
2c
2d
1a
AcCl o
(252)
Ac2O o
(265)
Ac2O
(159)
C, Fo
C, E, A, G, H
C, D o
35
70
91[e]
(EtOH)
80
(hexane)
92-94[f]
96 (Et2O–
hexane)
104-106[f]
107 (2-PrOH–
hexane)
C16H14N2O2
(266.3) o
C16H13N2O2Cl
(300.7)
(9) o
1c
(6)
bp o
(2)
(20) o
1d
(15) o
150±5 o
(2.5)
68 [g]
C11H11N3O4
(249.2)
o
2e
2f
1e
(26) o
Ac2O
(371)
150 o
(2)
C, D o
C, D o
76
86
C16H13N3O4
(311.3)
o
1f
(10) o
Ac2O (265)
py[h] (31)
105±2 o
(5)
129-130
(EtOAc–
hexane)
C15H11N3O2Cl2
(336.2)
o
2g
2h
1g
Ac2O (42.5)
py[h] (12.4)
105 o
(4.25)
bp o
C, Eo
C, D o
73
70
140-141
C18H14N2O4Cl2
(393.2)
C11H10N2O2Cl2
(3) o
1h
(2-PrOH–H2O)
140-141
141 (2-PrOH–
H2O)
164-165[f]
169-170
(EtOAc)
153-156[f]
158 (EtOAc)
130 (EtOAc–
hexane)
Ac2O (901)
(74) o
(3.5)
(273.1)
o
o
2i
1i
(24) o
Ac2O (742)
bp o
(2)
C, D o
93
C16H12N2O2Cl2
o
(335.2)
o
2k
2o
1k
Ac2O (212)
150 o
(1)
118 o
(6)
C, E, I o
B o
52
C18H19N3O2
(309.4)
C18H16N2O4
(324.3) o
(20) o
1o
Ac2O (106)
py[h] (12.4)
78 [i]
(3) o
[a] Bath if not bp. [b] For general operation of processing the reaction mixtures see EXPERIMENTAL. [c] Without workup of the mother
liquors. [d] The C, H, N, as well as Br or Cl analyses data for the products are agreeing with the theoretical values within ±0.3–0.4% limit. [e]
o
o
o
Lit. m.p. 84–86 C (ethanol), ref. 72; 98 C (ethanol), ref. 73; 98–93 C (ethanol), ref. 18. [f] Crude product. [g] After purification by column
chromatography (Silica Woelm, 100-200 μm, chloroform) and subsequent crystallization. [h] Anhydrous. [i] Tlc chloroform:ethyl acetate (95:5,
v/v) homogeneous.

Nov-Dec 2007
Synthesis, Oxidation and Dehydrogenation of Cyclic N,O- and N,S-Acetals. Part III
1241
CH), 127.48 (2 aromatic CH), 24.82 (CH3). Anal. Calcd. for
C11H12N2O3: C, 59.99; H, 5.49; N, 12.72. Found: C, 60.10; H,
5.44; N, 12.63.
Procedure B. A similar treatment of the lower-melting
isomer [24d,f] of 9 (mp 140 °C) afforded crude (yield 89%) or
recrystallized 5f, mp 148-149 °C, in 43% yield.
131.70, 129.36 (2C), and 129.08 (2C) (6 aromatic C), 26.22 (2
CH3). For 1H nmr data see Table 1. Anal. Calcd. for
C11H11N2O2Cl: C, 55.35; H, 4.65; N, 11.74; Cl, 14.86. Found: C,
55.39; H, 4.41; N, 11.64; Cl, 15.24.
Benzaldehyde N-(2-acetoxybenzoyl)-N-acetylhydrazone (6b)
and Benzaldehyde 2-acetoxybenzoylhydrazone (6c). A mixture
of acetic anhydride (5 mL, 53 mmol), anhydrous pyridine (1.5
mL, 18.5 mmol) and salicyloylhydrazone (10) (0.3604 g, 1.5
mmol) was stirred until dissolution was complete (~5 minutes)
and kept at room temperature for 1 day, then poured into ice–
water to give a mixture (0.418 g) of oxadiazoline (2o) (for
preparation and spectral characteristics see Tables 2,4 and 5), and
hydrazones (6b,c). Separation by column chromatography
(Kieselgel 60 (0.040-0.063 mm, Merck), chloroform:ethyl acetate
(98:2, v/v)) afforded pure N-diacylhydrazone (6b, 0.010 g, 2.1%;
during separation it was, in part, transformed into 6c), mp 108-110
Procedure C. A solution of benzohydrazide (5b, 0.408 g, 3
mmol) in a mixture of acetic anhydride (5 mL, 53 mmol) and
trifluoroacetic acid (0.5 mL, ~6.5 mmol, > 98%) was kept at 48-
50 °C for 7 hours and then concentrated. A solution of the
residue in chloroform was washed with water, aq. sodium
hydrogen-carbonate, and water, dried (magnesium sulfate) and
concentrated. The residue was treated with a small amount of
diethyl ether to give 5f (0.103 g, 16%), mp 149-150 °C [ref. 54a:
152 °C (from water); ref. 54b: 149 °C (from benzene)], identical
(tlc, 1H nmr) with the product obtained in (A) and (B).
4-Chlorobenzaldehyde diacetylhydrazone (6a). A mixture
of acetylhydrazone (1b, 3.343 g, 17 mmol) and acetic anhydride
(30 mL, 318 mmol) was boiled for 2 hours and then
concentrated. The cold residue was triturated with anhydrous
ethanol (1 mL), kept at room temperature for 1 h and, after
addition of hexane (4 mL) in small portions, at 5 °C for 2 hours
to give 6a (1.091 g, 27%), mp 109 °C. 13C nmr (50 MHz,
deuteriochloroform): ꢀ 171.29 (2C=O), 161.90 (CH=N), 137.80,
1
°C (from hexane). Ir: 1772, 1694, 1658, 1604, 1540 cm-1. For H
nmr data see Table 1. Anal. Calcd. for C18H16N2O4: C, 66.66; H,
4.97; N, 8.64. Found: C, 66.74; H, 4.94; N, 8.66.
Second eluate was 6c (0.105 g, 25%), mp 159-160 °C (from
ethyl acetate). Ir: 3228, 3062, 2982, 2832, 1766, 1652, 1606,
1562 cm-1. For 1H nmr data see Table 4. Anal. Calcd. for
C16H14N2O3: C, 68.07; H, 5.00; N, 9.92. Found: C, 68.20; H,
5.04; N, 9.98.
Table 5
Preparation and properties of oxadiazoles (3) [a]
Product Substrate
o (mmol) o
Agento
(mmol) o
Solvento
(mL) o
Reactiono
temp. (°C) o
(time, h)[b,c]
Workup[d] Yield
%
Mp (°C)
(solvent)o
Lit. mpo (°C)
(solvent)o
Formula[e]
(mol. mass)
3a
2a
(0.5) o
1a
CANo
(0.99) o
CANo
MeCN (3) o
o H2O (1) o
MeCN (10)
H2O (3)
23o
(0.17; 0.25)o
23 o
K, Ao
C, Go
K, Ao
K, Ao
K, Ao
60
14
59
33
77
139[f]
139-140o
(Et2O)[g]
138[h]
(petr. ether)
163[i]
C14H10N2Oo
(222.2)
138o
o
(0.5) o
2c
(1.07) o
CAN
(0.3; 0.5)o
23 o
(heptane) o
158[f]
3c
3d
3e
MeCN (10)
o oH2O (3)
MeCN (15)
C14H9N2OClo
(256.7) o
(3) o
2d
o (5.48) o
CAN
(0.4; 0.1)o
23 o
166 (MeOH) o
171[f]
(EtOH)
169-170o
(MeOH)[j]
210-211o
(PhH)[k]
C9H7N3O3
o
(6) o
2e
o (11.6) o
CANo
H2O (1.5)
(0.6; 0.5)o
23 o
172 (2-PrOH) o
205-206[f]
211 (CHCl3–
MeOH) o
(205.2) o
o
o
MeCN (15)
C14H9N3O3
(3) o
(5.99) o
o H2O (4)
(0.3; 0.25) o
(267.2) o
o
3f
3g
3h
2f
(3) o
2g
KMnO4
o (15.4) o
CANo
(1) o
KMnO4
o (10.2) o
CANo
(4) o
KMnO4
o (2.5) o
CANo
(1.85) o
AcOH (20)
o H2O (10)
MeCN (8) o
H2O (0.6)
AcOH (9) o
H2O (1)
< 20 o
(3.5; 4) o
23 o
J, C, Go
K, Ao
J, C, Go
C, Go
16[l]
80[m]
24
150 (EtOAc)o
C13H7N2O3Cl2
(292.1) o
C16H10N2O3Cl2
(349.2) o
C9H6N2OCl2
o (229.1)
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
162o
(EtOAc–heptane)
125o
(Et2O–hexane) o
126-127
(Et2O)
(0.5) o
2h
(1.5; 1) o
< 20 o
o
(2)
2h
(2)
(5; 4) o
23 o
MeCN (10)
o H2O (1)
35
o
(0.75; 1) o
< 20 o
o
3i
2i
AcOH (7)
J, Ko
72
96-98[f,n]
(0.5) o
2i
H2O (3)
MeCN (10) o
H2O (2)
(3; 3) o
23 o
K, Ao
76
106[f]
98-99 (EtOAc–
hexane)[n]
C14H8N2OCl2
(291.1) o
(1) o
(2; 1)[o]o
3o
2o
(0.5)
CAN
o (0.98) o
MeCN (4)
o H2O (0.3)
23 o
(0.45; 1.5)
K, Ao
66
96o
C16H12N2O3
(280.3) o
ꢀ
(2-PrOH–hexane) o
[a] For a general method of preparation see EXPERIMENTAL. [b] Input. [c] Additional reaction time. [d] For general operations of processing the
reaction mixtures see EXPERIMENTAL. [e] The C, H, N, as well as Br or Cl analyses data for the products are agreeing with the theoretical values
within ±0.3–0.4% limit. [f] Crude product. [g] Ref. 74; 139.5 °C (ethanol), ref. 75; 140 °C (methanol), ref. 76; 140-141 °C (benzene), ref. 77; 138-139
°C (ethanol), ref. 18; 138 °C (ethanol), ref. 78. [h] Ref. 79; the product is identical (tlc) with that obtained from 2a. [i] Ref. 78; 162 °C (ethanol), ref.
75; 156-157 °C (ethanol), ref. 80; 155-157 °C (methanol), ref. 76; 130 °C, ref. 8b. [j] Ref. 81; 172-173.5 °C (benzene), ref. 82. [k] Ref. 83; 209-210 °C
(benzene), ref. 84; 209 °C (ethanol), ref. 75; 206.5-208 °C (acetone), ref. 82. [l] After purification by column chromatography: silica gel 60,
chloroform:methanol (95:5, v/v). [m] tlc chloroform:ethyl acetate (95:5, v/v) homogeneous. [n] The crystals, formed from the melt upon cooling, had
mp 106 °C. [o] During the reaction the substrate dissolves with difficulty.

1242
L. Somogyi
Vol 44
2,4-Dichlorobenzaldehyde N-(2-acetoxybenzoyl)-N-acetyl-
presumably to hindered rotations. Ir: 1740, 1718, 1702, 1600
cm-1.
hydrazone (6d). A mixture of acetic anhydride (10 mL, 106
mmol), anhydrous pyridine (10 mL, 124 mmol) and
salicyloylhydrazone (1g, 1.000 g, 3.235 mmol) was kept at room
temperature for 3.5 days and then concentrated. The cold residue
was triturated with ice-water to give crude (1.251 g, 98%) or
recrystallized 6d (0.836 g, 66%), mp 121-122 °C (from
Procedure B. A mixture of acetic anhyride (2 mL, 21.2
mmol), trifluoroacetic acid (0.2 mL, ~2.6 mmol, >98%) and
diacetylhydrazone (6a, 0.2387 g, 1 mmol) was stirred until
dissolution was complete (~15 minutes), kept at room
temperature for 2 days, and then concentrated. The residue was
crystallized from diethyl ether (0.5 mL) to give 7a (0.168 g,
49%), mp 83 °C, identical (tlc, ir) with the product obtained in
(A). Anal. Calcd. for C15H17N2O5Cl: C, 52.87; H, 5.03; N, 8.22;
Cl, 10.41. Found: C, 52.60; H, 5.04; N, 8.30; Cl, 10.42.
1
isopropyl alcohol with addition of water). For H nmr spectral
data see Table 1. For preparation and spectral characteristics of
the structure-isomer oxadiazoline (2g) see Tables 4 and 1. Anal.
Calcd. for C18H14N2O4Cl2: C, 54.98; H, 3.59; N, 7.12. Found: C,
55.14; H, 3.62; N, 7.08.
1-(ꢀ-Acetoxy-4-nitrobenzyl)-1,2,2-triacetylhydrazine (7b).
To a mixture of acetic anhydride (15 mL, 159 mmol) and
trifluoroacetic acid (>98%, 1.5 mL, 19.5 mmol) was added
acetylhydrazone (1d, 3.000 g, 14.48 mmol). The mixture was
stirred for 15 hours, kept at room temperature for additional 48
hours, and then concentrated. A chloroform solution of the
residue was washed with aq. sodium hydrogen carbonate and
water, dried (magnesium sulfate), treated with charcoal, and
concentrated. The residue was triturated with diethyl ether (4
mL) to give tlc chloroform:ether (8:2, v/v) homogeneous
7b (3.409 g, 67%), mp 123 °C. 1H nmr (200 MHz,
deuteriochloroform): ꢁ 8.29-8.20 (m, 2H, 3,5-H), 8.13 (s, 2/3H,
O-CHR-N), 7.64-7.55 (m, 2.4H, 1/3 O-CHR-N superimposed on
the signals of 2,6-H), 2.60 (s, ~1H, ~1/3Ac), 2.55 (s, ~2H,
~2/3Ac), 2.43 (s, ~1H, ~1/3Ac), 2.20 (s, ~1H, ~1/3Ac), 2.15 (s,
~2H, ~2/3Ac), 1.99 (s, ~2H, ~2/3Ac), 1.95 (s, ~2H, ~2/3Ac),
1.78 (s, ~1H, ~1/3Ac), thus altogether 4Ac. 13C nmr (50.3 MHz,
deuteriochloroform): ꢁ 172.63, 171.89, 170.64, 168.81, 168.43,
and 167.72 (C=O), 81.66 and 78.29 (AcO-CHR-N; signals of the
solvent 77.63, 77.00 and 76.36), 24.74, 24.32, 23.78, 21.16,
20.44, and 20.24 (CO–CH3). The product seems to be a mixture
of rotamers also in a dimethylsulfoxide-d6 solution. Ir: 1774,
1732, 1696, 1608, 1558, 1522 cm-1. Anal. Calcd. for
C15H17N3O7: C, 51.28; H, 4.88; N, 11.96. Found: C, 50.94; H,
4.89; N, 11.85.
Ammonium cerium(IV) nitrate Oxidation of Diacyl-
hydrazone (6d): Regeneration to 2,4-Dichlorobenzaldehyde
(4g). To a solution of diacylhydrazone (6d, 0.0983 g, 0.25
mmol) in acetonitrile (3 mL) were added water (0.3 mL) and in
small portions during 1.5 hours CAN (0.2737 g, 98%, ~0.5
mmol) with stirring. The solution was stirred for an additional 1
hour and then diluted with water (20 mL) to give 4g (0.0292 g,
67%), mp 68-73 °C, tlc hexane:chloroform (1:1, v/v)
homogeneous and identical with an authentic (Aldrich, 99%, mp
69-73 °C) specimen.
1-(ꢀ-Acetoxy-4-chlorobenzyl)-1,2,2-triacetylhydrazine (7a).
Procedure A. A mixture of acetic anhydride (25 mL, 265
mmol), trifluoroacetic acid (2.5 mL, 32.5 mmol, >98%) and
acetylhydrazone (1b, 5.000 g, 25.43 mmol) was stirred until
dissolution was complete, kept at room temperature for an
additional 28 hours, and then concentrated. The cold residue was
triturated with ice-water to give crystalline material. A solution
of the crude product in chloroform was washed with aq. sodium
hydrogencarbonate and water, dried (magnesium sulfate),
treated with charcoal, and then concentrated. Crystallization of
the residue twice from diethyl ether (5 mL) with addition of
hexane (5 mL) afforded pure tlc chloroform:diethyl ether (9:1,
1
v/v) homogeneous 7a (4.412 g, 51%), mp 83 °C. H nmr (200
1-(ꢀ-Acetoxy-4-nitrobenzyl)-1,2-diacetyl-2-ethoxycarbo-
nylhydrazine (7d). To a solution of anhydrous zinc chloride
(5.00 g, 36.7 mmol) in acetic anhydride (50 mL, 530 mmol) was
added ethoxycarbonylhydrazone (1m, 4.744 g, 20 mmol). The
solution was kept at 40-41 °C (bath temp.) for 22 hours, then
cooled and poured into ice–water. A chloroform solution of the
MHz, deuteriochloroform): ꢁ 8.01 (s, ~0.6H) and 7.49 (s, ~0.4H)
AcO-CHR-N, 7.37-7.30 (m, 4H, H-Ar), 2.57 (s, ~1.3H, 0.43Ac),
2.54 (s, 1.8H, 0.6Ac), 2.45 (s, 1.1H, 0.37Ac), 2.14 (s, 1.3H,
0.43Ac), 2.10 (s, 1.8H, 0.6Ac), 1.97 (s, 1.8H, 0.6Ac), 1.86 (s,
1.8H, 0.6Ac) and 1.68 (s, 1.1H, 0.37Ac), altogether 4Ac. The
double singlets of carbinolamine and the acetyl groups are due
Table 6
Ammonium cerium(IV) nitrate oxidation of 2,2-disubstituted 1,3,4-oxadiazolines (8)
Substrateo
(mmol) o
CAN
mmolo
Solvents (mL) o
Reaction[a]
time, h [b]
Workup[c]
Product[d]
Ph2COo
Yieldo
%
Mp (ºC)[e]
46-48o
8a[f,k]
(1)
8b[f]
(1)
8c[f]
(1)
8d[i]
(1)
2.88o
2.08o
1.92o
2.11o
7.20o
MeCN (5) o
H2O (1) o
3.5+1o
K,Lo
99o
MeCN (10) o
H2O (2) o
5+2o
K,L [g]
K,L [g]
K,L [g]
K,L [g]
Ph2COoo
PhCO2Hoo
Ph2COoo
PhCO2Ho
4-BrC6H4Aco
oPhCO2H
PhCO2Ho
92o
25o
96o
30[h]
81o
28o
25o
47-48o
118-119o
46-48o
MeCN (10) o
H2O (2) o
5+2o
121-123o
48-50o
MeCN (5) o
H2O (1) o
1.75+0.75o
1.3+0.5o
119-121o
118-119o
8e[j]
(4)
MeCN (5) o
H2O (1.5) o
[a] At room temperature. [b] Input + additional. [c] For general operations of processing the reaction mixtures see EXPERIMENTAL. [d] Identical
(mp, tlc, ir) with an authentic sample. [e] For the crude product. [f] Ref. 85. [g] The aq. sodium hydrogen carbonate extract was acidified with 5 N
hydrochloric acid to Congo Red and kept at 5 °C to give benzoic acid. [h] Note, 1 mol 8c should give 2 mols of benzoic acid. [i] Ref. 24d. [j] Ref.
86. [k] Analogous treatment of the structure-isomer benzophenone diacetylhydrazone[85] with ammonium cerium(IV) nitrate (2.66 mmol)
afforded similarly benzophenone (99.3%), mp 46-48 °C.

Nov-Dec 2007
Synthesis, Oxidation and Dehydrogenation of Cyclic N,O- and N,S-Acetals. Part III
1243
doughy product, containing (tlc) traces of the starting material,
was washed with aq. sodium hydrogen carbonate and water,
dried (magnesium sulfate), treated with charcoal, and
concentrated. The syrupy residue was triturated with ether (6
mL) to give crude (4.656 g, 61%, mp 127-128 °C) or
recrystallized, tlc homogeneous 7d (4.602 g, 60%), mp 132-133
ammonium acetate (0.463 g, 6 mmol), water (6 mL), and in
small portions, during 1.5 hours, ammonium cerium(IV) nitrate
(2.149 g, 3.92 mmol). The mixture was stirred for an additional
7 hours and then concentrated. The residue was diluted with
water (~30 mL) and extracted several times with chloroform.
The chloroform solution was washed with aq. sodium
hydrogencarbonate and water, dried (magnesium sulfate),
treated with charcoal and concentrated. The solid residue was
boiled in anhydrous ethanol (6 mL) for 30 minutes and then
hexane (12 mL) was added to give a crude product (1.174 g,
90%). Purification by column chromatography (Silica Woelm
100-200 μm, chloroform:acetone (95:5, v/v)) and subsequent
crystallization from anhydrous ethanol with addition of hexane
afforded pure 11 (0.793 g, 60.5%), mp 127-129 °C, identical tlc
1
°C (from ethyl acetate with addition of hexane). H nmr (200
MHz, deuteriochloroform): ꢀ 8.26-8.16 (m, 2 H, 3,5-H), 7.90 (s,
0.75 H, AcO-CHR-NAc), 7.70-7.59 (m, 2H, 2,6-H), 7.47 (s,
0.25H, AcO-CHR-NAc), 4.53-4.29 (m, 2H, CH2), 2.62-1.92 (7
s, 9H, 3Ac), 1.48-1.33 and 1.06-0.97 (mixtures of triplets, 2.7H,
and 0.3H, 0.9 and 0.1 CH2CH3, respectively). 13C nmr (90 MHz,
deuteriochloroform): ꢀ 171.42, 170.21, 169.45, 166.42, and
166.33 (C=O), 81.31, 80.46, 78.00, and 76.43 (AcO-CHR-NAc;
signals of the solvent at 77.35, 77.00 and 76.65, distinguished by
J-echo techniques), 64.82, 64.36, 64.27, and 63.72 (CH2CH3),
25.53, 25.02, 21.43, 20.63, 20.52, and 20.28 (CO-CH3), 14.16
and 13.73 (CH2CH3). Ir: 1760, 1750, 1740, 1702, 1610, 1526
cm-1. Anal. Calcd. for C16H19N3O8: C, 50.39; H, 5.02; N, 11.02.
Found: C, 50.40; H, 5.05; N, 10.97.
1-(ꢁ-Acetoxy-4-nitrobenzyl)-1-acetyl-2-ethoxycarbonyl-
hydrazine) (7e). To a solution of anhydrous zinc chloride (7.5 g,
55 mmol) in acetic anhydride (75 mL, 795 mmol) was added
ethoxycarbonylhydrazone (1m, 6.908 g, 29.12 mmol). The
solution was kept at room temperature for 15 hours and then
poured into ice–water to give a tlc-multicomponent solid (6.821
g). A chloroform solution of the crude product was treated with
fuller’s earth and charcoal then concentrated. The residue was
crystallized from ethyl acetate (8 mL) with addition of heptane
(5 mL) to give the tlc homogeneous title compound (7e, 3.881 g,
39%), mp 131 °C. Due to the formation of isomers (tautomers
and rotamers) in deuteriochloroform or dimethylsulfoxide-d6
solution some signals in the 1H nmr (200 MHz) spectra are
doubled e.g. (deuteriochloroform): ꢀ 10.17 and 7.90 (s and br s,
respectively, each 0.5H, NH) or 2.21-2.04 (4 s, altogether 6H,
2Ac). Ir: 3444, 1770, 1744, 1662, 1606, 1518 cm-1. From the
ethyl acetate–heptane mother liquor of 7e pure unchanged 1m
(0.213 g, 3.1%) could be recovered. Anal. Calcd. for
C14H17N3O7: C, 49.55; H, 5.05; N, 12.39. Found: C, 49.54; H,
5.13; N, 12.37.
1
chloroform:acetone (9:1, v/v), ir (potassium bromide), H nmr
(deuteriochloroform) with an authentic [58] specimen.
Names of Substrates and Products Figuring in Tables 1-6.
Benzaldehyde benzoylhydrazone (1a); 4-Chlorobenzaldehyde
acetylhydrazone (1b); 4-Chlorobenzaldehyde benzoylhydrazone
(1c); 4-Nitrobenzaldehyde acetylhydrazone (1d); 4-Nitrobenz-
aldehyde benzoylhydrazone (1e); 2‚4-Dichlorobenzaldehyde iso-
nicotinoylhydrazone (1f); 2‚4-Dichlorobenzaldehyde salicyloyl-
hydrazone (1g); 2,6-Dichlorobenzaldehyde acetylhydrazone
(1h); 2,6-Dichlorobenzaldehyde benzoylhydrazone (1i);
4-Dimethylaminobenzaldehyde acetylhydrazone (1j);
4-Dimethyiaminobenzaldehyde benzoylhydrazone (1k);
4-Dimethylaminobenzaldehyde ethoxycarbonylhydrazone (1l);
4-Nitrobenzaidehyde ethoxycarbonylhydrazone (1m); 5-Bromo-
4-hydroxy-3-methoxybenzaldehyde ethoxycarbonylhydrazone
(5-Bromovanillin ethoxycarbonylhydrazone) (1n); Benzaldehyde
salicyloylhydrazone (1o); 3-Acetyl-2‚5-diphenyl-1‚3‚4-oxadia-
zoline (2a); 3-Acetyl-2-(4-chlorophenyl)-5-phenyl-1‚3‚4-oxa-
diazoline (2c); 3-Acetyl-5-methyl-2-(4-nitrophenyl)-1,3‚4-oxa-
diazoline (2d); 3-Acetyl-2-(4-nitrophenyl)-5-phenyl-1‚3‚4-oxa-
diazoline (2e); 3-Acetyl-2-(2,4-dichlorophenyl)-5-(4-pyridyl)-
1,3‚4-oxadiazoline (2f); 5-(2-Acetoxyphenyl)-3-acetyl-2-(2,4-
dichlorophenyl)-1,3‚4-oxadiazoline (2g); 3-Acetyl-2-(2,6-
dichlorophenyl)-5-methyl-1,3,4-oxadiazoline (2h); 3-Acetyl-2-
(2‚6-dichlorophenyl)-5-phenyl-1,3‚4-oxadiazoline
(2i);
Transformation of Acetylhydrazone (1d) into 4-Nitro-
benzylidene diacetate. To a solution of anhydrous zinc chloride
(2.07 g, 14.68 mmol) in acetic anhydride (20 mL, 212 mmol)
was added acetylhydrazone (1d, 2.072 g, 10 mmol). The
solution was kept at 40-41 °C (bath temp.) for 2.5 days and then
poured into ice– water to give crystalline crude (2.263 g, 91%)
or pure title product (2.093 g, 84%), mp 126.5-127.5 °C (from
ethyl acetate with addition of hexane), ref. 55, mp 126.5 °C
(from ethanol); ref. 56, mp 127 °C (from ethanol); ref. 57, mp
3-Acetyl-2-(4-dimethylaminophenyl)-5-phenyl-1,3‚4-oxadiazoline
(2k); 5-(2-Acetoxyphenyl)-3-acetyl-2-phenyl-1,3‚4-oxadiazoline
(2o); 2,5-Diphenyl-1,3‚4-oxadiazole (3a); 2-(4-Chlorophenyl)-
5-phenyl-1,3‚4-oxadiazole (3c); 5-Methyl-2-(4-nitrophenyl)-
1,3‚4-oxadiazole (3d); 2-(4-Nitrophenyl)-5-phenyl-1‚3‚4-
oxadiazole (3e); 2-(2,4-Dichlorophenyl)-5-(4-pyridyl)-1‚3‚4-
oxadiazole (3f); 5-(2-Acetoxyphenyl)-2-(2,4-dichlorophenyl)-
1,3‚4-oxadiazole (3g); 2-(2,6-Dichlorophenyl)-5-methyl-1‚3‚4-
oxadiazole (3h); 2-(2‚6-Dichlorophenyl)-5-phenyl-1,3‚4-oxadia-
zole (3i); 5-(2-Acetoxyphenyl)-2-phenyl-1‚3‚4-oxadiazole (3o);
Benzaldehyde (4a,o); 4-Chlorobenzaldehyde (4b,c); 4-Nitro-
benzaldehyde (4d,e‚m); 2‚4-Dichlorobenzaldehyde (4f,g); 2‚6-
Dichlorobenzaldehyde (4h,i); 4-Dimethylaminobenzaldehyde
(4j‚k,1); 5-Bromo-4-hydroxy-3-methoxybenzaldehyde (5-
Bromovanillin) (4n); Acetohydrazide (5a); Benzohydrazide
(5b); Salicylohydrazide (5c); Isonicotinohydrazide (Isoniazid)
1
125-126 °C (from ethanol). H nmr (200 MHz, deuteriochloro-
form): ꢀ 8.30-8.25 (d shaped m, 2H, 3,5-H), 7.73 (s, 1H,
superimposed on one of the signals of 2,6-H, O-CHR-O), 7.73-
7.68 (d shaped m, 2H, 2,6-H), 2.16 (s, 6H, 2Ac). 13C nmr (90
MHz, deuteriochloroform): ꢀ 168.43 (2C!, C=O), 148.80,
142.03, 127.84 (2C), and 123.83 (2C) C-Ar, 88.44 (O-CHR-O),
20.64 (2C, 2CO-CH3). Ir: 1764, 1610, 1530 cm-1. Anal. Calcd.
for C11H11NO6: C, 52.17; H, 4.38; N, 5.53. Found: C, 52.13; H,
4.21; N, 5.44.
Ammonium cerium(IV) nitrate Degradation of 2,3,4,5,6-
Penta-O-acetyl-D-galactose diacetylhydrazone (10) to Ethyl
hemiacetal (11). To a stirred suspension of powdered 10[58]
(1.465 g, 3 mmol) in acetonitrile (45 mL) were added
(5d);
Ethoxycarbohydrazide
(ethyl
carbazate)
(5e);
4-Chlorobenzaldehyde diacetylhydrazone (6a); Benzaldehyde
N-(2-acetoxybenzoyl)-N-acetylhydrazone (6b); Benzaldehyde
2-acetoxybenzoylhydrazone (6c); 2‚4-Dichlorobenzaldehyde
N-(2-acetoxybenzoyl)-N-acetylhydrazone (6d); 1-(ꢁ-Acetoxy-4-
chlorobenzyl)-1,2,2-triacetylhydrazine (7a); 1-(ꢁ-Acetoxy-4-

1244
L. Somogyi
Vol 44
Tetrahedron Lett., 42, 2583 (2001), and references cited therein; [h] S.
Rollas, N. Gulerman and H. Erdeniz, Farmaco, 57, 171 (2002); [i] F.
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Corrosion Science, 44, 2271 (2002); Chem. Abstr., 137, 96796k (2002);
[j] X.-J. Zou, L. H. Lai, G.-Y. Jin and Z.-X. Zhang, J. Agric. Food
Chem., 50, 3757 (2002); [k] M. J. Hearn (Wellesley College, USA) PCT
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U. Hacksell, Methods Mol. Med., 23 (Peptidomimetics Protocols), 1
(1999); Chem. Abstr., 132, 334729j (2000); [c] S. Borg, R. C. Vollinga,
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4331 (1999); [d] A. Cheguillaume, A. Salaün, S. Sinbandhit, M. Potel, P.
Gall, M. Baudy-Floc’h and P. Le Grel, J. Org. Chem., 66, 4923 (2001);
[e] N. Brosse, A. Grandeury and B. Jamart-Grégoire, Tetrahedron Lett.,
43, 2009 (2002).
[6] R. Stollé, J. Prakt.Chem., [2], 85, 388 (1912); Beilst., 27 I,
577.
[7] R. Stollé and G. Münch, J. Prakt. Chem., [2], 70, 416 (1904);
Beilst., 9, 321; 27, 591.
[8] [a] H. El Khadem, M. A. E. Shaban and M. A. M. Nassr,
Carbohydr. Res., 13, 470 (1970); [b] H. El Khadem, M. Shaban and M.
Nassr, Carbohydr. Res., 23, 103 (1972); [c] C. E. Cannizzaro, I. M. E.
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Linganna and K. M. L. Rai, Synth. Commun., 28, 4611 (1998), and
references cited therein.
nitrobenzyl)-1,2,2-triacetylhydrazine (7b); 1-(ꢀ-Acetoxy-5-nitro-
2-furylmethyl)-1,2‚2-triacetylhydrazine (7c); 1-(ꢀ-Acetoxy-4-
nitrobenzyl)-1,2-diacetyl-2-ethoxycarbonylhydrazine (7d); 1-(ꢀ-
Acetoxy-4-nitrobenzyl)-1-acetyl-2-ethoxycarbonylhydrazine (7e);
3-Acetyl-5-methyl-2‚2-diphenyl-1‚3,4-oxadiazoline (8a);
3-Acetyl-2‚2‚5-triphenyl-1‚3‚4-oxadiazoline (8b); 3-Benzoyl-
2‚2‚5-triphenyl-1,3‚4-oxadiazoline (8c); 3-Acetyl-2-(4-bromo-
phenyl)-2-methyl-5-phenyl-1,3,4-oxadiazoline (8d); 3-Acetyl-
2,2-dimethyl-5-phenyl-1,3,4-oxadiazoline (8e).
Acknowledgements. The author thanks Mrs. Katalin Tréfás
for the microanalyses and recording the ir spectra, Mme. Sára
Balla and Mrs. Éva Józsa for recording the nmr spectra, Gyula
Batta, D.Sc. (Research Group for Antoboitics, Hungarian
Academy of Sciences, Debrecen) for the 500 MHz nmr
measurements, and Cs. Bényei, Ph.D. (Laboratory for X-ray
Diffraction, University of Debrecen) for the X-ray diffraction
investigations supported by Tempus JEP (Grant No. 9252-95)
and the Hungarian Scientific Research Fund (OTKA Grant No.
D25136 and M28249). Grants from the Hungarian Scientific
Research Fund (OTKA T025016 and T037201) for this work are
also gratefully acknowledged.
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Synthesis, Oxidation and Dehydrogenation of Cyclic N,O- and N,S-Acetals. Part III
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