THIANTHRENE CATION RADICAL INDUCED REACTIONS
OF SEMICARBAZONES AND ACYLHYDRAZONES
by
HARI DAS MANDAL, B.S., M.S.
A DISSERTATION
IN
CHEMISTRY
Submitted to the Graduate Faculty
of Texas Tech University in
Partial Fulfillment of
the Requirements for
the Degree of
DOCTOR OF PHILOSOPHY
Approved
August, 1996
T3
ACKNOWLEDGEMENTS
With deep gratitude I would like to thank my research advisor, Dr. Henry
J. Shine, for his enduring support, patience, criticism, guidance, advice and
encouragement during my graduate career.
I am also very grateful to my committee members. Dr. John N. Marx, Dr.
Robert D. Walkup, Dr. David M. Birney and Dr. Bruce R. Whittlesey, for their
valuable suggestions and criticisms throughout this research work.
Many thanks are also extended to Dr. Shine's Research Group for their
friendship, cooperation and valuable suggestions.
I gratefully acknowledge the financial support from Texas Tech University
(In the form of teaching asslstantship), and the Robert A. Welch Foundation.
I am especially indebted to my wife Anita and my son Anuron for their
sacrifice, cooperation, support and understanding throughout the course of this
study.
II
CONTENTS
ACKNOWLEDGEMENTS
ii
LIST OF TABLES
xiii
CHAPTER
I. INTRODUCTION
1
Purpose of this Research
1
Structures
2
General Review of Cation Radical Chemistry
3
Formation of Cation Radicals
3
Preparation of Cation Radicals
3
Structure of Cation Radicals
3
Reactions of Cation Radicals
5
With Nucleophiles
5
Electron Transfer Reactions
7
Diels-Alder Reactions
10
Oxidative Cycloaddition Reactions
11
Review of the Oxidative Reactions
12
Oxidative Reactions of Semicarbazones
12
Oxidative Reactions of Hydrazones
15
Oxidative Reactions of N-Acylhydrazones
20
III
II. EXPERIMENTAL SECTION
30
General Information
30
Solvents, Reagents and Purification Techniques
30
Chromatographic Techniques
30
Spectroscopic Measurements
31
Elemental Analyses
32
Melting Point Apparatus
32
Preparation of Thianthrene Cation Radical Perchlorate
32
lodometric Assay of Cation Radical Purity
32
Determination of Cation Radical Purity
33
Preparation of Thianthrene 5-Oxide (ThO)
33
Preparation of Aldehyde Semicarbazones
34
Benzaldehyde Semicarbazone
34
Cinnamaldehyde Semicarbazone
34
Preparation of Benzaldehyde C^oiSemicarbazone
35
Preparation of C^OlUrea
35
Measurement of ^^O Enrichment (MS-DIP) of [isojUrea
35
Preparation of [isoiSemicarbazide
36
Preparation of Benzaldehyde [i^oiSemicarbazone
36
Measurement of '•^O Enrichment (SIM) of Benzaldehyde
[i80]Semicarbazone
36
IV
Preparation of 2-Amino-5-Substituted-1,3,4-Oxadiazoles
37
2-Amino-5-Phenyl-1,3,4-OxadiazoIe
37
2-Amino-5-Styryl-1,3,4-Oxadiazole
37
Reactions of Thianthrene Cation Radical Perchlorate with
Benzaldehyde Semicarbazones in Acetonitrile Solvent
38
In the Presence of Ordinary Water
38
In the Presence of [isoj-Labeled Water
38
Selected Ion Monitoring (SIM) Mass Spectrometry of the
Isolated 2-Amino-5-Phenyl-1,3,4-Oxadiazole (From the
Reaction of Benzaldehyde Semicarbazone in the Presence
of 180-Labeled Water)
39
Reaction of Benzaldehyde C^OlSemicarbazone in the
Presence of Ordinary Water
40
Selected Ion Monitoring (SIM) Mass Spectrometry of the
Isolated 2-Amino-5-Phenyl-1,3,4-Oxadiazole (From the
Reaction of Benzaldehyde [i^oiSemicarbazone in the
Presence of Ordinary Water)
40
Reaction of Cinnamaldehyde Semicarbazone in the Presence
of Ordinary Water
Preparation of Esters from Carboxylic Acids
41
41
General Procedure
41
Methyl 4-Chlorobenzoate
42
Methyl 4-Methylbenzoate
42
Methyl 2-Naphthoate
42
Methyl 3-Nitrobenzoate
42
Methyl 4-Nitrobenzoate
42
Methyl 2-Methoxybenzoate
43
Preparation of Acid Chlorides
43
General Procedure
43
CinnamoyI Chloride
43
CrotonoyI Chloride
44
Preparation of 1,2-Diacylhydrazines
44
1-Benzoyl-2-Cinnamoyl Hydrazine
44
1-Benzoyl-2-(4-Dlmethylaminobenzoyl) Hydrazine
45
1-Benzoyl-2-Crotonoyl Hydrazine
45
Preparation of Acid Hydrazides
45
General Procedure
45
Benzoic Acid Hydrazide
46
4-Chlorobenzoic Acid Hydrazide
46
4-Methy I benzoic Acid Hydrazide
46
3-Nitrobenzoic Acid Hydrazide
46
4-Nitrobenzoic Acid Hydrazide
46
2-Naphthoic Acid Hydrazide
47
2-Methoxybenzoic Acid Hydrazide
47
Preparation of Aldehyde N-Acylhydrazones
47
General Procedure
47
Benzaldehyde Benzoylhydrazone
47
1-Naphthaldehyde Benzoylhydrazone
48
vi
Benzaldehyde 1-Naphthoylhydrazone
1 -Naphthaldehyde 1 -Naphthoylhydrazone
48
48
2-Naphthaldehyde Benzoylhydrazone
49
Benzaldehyde 2-Naphthoylhydrazone
49
2-Naphthaldehyde 2-Naphthoylhydrazone
49
2-Methoxybenzaldehyde Benzoylhydrazone
49
Benzaldehyde 2-Methoxybenzoylhydrazone
50
2-Methoxybenzaldehyde 2-Methoxybenzoylhydrazone
50
4-Methoxybenzaldehyde Benzoylhydrazone
50
Benzaldehyde 4-Methoxybenzoylhydrazone
50
4-Methoxybenzaldehyde 4-Methoxybenzoylhydrazone
50
4-Methylbenzaldehyde Benzoylhydrazone
51
Benzaldehyde 4-Methylbenzoylhydrazone
51
4-Methylbenzaldehyde 4-Methylbenzoylhydrazone
51
4-Chlorobenzaldehyde Benzoylhydrazone
51
Benzaldehyde 4-Chlorobenzoylhydrazone
52
4-Chlorobenzaldehyde 4-Chlorobenzoylhydrazone
52
4-Nitrobenzaldehyde Benzoylhydrazone
52
Benzaldehyde 4-Nitrobenzoylhydrazone
52
3-Nitrobenzladehyde Benzoylhydrazone
52
Benzaldehyde 3-Nitrobenzoylhydrazone
53
Cinnamaldehyde Benzoylhydrazone
53
vii
Crotonaldehyde Benzoylhydrazone
53
Phenylacetaldehyde Benzoylhydrazone
53
Benzaldehyde Phenylacetylhydrazone
54
Trimethylacetaldehyde Benzoylhydrazone
54
4-Dimethylaminobenzaldehyde Benzoylhydrazone
55
Preparation of Authentic 2-R-5-R'-1,3,4-Oxadiazoles
55
General Procedure
55
2,5-Diphenyl-1,3,4-Oxadiazole
55
2-(1 -Naphthyl)-5-Phenyl-1,3,4-Oxadiazole
56
2,5-Di-(1-Naphthyl)-1,3,4-Oxadiazole
56
2-(2-Naphthyl)-5-Phenyl-1,3,4-Oxadiazole
56
2.5-Di-(2-Naphthyl)-1,3,4-Oxadiazole
56
2-(2-Methoxyphenyl)-5-Phenyl-1,3,4-Oxadiazole
57
2,5-Di-(2-Methoxyphenyl)-1,3,4-Oxadiazole
57
2-(4-Methoxyphenyl)-5-Phenyl-1,3,4-Oxadiazole
57
2.5-Di-(4-Methoxyphenyl)-1,3,4-Oxadiazole
58
2-(4-Methylphenyl)-5-Phenyl-1,3,4-Oxadiazole
58
2,5-DI-(4-Methylphenyl)-1,3,4-Oxadiazole
58
2-(4-Chlorophenyl)-5-Phenyl-1,3,4-Oxadiazole
58
2,5-Di-(4-Chlorophenyl)-1,3,4-Oxadiazole
59
2-(4-Nitrophenyl)-5-Phenyl-1,3,4-Oxadiazole
59
VIII
2-(3-Nitrophenyl)-5-Phenyl-1,3,4-Oxadiazole,
from 3-Nitrobenzaldehyde Benzoylhydrazone
59
2-(3-Nitrophenyl)-5-Phenyl-1,3,4-Oxadiazole,
from Benzaldehyde 3-Nitrobenzoylhydrazone
60
2-Phenyl-5-Styryl-1,3,4-Oxadiazole
60
2-Crotyl-5-Phenyl-1,3,4-Oxadiazole
61
2-Benzyl-5-Phenyl-1,3,4-Oxadiazole
61
2-teAt-Butyl-5-Phenyl-1,3,4-Oxadiazole
61
2-(4-Dimethylaminophenyl)-5-Phenyl-1,3,4-Oxadiazole
62
Reactions of Aldehyde N-Acylhydrazones with Thianthrene Cation
Radical Perchlorate in Acetonitrile
Benzaldehyde Benzoylhydrazone in the Absence of
2,6-Di-terf-Butyl-4-Methylpyridine (DTBMP)
62
62
Benzaldehyde Benzoylhydrazone
in the Presence of DTBMP
63
Phenylacetaldehyde Benzoylhydrazone
in the Presence of DTBMP
63
Trimethylacetaldehyde N-Benzoylhydrazone
in the Presence of DTBMP
64
Reactions of Aldehyde N-Acylhydrazones with Thianthrene Cation
Radical Perchlorate in Dichloromethane in the Presence of DTBMP
64
General Procedure
64
Benzaldehyde Benzoylhydrazone
65
1 -Naphthaldehyde Benzoylhydrazone
65
Benzaldehyde 1-Naphthoylhydrazone
65
1 -Naphthaldehyde 1 -Naphthoylhydrazone
IX
66
2-Naphthaldehyde Benzoylhydrazone
66
Benzaldehyde 2-Naphthoylhydrazone
66
2-Naphthaldehyde 2-Naphthoylhydrazone
67
2-Methoxybenzaldehyde Benzoylhydrazone
67
Benzaldehyde 2-Methoxybenzoylhydrazone
67
2-Methoxybenzaldehyde 2-Methoxybenzoylhydrazone
68
4-Methoxybenzaldehyde Benzoylhydrazone
68
Benzaldehyde 4-Methoxybenzoylhydrazone
68
4-Methoxybenzaldehyde 4-Methoxybenzoylhydrazone
69
4-Methylbenzaldehyde Benzoylhydrazone
69
Benzaldehyde 4-Methylbenzoylhydrazone
69
4-Methylbenzaldehyde 4-Methylbenzoylhydrazone
70
4-Chlorobenzaldehyde Benzoylhydrazone
70
Benzaldehyde 4-Chlorobenzoylhydrazone
70
4-Chlorobenzaldehyde 4-Chlorobenzoylhydrazone
71
4-Nitrobenzaldehyde Benzoylhydrazone
71
Benzaldehyde 4-Nitrobenzoylhydrazone
71
3-Nitrobenzaldehyde Benzoylhydrazone
72
Benzaldehyde 3-Nitrobenzoylhydrazone
72
Cinnamaldehyde Benzoylhydrazone
72
Crotonaldehyde Benzoylhydrazone
73
Phenylacetaldehyde Benzoylhydrazone
73
Benzaldehyde Phenylacetylhydrazone
73
Trimethylacetaldehyde Benzoylhydrazone
74
4-Dimethylaminobenzaldehyde Benzoylhydrazone
74
III. RESULTS AND DISCUSSIONS
75
Reactions of Aldehyde Semicarbazones with Thianthrene Cation
Radical Perchlorate
75
Reactions of Aldehyde N-Acylhydrazones with Thianthrene Cation
Radical Perchlorate
81
Reactions of Aldehyde N-Acylhydrazones in Acetonitrile
83
Reactions of Aldehyde N-Acylhydrazones in Dichloromethane
85
Oxidation of the Aldehyde N-Acylhydrazone and Competitive
Formation of Aldehyde and Oxadiazole
87
Reactivity Patterns of the Aldehyde N-Acylhydrazones
88
Effect of the R Group on the Oxidizability of the
N-Acylhydrazone Molecule (RCH=NNHCOR')
89
Factors Affecting the Yield of Oxadiazole
92
Competition Between the Formation of Aldehyde (RCHO)
and Oxadiazole
94
Mechanism for the Formation of Aldehydes (RCHO)
95
Oxadiazole from Two Routes (from RCH=NNHCOR' and
R'CH=NNHCOR)
Mechanism for the Formation of 2,5-Disubstituted-1,3,4Oxadiazoles
Cycloaddition to Solvent RCN Versus Intramolecular Cyclization
Comparison of Conventional Versus Thianthrene Cation
Radical Routes to Oxadiazole
XI
97
99
101
102
IV. CONCLUSIONS
^^9
REFERENCES
.^21
XII
LIST OF TABLES
1.
2.
3.
4.
5.
6.
7.
8.
Yields of the Products of Reactions of Thianthrene Cation
Radical Perchlorate (Th-*-CI04-) with Aldehyde
Semicarbazones (RCH=NNHC0NH2) in Acetonitrile
104
List of Aldehyde N-Acylhydrazones (RCH=NNHCOR')
Synthesized According to the Given Scheme
105
List of the Authentic 2-R-5-R'-1,3,4-Oxadiazoles Synthesized
According to the Given Scheme
107
List of the Authentic 2-R-5-R'-1,3,4-Oxadiazoles Synthesized
According to the Given Scheme
108
Yields of the Products of Reactions of Thianthrene Cation
Radical Perchlorate (Th+CI04") with Aldehyde
N-Acylhydrazones (PhCH=NNHCOPh) in Acetonitrile Solvent
109
Yields of the Products of Reactions of Thianthrene Cation
Radical Perchlorate (Th+CI04-) with Aldehyde
N-Acylhydrazones (RCH=NNHCOR') in Dichloromethane
Solvent
110
Yields of the 2-R-5-R'-1,3,4-Oxadiazoles From the Reactions
of Thianthrene Cation Radical (Th'*'CI04") with Aldehyde
N-Acylhydrazones (RCH=NNHCOR')
115
List of the Pairs of Hydrazones (RCH=NNHCOR') Producing
the Same Oxadiazoles (and their % Yields) in Thianthrene
Cation Radical (Th+CI04-) Reactions
117
XIII
CHAPTER I
INTRODUCTION
Purpose of this Research
Single-electron transfer (SET) reactions of cation radicals have been
widely studied."• Recently, cation radical induced oxidative intramolecular
cyclization reactions2 and oxidative cycloaddition reactions^-^ involving nitrile
solvents have been discovered. It was found that cation radicals are capable of
causing the oxidative cyclization of arylhydrazones of chalcones and
benzalacetones to pyrazoles In acetonitrile solvent. On the other hand, reactions
of thianthrene cation radical with arylhydrazones and oximes of non-conjugated
aldehydes in nitrile solvents can cause oxidative cycloaddition to the nitrile
group with the formation of 1,2,4-triazoles.
Shin^ investigated the reactions of aldehyde semicarbazones with
thianthrene cation radical perchlorate in acetonitrile solvent. These reactions
caused oxidative intramolecular cyclization, producing 1,3,4-oxadiazoles as the
major product. During this investigation some interesting observations were
made. Reactions were generally slow and the yield of the product oxadiazole
was moderate. However, addition of a small amount of water to the reaction
mixture dramatically accelerated the reaction and increased the yield of the
oxadiazole.
Therefore, it was of interest to explore the mechanistic aspects of these
reactions further and to probe the possible role of added water in enhancing the
reaction and product yield.
Acylhydrazones are structurally and electronically analogous to
hydrazones, oximes and semicarbazones. From the Investigations discussed
above it was expected that the reaction of thianthrene cation radical with
acylhydrazones could lead to either 1,2,4-triazoles by oxidative cycloaddition to
nitrile solvents or to 1,3,4-oxadiazoles by oxidative intramolecular cyclization. In
addition, Chlba and coworkers® had recently reported that anodic oxidation of
acylhydrazones in acetonitrile solvent led to the formation of 1,3,4-oxadiazoles.
Therefore, it was of interest to investigate the analogous oxidations of aldehyde
N-acylhydrazones by thianthrene cation radical.
Structures
Following are the structures and common abbreviations of some of the
compounds used in this research. For convenience, the abbreviations will be
used throughout the dissertation.
Thianthrene (Th)
Thianthrene 5-Oxide (ThO)
CI04-
t-Bu
Thianthrenen Cation Radical Perchlorate
(Th^CIO/)
2,6-Di-terf-ButyM-Methylpyridine
(DTBMP)
General Review of Cation Radical Chemistry
Formation of Cation Radicals
A cation radical is formed by the removal of an electron from a neutral
molecule. The species thus formed is at the same time a cation and a radical.
Molecules containing 7c-electrons and heteroatoms with unshared electrons are
most easily oxidized. Organosulfur cation radicals, particulariy the cation
radicals of heterocyclic compounds such as thianthrene, phenoxathiin and
phenothiazine, have been extensively studied. These cation radicals are
stabilized by electron delocalization and can be isolated as crystalline salts.
Preparation of Cation Radicals
Cation radicals have been prepared by a variety of methods such as
anodic oxidation, chemical oxidation, and photoionization. Among these,
chemical oxidation is the most common method for the preparation of cation
radicals. A wide variety of reagents have been used as the oxidizng agents such
as perchloric acid,^ persulfuric acid,''o concentrated sulfuric acid'"'' nitrosonium
tetrafluoroborate''2 and some Lewis acids such as antimony pentachloride.''^
Phenothiazine cation radical was made by oxidation with iodine-silver
perchlorate.''^ Some organonitrogen cation radicals such as tris(pbromophenyl)amine and tris(2,4-dibromophenyl)amine have also been well
studied.
Stmcture of Cation Radicals
In 1868, Stenhouse observed for the first time that thianthrene when
dissolved in concentrated sulfuric acid, produced a purple-colored solution, and
that sulfur dioxide was given off in the process.''^ Many years later, it was shown
that the purple color was caused by the thianthrene cation radical, which had
been formed in the solution by the oxidation of thianthrene with sulfuric acid
(equation 1).
+
3H2SO4
•^
2
+ 2HSO4- + SO2 + H2O
(1)
A number of investigators have studied the Electron Spin Resonance
Spectroscopy (ESR) of thianthrene cation radical.9. ""6-19 |n the period 19611962,'' the correct identification of thianthrene cation radical was made with
ESR. A five-line ESR spectrum was obtained from the purple-colored solution of
thianthrene in sulfuric acid.^. ''3 (b). I8-21 |t was caused by coupling of the electron
spin with one of the two sets of four equivalent protons. However, the ESR
spectrum could not distinguish which set of four equivalent protons was
responsible for the five lines.
To solve this problem, the ESR spectra of appropriately substituted
thianthrene cation radicals were taken. A number of 1-substituted thianthrenes
gave a five-line ESR spectrum like that of thianthrene cation radical itself. On the
other hand, a number of 2-substituted thianthrenes gave distorted three or fourline spectra.22 The complete resolution of the ESR spectrum of thianthrene
cation radical was achieved by carrying out the experiment at low temperatures
and in a different medium (nitromethane-aluminium chloride).23 The spectrum
showed the expected 25 proton lines and hyperfine splitting by naturally
occuring ^^S.
Reactions of Cation Radicals
With Nucleophiles
Among the common reactions that cation radicals undergo are those with
nucleophiles. Thianthrene cation radical was at the center of these studies. It
was found that reactions of thianthrene cation radical with nucleophiles take
place usually at the sulfur atom (equation 2) and sometimes at a ring position
(equation 3). Various reactions of cation radicals with nucleophiles have been
studied, some of them kinetically. Shine and coworkers have studied the
reactions of thianthrene cation radical perchlorate with a variety of nucleophiles
such as water,24.25 ammonia,26 amines,27.28 aromatics,29.30 organometallics,^''33 ketones,34-36 alkenes,37 alkynes,37 chloride,24 nitrite24 and nitrate ion.''^
NuH
NuH
+
Th
+
H
(2)
+
Th
+
2H^
(3)
Hammerich and Parker38 investigated the mechanism of the reactions of
thianthrene cation radical with nucleophiles. In general, three different
mechanisms were proposed for these reactions. These were designated as (a)
disproportionation (equations 4 and 5), (b) complexation (equations 6-8) and (c)
half-generation (equations 9-11). In the disproportionation mechanism, the
dication is the reacting species, whereas in other two mechanisms the cation
radical is the reacting species. The complexation mechanism and the half-
generation mechanism are very similar, except that in the former a jt-complex is
formed from the initial interaction, and covalent bonding does not occur until
later.
2Th+
Th2+
Th2+
+
Th+
+
(Th/NuH)f
NuH
(Th/NuH)2+
Th+
Th-i-
^
^
•
+
(Th-NuH)-I-
— •
NuH
+
(Th-NuH)2+
Th-i^
Th
(4)
Products
(5)
(Th/NuH)+
(6)
(Th/NuH)2+
+
Th
(7)
Products
NuH
+
+
^
(8)
(Th-NuH)4-
^
(Th-NuH)2+
(9)
+
Jh
Products
(10)
(11)
The reaction of thianthrene cation radical with water was studied in detail.
The mechanism of the reaction turned out to be a complex one. In 1969, Shine
and Murata24.39 suggested that the reaction involved a disproportionation
pathway. However, Parker and Eberson^o found that a direct reaction occurred
between the cation radical and water. Several years later, Evans and Blount^''
suggested that the reaction was second order in thianthrene cation radical, third
order in water and inverse first order in acid. Based on these observations the
following mechanisms were proposed (equations 12-15).
Th+
+
H2O
^
(Th-0H2)+
(12)
(Th-0H2)+
(Th-OH)-
+
H2O
+
(Th-OH)""
^
(Th-0H2)+
+
(Th-OH).
^
H2O
(Th-OH)""
>-
+
-»- Th
ThO
-•-
HaO""
-•-
(13)
H2O
H^d
(14)
(15)
Electron Transfer Reactions
Cation radicals also undergo electron transfer reactions as represented
by equation 16. Electron transfer in cation radical chemistry causes reduction of
the cation radical.
TM-
+
NuH
^
Th
-I-
(NuH>f
(16)
Parker and coworkers42 proposed the complexation mechanism
(equations 17-20) for the reaction of thianthrene cation radical with anisole.
They found that thianthrene cation radical reacted with anisole to form a complex
which reacted further by one of the two different pathways depending on the
concentration of thianthrene cation radical. At low concentration of thianthrene
cation radical, first-order kinetics in both thianthrene cation radical and anisole
were observed (equations 17 and 18). At higher concentration of thianthrene
cation radical, the reaction was found to be second order in thianthrene cation
radical. Equations 17 and 18 show a net electron transfer.
Th-^
+
(Th/AnH)+
AnH
^
=5—=^
Th
(Th/AnH)+
+
AnH-f-
(17)
(18)
(Th/AnH)^
(Th/AnH)2^
Th-^
(Th/AnH)2H
(Th/AnH)-
Th
(19)
(20)
H+
Shine and coworkers3''-33 investigated the reactions of organometallic
compounds with thianthrene cation radical. From the reaction of MeHgR (R = Et,
i-Pr, t-Bu) it was found that the reaction begins with electron transfer rather than
with electrophilic cleavage of an alkyl-mercury bond (equations 21-23). The
radical (2) that was generated from the decomposition of 1 was trapped at a
sulfur atom of thianthrene cation radical to form a 5-alkyl- or arylthianthrenlumyl
perchlorate (3). Also, hydrogen atom abstraction from the solvent was observed.
R2Hg
+
R2Hg+
-^
RHg
R«
2
1
+
R2Hg+
(21)
(22)
(23)
R2
Formation of alkyl and aryl radicals was also reported as the evidence for
electron transfer from the reactions of Grignard reagents and aryllithiums (ArLi)
with thianthrene cation radical.-*. 33.43 Radicals generated from the
decomposition of Grignard reagents and ArLi caused alkylation or arylation on
8
sulfur. Hydrogen abstraction from solvent molecules by the radicals was also
observed.
Shine and coworkers^ reported the reaction of 1,1'-azoadamantane
(AdN=NAd) with thianthrene cation radical in acetonitrile solvent. The reaction
produced nitrogen and thianthrene in quantitative yields. The adamantyl cation
(Ad+) that was formed in the process was trapped by the acetonitrile solvent to
give, eventually, adamantylacetamide (AdNHCOMe). The mechanism proposed
was as follows (equations 24-27).
Th+
+
(AdN=NAd) 4-
Ad
Ad
-I-
H2O
•^
MeCN
+
(AdN=NAd)+
Ad^
N-
Ad^
Th+
Ad
Th
AdN=NAd
(25)
(26)
Th
AdNHCOMe
(24)
+
H
(27)
In contrast, Engel and Shine^^ reported that the reaction of thianthrene
cation radical and tris(p-bromophenyl)amine cation radical (TBPA+) with
+ Th
2Th-H
(28)
2,3-diazabicyclo[2.2.2]oct-2-ene (4) formed 5 (equation 28) and 6 (equation 29)
respectively, without the loss of nitrogen.
(29)
2TBPA-^
TBPA
Diels-Alder Reactions
Cation-radical induced Diels-Alder cycloaddition reactions have attracted
much Interest. Bauld^s and Gassman^e have reported that the rates of the DielsAlder reactions are enhanced enormously by the catalysis of tris(pbromophenyl)amine cation radical (TBPA"*"). Electron-rich or neutral dienophiles
were converted via electron transfer to highly electron deficient cation radicals
and thus acted as extremely reactive dienophiles. Bauld and coworkers'^5(d)
proposed the following mechanism for the catalytic reaction which involves: (a)
electron transfer (equation 30), (b) pericyclic reaction (equation 31) and (c)
electron transfer (equation 32) in sequence.
^
(TBPA)-f-
^
+
(TBPA)
(30)
(31)
k
10
(32)
Oxidative Cycloaddition Reactions
Shine and coworkers have discovered the cation radical induced
oxidative cycloaddition of arylhydrazones of benzaldehyde (7)^ (equation 33)
and oximes (9)5 (equation 34) to nitrile solvents, and oxidative intramolecular
cyclization of arylhydrazones (12) of chalcones and benzalacetones to form
pyrazoles (13) (equation 35).2
/A'
.
Pli—CH=N—NH—Ar + 2Th+
N—N
RCN
*^
+ 2Th + H
R'
Ph
MeCN
R—CH=N—OH + 2Th+
•
>
Me Me
N
RCHO
2Th-^
+
RCN
N—N
Ar—CH=CH—C=N—NH—Ar'
12
13
11
N
11
10
R
N—O
N—O
H2O
R
+
(33)
+ Th -H ThO
(34)
+ 2Th + H
(35)
^ ^
Later, Shine and coworkers^^ reported the reactions of thianthrene cation
radical with phenols. 2,4,6-Trisustituted-phenols (14) having one or more tertbutyl substituents in the 2 and/or 6-positions underwent oxidative cycloadditions
to the nitrile group of the solvent nitrile, and benzoxazoles (15) were formed.
However, mono- and 2,6-disubstituted-phenol gave 5-(hydroxyaryl)thlanthreniumyl perchlorates. When 5-(hydroxyaryl)-thianthreniumyl perchlorates
were treated with base or water, deprotonation occurred, and quinones were
obtained (16). 2,4-Di-terf-butylphenol gave 4-acetamido-2-terf-butylphenol, while
2,5-di-terf-butyl-hydroquinone was oxidized to 2,5-di-te/t-butyl-p-benzoquinone.
*^^ 2Th^ R
RCN
+ t-Bu-NHCOR +
18
t-BuOH + Me2C=CH2 + Th + ThO
19
(36)
20
Review of the Oxidative Reactions
Oxidative Reactions of Semicarbazones
It has been reported that semicarbazones (21) can undergo oxidative
intramolecular cyclization both anodlcally^s and chemically with a variety of
oxidizing agents.-^^-^s Maggio and coworkers were the first to observe that an
oxadiazole (23) was formed when semicarbazone (21) was oxidized with
12
aqueous sodium hypobromite^^' 5° and iodine in sodium carbonate.^^ Later, the
oxidative cyclization of semicarbazones (21) was studied further with several
other oxidizing agents, such as iodine-potassium iodide,^'' bromine,52.55 and
lead tetraaceate.53 On the other hand, it was reported long ago that oxidation of
semicarbazones by heating with alcoholic ferric chloride led to triazolinones (24)
isomeric with oxadiazoles (23).^4
Scott and coworkers^s studied the oxidative intramolecular cyclization
reactions of semicarbazones with bromine in acetic acid solution. Their interest
was to find out whether an oxadiazole (23) or a triazolinone (24) should be
0
II
Ar—CH=N—NH—C—NH2
Br2
-»•
Br
I
Ar—C=N—NH—C—NH2
(37)
22
21
AcONa
(38)
and/or H2O
22
.H
H
AC2O
N—N
N—N
+ 23
(39)
formed in this reaction. They observed that the reaction led to the formation of
an oxadiazole (23) in the presence of either (or both) sodium acetate or water
but led mostly to a triazolinone (24) and a small amounts of oxadiazole (23) in
anhydrous acetic acid (equations 37-39).
13
Hammerich and Parker*® studied the anodic oxidation of semicarbazones
(21). They reported that only oxadiazoles (23) were formed when oxidation was
carried out in acetic acid/sulfuric acid medium, whereas only triazolinones (24)
were formed in acetic acid/acetic anhydride/sulfuric acid medium. In neither
solvent was a mixture of oxadiazole (23) and triazolinone (24) formed. It was
proposed that triazolinone (24) was formed from the nitriliminlum ion (26) while
oxadiazole (23), most probably, was formed from the enolic form (27) of aroyi
semicarbazide (28) generated in solution by hydration of 26 (equation 40).
-H+
Ar—CH=N—NH—C—NH2
21
-2e-
Ar—C=N—NH—C—NH2
26
H2O
OH
O
I
II
Ar—C=N—NH-C-NH2
0
O
II
II
Ar—C—NH—NH—C-NH2
28
27
H2O
(40)
Shin^ studied the reactions of thianthrene cation radical with aldehyde
semicarbazones (21) in nitrile solvents. Semicarbazones (21), being
electronically and structurally analogous to hydrazones and oximes, were
expected to undergo cycloaddition similar to that of hydrazones. Instead,
14
intramolecular cyclization occurred. Oxidative cycloaddition to the solvent was
not detected. Oxadiazoles (23) were formed in moderate yields, whereas
triazolinones (24) were formed either not at all or in small amounts (equation
41). The reactions, in general, were found to be slow. In contrast, the rate of the
reactions were dramatically enhanched when the reactions were carried out in
presence of a small amount of added water.
0
II
Ar—CH=N—NH—C—NH2
2-1
2Th+
MeCN, H2O
+
2Th + 2H+
(41)
Oxidative Reactions of Hvdrazones
56-59
Hydrazones are oxidized by a large variety of oxidizing agents.
Unsubstituted hydrazones can be oxidized to diazoalkanes (R2C=N2) by
mercuric oxide.56 |n addition to diazoalkanes, some azines are almost always
formed. It has been proposed that the azines are formed by the loss of nitrogen
from the dimers of the diazoalkanes. Atmospheric oxygen reacts with aryl
hydrazones of aldehydes to form azo hydroperoxides [RCH(00H)N=NArl.56.60
Since a wide variety of synthetically important intermediates can be
prepared by lead tetraacetate oxidation of hydrazones, this method, therefore,
has drawn much interest.6i-66 Butler and King^s reported that azoacetates (30)
and diacylhydrazines (31) are formed in the oxidation of aliphatic and aromatic
aldehyde phenyl hydrazones (29) (equation 42). Aromatic aldehyde
15
phenylhydrazones favored the formation of diacylhydrazines (31). For aliphatic
aldehyde phenylhydrazones, the product formation was directed by the
substituent on the N-phenyl ring. For example, para-nitro group gave mainly 31
whereas oiiho-nWro group or 2,4-dinitro groups favored the formation of 30. In
the case of aromatic aldehyde phenylhydrazones further oxidation of 31 gave
the azodiacetates (32) and aroylazobenzenes (33) (equation 43).^
UAC
Pb(0Ac)4
R—CH=N—NH—Ar
29
R—CH—N=N—Ar
HOAc
30
0
^
(42)
Ac
R—C—NH—N—Ar
31
0
Ac
II
1
R—C—NH—N—Ar
OAc
1
R—C—N=N—Ar
Pb(0Ac)4
OAc 32
+
0
II
R—C—N=N—Ar
31
(R = aryl)
(43)
33
Two equivalents of lead tetraacetate were required for the oxidation of
aldehyde or ketone N,N-disubstituted hydrazones (34). The first equivalent
brought about the formation of the aldehyde (36) and the monosubstituted
hydrazone (35), and the second equivalent oxidized 35 to the diacylhydrazine
(37) (equation 44).63
16
CH2R2
Ri-CH=N—N—R3
34
Pb(0Ac)4
^
-HOAc
Ri—CH=N—NH—R3
+
35
0
R2—C—H
36
Pb(0Ac)4
O
(44)
Ac
II
I
Ri—C—NH—N—R3
37
Oxidation of keto-hydrazones (38) produced azoacetate (39). Hydrolysis
of the azoacetate yielded the parent ketone (40) (equation 45).62.66 Hydrazones
of 7-ketoderivatives of lanosterol have been oxidized by lead tetraacetate to the
corresponding 7-a-acetoxy derivatives which are important in cholesterol
biosynthesis.64
R2
Ri—C=N—NH—Ar
Pb(0Ac)4
*-
R2
Ri—C—N=N—Ar
OAc
39
38
H2O
(45)
O
Ri—C—R2 + ArtH + N2
40
Gladstone and coworkers^e reported that oxidation of a number of
aldehyde arylhydrazones (29) with lead tetraacetate generated nitrilimines (41)
as intermediates. Nitrilimines thus generated have been trapped by acrylonitrile
17
to give 5-cyanopyrazolines (42) which on further oxidation formed 5cyanopyrazoles (43) (equation 46).
Pb(0Ac)4
3 ^
^ 3
R—CH=N—NH—Ar
• R—c=N=N—Ar -^
• R—C=N—N—Ar
29
-HOAc
^^
H2C=CH—CN
__
(46)
^r
Pb(0Ac)4
M
In contrast, aldehyde N-acylhydrazones (44) upon oxidation with lead
tetraacetate in dichloromethane underwent oxidative cyclization via nitrilimine
Intermediates (45-47) to give the oxadiazoles (48) (equation 47).^^
O
Ph—CH=N—NH—C—R
Pb(0Ac)4
•
44
-"°^"
© ^
O
Ph—C=N=N—C—R
45
A
(47)
(
48
N—N
47
^ 0
+
e II
Ph—C=N—N—C—R
46
Hydrazones have also been oxidized anodically. Anodic oxidation of ketoarylhydrazones in presence of water produced the parent ketone.62 Two-electron
18
oxidation of the hydrazone followed by hydrolysis with water caused the
formation of the ketone. Tabakovic and coworkers^^. 68 have investigated the
anodic oxidation of a series of hydrazones (49) in the presence of
heteroaromatic bases. For example, oxidation of hydrazones (49) in the
presence of pyridine gave s-triazolo[4,3-a]pyridinium salts (50). Similariy,
oxidation in the presence of quinoline and Isoquinoline gave s-triazolo- [4,3a]quinolinium salts (51) and s-triazolo [4,3-a]isoquinolinium salts (52)
respectively. The salts were obtained in yields ranging from 30% to 90%
(equation 48).
Ar
Ar*—CH=N—NH—Ar
49
+
-4e-
S/N
N
II
N
-3H+
cid? W
50
CIO®
(48)
^^N../Ar
N'
-N
CIC§
Ar*
51
Ar'
N-N
52
Upon electrochemical oxidation in acetonitrile, benzaldehyde N,Ndiphenylhydrazone (53) underwent dehydrodimerizatlon with the formation of
dibenzylideniminio-N,N'-diphenyl-N,N'-benzidine (54) in about 50% yield
(equation 49).69 In addition, benzonitrile was also obtained in 20-30% yield.
19
-e-
Ph—CH=N—N—Ph
53
Ph
Ph—CH=N—N—^
Ph
^
h
<^
'
'
\ — N — N = C H — P h + PhCN (49)
'
Ph
54
Electron transfer oxidation of hydrazones of aromatic ketones (R2C=NNH2) by tris(p-bromophenyl)ammoniumyl perchlorate led to the formation of the
corresponding azines (R2C=N-N=CR2)70 Kovelesky and Shine2 studied the
reactions of thianthrene cation radical with arylhydrazones of chalcones (55),
benzalacetones (56) and some of their derivatives. The hydrazones undenvent
oxidative cyclization to give, respectively, 1,3,5-triaryl- and 3-methyl-1,5diarylpyrazoles (57 and 58) in excellent yields (equation 50). Cyclization
appeared to occur by the way of the arylhydrazone cation radical.
^
Ar—CH=CH—C=N—NH—Ar*
2Th+
^
55, R = aryl
56, R = methyl
57, R = aryl
58, R = methyl
Oxidative Reactions of N-Acvlhvdrazones
Balachandran and George^'' reported the nickel peroxide oxidation of
benzoylhydrazones of aldehydes and ketones. Benzaldehyde Nbenzoylhydrazone on treatment with nickel peroxide in refluxing chloroform gave
30% yield of 2,5-diphenyl-1,3,4-oxadiazole and 47% yield of a nickel complex.
20
frans-nickel-6/s-benzaldehyde benzoylhydrazone (64a). Similariy the oxidation of
N-benzoylhydrazones of para-tolualdehyde, o/t/70-methoxybenzaldehyde paramethoxybenzaldehyde with nickel peroxide in chloroform gave the
corresponding oxadiazoles (48) in yields ranging from 20-35% and the nickel
complexes (64) in 23-41 %. In the case of orf/70-methoxybenzaldehyde Nbenzoylhydrazone, however, in addition to the oxadiazole derivative a 20% yield
of orf/)o-methoxybenzaldehyde (66) was also formed.
N^N
N—N
Ni02
N-NH
R-^
>-Ph
H O
59
R-</
)-Ph
H O
60
R = (a)Ph
(b)p-MePh
(c) o-MeOPh
(d)p-MeOPh
R-CH(OH)-N=N-COPh
ec
N-N
H .0
62
RCHO(R = o-MeOPh)
66
Ph
NNl
/
Ph
^O
64
> K . - ^
Ni02
N
^
A
R
Scheme 1. Mechanism for the Nickel Peroxide Induced Oxidative Cyclization of
N-Acylhydrazones.
The formation of both oxadiazole (48) and the nickel complex (64) in the
oxidation of aldehyde benzoylhydrazone (59) was explained by the pathway
21
shown In Scheme 1. It was proposed that nickel peroxide abstracts a hydrogen
atom from the hydrazone (59) giving rise to a resonance stabilized radical
intermediate (60), which could be represented by any one of the forms such as
61 and 62. The radical intermediate 62 could undergo an intramolecular
cyclization to 63, which on further loss of a hydrogen atom will lead to the
oxadiazole (48). The formation of o-methoxybenzaldehyde (66) was suggested
to be coming from 65 formed from 61, which could subsequently undergo
oxidative fragmentation.
Milcent and Barbier72 reported that the reactions between lead oxide and
aldehyde N-acylhydrazones (67) led to the oxidative intramolecular cyclization of
O
Pb02
R.,—CH=N—NH-C-R2
67
•
r^^X,
>^D
^^''^
AcOH
(Ri = Ph. subst. Ph)
(R2 = Ph, subst. Ph)
the hydrazones (equation 51). Reactions were carried out in acetic acid solvent
and in the process 2,5-disubstituted-1,3,4-oxadiazoles (68) were obtained as the
major product.
22
The following mechanism was proposed for the oxidative cyclization reaction
(Scheme 2).
Pb02
R^—C H=N—NH—C —R2
^
O
. II
R i —CH=N—N—C—R2
67
+
H2O
69
A
Ri—CH—N==N—C—R2
71
-•
R ,—CH=N—N=C— R2
70
-H''
N—N
Ri^^o"''^R2
68
Scheme 2. Mechanism for the Lead Oxide Induced Oxidative Cyclization of NAcylhydrazones.
In 1969, Gladstone and coworkers^s reported the lead tetraacetate
oxidation of aldehyde N-acylhydrazones (44) leading to 1,3,4-oxadiazoles (48)
Pb(0Ac)4
Ph—CH=N—NH—C—R
(52)
-HOAc
44
(a) R = Ph, (b) R = NPh2
23
(equation 52). The acylhydrazones (44a) and (44b) reacted with lead
tetraacetate in dichloromethane at room temperature to give the corresponding
oxadiazoles (48a), and (48b) in 87 and 76% yields, respectively. Acetaldehyde
acetylhydrazone gave nitrogen and some acetaldehyde but no oxadiazole.
The following mechanistic pathways (Scheme 3) were suggested for the
lead tetraacetate oxidative cyclization of aldehyde N-acylhydrazones.
0
II
Ph—CH=N—NH—C—R
Pb(0Ac)4
-HOAc
44
^1
^
II
Ph—C=N—N—C—R
72
^Pb(0Ac)2
C"<OAc
(a)R=Ph, (b)R = NPh2
-HOAc
PfY—C=N=N—C-R
Ph—C=N—N—C-R
73
74
N—N^C—Ph
R
'-<o-J
(a) R = Ph
(b) R = NPh2
75
Scheme 3. Mechanism for the Lead Tetraacetacte Induced Oxidative Cyclization
of N-Acylhydrazones.
In 1990, Chiba and coworkers73foundthat upon electrochemical
oxidation in methanolic solution of sodium cyanide ketone N-acylhydrazones
(76) gave nitrogen and the corresponding nitriles (77) and methyl esters (78)
(equation 53).
24
^2
0
^
I
II
Ri—C=N—NH—C—R3
^,.
-2e" -H'*'
•
•
NaCN/MeOH
R2
0
I
II
Ri—CH—CN + R 3 — C - O M e
76
77
(53)
78
In 1992, Chiba and Okimoto^ reported that the electrochemical oxidation
of N-acylhydrazones of aldehydes (67) and ketones (79) in methanolic sodium
acetate solution afforded oxadiazoles (68) (equation 54) and oxadiazolines (80)
(equation 55), respectively The thermal decomposition of products was also
studied.
H
O
R^—6=N—NH-C-R2
-2e-, -H+
•
•
NaCN/MeOH
67
?^
N—N
1 k
r.^^
J^r.
(^)
68
I?
R.,—c=N—NH-C-R2
79
-2e-, -H+
^.
_,]_ _>
NaCN/MeOH
'^^v >A"
R/
0
R2
80
(^^)
In the case of aliphatic ketone N-acylhydrazone (79), the starting
compound was almost completely consumed and was converted into 2-methoxy1,3,4-oxadiazoline (80) in yields of 30-77%. The yield of oxadiazolines (80) as a
function of the N-acyl group was benzoyl> aliphatic acyl > carbomethoxy.
Increasing the bulkiness of the alkyl groups on the azomethinyl carbon did not
significantly affect the yield of the cyclic product.
The aldehyde N-acylhydrazones (67) gave the corresponding 1,3,4oxadiazoles (68). As the N-benzoylhydrazones of aliphatic ketones gave
25
relatively high yields of oxadiazolinones, so also the N-benzoylhydrazones of
aliphatic aldehydes gave relatively high yields of oxadiazoles. The yields did not
depend on the nature of the substituents Ri and R2. However, it was found that
the N-acylhydrazones of aromatic aldehydes gave only low yields of
oxadiazoles. For example, both butyraldehyde N-benzoylhydrazone and
benzaldehyde N-butyrylhydrazone gave the same product, 2-n-propyl-5-phenyl1,3,4-oxadiazole. However, the yield of 2-n-propyl-5-phenyl-1,3,4-oxadiazole
from the former compound was 86%, whereas that from the latter compound was
only 22%. Besides the oxadiazole, benzaldehyde N-butyrylhydrazone also
produced methyl butyrate (60%), benzaldehyde dimethyl acetal (22%), methyl
benzoate (18%), benzyl alcohol (12%), and benzaldehyde (10%).
The mechanism for the electrooxidative cyclization of N-acylhydrazones
was suggested to be as shown in Scheme 4. Electrooxidation of the
acylhydrazone (67 or 79) would generate the cationic intermediate (81). In the
absence of a strong nucleophile, the cationic center at the azomethinyl carbon of
the intermediate (81) would be attacked intramoleculariy by the carbonyl oxygen.
In the case of aldehyde N-acylhydrazones, the product (82) of such an attack
can lose a proton and form a stable oxadiazole (68). However, in the case of
ketone N-acylhydrazones (79), which do not bear a hydrogen atom on the
azomethinyl carbon, such a pathway is not open. One way the cationic
intermediate (83) can then form a stable product is by reacting with a
nucleophile such as methanol, to form a 2-methoxyoxadiazoline (80).
26
N^N
-2e-. -H+
Ri—C=N—NH—C— R2
I
R3
R/
0^
R2
81
67, R3 = H; 79, R3 = alkyl/aryl
R3 = H
N^N^
-H+
"5C
H
"O'
^2
82
68
81
H
,>CA
R
R3 = alkyl/aryl
N-=N ^.A_
:0—Me
R3
N=-N
-H+
R2
O
R W
V^OMe
R 3 ^ 0 ^ R 2
80
83
Scheme 4. Mechanism for the Electrooxidative Cyclization of N-Acylhydrazones.
Wang and Dai^^ reported that the oxidative cyclization of aldehyde and
ketone N-acylhydrazones can be achieved with the hypervalent iodine reagent
phenyliodoso diacetate (PIDA). The reaction afforded the derivatives of 1,3,4oxadiazolines and 1,3,4-oxadiazoles. Reactions of ketone N-acylhydrazones in
methanolic solution gave 2-methoxy-1,3,4-oxadiazolines (equation 56) in 90%
yields. The substituents (R''-R3) of the ketone hydrazones had no significant
influence on the yields of the products. When ethanol was used as solvent, 2ethoxy-1,3,4-oxadiazolinones was obtained in 73% yield.
27
O
R2
R1—C—NH—N=C—R3
^^
PhKOAcb
R.
•
R40H, 0 OC
f*=\
R2
>C
>^
R40^0 A . 3
y^oK
(56)
85
Reactions of aldehyde N-acylhydrazones with PIDA gave 1,3,4oxadiazoles (equation 57). Reactions in methanol or methylene chloride gave
products only in moderate yields. However, when two equivalents of sodium
acetate was added to the methanol the yield was increased. NBenzoylhydrazones of aliphatic aldehydes generally gave slightly higher yields
of oxadiazoles than those of aromatic aldehyde N-acylhydrazones.
O
R2
RI—C—NH—N=C—H
phl(0Ac)2
^
86
^.JL
^^^
(^^)
87
The reaction pathways for these oxidative cyclizations was proposed to
be as follows (Scheme 5). First, the exchange of an acetoxy ligand of PIDA
forms a hypervalent Iodine intermediate (88). The cyclization of 88 then is
accomplished by an intramolecular carbonyl oxygen attack to fomri hypervalent
iodine intermediates with ligands 89 or 90. When R3 is hydrogen, 90 undergoes
an acetate-catalyzed intramolecular elimination of Phi to give the 1,3,4oxadiazole 87. When R3 is not hydrogen, an intramolecular elimination of Phi
can not occur. Therefore, intermediate 89 can only be attacked by nucleophilic
solvent (alcohol) with the elimination of Phi to form compound 87.
28
O
R2
^
^
^
OAc
Phl(0Ac)2
R2^
R1—C—NH—N=C—R3
84, R3 i^ H
86, R3 = H
.N+
M f'OAc
0^^R1
88
N^-N
-Phi, -HOAc
R40
0
R3
85
-Phi. -HOAc
-OAc"
90
Scheme 5. Mechanism for the Phenyliodoso Diacetate (PIDA) Induced Oxidative
Cyclization of N-Acylhydrazones.
29
CHAPTER II
EXPERIMENTAL SECTION
General Information
Solvents. Reaaents and Purification Techniques
Acetonitrile (Eastman Kodak) was dried by distillation over phosphorous
pentoxide under nitrogen prior to use. Dichloromethane was dried over calcium
hydride. Carbon tetrachloride (Aldrich, NMR grade) was used as obtained. All
other solvents, unless otherwise specified, were technical grade and were
distilled over phosphorous pentoxide prior to use.
Thianthrene (97%, Fluka) was purified by column chromatography. Silica
gel was used as stationary phase and petroleum ether (b. p. 40-60 ^C) was used
as eluent. The column purified thianthrene was then crystallized from acetone,
and had m. p. 158-159 OC (lit.75 m. p. 159 OC).
All aldehydes, semicarbazide hydrochloride, hydrazines, acid hydrazides
and other compounds were obtained from chemical suppliers and were used
without further purification.
Chromatooraphic Technioues
Diagnostic thin layer chromatography (TLC) was carried out on Eastman
Kodak Chromatogram silica gel sheets (Cat. no. 6060). Preparative scale TLC
was carried out on plates made from MN-Kieselgel (Cat. no. 816-38), Brinkman
Instrument Co. Column chromatography was performed with silica gel (Baker,
3405R, 60-200 mesh).
Gas chromatographic (GC) analysis were made with a Varian Model 3740
gas chromatograph, attached to a Varian Model 4270 integrator. The column
used was 10% OV-101 on 80-100 mesh Chrom WHP, 6 ft., 1/8 in., stainless
steel. The following conditions were used: Injector temperature: 250 OC, detector
30
temperature: 250 Oc, initial temperature: 50 Oc, final temperature: 250 OC.
program rate: 10 OC/min, chart speed: 1 cm/min.
Quantitative analysis of the reaction products was made by GC.
Naphthalene was used as an internal standard and authentic compounds were
used as controls. First, the response factor (Rf) of each compound (a) was
determined separately by comparing the concentration factor of the compound
(Cfa) with that of the internal standard (CfS).
^
Area of GC peak of compound (a)
Amount (in mmol) of compound (a)
_
L^s-
Area of GC peak of standard
Amount (in mmol) of standard
Cfa
Rf =
Next, the area of each peak in the GC of the mixture of products and
added standard was measured.
Amount (In mmol)
of a compound (a)
[Area of peak (a)] X [Amount of standard]
[Rf of the compound (a)] X [Area of peak of
standard]
Spectroscopic Measurements
"•H NMR spectra were recorded with IBM-Bruker 200 and 300 MHz
spectrometers. ''H NMR chemical shifts were measured in 5 (ppm) relative to
tetramethylsilane (TMS). The coupling constants (J) were measured in Hz. The
following notations are used for multiplicity: s = singlet, d = doublet, t = triplet, q
= quartet, m = multiplet.
31
All mass Spectra: GC-MS (Gas Chromatography-Mass Spectra), MS-DIP
(Mass-Direct Insertion Probe) and MS-SIM (Mass-Single Ion Monitoring) were
recorded on a Hewlett-Packard GC-Mass spectrometer. Model 5995.
Elemental Analvses
All elemental analyses were performed by Desert Analytics, Tucson,
Arizona.
Meltino Point Apparatus
Melting points were determined with a Mel-Temp apparatus, and are
corrected against standards.
Preparation of Thianthrene Cation Radical Perchlorate
To a solution of 0.50 ml of perchloric acid (70%) in 33 ml of acetic
anhydride was added a solution of 1.0 g (4.63 mmol) of thianthrene in 66 ml of
carbon tetrachloride. The reaction mixture was then allowed to stand for 24
hours in the dark at room temperature. Dark-purple colored crystals were formed
and were collected by suction filtration and washed with carbon tetrachloride
until the filtrate was coloriess. The product 1.30 g (4.13 mmol, 89.2%), was dried
under high vacuum and stored in the dark in an aluminium foil covered vial. The
cation radical was dried again for short periods just before use.
lodometric Assay of Cation Radical Purity
One liter of distilled water was boiled for about 5 minutes. After cooling to
room temperature, 20 g (0.13 mol) of sodium thiosulphate and 0.10 g of sodium
carbonate was added. The solution was stored in a brown-colored bottle In the
dark. Thereafter, potassium iodate solution for standardization of the sodium
thiosulphate was prepared. Potassium iodate (0.25 g, 1.1 mmol) was weighed
32
into a 100-ml volumetric flask and dissolved in water. After the iodate had
dissolved, 2.0 g (0.012 mol) of potasssium iodide and 10 ml of 1.0 N
hydrochloric acid were added. This led to a deep-brown colored solution. The
solution was diluted to 100 ml. Ten ml of this solution was titrated immediately
with sodium thiosulphate until a pale yellow color developed. To the yellow
solution was added 1 ml of starch indicator solution, and titration was continued
until the blue color disappeared. The concentration of sodium thiosulphate
solution was calculated from the data.
Determination of Cation Radical Purity
A precise amount of thianthrene cation radical perchlorate was dissolved
in 30 ml of dichloromethane and 20 ml of 2.41 M potassium iodide was added.
The liberated iodine was titrated with sodium thiosulphate solution as described
above. The purity of the cation radical was 98-100%.
Preparation of Thiantherene 5-Oxide (ThO)
A solution of 5.0 g (0.023 mol) of thianthrene in 150 ml of glacial acetic
acid was placed in a 500-ml round-bottomed flask. The solution was heated on a
water bath with stirring until the thianthrene dissolved completely. Thereafter,
100 ml of dilute nitric add (HNO3 : H2O = 1:1, v:v) was added dropwise to the
warm solution still on the bath. The first few drops produced a very short-lived
violet color. The water bath was then removed and the rest of the nitric acid
solution was added during a period of 25 minutes. With the addition of nitric
acid, the color of the solution became yellow. After stirring for 1 hour, the
solution was poured Into 1500 ml of ice-water. A coloriess precipitate formed that
was allowed to stand for 1.5 hours and then collected by suction filtration,
washed with water and dried In the air and under vacuum to give 3.85 g (72.2%)
33
of the crude product. The product was crystallized from ethanol and had m. p.
140-141 OQ (lit76 m. p. 143-143.5 OC)
Preparation of Aldehyde Semicarbazones
Benzaldehyde Semicarbazone (91^
A solution of 5.6 g (0.05 mol) of semicarbazide hydrochloride and 14 g
(0.10 mol) of sodium acetate trihydrate in 20 ml of water was added to a solution
of 5.1 g (0.05 mol) of benzaldehyde in 70 ml of ethanol. The reaction mixture
was heated under reflux for 3 hours. After the solution was cooled to room
temperature, the precipitated semicarbazone was collected by suction filtration
washed with cold water and cold ethanol and dried in the air and under vacuum
to give 7.40 g (94%) of the product. The product was crystallized from ethanol,
m. p. 219-220 OC (lit.77 m. p. 222 OC).
1H NMR (DMSO-de): 5 (ppm): 10.26 (s, 1H), 7.83 (s, 1H), 7.68 (m, 2H),
7.29 (m, 3H), 6.48 (s, 2H).
MS-DIP: m/z (relative intensity): 163 (M+, 29.6), 119 (54.1). 89 (47.8). 77
(47.1). 65 (58.2). 60 (64.1). 44 (100).
Cinnamaldehyde Semicarbazone (92)
Cinnamaldehyde semicarbazone was prepared by the same method as
described for the preparation of benzaldehyde semicarbazone using 5.6 g (0.05
mol) of semicarbazide hydrochloride. 14 g (0.10 mol) of sodium acetate
trihydrate and 6.6 g (0.05 mol) of cinnamaldehyde. The yield of the
semicarbazone was 8.58 g (90.8%). The semicarbazone was crystallized from
ethanol. m. p. 208-209 OC (lit.54 m. p. 215-216 OC).
34
Benzaldehyde f^OISemicarbazone (93)
Preparation of ["'^OjUrea
Cyanamide (0.30 g) was dissolved in a mixture of 3 ml of Hj^'^O (7.8%
enriched in ''^O) and 0.50 ml of concentrated hydrochloric acid. The solution was
heated under reflux for 10 minutes and then cooled, neutralized with sodium
bicarbonate and evaporated to dryness under vacuum. The residue was
extracted with small portions of boiling ethanol followed by boiling acetone. The
combined ethanol-acetone extract was evaporated to dryness and dried under
high vacuum. The yield of the urea-''80 was 0.39 g (90%), m. p. 133-135 ^C
(lit.78m. p. 133-135 OC).
MS-DIP: m/z (relative intensity): 62 [(M-i-2), 7.35], 60 (M+. 95.2), 44 (99.5),
43(33.7), 17(100), 16(39.8).
Measurement of ^®0 Enrichment (MS-DIP) on [^®0]Urea
Measurements (MS-DIP) were made on the synthesized [""SOjurea (data
given below). The following two important m/z values were obtained:
(a)
m/z = 60 (M+) = 95.2 (relative intensity).
(b)
m/z = 62 (M+2) = 7.35 (relative intensity).
From these two numbers the ''^O enrichment of the urea could be
calculated by the following expression:
[(M+2/M) X 100] = [(7.35/95.2) x 100] = 7.72%.
This value Indicated that the synthesized urea was 7.72% enriched in
180. However, the (M+2) enrichment in naturally abundant urea is 0.21 %.79
35
Therefore the corrected '"^O enrichment value for the synthesized urea would be
(7.72-0.21)% = 7.51%.
Preparation of [''sojSemicarbazide
A mixture of [''^Ojurea (240 mg, 4.0 mmol), anhydrous hydrazine (135 mg,
4.2 mmol) and distilled water (81 mg, 4.5 mmol) in isoamyl alcohol (0.64 ml) and
absolute ethanol (0.60 ml) was heated under reflux for 12 hours. Ice-cold water
was pumped through the condenser during the refluxing. The solution was taken
to dryness on a water aspirator and the residue of crude semicarbazide was
dried under vacuum and dissolved in absolute ethanol. This solution was filtered
and the filtrate was taken to dryness.
Preparation of Benzaldehyde [''^OjSemicarbazone (93)
Instead of preparing semicarbazide hydrochloride the [''80]semicarbazide
thus synthesized was used directly for the preparation of benzaldehyde
[i80]semicarbazone and had m. p. 219-220 OC (lit.77 m. p. 222 OC).
Measurement of ''^0 Enrichment (SIM) on Benzaldehyde
[i80]semicarbazone
Selected Ion monitoring (SIM) mass spectrometry was performed on the
synthesized [''80]semicarbazone. Twenty five (25) measurements (scans) were
averaged to calculate the mean ion abundance. The following two data were
obtained:
(a)
Mass of ion = 161 (M+)
Mean of ion abundance (for this ion) after normalization = 100%.
36
(b)
Mass of ion = 163 (M-t-2),
Mean of Ion abundance (for this Ion) after nomnalization = 8.28%.
The second number indicated that synthesized semicarbazone was
8.28% enriched in ^^0. Correction for (M+2), 0.65%,79 in the naturally abundant
semicarbazone gave the corrected ''80 enrichment value of (8.28-0.65)% =
7.63%.
Preparation of 2-Amino-5-Arvl-1.3.4-Oxadiazoles
2-Amino-5-Phenvl-1 •3.4-Oxadiazole (94)
To a stirred solution of 1.5 g (9.2 mmol) of benzaldehyde semicarbazone
and 3.0 g (37 mmol) of anhydrous sodium acetate in 12 ml of acetic add was
added dropwise a solution of 0.84 g (5.3 mmol) of bromine in 1.0 ml of acetic
acid at room temperature. The mixture was stirred for 30 minutes and then to It
was added 100 ml of water. The precipitated product was collected by suction
filtration and washed with water. The product was dried in the air and under
vacuum, and was decolorized and crystallized from ethanol to give 0.73 g
(49.3%) of the product, m. p. 240-243 OC (lit.52 m. p. 241-243 OC).
1H NMR (DMSO-de): 5 (ppm): 7.80 (m. 2H). 7.53 (m. 3H). 7.29 (s. 2H).
MS-DIP: m/z (relative intensity): 161 (M+, 100), 118 (67.5). 105 (49.6). 91
(50.1), 77 (94.2), 62 (13.1). 51 (66.8). 44 (35.6).
2-Amino-5-Styryl-1.3.4-Oxadiazole (95)
Into 50 ml of an aqueous suspension of 0.42 g of cinnamaldehyde
semicarbazone was added 25 ml of NaOl solution. NaOl solution was prepared
by dissolving 0.43 g of sodium carbonate monohydrate. 0.85 g of iodine and
0.75 g of Kl in 25 ml of water. The combined mixture was heated at 80-85 OC
with continuous stirring for 3 hours. A yellow colored precipitate formed on
37
standing. The mixture was cooled and the precipitated oxadiazole was collected
by suction filtration, washed well with cold water and dried. The product (0.32 g,
78%) was decolorized and crystallized from ethanol, m. p. 238-240 ^C (lit.^o m.
p. 240-241 OC).
Reactions of Thianthrene Cation Radical Perchlorate
with Benzaldehyde Semicarbazone in Acetonitrile
In the Presence of Ordinary Water
Thianthrene cation radical perchloate (0.252 g, 0.800 mmol) and
benzaldehyde semicarbazone (0.065 g. 0.400 mmol) were placed in a septumcapped. 50-ml round-bottomed flask. The flask was evacuated under high
vacuum and filled with nitrogen. Thereafter, 20 ml of acetonitrile was added by
syringe. After 5 minutes, 10 mmol of water was added to the stirred silution with
a microsyringe. The reaction mixture was stirred at room temperature overnight,
diluted with 5 ml of distilled water, neutralized with aqueous sodium bicariDonate
solution and extracted with 6x25 ml of methylene chloride. The methylene
chloride solution was dried over anhydrous magnesium sulfate. After filtration,
the solvent was evaporated at aspirator pressure to give a solid residue. The
solid residue was dissolved In 10 ml of a mixture of methylene choride and
ethanol (v:v, 1:1). This solution was assayed by CG.
The products and their percent yields were: Th (144.7 mg, 0.670 mmol,
83.4%). ThO (10.7 mg. 0.046 mmol, 5.70%) and 2-amino-5-phenyl-1.3,4oxadiazole (53.5 mg. 0.332 mmol. 82.9%).
In the Presence of ''80-Labeled Water
The reaction was carried out with 0.250 g (0.800 mmol) of thianthene
cation radical perchlorate. 0.065 g (0.400 mmol) of benzaldehyde
semicarbazone and 10 mmol of H2IS0 (50% enriched In ^^O). The procedure
38
and the workup were the same as described eariier. The solid residue was
dissolved in 10 ml of a mixture of methylene chloride and ethanol (v:v. 1:1). A 5
ml portion of this solution was assayed for thianthrene (Th) and thianthrene 5oxide (ThO) by GC.
From the remaining 5 ml solution 2-amino-5-phenyl-1.3.4-oxazdiazole
was Isolated by column chromatography. Silica gel was used as stationary
phase and ethyl acetate was used as eluent. Authentic oxadiazole was used for
comparison.
The products and their yields were: Th (145.2 mg. 0.672 mmol. 84.6%).
ThO (9.10 mg, 0.039 mmol. 4.90%) and 2-amino-5-phenyl-1,3,4-oxadlazole
(55.2 mg. 0.343 mmol. 85.3%).
Selected Ion Monitoring (SIM) Mass Spectrometry of the
Isolated 2-Amino-5-Phenyl-1.3.4-Oxadiazole (From the
Reaction of Benzaldehyde Semicarbazone in the
Presence of ''80-Labeled Water)
Selected ion monitoring (SIM) mass spectrometry was carried out with the
oxadiazole isolated from the reaction mixture. Twenty-five (25) measurements
(scans) were averaged to calculate the mean of ion abundance. The following
two data were obtained:
(a)
Mass of ion = 161 (M+)
Mean of ion abundance (for this ion) after normalization = 100%.
(b)
Mass of ion = 163 (M+2),
Mean of ion abundance (for this ion) after normalization = 1.05%.
The second number indicated that the Isolated oxadiazole was 1.05%
enriched in ''^O. However, the [(M+2/M) x 100] value for unenriched oxadiazole
39
was 0.6579. Therefore the corrected ''80 enrichment value was (1.05-0.65)% =
0.40%. This number indicated that no ''80 enrichment of the oxadiazole had
taken place. The small difference between the two numbers (1.05 and 0.65) Is
attributed to the instrumental errors.
Reaction of Benzaldehyde f^OISemicarbazone in the
Presence of Ordinary Water
The reaction was carried out with 0.252 g (0.800 mmol) of thianthrene
cation radical perchlorate, 0.066 g (0.404 mmol) benzaldehyde
[i8o]semlcariDazone (7.63% enriched in ^^O) and 10 mmol (0.18 g) of ordinary
water. The procedure and workup were the same as described eariier.
2-Amino-5-phenyl-1.3.4-oxadiazole was isolated from the residue by
column chromatography.
Selected Ion Monitorino (SIM) Mass Spectrometry of the
Isolated 2-Amino-5-Phenvl-1 •3.4-Oxadiazole (From the
Reaction of Benzaldehyde fSOISemicartjazone in the
Presence of Ordinary Water)
Selected ion monitoring (SIM) mass spectrometry was earned out with the
oxadiazole isolated from the reaction mixture. Twenty-five (25) measurements
(scans) were averaged to calculate the mean of ion abundance. The following
data were obtained:
(a)
Mass of ion = 161 (M+).
Mean of ion abundance (for this ion) after normalization = 100%.
(b)
Mass of ion = 163 (M+2)
Mean of Ion abundance (for this ion) after normalization = 7.86%.
40
The second number indicated that the isolated oxadiazole was 7.86%
enriched in '•^o. However, the [(M+2/M) x 100] value for the naturally abundant
oxadiazole was 0.65%.79 Therefore, the corrected ""^O enrichment value for this
oxadiazole was (7.86-0.65)% = 7.21%.
Reaction of Cinnamaldehyde Semicarbazone in the
Presence of Ordinary Water
The reaction was carried out with 0.252 g (0.800 mmol) of thianthrene
cation radical perchlorate. 0.077 g (0.400 mmol) of cinnamaldehyde
semicarbazone and 10 mmol of ordinary water. The procedure and the workup
were the same as described eariier. The solid residue was dissolved in 10 ml of
methylene chloride. A 5 ml portion of this solution was used for assay of
thianthrene (Th) and thianthrene 5-oxide (ThO) by GC.
From the remaining 5 ml solution 2-amino-5-phenyl-1,3.4-oxadiazole was
Isolated by column chromatography.
The products and their yields were: Th (155.1 mg. 0.718 mmol. 89.7%).
ThO (5.34 mg. 0.023 mmol, 2.80%) and 2-amino-5-styryl-1,3,4-oxadlazole (68.9
mg, 0.367 mmol, 90.3%).
Preparation of Esters from Carboxylic Acids
General Procedure
The substituted benzoic acid and methanol were placed in a roundbottomed flask. Four ml of concentrated sulfuric acid was added to the solution.
The mixture was heated under reflux for 2 hours. After being cooled to room
temperature the reaction mixture was poured into 700-800 ml of ice-water. A
precipitate formed which was collected by suction filtration, washed with cold
water and dried in the air and under vacuum to give the crude product. The
crude product was crystallized from ethanol.
41
Methyl 4-Chlorobenzoate
Methyl 4-chlorobenzoate was prepared from 20 g (0.128 mol) of 4chlorobenzoic acid, and 50 ml of methanol. The crude coloriess product (20.3 g,
93.0%) was crystallized from ethanol, m. p. 44-45 OC (lit.so m. p. 44-45 OC)
Methyl 4-Methylbenzoate
Methyl 4-methylbenzoate was prepared from 20 g (0.147 mol) of 4methylbenzoic acid, and 50 ml of methanol. The crude colorless product (20.1 g,
90.0%) was crystallized from ethanol, m. p. 33-36 Oc (lit.8i m. p. 33-36 OC).
Methyl 2-Naphthoate
Methyl 2-naphthoate was prepared from 10.0 g (0.058 mol) of 2-naphtholc
acid, and 50 ml of methanol. The crude coloriess product (10.1 g, 93.0%) was
crystallized from ethanol. m. p. 71-74 Oc (lit.82 m. p. 71-74 OC).
Methyl 3-Nitrobenzoate
Methyl 3-nitrobenzoate was prepared from 20 g (0.120 mol) of 3nitrobenzoic acid, and 50 ml of methanol. After the refluxing was completed the
reaction mixture was cooled in the refrigerator. Coloriess crystals formed. The
product was collected by suction filtration, washed with cold methanol and cold
water and dried in the air and under vacuum. The crude product (19.8 g, 91.2%)
was crystallized from ethanol. m. p. 78-80 ^C (lit.83 m. p. 78-80 OC).
Methyl 4-Nitrobenzoate
Methyl 4-nitrobenzoate was prepared from 20 g (0.120 mol) of 4nitrobenzoic acid, and 50 ml of methanol by the same method as described for
the preparation of methyl 3-nitrobenzoate.The crude product (20.1 g, 92.6%), a
42
yellowish-white predpitate, was crystallized from ethanol, m. p. 94-96 ^C (lit.84
m. p. 94-96 OC).
Methyl 2-Methoxybenzoate
2-Methoxybenzoic add (15.0 g, 0.099 mol) and methanol (50 ml) were
placed In a round-bottomed flask. Four ml of cone, sulfuric acid was added
dropwise with stirring. The mixture was heated under reflux for two hours. After
cooling to room temperature the reaction mixture was poured into 100 ml of icecold water. The cold water mixture was extracted with dichloromethnae (3x100
ml). The dichloromethane extract was washed sequentially with water, saturated
sodium bicarbonate solution and water, and was dried over anhydrous
magnesium sulphate. After filtration the solvent was removed in a rotary
evaporator at aspirator pressure to give a oily liquid. The crude product (14.4 g,
87.6%) was dried under vacuum and had b. p. 71-74 Oc (lit.85 b. p. 71-74 OC).
Preparation of Acid Chlorides
General Procedure
The carboxylic acid and thionyl chloride were placed in a round-bottomed
flask. The flask was fitted with a reflux condenser and a calcium chloride drying
tube. The mixture was heated under reflux for 2 hours. Thionyl chloride was then
removed in a rotary evaporator at aspirator pressure to give either a liquid or a
solid residue. The liquid residue was purified by fractional distillation under
atmospheric pressure and the solid residue was purified by crystallization from
ethanol.
CinnamoyI Chloride
CinnamoyI chloride was prepared from 10 g (0.068 mol) of frans-cinnamic
acid and 50 ml of thionyl chloride. The crude product (11.0 g, 98.3%), a gummy
43
residue, which turned into light violet crystals after being dried in the air and
under vacuum, had m. p. 35-37 Oc after crystallization (lit.86 m. p. 35-37 OC).
Crotonvl Chloride
Crotonyl chloride was prepared from 10 g (0.116 mol) of crotonic acid and
25 ml of thionyl chloride. The crude product (12.2 g, 100%), was purified by
fractional distillation under atmospheric pressure and had b. p. 120-123 Oc (lit.87
b. p. 120-123 OC).
Preparation of 1.2-Diacylhydrazines
1-Benzovl-2-Cinnamoyl Hydrazine
To a solution of 4.38 g (0.032 mol) of benzoic acid hydrazide in 50 ml of
dry pyridine was added 5.36 g (0.032 mol) of CinnamoyI chloride In small
portions with vigorous stirring. During the addition the temperature was kept
below 60 Oc. After all of the cinnamoyI chloride had been added, the reaction
mixture was stirred at room temperature for 3 hours and poured into 500 ml of
ice-water with stirring. After the mixture had stood for 30 min the precipitated
hydrazine was collected by suction filtration, washed with cold water until the
odor of pyridine had disappeared completely, with cold ethanol, and was dried In
the air and under vacuum. The crude product (8.3 g, 97.5%) was crystallized
from ethanol and had m. p. 215-216 Oc.
MS-DIP: m/z (relative intensity): 266 (M+, 4.16). 145 (16.8). 132 (13.9).
131 (100). 105 (45.1), 103 (48.7), 77 (75.5). 51 (29.7).
Anal. Calcd. for C16H14N2O2: C, 72.18; H, 5.26; N, 10.53
Found: C. 72.08; H, 5.20; N, 10.55
44
1 -Benzoyl-2-(4-Dimethylaminobenzovl) Hydrazine
1-Benzoyl-2-(4-dimethylaminobenzoyl) hydrazine was prepared from 3.58
g (0.020 mol) of 4-dimethylaminobenzoic acid hydrazide, 25 ml of dry pyridine
and 2.81 g ( 0.02 mol) of benzoyl chloride following the same procedure as for
the preparation of 1-benzoyl-2-cinnamoyl hydrazine. The crude product (5.55 g,
98.0%) was crystallized from ethanol, m. p. 236-237 Oc (lit.88 m. p. 236 OC).
1 -Benzoyl-2-Crotonoyl Hydrazine
To a solution of 6.48 g (0.05 mol) of benzoic acid hydrazide in 100 ml of
carbon tetrachloride was added 5.29 g (0.05 mol) of crotonoyI chloride. The
mixture was heated under reflux for 4 hours. After cooling to room temperature
the reaction mixture was poured into 500 ml of Ice-water. A white precipitate
formed. The precipitate was collected by sudion filtration and washed with cold
water and dried in the air and under vacuum to give 9.35 g (92.0%) of the crude
product. The crude product was crystallized from a mixture of ethanol and water
(1:1. y:v). m. p. 185-186 Oc (lit.89 m. p. 176 OC).
MS-DIP: m/z (relative intensity): 204 (M+. 7.88). 189 (23.9). 106 (11.7).
105 (100). 77 (75.5). 69 (95.8). 51 (33.9). 41 (57.2), 41 (47.9).
Preparation of Acid Hydrazides
General procedure
To a solution of an ester in ethanol was added hydrazine monohydrate
with stirring. The reaction mixture was heated under reflux for 4 hours. When the
reaction mixture was cooled In the refrigerator a precipitate formed. The
precipitate was collected by sudionfiltration,washed with cold ethanol and dried
in the air and under vacuum to give the crude acid hydrazide. The crude produd
was crystallized from ethanol.
45
Benzoic Acid Hydrazide
Benzoic acid hydrazide was prepared from 10.0 g (0.074 mol) of methyl
benzoate, 25 ml of ethanol and 10.0 ml of hydrazine monohydrate. The acid
hydrazide (9.03 g, 89.7%) had m. p. 113-117 Oc (lit.90 m. p. 113-117 OC).
4-Chlorobenzoic Acid Hydrazide
4-Chlorobenzoic acid hydrazide was prepared from 6.0 g (0.035 mol) of
methyl 4-chlorobenzoate, 25 ml of ethanol and 6.0 ml of hydrazine monohydrate.
The add hydrazide (5.02 g, 83.7%) had m. p. 164-165 Oc (lit.9i m. p. 163 OC).
4-Methylbenzoic Acid Hydrazide
4-Methylbenzoic acid hydrazide was prepared from 10.0 g (0.060 mol) of
methyl 4-methylbenzoate, 25 ml of ethanol and 10 ml of hydrazine monohydrate.
The add hydrazide (6.84 g, 68.4%) had m. p. 116-118 Oc (lit.92 m. p. 116-117
OC).
3-Nitrobenzoic Acid Hydrazide
3-Nitrobenzoic acid hydrazide was prepared from 10.0 g (0.055 mol) of
methyl 3-nitrobenzoate, 35 ml of ethanol and 10 ml of hydrazine monohydrate.
The add hydrazide (6.97 g ,69.7%) had m. p. 152-153 OC (lit.93 m. p. 153-154
OC).
4-Nitrobenzoic Acid Hydrazide
4-Nitrobenzoic acid hydrazide was prepared from 6.0 g (0.033 mol) of
methyl 4-nitrobenzoate, 30 ml of ethanol and 6.0 ml of hydrazine monohydrate.
The add hydrazide (4.62 g, 77.0%) had m. p. 217-219 Oc (dec.) [Iit.83 m. p. 218
oc(dec) ].
46
2-Naphthoic Acid Hvdrazide
2-Naphthoic acid hydrazide was prepared from 6.0 g (0.032 mol) of
methyl 2-naphthoate, 50 ml of ethanol and 6.0 ml of hydrazine monohydrate.
The add hydrazide (4.75 g, 79.2%) had m. p. 138-140 Oc (lit94 m. p. 138-140
OC).
2-Methoxybenzoic Acid Hvdrazide
2-Methoxybenzoic acid hydrazide was prepared from 10.0 g (0.060 mol)
of methyl 2-methoxybenzoate, 25 ml of ethanol and 10 ml of hydrazine
monohydrate. The add hydrazide (9.17 g, 91.7%) had m. p. 83-84 Oc (lit.95 m. p.
85 OC).
Preparation of Aldehyde N-Acylhydrazones
General Procedure
The aldehyde, the acid hydrazide and methanol were placed in a roundbottomed flask. A few drops of acetic acid was added. The mixture was heated
under reflux for six hours. After the solution was cooled in the refrigerator a
precipitate formed. The precipitate was collected by sudionfiltration,washed
with cold methanol and was dried in the air and under vacuum. The crude
hydrazone was crystallized from ethanol unless othen^^ise specified.
Benzaldehyde Benzoylhydrazone (96)
Benzaldehyde benzoylhydrazone was prepared from 2.12 g (0.02 mol) of
benzaldehyde and 2.72 g (0.02 mol) of benzoic add hydrazide in 100 ml of
methanol. The hydrazone (2.61 g, 58.0%) had m. p. 205-207 oc (lit.73 m. p. 205207 OC).
1H NMR (DMSO-d): 6 (ppm): 11.89 (s, 1H), 8.49 (s. 1H). 7.94 (d. 2H).
7.74 (d. 2H). 7.55 (m. 6H).
47
GC-MS: m/z (relative intensity): 224 (M+, 7.93). 165 (12.3), 121 (63.3).
106 (16.2). 105 (100), 77 (95.2), 51 (35.0).
1 -Naphthaldehyde Benzoylhydrazone (97)
1-Naphthaldehyde benzoylhydrazone was prepared from 3.12 g (0.02
mol) of 1-naphthaldehyde and 2.72 g (0.02 mol) of benzoic acid hydrazide in 100
ml of methanol. The hydrazone (4.96 g, 90.5%) had m. p. 179-180 oc (\\t^ m. p.
180 OC).
Benzaldehyde 1-Naphthoylhydrazone (98)
Benzaldehyde 1-Naphthoylhydrazone was prepared from 1.06 g (0.01
mol) of benzaledhyde and 1.86 g (0.01 mol) of 1-naphthoic acid hydrazide in 50
ml of methanol. The hydrazone (2.29 g, 84.0%) had m. p. 228-229 Oc.
MS-DIP: m/z (relative intensity): 274 (M+, 6.25), 171 (34.0), 156 (14.2).
155 (100), 127 (91.2). 126 (12.0). 77 (12.9). 51 (10.4).
Anal. Calcd. for C18H14N2O: C, 78.83; H. 5.11; N. 10.22
Found: C. 79.04; H, 5.04; N, 10.40
1-Naphthaldehyde 1-Naphthoylhydrazone (99)
1-Naphthaldehyde 1-naphthoylhydrazone was prepared from 1.17 g
(0.008 mol) of 1-naphthaldehyde and 1.40 g (0.008 mol) of 1-naphthoic add
hydrazide in 50 ml of methanol. The hydrazone (2.27 g, 93.4%) had m. p. 238240 OC.
MS-DIP: m/z (relative intensity): 324 (M+, 10.8), 171 (46.1). 170 (12.5),
156(10.3). 155(100). 139(11.1). 127(94.7). 126(12.5), 115 (11.5), 77 (11.8).
Anal. Calcd. for C22H16N2O: C, 81.48; H, 4.94; N, 8.64
Found:C, 81.44; H, 4.82; N, 8.58
48
2-Naphthaldehvde Benzoylhydrazone (100)
2-Naphthaldehyde benzoylhydrazone was prepared from 2.34 g (0.015
mol) of 2-naphthaldehyde and 2.04 g (0.015 mol) of benzoic add hydrazide in 75
ml of methanol. The hydrazone (3.60 g, 87.6%) had m. p. 216-217 Oc (lit96 m. p.
216 OC).
Benzaldehyde 2-Naphthoylhvdrazone (101)
Benzaldehyde 2-naphthoylhydrazone was prepared from 1.59 g (0.015
mol) of benzaldehyde and 2.79 g (0.015 mol) of 2-naphthoic add hydrazide In 75
ml of methanol. The hydrazone (3.10 g, 75.6%) had m. p. 216-217 Oc (lit97 m. p.
216 OC).
2-Naphthaldehyde 2-Naphthoylhydrazone (102)
2-Naphthaldehyde 2-naphthoylhydrazone was prepared from 1.56 g (0.01
mol) of 2-naphthaldehyde and 1.86 g (0.01 mol) of 2-naphthoic acid hydrazide in
50 ml of methanol. The hydrazone (2.65 g, 82.0%) had m. p. 232-234 Oc.
MS-DIP: m/z (relative intensity): 324 (M+, 10.9), 171 (48.1), 156 (11.4),
155(100), 139(12.1), 127(74.6), 126(12.6), 115(12.6).
Anal. Calcd. for C18H14N2O: C. 81.48; H, 4.94; N, 8.64
Found: C, 81.09; H. 4.82; N, 8.40
2-Methoxybenzaldehyde Benzoylhydrazone (103)
2-Methoxybenzaldehyde benzoylhydrazone was prepared from 2.72 g
(0.02 mol) of 2-methoxybenzaldehyde and 2.72 g (0.02 mol) of benzoic acid
hydrazide in 50 ml of methanol. The hydrazone (4.75 g, 95.0%) had m. p. 196197 0C(lit.98m. p. 194 OC).
49
Benzaldehyde 2-Methoxvbenzoylhydrazone (104)
Benzaldehyde 2-methoxybenzoylhydrazone was prepared from 2.12 g
(0.02 mol) of benzaldehyde and 3.32 g (0.02 mol) of 2-methoxybenzoic acid
hydrazide in 25 ml of methanol. The hydrazone (4.25 g, 83.7%) had m. p. 175176 0C(lit.95m. p. 176 OC).
2-Methoxybenzaldehyde 2-Methoxybenzoylhydrazone (105)
2-Methoxybenzaldehyde 2-methoxybenzoylhydrazone was prepared from
3.32 g (0.02 mol) of 2-methoxybenzaldehyde and 3.32 g (0.02 mol) of 2methoxybenzoic acid hydrazide in 50 ml of methanol. The hydrazone (5.17 g.
91.0%) had m. p. 149-150 OC (lit99 m. p. 147-148 OC).
4-Methoxybenzaldehyde Benzoylhydrazone (106)
4-Methoxybenzaldehyde benzoylhydrazone was prepared from 2.72 g
(0.02 mol) of 4-methoxybenzaldehyde and 2.72 g (0.02 mol) of benzoic acid
hydrazide In 50 ml of methanol. The hydrazone (4.44 g. 87.6%) had m. p. 156157 0C(lit98m. p. 158 0C).
Benzaldehyde 4-Methoxybenzoylhydrazone (107)
Benzaldehyde 4-methoxybenzoylhydrazone was prepared from 1.06 g
(0.01 mol) of benzaldehyde and 1.66 g (0.01 mol) of 4-methoxybenzoic acid
hydrazide in 50 ml of methanol. The hydrazone (2.03 g, 80.0%) had m. p. 196198 OC (lifoom. p. 195-197 OC).
4-Methoxybenzaldehyde 4-Methoxybenzoylhydrazone (108)
4-Methoxybenzaldehyde 4-methoxybenzoylhydrazone was prepared from
1.36 g (0.01 mol) of 4-methoxybenzaldehyde and 1.66 g (0.01 mol) of 4-
50
methoxybenzoic acid hydrazide in 30 ml of methanol. The hydrazone (2.77 g.
97.0%) had m. p. 174-175 Oc (lifo^ m. p. 174-175 OC).
4-Methylbenzaldehyde Benzoylhydrazone (109)
4-Methylbenzaldehyde benzoylhydrazone was prepared from 2.40 g (0.02
mol) of 4-methylbenzaldehyde and 2.72 g (0.02 mol) of benzoic acid hydrazide
in 50 ml of methanol. The hydrazone (3.62 g. 76.0%) had m. p. 156-157 OC
(11^102 m. p. 156 OC).
Benzaldehyde 4-Methylbenzoylhydrazone (110)
Benzaldehyde 4-methylbenzoylhydrazone was prepared from 2.12 g (0.02
mol) of benzaldehyde and 3.0 g (0.02 mol) of 4-methylbenzoic acid hydrazide in
30 ml of methanol. The hydrazone (2.03. 80.0%) had m. p. 236-237 oc (lifoo m.
p. 234-235 OC).
4-Methylbenzaldehyde 4-Methvlbenzoylhydrazone (111)
4-Meythylbenzaldehyde 4-methylbenzoylhydrazone was prepared from
1.20 g (0.01 mol) of 4-methylbenzaldehyde and 1.50 g (0.01 mol) of 4methylbenzoic acid hydrazide in 50 ml of methanol. The hydrazone (2.09 g.
83.0%) had m. p. 203-205 Oc (lifo^ m. p. 174-175 OC).
4-Chlorobenzaldehyde Benzoylhydrazone (112)
4-Chlorobenzaldehyde benzoylhydrazone was prepared from 2.81 g,
(0.02 mol) of 4-chlorobenzaldehyde. 2.72 g (0.02 mol) of benzoic acid hydrazide
in 50 ml of methanol. The hydrazone (4.03 g, 78.0%) had m. p. 176-177 Oc (lit89
m. p. 173 0C).
51
Benzaldehyde 4-Chlorobenzovlhydrazone (113)
Benzaldehyde 4-chlorobenzoylhydrazone was prepared from 1.59 g
(0.015 mol) of benzaldehyde and 2.55 g (0.015 mol) of 4-chlorobenzoic acid
hydrazide in 70 ml of methanol. The hydrazone (2.97 g, 80.0%) had m. p. 255257 Oc (lit''00 m. p. 237-238 OC).
4-Chlorobenzaldehyde 4-Chlorobenzoylhydrazone (114)
4-Chlorobenzaldehyde 4-chlorobenzoylhydrazone was prepared from
1.41 g (0.01 mol) of 4-chlorobenzaldehyde and 1.71 g (0.01 mol) of 4chlorobenzoic acid hydrazide in 50 ml of methanol. The hydrazone (2.73 g,
93.2%) had m. p. 225-227 OC (lifo^ m. p. 207-208 OC).
4-Nitrobenzaldehyde Benzoylhydrazone (115)
4-Nitrobenzaldehyde benzoylhydrazone was prepared from 3.02 g (0.02
mol) of 4-nitrobenzaldehyde and 2.72 g (0.02 mol) of benzoic add hydrazide in
100 ml of methanol. The hydrazone (5.05 g. 94.0%) had m. p. 249-250 Oc (lit98
m. p. 245 OC).
Benzaldehyde 4-Nitrobenzoylhydrazone (116)
Benzaldehyde 4-nitrobenzoylhydrazone was prepared from 2.12 g (0.02
mol) of benzaldehyde and 3.62 g (0.02 mol) of 4-nitrobenzoic add hydrazide in
100 ml of methanol. The hydrazone (4.52, 84.0%) had m. p. 255-257 Oc (lifoo
m. p. 254-256 OC).
3-Nitrobenzaldehyde Benzoylhydrazone (117)
3-Nitrobenzaldehyde benzoylhydrazone was prepared from 3.02 g (0.02
mol) of 3-nitrobenzaldehyde and 2.72 g (0.02 mol) of benzoic acid hydrazide in
52
50 ml of methanol. The hydrazone (4.63 g, 86.1%) had m. p. 197-198 Oc (lit98
m. p. 198 OC).
Benzaldehyde 3-Nitrobenzovlhydrazone (118)
Benzaldehyde 3-nitrobenzoylhydrazone was prepared from 2.12 g (0.02
mol) of benzaldehyde and 3.62 g (0.02 mol) of 3-nitrobenzoic acid hydrazide in
70 ml of methanol. The hydrazone (4.22, 80.0%) had m. p. 206-208 Oc (lifoo m.
p. 206-208 OC).
Cinnamaldehyde Benzoylhydrazone (119)
Cinnamaldehyde benzoylhydrazone was prepared from 5.28 g (0.04 mol)
of cinnamaldehyde and 5.45 g (0.04 mol) of benzoic acid hydrazide in 50 ml of
methanol. The hydrazone (8.50 g, 85.0%) had m. p. 195-196 oc (lit98 m. p. 198
OC).
Crotonaldehyde Benzoylhydrazone (120)
Crotonaldehyde benzoylhydrazone was prepared from 4.21 g (0.04 mol)
of crotonaldehyde and 8.17 g (0.04 mol) of benzoic acid hydrazide in 50 ml of
methanol. The hydrazone (5.60 g, 49.5%) had m. p. 155-156 Oc (lit98 m. p. 155156 OC).
Phenylacetaldehyde Benzoylhydrazone (121)
Phenylacetaldehyde benzoylhydrazone was prepared from 2.4 g (0.02
mol) of phenylacetaldehyde and 2.72 g (0.02 mol) of benzoic acid hydrazide in
50 ml of methanol. The hydrazone (3.27 g, 68.7%) was crystallized from a
mixture of ethanol and water (1:1, v:v), m. p. 155-156 Oc (lit''03 m. p. 148-149
OC).
53
MS-DIP: m/z (relative intensity): 238 (M+, 3.58), 148 (22.4), 147 (98.4),
106 (22.0), 105 (100), 91 (22.3), 78 (22.3), 77 (98.4), 51 (57.4). 50 (16.6).
Benzaldehyde Phenylacetylhydrazone (122)
Benzaldehyde phenylacetylhydrazone was prepared from 2.12 g (0.02
mol) of benzaldehyde and 3.0 g (0.02 mol) of phenylacetic acid hydrazide in 50
ml of methanol. The hydrazone (3.86 g. 81.0%) was crystallized from a mixture
of ethanol and water (1:1, v:v), m. p. 156-157 Oc (lit''04 m. p. 154 OC).
1H NMR (CDCI3): 5 (ppm): 10.05 (s, 1H), 7.80 (s, 1H), 7.66 (m, 2H), 7.34
(m, 10H), 4.12(s, 2H).
MS-DIP: m/z (relative intensity): 238 (M+, 10.4), 135 (94.7). 134 (22.7),
120 (75.7), 119 (70.0), 118 (33.3), 93 (45.2), 91 (100), 90 (66.4), 89 (70.1), 77
(41.5), 65 (99.7), 64 (24.9), 63 (58.5).
Trimethylacetaldehyde Benzoylhydrazone (123)
Trimethylacetaldehyde benzoylhydrazone was prepared from 2.58 g (0.03
mol) of trimethylacetaldehyde and 4.08 g (0.03 mol) of benzoic acid hydrazide in
50 ml of methanol. The hydrazone (5.15 g, 84.2%) was crystallized from a
mixture of ethanol and water (1:1, v:v), m. p. 171-172 ^C.
GC-MS: m/z (relative intensity): 204 (M+, 6.60 ), 147 (16.9), 105 (18.3),
77(100), 57(28.3)
1H NMR (CDCI3): 5 (ppm): 8.05 (d. 2H). 7.45 (m. 3H). 1.50 (s, 9H)
Anal. Calcd. for C12H16N2O: C. 70.59; H, 7.84; N, 13.73
Found: C, 70.44; H, 7.98; N, 13.76
54
4-Dimethylaminobenzaldehvde Benzoylhydrazone (124)
4-Dimethylaminobenzaldehyde benzoylhydrazone was prepared from
2.98 g (0.02 mol) of 4-Dimethylaminobenzaldehyde and 2.72 g (0.02 mol) of
benzoic acid hydrazide in 50 ml of methanol. The hydrazone (3.82 g, 71.5%) had
m. p. 188-190 Oc (lit''05 m. p. 185-186 OC).
Preparation of Authentic 2-R-5-R'-1.3.4-Oxadiazoles
General Procedure
A solution of lead tetraacetate in dichloromethane was added at room
temperature to a stirred solution/suspension of an appropriate acylhydrazone in
dichloromethane. After stirring for 20-60 min the reaction mixture was poured
into ice-water. The ice-water mixture was extracted with diethyl ether. The ether
extract was washed sequentially with cold water, saturated sodium bicarbonate
solution and cold water, and was then dried over anhydrous magnesium sulfate.
Afterfiltrationthe ether was removed in a rotary evaporator at aspirator pressure
to give the crude oxadiazole. The crude produd was purified by crystallization.
2.5-Diphenyl-1.3.4-Oxadiazole (125)
2,5-Diphenyl-1,3,4-oxadiazole was prepared from 0.98 g (2.21 mmol) of
lead tetraacetate in 10 ml of dichloromethane and 0.05 g (2.21 mmol) of
benzaldehyde benzoylhydrazone in 25 ml of dichloromethane. The readion
mixture was stirred at room temperature for 20 minutes and then poured into 100
ml of Ice-water. The crude oxadiazole (0.42 g. 85.0%) was crystallized from a
mixture of ethanol and water (1:1, y:v) and had m. p. 139-140 oc (lit^e m. p. 141
OC).
55
2-(1-Naphthyl)-5-Phenvl-1.3.4-Oxadiazole (126)
2-(1-Naphthyl)-5-phenyl-1,3,4-oxadiazole was prepared from 1.47 g (3.32
mmol) of lead tetraacetate in 15 ml of dichloromethane and 0.90 g (3.32 mmol)
of naphthaldehyde benzoylhydrazone in 38 ml of dichloromethane. The reaction
mixture was stirred at room temperature for one hour and then poured into 100
ml of ice-cold water. The crude oxadiazole (0.81 g, 91.0%) was crystallized from
a mixture of ethanol and had m. p. 120-121 Oc (lit''06 m. p. 120 OC).
2.5-Di-(1 -Naphthvl)-1 •3.4-Oxadiazo!e (127)
2,5-Di-(1-naphthyl)-1,3,4-oxadiazole was prepared from 0.98 g (2.21
mmol) of lead tetraacetate in 10 ml of dichloromethane and 0.72 g (2.21 mmol)
of 1-naphthaldehyde 1-naphthoylhydrazone in 25 ml of dichloromethane. The
reaction mixture was stirred at room temperature for one hour and then poured
into 35 ml of ice-cold water. The crude oxadiazole (0.68 g, 95.5%) was
crystallized from ethanol and had m. p. 179-181 Oc (lit''07 m. p. 181-183 OC).
2-(2-Naphthyl)-5-Phenyl-1 •3.4-Oxadiazole (128)
2-(2-Naphthyl)-5-phenyl-1,3,4-oxadiazole was prepared from 1.47 g (3.32
mmol) of lead tetraacetate in 15 ml of dichloromethane and 0.90 g (3.32 mmol)
of 2-naphthaldehyde benzoylhydrazone in 38 ml of dichloromethane. The
reaction mixture was stirred at room temperature for one hour and then poured
into 100 ml of ice-cold water. The crude oxadiazole (0.83 g, 93.0%) was
crystallized from, ethanol and had m. p. 124-125 OC (lit''06 m. p. 122-124 OC).
9,5-Di-(2-NaPhthyl)-1.3.4-Oxadiazole (129)
2,5-Di-(1-naphthyl)-1,3,4-oxadiazole was prepared from 0.98 g (2.21
mmol) of lead tetraacetate in 10 ml of dichloromethane and 0.72 g (2.21 mmol)
of 2-naphthaldehyde 2-naphthoylhydrazone in 25 ml of dichloromethane. The
56
reaction mixture was stirred at room temperature for one hour and then poured
into 35 ml of ice-cold water. The cmde oxadiazole (0.68 g, 95.5%) was
crystallized from ethanol and had m. p. 188-190 Oc (11^07 m. p. 190-192 OC).
2-(2-Methoxyphenvl)-5-Phenvl-1 •3.4-Oxadiazole (130)
2-(2-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazole was prepared from 1.47 g
(3.32 mmol) of lead tetraacetate in 15 ml of dichloromethane and 0.84 g (3.32
mmol) of 2-methoxybenzaldehyde benzoylhydrazone in 38 ml of
dichloromethane. The reaction mixture was stirred at room temperature for one
hour and then poured into 50 ml of ice-cold water. The product (0.79 g, 94.4%)
was crystallized from ethanol and had m. p. 95-96 Oc (lit.''08 m. p. 96-97 OC).
2^5-DI-(2-Methoxvphenyl)-1 •3.4-Oxadiazole (131)
2.5-Di-(2-methoxyphenyl)-1.3,4-oxadiazole was prepared fromi .47 g
(3.32 mmol) of lead tetraacetate in 15 ml of dichloromethane and 0.94 g (3.32
mol) of 2-methoxybenzaldehyde 2-methoxybenzoylhydrazone in 38 ml of
dichloromethane. The readion mixture was stirred at room temperature for one
hour and then poured into 50 ml of ice-cold water. The product (0.87 g, 93.5%)
was crystallized from amixture of ethanol and water (1:1, y:v) and had m. p. 109110 OC (lit''09 m. p. 109-110.5 OC).
2-(4-Methoxyphenvl)-5-Phenvl-1 •3^4-Oxadiazole (132)
2-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazole was prepared from 1.96 g
(4.42 mmol) of lead tetraacetate in 20 ml of dichloromethane and 1.12 g (4.42
mmol) of 4-methoxybenzaldehyde benzoylhydrazone in 50 ml of
dichloromethane. The reaction mixture was stirred at room temperature for one
hour and then poured into 100 ml of ice-cold water. The product (0.96 g, 86.5%)
was crystallized from ethanol and had m. p. 145-146 Oc (lit''''o m. p. 146.5 OC).
57
2.5-Di-(4-Methoxvphenvl)-1 •3^4-Oxadiazole (133)
2.5-Di-(4-methoxyphenyl)-1,3,4-oxadiazole was prepared fromi .47 g
(3.32 mmol) of lead tetraacetate in 15 ml of dichloromethane and 0.94 g (3.32
mol) of 4-methoxybenzaldehyde 4-methoxybenzoylhydrazone in 38 ml of
dichloromethane. The reaction mixture was stirred at room temperature for one
hour and then poured into 50 ml of ice-cold water. The product (0.89 g, 95.0%)
was crystallized from ethanol and had m. p. 155-156 Oc (lifo^ m. p. 160 OC).
2-(2-Methylphenyl)-5-Phenyl-1.3.4-Oxadiazole (134)
2-(2-Methylphenyl)-5-phenyl-1,3,4-oxadiazole was prepared from 1.96 g
(4.42 mmol) of lead tetraacetate in 20 ml of dichloromethane and 1.05 g (4.42
mmol) of 2-methylbenzaldehyde benzoylhydrazone in 50 ml of dichloromethane.
The reaction mixture was stirred at room temperature for one hour and then
poured into 70 ml of Ice-cold water. The produd (0.89 g, 85.3%) was crystallized
from ethanol and had m. p. 126-127 OC ( l i f ^ i m. p. 125.5-126 OC).
2.5-DI-(4-Methvlphenyl)-1 •3.4-Oxadiazole (135)
2,5-Di-(4-methylphenyl)-1,3,4-oxadiazole was prepared from 0.98 g (2.21
mmol) of lead tetraacetate in 10 ml of dichloromethane and 0.56 g (2.21 mmol)
of 4-methylbenzaldehyde 4-methylbenzoylhydrazone in 25 ml of
dichloromethane. The readion mixture was stirred at room temperature for one
hour and then poured into 35 ml of ice-cold water. The produd (0.45 g, 81.8%)
was crystallized ethanol and had m. p. 175-176 OC ( l i f ^ i m. p. 175-176 OC).
2-(4-Chlorophenyl)-5-phenyl-1.3.4-Qxadiazole (136)
2-(4-Chlorophenyl)-5-phenyl-1,3,4-oxadiazole was prepared from 1.96 g
(4.42 mmol) of lead tetraacetate in 20 ml of dichloromethane and 1.14 g (4.42
mmol) of 4-chlorobenzaldehyde benzoylhydrazone in 50 ml of dichloromethane.
58
The readion mixture was stirred at room temperature for one and a half hours
and then poured Into 70 ml of Ice-cold water. The produd (1.02 g, 90.3%) was
crystallized from ethanol and had m. p. 162-163 Oc (lif^o m. p. 162 OC).
2.5-Di-(4-Chlorophenvl)-1 •3.4-Oxadiazole (137)
2.5-Di-(4-chlorophenyl)-1.3.4-oxadiazole was prepared from 1.47 g (3.32
mmol) of lead tetraacetate in 20 ml of dichloromethane and 0.97 g (3.32 mmol)
of 4-chlorobenzaldehyde 4-chlorobenzoylhydrazone in 38 ml of
dichloromethane. The reaction mixture was stirred at room temperature for one
hour and then poured into 50 ml of ice-cold water. The produd (0.83 g, 86.5%)
was crystallized from ethanol and had m. p. 246-247 Oc (lit'•'''' m. p. 245 OC).
MS-DIP: m/z (relative intensity): 290 (M. 18.9). 201 (11.6), 199 (40.3). 141
(29.3). 139(100). 131 (13.8), 123(15.1), 113(32.5), 111 (97.9). 87 (13.7). 76
(22.8), 75 (73.6), 74 (17.2), 73 (24.8), 69 (69.6), 63 (20.5), 51 (15.6), 50 (18.5),
32(22.4), 28(46.7), 18(10.8).
2-(4-Nitrophenvl)-5-phenvl-1.3.4-Oxadiazole (138)
2-(4-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole was prepared from 1.96 g
(4.42 mmol) of lead tetraacetate in 20 ml of dichloromethane and 1.18 g (4.42
mmol) of 4-nitrobenzaldehyde benzoylhydrazone in 50 ml of dichloromethane.
The reaction mixture was stirred at room temperature for two hours and then
poured into 70 ml of ice-cold water. The product (1.09 g, 92.4%) was crystallized
from ethanol and had m. p. 207-209 Oc (lif^o m. p. 209 OC).
2-(3-Nitrophenyl)-5-phenvl-1 •3.4-Oxadiazole (139). from
3-Nitrobenzaldehvde Benzoylhydrazone
2-(3-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole was prepared from 1.96 g
(4.42 mmol) of lead tetraacetate in 20 ml of dichloromethane and 1.18 g (4.42
59
mmol) of 3-nitrobenzaldehyde benzoylhydrazone in 50 ml of dichloromethane.
The reaction mixture was stirred at room temperature for one hour and then
poured into 70 ml of ice-cold water. The product (0.93 g, 89.0%) was crystallized
from ethanol and had m. p. 153-154 Oc (lit.73 m. p. 153 OC).
2-(3-Nitrophenyl)-5-phenyl-1 •3.4-Oxadiazole (139)^ from
Benzaldehyde 3-Nitrobenzoylhydrazone
2-(3-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole was prepared from 1.96 g
(4.42 mmol) of lead tetraacetate in 20 ml of dichloromethane and 1.18 g (4.42
mmol) of benzaldehyde 3-nitrobenzoylhydrazone in 50 ml of dichloromethane.
The reaction mixture was stirred at room temperature for one hour and then
poured Into 70 ml of Ice-cold water. The product (1.07 g, 90.7%) was crystallized
from ethanol and had m. p. 153-154 Oc (lit73 m. p. 153 OC).
2-Phenvl-5-Stvryl-1 •3.4-Oxadiazole (140)
1-Benzoyl-2-cinnamoyl hydrazine (2.66 g, 0.01 mol) and phosphorous
oxychloride were placed In a round-bottomed flask. The mixture was heated
under reflux for 12 hours. After removing most of the phosphorous oxychloride in
a rotary evaporator at aspirator pressure, the reaction mixture was poured Into
500 ml of ice-water with stirring. The mixture evolved heat and temperature was
not allowed to rise above 50 oc. After the mixture had cooled, the precipitated
oxadiazole was colleded by suction filtrafion. washed with cold water and cold
ethanol and dried in the air and under vacuum. The crude produd (2.40 g.
96.8%) was crystallized from ethanol and had m. p. 128-129 OC (Iit''i2 m. p. 128
OC).
60
2-Crotvl-5-Pheny|-1 •3.4-Oxadiazole (141)
1-Benzoyl-2-crotonoyl hydrazine (3.06 g, 0.015 mol) and
polyphosphosphoric add (10 g) were placed in a round-bottomed flask. The
mixture was heated at 140 Oc with stirring for 3 hours. After cooling to room
temperature the reaction mixture was dissolved in 50 ml of water and neutralized
with 20% aqueous solution of sodium hydroxide. The reaction mixture was
extracted with diethyl ether, and the ether extract was dried over anhydrous
sodium sulphate. Afterfiltrationether was removed in a rotary evaporator at
aspirator pressure to give 2.91 g of a gummy oily residue.
1H NMR (CDCI3): 5 (ppm): 2.04 (dd, 3H), 6.46 (d, J =16, 1H), 6.90 (d, J =
16.9, 1H), 7.31 (s, 5H).
GC-MS: m/z (relative intensity): 186 (M, 33.2), 105 (73.8), 77 (100), 69
(53.2), 51 (85.5), 50 (46.2), 41 (69.6), 40 (98.4), 39 (97.9)
2-Benzyl-5-Phenyl-1 •3.4-Oxadiazole (142)
2-Benzyl-5-phenyl-1,3,4-oxadiazole was prepared from 1.96 g (4.42
mmol) of lead tetraacetate in 20 ml of dichloromethane and 1.06 g (4.42 mmol)
of phenylacetaldehyde benzoylhydrazone In 50 ml of dichloromethane. The
readion mixture was stirred at room temperature for one hour and then poured
into 100 ml of ice-cold water. The produd (0.19 g. 18.2%) was decolorized and
crystallized from ethanol and had m. p. 99-100 oc (lif^i m. p. 101-102.5 OC).
2-te/t-Butyl-5-phenyl-1 •3.4-Oxadiazole (143)
2-terf-Butyl-5-phenyl-1.3.4-oxadiazole was prepared from 5.88 g (13.3
mmol) of lead tetraacetate in 60 ml of dichloromethane and 2.70 g (13.3 mmol)
of trimethylacetaldehyde benzoylhydrazone in 75 ml of dichloromethane. The
readion mixture was stirred at room temperature for one hour and then poured
into 100 ml of ice-cold water. The product (1.86 g. 69.7%) was a oily liquid.
61
1H NMR (CDCI3): 5 (ppm): 1.50 (s. 9H). 7.50 (m. 3H), 8.05 (d. 2H).
MS-DIP: m/z (relative intensity): 202 (M+, 7.79), 187 (47.3), 105 (100), 77
(94.3). 57 (68.0)
2-(4-Dimethvlaminophenvl)-5-Phenvl-1 •3.4-Qxadiazole (144)
1-Benzoyl-2-(4-dimethylaminophenyl) hydrazine (2.66 g, 0.01 mol) and
phosphorous oxychloride were placed in a round-bottomed fiask. The mixture
was heated under reflux for 12 hours. After removing most of the phosphorous
oxychloride in a rotary evaporator at aspirator pressure the readion mixture was
poured into 500 ml of ice-water with stirring. The mixture evolved heat and
temperature was not allowed to rise above 50 oc. After the mixture had cooled
the precipitated oxadiazole was collected by sudionfiltration,washed with cold
water and cold ethanol and dried in the air and under vacuum. The crude
product (2.4 g, 96.8%) was crystallized from ethanol and had m. p. 143-144 Oc
(Iit88m. p. 142-144 OC).
Reactions of Aldehyde N-Acvlhvdrazones with
Thianthrene Cation Radical Perchlorate in Acetonitrile
Benzaldehyde Benzoylhydrazone in the Absence
of 2.6-Di-terr-Butyl-4-Methy|pyridine (DTBMP)
Thianthrene cation radical perchlorate (0.250 g, 0.80 mmol) and
benzaldehyde benzoylhydrazone (0.090 g, 0.40 mmol) were placed in a septumcapped round-bottomed fiask. The fiask was evacuated under high vacuum and
filled with nitrogen. Thereafter, 20 ml of acetonitrile was added by syringe. The
reaction mixture was stirred at room temperature overnight and then diluted with
5 ml of water, neutralized with aqueous sodium bicarbonate solution and
extraded with 5 x 25 ml of dichloromethane. The dichloromethane solution was
dried over anhydrous magnesium sulphate. Afterfiltration,the solvent was
removed in a rotary evaporator at aspirator pressure to give a solid residue. The
62
solid residue was dissolved in 10 ml of dichloromethane and the resulting
solution was assayed by GC.
The products and their yields were: Th (160.5 mg, 0.743 mmol, 92.9%),
ThO (2.08 mg, 0.009 mmol, 1.10%), 2,5-diphenyl-1,3,4-oxadiazole (31.8 mg,
0.143 mmol, 35.6%) and benzaldehyde benzoylhydrazone (46.6 mg, 0.202
mmol, 51.9%).
Benzaldehyde Benzoylhydrazone in the Presence
of DTBMP
Thianthrene cation radical perchlorate (0.125 g, 0.40 mmol) was placed in
a septum-capped volumetric flask. The flask was evacuated under high vacuum
and filled with nitrogen. Thereafter, 10 ml of acetonitrile was added by syringe.
After 10 minutes a solufion of benzaldehyde benzoylhydrazone (0.045 g, 0.20
mmol) and DTBMP (0.082 g, 0.40 mmol) in 15 ml of acetonitrile was added to
the stirred solution by syringe. The reaction mixture was stirred at room
temperature overnight. Then 0.50 ml of saturated potassium carbonate solution
was added. The resulting solution was assayed by GC.
The products and their yields were: Th (79.7 mg, 0.369 mmol. 91.9%),
ThO (5.80 mg, 0.025 mmol. 6.23%). DTBMP (80.3 mg. 0.391 mmol. 97.4%). and
2.5-diphenyl-1,3.4-oxadiazole (35.7 mg. 0.161 mmol. 81.4%).
Phenylacetaldehyde Benzoylhydrazone in the Presence
of DTBMP
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.048 g (0.20
mmol) of phenylacetaldehyde benzoylhydrazone following the same procedure
as described above.
63
The products and their yields were: Th (79.1 mg, 0.366 mmol, 91.5%),
ThO (7.19 mg, 0.031 mmol, 7.80%), DTBMP (82.6 mg. 0.402 mmol, 99.9%) and
2-benzyl-5-phenyl-1,3,4-oxadiazole (19.1 mg, 0.081 mmol, 40.4%).
Trimethylacetaldehyde Benzoylhydrazone in the Presence
of DTBMP
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.041 g (0.20
mmol) of trimethylacetaldehyde benzoylhydrazone following the same procedure
as described before.
The products and their yields were: Th (78.4 mg, 0.363 mmol, 90.7%),
ThO (7.42 mg, 0.032 mmol, 7.90%), DTBMP (78.9 mg, 0.384 mmol, 96.5%), 2te/t-butyl-5-phenyl-1,3,4-oxadiazole (21.2 mg, 0.105 mmol, 52.1%) and
trimethylacetaldehyde benzoylhydrazone (9.59 mg, 0.047 mmol, 23.4%).
Reactions of Aldehyde N-Acvlhvdrazones with
Thianthrene Cation Radical Perchlorate in
Dichloromethane in Presence of DTBMP
General Procedure
Thianthrene cation radical perchlorate and the hydrazone were placed in
a septum-capped volumetric fiask. Theflaskwas evacuated under high vacuum
and filled with nitrogen. Thereafter, 15 ml of dichloromethane was added by
syringe. After 10 minutes a solution of DTBMP In 10 ml of dichloromethane was
added to the stirred solution by syringe. The reaction mixture was stirred at room
temperature overnight. Then 0.50 ml of saturated potassium carbonate solution
was added. The resulting solution was assayed by GC.
Each readion was carried out twice. A summary of products and yields is
given in Table 6 and the details of particular reacfions are given below.
64
Benzaldehyde Benzoylhydrazone (96)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.045 g (0.20
mmol) of benzaldehyde benzoylhydrazone. The produds and their yields were:
Th (78.2 mg, 0.362 mmol, 90.7%), ThO (4.20 mg, 0.018 mmol, 3.00%), DTBMP
(80.1 mg, 0.390 mmol, 97.2%), benzaldehyde (4.30 mg, 0.041 mmol, 20.5% ),
2,5-diphenyl-1,3,4-oxadiazole (28.6 mg, 0.129 mmol, 64.3%) and benzaldehyde
benzoylhydrazone (4.10 mg, 0.018 mmol, 9.10%).
1-Naphthaldehyde Benzoylhydrazone (97)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.055 g (0.20
mmol) of 1-naphthaldehyde benzoyl hydrazone. The products and their yields
were: Th (83.1 mg, 0.385 mmol, 95.6%), ThO (1.90 mg, 0.008 mmol, 2.00%),
DTBMP (78.2 mg, 0.381 mmol, 95.1%), 1-naphthaldehyde (1.30 mg, 0.009
mmol, 4.30%) and 2-(1-naphthyl)-5-phenyl-1,3,4-oxadiazole (50.1 mg, 0.183
mmol, 91.4%).
Benzaldehyde 1 -Naphthoylhydrazone (98)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.055 g (0.20
mmol) of benzaldehyde 1-naphthoyl hydrazone. The products and their yields
were: Th (79.9 mg, 0.370 mmol, 92.0%), ThO (3.00 mg, 0.013 mmol, 3.25%),
DTBMP (77.9 mg, 0.379 mmol, 94.5%), benzaldehyde (3.10 mg, 0.029 mmol.
14.3%) 2-(1-naphthy)-5-phenyl-1.3.4-oxadiazole (33.4 mg. 0.122 mmol. 60.6%).
65
1-Naphthaldehyde 1-Naphthoylhydrazone (99)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cafion radical perchlorate. 0.082 g (0.40 mmol) of DTBMP and 0.065 g (0.20
mmol) of 1 -naphthaldehyde 1 -naphthoyi hydrazone. The products and their
yields were: Th (82.8 mg, 0.384 mmol, 95.7%), ThO (1.70 mg. 0.007 mmol,
1.80%), DTBMP (78.4 mg, 0.382 mmol, 95.0%), 1-naphthaldehyde (6.30 mg,
0.040 mmol, 20.3%) and 2.5-di-(1-naphthy)-1.3.4-oxadiazole (46.4 mg. 0.144
mmol, 72.3%).
2-Naphthaldehyde Benzoylhydrazone (100)
The reacfion was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.055 g (0.20
mmol) of 2-naphthaldehyde benzoyl hydrazone. The products and their yields
were: Th (81.0 mg, 0.375 mmol, 93.6%), ThO (2.00 mg, 0.009 mmol, 2.10%),
DTBMP (77.4 mg, 0.377 mmol, 93.9%), 2-naphthaldehyde (1.20 mg, 0.008
mmol, 3.85%) and 2-(2-naphthyl)-5-phenyl-1,3,4-oxadiazole (51.2 mg, 0.188
mmol, 93.5%).
Benzaldehyde 2-Naphthovlhydrazone (101)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.055 g (0.20
mmol) of benzaldehyde 2-naphthoyl hydrazone. The products and their yields
were: Th (76.4 mg, 0.354 mmol, 88.5%), ThO (2.20 mg, 0.010 mmol, 2.45%),
DTBMP (77.8 mg, 0.379 mmol, 94.6%), benzaldehyde (3.80 mg. 0.036 mmol,
18.1%) and 2-(2-naphthy)-5-phenyl-1,3,4-oxadiazole (34.2 mg, 0.126 mmol,
62.9%).
66
2-Naphthaldehyde 2-Naphthovlhydrazone (102)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.065 g (0.20
mmol) of 2-naphthaldehyde 2-naphthoyl hydrazone. The products and their
yields were: Th (82.6 mg, 0.383 mmol, 95.7%). ThO (1.50 mg, 0.006 mmol,
1.60%), DTBMP (76.2 mg, 0.371 mmol, 92.8%), 2-naphthaldehyde (4.00 mg,
0.026 mmol, 12.8%) and 2,5-di-(2-naphthy)-1,3,4-oxadiazole (56.3 mg, 0.174
mmol, 86.7%).
2-Methoxybenzaldehvde Benzoylhydrazone (103)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.051 g (0.20
mmol) of 2-methoxybenzaldehyde benzoyl hydrazone. The products and their
yields were: Th (79.4 mg, 0.368 mmol, 91.6%), ThO (2.60 mg, 0.011 mmol,
2.75%), DTBMP (76.6 mg, 0.373 mmol. 93.4%), 2-methoxybenzaldehyde (1.20
mg, 0.009 mmol, 4.50%) and 2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole
(43.1 mg, 0.171 mmol, 84.9%).
Benzaldehyde 2-Methoxvbenzoylhydrazone (104)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cafion radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.051 g (0.20
mmol) of benzaldehyde 2-methoxybenzoyl-hydrazone. The produds and their
yields were: Th (79.8 mg, 0.369 mmol, 92.3%), ThO (3.30 mg, 0.014 mmol,
3.60%), DTBMP (79.1 mg, 0.385 mmol, 95.9%), benzaldehyde (2.90 mg, 0.027
mmol, 13.7%), 2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole (37.1 mg, 0.146
mmol, 73.0%) and benzaldehyde 2-methoxybenzoylhydrazone (3.70 mg, 0.015
mmol, 7.35%).
67
2-Methoxybenzaldehvde 2-Methoxybenzovlhydrazone (105)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cafion radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.057 g (0.20
mmol) of 2-methoxybenzaldehyde 2-methoxybenzoylhydrazone. The products
and their yields were: Th (78.2 mg, 0.362 mmol, 90.5%), ThO (4.20 mg, 0.018
mmol, 4.50%), DTBMP (79.5 mg, 0.387 mmol, 96.1%), 2-methoxybenzaldehyde
(2.00 mg, 0.013 mmol, 6.20%) and 2,5-di-(2-methoxyphenyl)-1,3,4-oxadiazole
(44.1 mg. 0.155 mmol. 77.0%).
4-Methoxvbenzaldehvde Benzoylhydrazone (106)
The reaction was carried out with 0.126 (0.40 mmol) of thianthrene cafion
radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.051 g (0.20 mmol) of
4-methoxybenzaldehyde benzoyl hydrazone. The products and their yields were:
Th (80.3 mg, 0.372 mmol, 92.8%), ThO (1.90 mg, 0.008 mmol, 1.95%). DTBMP
(78.9 mg. 0.384 mmol. 96.0%) and 2-(4-methoxyphenyl)-5-phenyl-1,3,4oxadiazole (45.5 mg, 0.180 mmol, 90.2%).
Benzaldehyde 4-Methoxybenzoylhvdrazone (107)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.051 g (0.20
mmol) of benzaldehyde 4-methoxybenzoyl hydrazone. The products and their
yields were: Th (75.5 mg, 0.350 mmol, 87.4%), ThO (2.30 mg, 0.010 mmol,
2.50%), DTBMP (76.2 mg, 0.371 mmol, 92.2%), benzaldehyde (2.30 mg, 0.22
mmol. 10.7%) and 2-(4-methoxyphenyl)-5-phenyl-1.3.4-oxadiazole (31.5 mg.
0.125 mmol. 61.5%).
68
4-Methoxybenzaldehvde 4-Methoxybenzoylhydrazone (108)
The reacfion was carried out with 0.126 g (0.40 mmol) of thianthrene
cafion radical perchlorate. 0.082 g (0.40 mmol) of DTBMP and 0.057 g (0.20
mmol) of 4-methoxybenzaldehyde 4-methoxybenzoylhydrazone. The produds
and their yields were: Th (79.6 mg, 0.368 mmol. 91.9%). ThO (0.60 mg. 0.003
mmol. 0.62%), DTBMP (76.7 mg, 0.374 mmol, 93.6%) and 2,5-di-(4methoxyphenyl)-1,3,4-oxadiazole (47.1 mg, 0.166 mmol, 83.2%).
4-Methylbenzaldehvde Benzoylhydrazone (109)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.048 g (0.20
mmol) of 4-methylbenzaldehyde benzoylhydrazone. The produds and their
yields were: Th (83.1 mg, 0.385 mmol, 96.4%), ThO (1.80 mg, 0.008 mmol,
1.92%), DTBMP (79.8 mg, 0.389 mmol, 96.8%), 4-methylbenzaldehyde (3.90
mg, 0.033 mmol, 16.3%), 2-(4-methylphenyl)-5-phenyl-1,3,4-oxadiazole (35.4
mg, 0.150 mmol, 75.0%) and 4-methylbenzaldehyde benzoylhydrazone (0.60
mg, 0.003 mmol, 1.30%).
Benzaldehyde 4-Methvlbenzoylhydrazone (110)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.048 g (0.20
mmol) of benzaldehyde 4-methylbenzoyl hydrazone. The produds and their
yields were: Th (79.0 mg, 0.366 mmol 91.5%). ThO (0.93 mg. 0.004 mmol
3.85%), DTBMP (79.8 mg. 0.389 mmol 96.5%) and 2-(4-methylphenyl)-5-phenyl1.3.4-oxadiazole (43.4 mg, 0.182 mmol, 89.9%).
69
4-Methylbenzaldehyde 4-Methylbenzoylhydrazone (111)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cafion radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.050 g (0.20
mmol) of 4-methylbenzaldehyde 4-methylbenzoylhydrazone. The products and
their yields were: Th (79.7 mg, 0.369 mmol, 92.1%), ThO (1.20 mg, 0.005 mmol,
1.35%), DTBMP (76.4 mg, 0.372 mmol. 92.7%). 4-methylbenzaldehyde (5.10
mg. 0.043 mmol. 21.4%) and 2.5-di-(4-methylphenyl)-1.3,4-oxadiazole (35.4 mg,
0.142 mmol, 71.0%).
4-Chlorobenzaldehvde Benzoylhydrazone (112)
The readion was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.052 g (0.20
mmol) of 4-chlorobenzaldehyde benzoyl hydrazone. The products and their
yields were: Th (84.0 mg, 0.372 mmol, 92.9%), ThO (2.70 mg, 0.012 mmol,
2.85%), DTBMP (77.4 mg, 0.377 mmol, 93.6%), 4-chlorobenzaldehyde (2.80 mg,
0.020 mmol, 9.95%). 2-(4-chlorophenyl)-5-phenyl-1,3.4-oxadiazole (40.1 mg.
0.156 mmol. 78.2%) and 4-chlorobenzaldehyde benzoylhydrazone (0.50 mg.
0.002 mmol. 1.05%).
Benzaldehyde 4-ChlorQbenzovlhydrazone (113)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cafion radical perchlorate. 0.082 g (0.40 mmol) of DTBMP and 0.052 g (0.20
mmol) of benzaldehyde 4-chlorobenzoyl hydrazone. The products and their
yields were: Th (81.5 mg. 0.378 mmol, 94.1%), ThO (2.50 mg. 0.011 mmol.
2.70%), DTBMP (77.1 mg. 0.376 mmol. 93.9%). benzaldehyde (2.80 mg. 0.026
mmol, 13.0%). 2-(4-chlorophenyl)-5-phenyl-1.3.4-oxadiazole (39.9 mg. 0.156
mmol. 77.5%) and benzaldehyde 4-chlorobenzoylhydrazone (0.60 mg, 0.003
mmol, 1.20%).
70
4-Chlorobenzaldehyde 4-Chlorobenzoylhydrazone (114)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.059 g (0.20
mmol) of 4-chlorobenzaldehyde 4-chlorobenzoylhydrazone. The produds and
their yields were: Th (76.7 mg, 0.355 mmol, 88.5%), ThO (4.20 mg, 0.018 mmol,
4.55%), DTBMP (78.2 mg, 0.381 mmol, 94.9%), 4-chlorobenzaldehyde (20.9 mg,
0.148 mmol, 74.3%), 2,5-di-(4-chlorophenyl)-1,3,4-oxadiazole (3.50 mg, 0.012
mmol, 6.05%) and 4-chlorobenzaldehyde 4-chlorobenzoyl hydrazone (9.50 mg,
0.033 mmol, 16.3%).
4-Nitrobenzaldehyde Benzoylhydrazone (115)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.054 g (0.20
mmol) of 4-nitrobenzaldehyde benzoyl hydrazone. The products and their yields
were: Th (70.2 mg, 0.325 mmol, 81.2%), ThO (8.58 mg, 0.037 mmol. 9.20%),
DTBMP (81.1 mg, 0.395 mmol, 98.3%), 4-nitrobenzaldehyde (2.57 mg, 0.017
mmol, 8.30%), 2-(4-nitrophenyl)-5-phenyl-1,3,4-oxadiazole (25.9 mg, 0.097
mmol, 48.5%) and 4-nitrobenzaldehyde benzoylhydrazone (10.7 mg, 0.0.040
mmol, 19.8%).
Benzaldehyde 4-Nitrobenzoylhvdrazone (116)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.054 g (0.20
mmol) of benzaldehyde 4-nitrobenzoyl hydrazone. The products and their yields
were: Th (74.3 mg, 0.344 mmol, 86.2%), ThO (7.90 mg, 0.034 mmol, 8.60%),
DTBMP (76.9 mg, 0.374 mmol, 93.8%), benzaldehyde (5.50 mg, 0.052 mmol,
26.2%), 2-(4-nitrophenyl)-5-phenyl-1,3,4-oxadiazole (22.1 mg, 0.083 mmol,
71
41.6%) and benzaldehyde 4-nitrobenzoylhydrazone (6.30 mg, 0.023 mmol,
11.7%).
3-Nitrobenzaldehvde Benzoylhydrazone (117)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.054 g (0.20
mmol) of 3-nitrobenzaldehyde benzoyl hydrazone. The products and their yields
were: Th (71.3 mg, 0.330 mmol, 82.9%), ThO (3.94 mg, 0.017 mmol, 4.20%),
DTBMP (78.2 mg, 0.381 mmol, 94.9%), 4-nitrobenzaldehyde (3.81 mg, 0.025
mmol, 12.6%), 2-(3-nitrophenyl)-5-phenyl-1,3,4-oxadiazole (25.1 mg, 0.094
mmol, 47.1%) and 3-nitrobenzaldehyde benzoylhydrazone (15.3 mg, 0.0.057
mmol, 28.5%).
Benzaldehyde 3-Nitrobenzoylhydrazone (118)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.054 g (0.20
mmol) of benzaldehyde 3-nitrobenzoyl hydrazone. The products and their yields
were: Th (78.8 mg, 0.365 mmol, 91.2%), ThO (4.30 mg, 0.019 mmol, 4.65%).
DTBMP (79.8 mg. 0.388 mmol, 96.6%), benzaldehyde (19.0 mg, 0.179 mmol,
89.5%) and 2-(3-nitrophenyl)-5-phenyl-1,3,4-oxadiazole (1.20 mg. 0.004 mmol,
2.20%).
Cinnamaldehyde Benzoylhydrazone (119)
The reaction was carried out with 0.063 g (0.20 mmol) of thianthrene
cation radical perchlorate, 0.041 g (0.20 mmol) of DTBMP and 0.025 g (0.10
mmol) of cinnamaldehyde benzoylhydrazone. The products and their yields
were: Th (41.5 mg, 0.192 mmol, 95.9%), ThO (0.23 mg, 0.001 mmol. 0.60%),
72
DTBMP (40.0 mg. 0.195 mmol, 97^0%) and 2-phenyl-5-styryl-1,3,4-oxadiazole
(24.1 mg, 0.098 mmol, 97.5%).
Crotonaldehyde Benzoylhydrazone (120)
The reacfion was carried out with 0.125 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.038 g (0.20
mmol) of crotonaldehyde benzoylhydrazone. The produds and their yields were:
Th (80.2 mg, 0.371 mmol, 92.4%), ThO (1.62 mg, 0.007 mmol, 1.70%), DTBMP
(78.1 mg, 0.373 mmol, 92.9%), and 2-crotyl-5-phenyl-1,3,4-oxadiazole (37.7 mg,
0.192 mmol, 96.4%).
Phenylacetaldehyde Benzoylhydrazone (121)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.048 g (0.20
mmol) of phenylacetaldehyde benzoyl hydrazone. The products and their yields
were: Th (76.2 mg, 0.353 mmol, 88.3%), ThO (5.30 mg, 0.023 mmol, 5.70%),
DTBMP (81.0 mg. 0.395 mmol. 97.8%) and 2-benzyl-5-phenyl-1.3,4-oxadiazole
(32.3 mg, 0.137 mmol, 68.8%).
Benzaldehyde Phenylacetylhydrazone (122)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cation radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.048 g (0.20
mmol) of benzaldehyde phenylacetyl hydrazone. The products and their yields
were: Th (72.1 mg, 0.334 mmol, 83.2%), ThO (7.00 mg, 0.030 mmol, 7.40%),
DTBMP (78.9 mg, 0.384 mmol, 96.0%), benzaldehyde (4.60 mg, 0.043 mmol,
21.7%), 2-benzyl-5-phenyl-1,3,4-oxadiazole (2.40 mg, 0.010 mmol, 5.15%) and
benzaldehyde phenylacetylhydrazone (23.3 mg, 0.098 mmol, 48.9%).
73
Trimethylacetaldehyde Benzoylhydrazone (123)
The reaction was carried out with 0.126 g (0.40 mmol) of thianthrene
cafion radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.041 g (0.20
mmol) of trimethylacetaldehyde benzoyl hydrazone. The products and their
yields were: Th (82.9 mg, 0.384 mmol, 95.8%), ThO (2.10 mg, 0.009 mmol,
2.25%), DTBMP (79.3 mg, 0.386 mmol, 96.8%), 2-terf-butyl-5-phenyl-1,3,4oxadiazole (33.0 mg, 0.163 mmol, 84.4%) and trimethylacetaldehyde
benzoylhydrazone (2.00 mg, 0.010 mmol, 4.85%).
4-Dimethylaminobenzaldehyde Benzoylhydrazone (124)
The reacfion was carried out with 0.125 g (0.40 mmol) of thianthrene
cafion radical perchlorate, 0.082 g (0.40 mmol) of DTBMP and 0.053 g (0.20
mmol) of 4-dimethylaminobenzaldehyde benzoylhydrazone. The products and
their yields were: Th (81.4 mg, 0.377 mmol, 94.4%), ThO (0.93 mg, 0.004 mmol,
1.05%), DTBMP (78.1 mg, 0.380 mmol, 95.2%), 4-dimethylaminobenzaldehyde
(4.72 mg, 0.032 mmol, 15.9%) and 2-phenyl-5-styryl-1.3.4-oxadiazole (39.1 mg.
0.147 mmol, 74.1%).
74
CHAPTER III
RESULTS AND DISCUSSIONS
Reactions of Aldehyde Semicarbazones with Thianthrene
Cation Radical Perchlorate
In 1985, Shine and coworkers3 reported that cation radicals can induce
the oxidative cycloaddition of arylhydrazones and oximes to nitrile solvents. In
addition, the oxidative cyclization of arylhydrazones of chalcones and
benzalacetones to form pyrazoles in acetonitrile solvent was also reported.
These observations led Shin, in Shine's laboratory, to study the reactions
of aldehyde semicarbazones with thianthrene cation radical.7 Semicarbazones
(21) are structurally and electronically analogous to hydrazones (7) and oximes
(9) (Scheme 6). Therefore, it was expected that semicarbazones (21) would
undergo cycloadditions similar to those of hydrazones (7).
N—N
2Th+
^r
Ph—CH=N—NH—Ar
R'CN
N—O
2Th+
R—CH=N—OH
R'CN
Y\
2Th+
Ar—CH=N—NH—C—NH2
^
R'CN
Cycloaddition
Produd (?)
+
2Th +
2H+
21
Scheme 6. Electronic and Structural Similarities Among Hydrazones, Oximes
and Semicarbazones.
75
However, it was found that the expected oxidative cydoaddition to nitrile
solvents did not occur. Instead, intramolecular cydization took place (Scheme
7).
0
Ar—C H=N—NH—C—NH2
21
[oxidation]
0-attack
N-attack
H
N—N
2H + Ar
A r ^ N ^ O
H
24
+ 2H
Scheme 7. Formation of Oxadiazole and Triazolinone from the Oxidative
Cyclization of Aldehyde Semicarbazone.
It was found by Shin that oxadiazoles (23) were formed in moderate
yields, whereas triazolinones (24) were formed either not at all or in small
amounts. The reactions were generally slow and unreacted semicarbazones
were frequently recovered. However, the reactions were faster in the presence
of the pooriy nucleophilic base 2,6-di-te/t-butyl-4-methylpyridine (DTBMP). It
was concluded that an oxidation step was enhanced by prior deprotonation.
During Shin's investigation another interesting observation was made:
addition of a small amount of water to the reaction mixture dramatically
accelerated the reaction, as judged by the disappearence of the thianthrene
cation radical color, and increased the yield of the product oxadiazole. No
76
certain explanation of this phenomenon could be found. In addition to that,
Hammerich and Parker had concluded from their anodic oxidation studies of the
semicarbazones that oxadiazoles were formed from the enolic form (27) of the
aroyI semicarbazide (28) generated in solufion by hydration of the nitriiiminium
48
ion 26 (equafion 40, p 13).'
.48
Bearing in mind the proposal by Hammerich and Parker**" and her results
from using H2O, Shin suggested that the enolic OH group of the hydrated
nitriiiminium ion caused cyclization to occur, and the enolic oxygen atom became
the oxygen atom of the oxadiazole ring (Scheme 8).
O
II
Ar—CH=N—NH—C-NH2
Th+
O
+
.
II
-^ Ar—CH—N—NH—C—NH2
+
Th
(step 1)
[21]+
21
H2O (step 2)
OH
O
1
+
II
Ar—CH—N—NH—C—NH2
146
OH
I
Ar—CH—N—NH—C—NH2
Th+
(-Th)
(step 3)
+
H
145
.H+ (step 4)
H
N—N
N—N
II y H
Ar
0''^^NH2
147
23
Scheme 8. Mechanism for the Oxidative Intramolecular Cyclization of Aldehyde
Semicarbazone.
77
In contrast. Shin suggested that triazolinone formation occurred by cyclization of
the nitriiiminium ion itself.
0
+
.
N
Ar—CH—N-NH-C-NH2
[21]+
^u.
Th+
•
N—NH
//
\
A r - ^ ' O >Wo
H2N
26
+
Th +
H
-H*
N—NH
H
24
Scheme 9. Formation of Triazolinone from the Cyclization of Nitriiiminium Ion.
Shin recognized that the route to oxadiazole formation could be tested by
using ^®0-labeled water, but she did not carry out the test. The use of H2^®0 in
tesfing Shin's suggesfion is part of this dissertation.
Before going into ''80-labeled water work the reaction of thianthrene
cation radical with benzaldehyde semicarbazone in the presence of a small
amount of ordinary water was repeated and was also extended to
cinnamaldehyde semicarbazone. This was done to check the observation made
by Shin7 that addition of a small amount of water accelerated the readion.
Results are given in Table 1 and the details are given in the experimental
section. Both reactions showed the behavior as reported by Shin.7 In each case
the readion was accelerated with the addition of a small amount of water and
the product oxadiazoles were obtained in good yields. In the case of
78
benzaldehyde semicarbazone a trace of triazolinone was also noticed but its
quantitafive measurement was not possible.
The details of the ''80-labeled water work were as follows. First, the
reaction of thianthrene cation radical perchlorate with benzaldehyde
semicarbazone (21) was carried out in acetonitrile in presence of 10 mmol of
added H2''S0 (50% 180). The reaction mixture was worked up the usual way and
the oxadiazole (23) was isolated by column chromatography and was subjected
to single ion monitoring (SIM) mass spectrometry. It was concluded with
certainty that no ''80 enrichment of the product oxadiazole had occurred (see
experimental section).
To explore the mechanistic aspects of this reaction further, authentic
benzaldehyde ['•^Ojsemicarbazone was synthesized according to the literature
method. The details are given in the experimental section. The SIM of the
synthesized semicarbazone showed that it was 7.63% enriched in 180.
Next, the reaction of thianthrene cation radical perchlorate with
benzaldehyde [''80]semicarbazone was carried out in acetonitrile solvent in
presence of 10 mmol of added ordinary water. The reaction mixture was worked
up the usual way and the oxadiazole (23) was isolated from the readion mixture
and was subjected to SIM mass spectrometry. SIM results showed that the ''80
enrichment in 23 was the same as that in the [''80]semicarbazone. Therefore, it
can be concluded that during the oxidative cyclization of the aldehyde
semicarbazone to oxadiazole the carbonyl oxygen is retained in the oxadiazole
molecule.
Thus the mechanism for oxadiazole formation (Scheme 8) suggested by
Shin is not substantiated by the oxygen labelling work, and again, the
mechanisms of both oxadiazole and triazolinone formation remain unsolved. In
this regard, a number of speculations may be made to accomodate the present
observations and the observations made by Shin. It may be that the role of water
79
is not to hydrate the nitriiiminium ion but to fadlitate deprotonation, analogously
to the effect of added DTBMP.
H i
N
N )
H2O:
(DTBMP)
N
^
H
Ar
NH2
[21]+
148
Th+
N
//
Ar-^
N
\\
^O^
H26: ->v
N
(DTBMP) I H ^ /
-H+
NH2
A^/
23
N
\\
^0-^
NH2
149
Scheme 10. Proposed Role of Added Water (and DTBMP) in the Formation of
Oxadiazole.
In that case, triazolinones would be formed only by competitive attack by
the NH2 group in the cyclization process. This explanation would not satisfy the
claims by Hammerich and Parker, however, and those would remain unresolved.
The role of H2O (and DTBMP) shown above (Scheme 10) would suit the
observations that oxadiazole formation was faster (as judged by the
disappearance of Th*) in its presence. It is striking that even when relatively
large amounts of H2O were used (15 mmol by Shin and 10 mmol In this work),
reaction of the water with Th"*" itself did not occur. Instead more rapid formation
of oxadiazole resulted.
80
Readions of Aldehyde N-Acvlhvdrazones with
Thianthrene Cation Radical Perchlorate
Shine and coworkers reported that arylhydrazones of benzaldehyde (7)8
and oximes (9)5 underwent thianthrene cation radical induced oxidafive
cydoaddifion to the nitrile solvents to form 1,2,4-triazoles (8) and 1,3,4oxadiazoles (10) respecfively at room temperature (Scheme 11). In addition,
arylhydrazones (12) of chalcones and benzalacetones undenA/ent oxidative
cyclization to form pyrazoles (13) rather than cycloaddition to solvent
acetonitrile.2
A
Ph—CH=N—NH-Ar
N—N
r,u^ ^ o .
Ph ^N
R
8
^
R'CN
7
^ .
''''
R'CN
R-CH=N-OH
2Th
+
2H*
^ 2^ ^ ^H^
XX..
_^ ^^,^ ^p,
R ^N
R
10
^
+
A
R
.^^^
Ar-CH=CH-i=N-NH-Ar'
^
12
N—N
R^^^N^J^Ar"
^^
"*"
^"^
2-m
+
2H*
13
O
D rw-M NH-r-R'
R-CH-N-NH C R
150
/COR
N—N
.
- ^ ^
^^^^
JL X^
+
R-^N^^Me
151
Scheme 11. Electronic and Structural Similarifies Among Hydrazones, Oximes
and N-Acylhydrazones.
81
The following mechanism (Scheme 12) was proposed for the formation of
1,2,4-triazole from the oxidative cydoaddition of the arylhydrazones to the nitrile
solvents.
Th+ + P^r-CH=N-NH-Ar
7
H
J.+ .
N—N—Ar
H ^
1^ Jh
H
•
I
N—N-Ar
\
H ^
%
+
Ph-CH-N-NH-Ar
152
R'CN
Ph—CH—N-NH—Ar
154
N—N^
PK
N^
.
^
N—N-^
p/ ^N-^ R
155
156
Scheme 12. Mechanism for the Formation of 1,2,4-Triazoles from the Oxidative
Cycloaddition of Hydrazones to Nitrile Solvents.
The cycloaddition was proposed to be a two-step oxidation process. The
hydrazone cation radical 152 is formed by an initial one-electron transfer. It then
attacks the nitrile group's nitrogen atom as in a Ritter reaction to give the
intermediate 153. Intermediate 153 then undergoes cyclization to give
intermediate 154. A successive proton loss from 154 gives the neutral radical
intermediate 155. A second oxidation of 155 leads to 156 which then loses
another proton to give the triazole 8.
82
Conde and coworkersii6 reported the formation of 1,2,4-triazoles (160) in
the readions of N-phenylhydrazidoyI chloride (157) with nitriles in the presence
of aluminium chloride. It was proposed that the cydoaddition was a two-step
process and a nitriiiminium ion (158) was the reactive intermediate (Scheme 13).
?'
R—C=N—NH—Ph
AICI3
»-
^
R—c=N—NH—Ph
157
RCN
158
R—C=N—NH—Ph
+N=C-R
Scheme 13. Conde's Mechanism for the Formation of 1,2,4-Triazole from the
Oxidative Cycloaddition of N-PhenylhydrazidoyI Choride.
These observations led to an interest in the study of readions of aldehyde
N-acylhydrazones with thianthrene cation radical. Since N-acylhydrazones (150)
are eledronically and structurally analogous to hydrazones (7) and oximes (9)
as shown in the Scheme 11, we asked if N-acylhydrazones (150) would undergo
intermolecular cycloadditions to acetonitrile solvent similar to those of
hydrazones to give 1,2,4-triazoles (151) or would cyclize intramoleculariy.
Reactions of Aldehyde N-Acylhydrazones
in Acetonitrile
Benzaldehyde N-benzoylhydrazone [PhCH=NNHCOPh] (96) seemed to
be the proper choice to begin answering this question. To that end, reaction of
96 was carried out with thianthrene cation radical perchlorate in acetonitrile
83
solvent. Products obtained from this reaction were thianthrene (Th), thianthrene
5-oxide (ThO) and 2,5-diphenyl-1,3,4-oxadiazole (125) (Scheme 14). Their
respecfive yields are given in Table 5 (run 1).
2Th+ +
O
PlT-CH=N—NH—C-Ph
CH3CN
•
96
N-N
JL
%^
+ Th + ThO
Ph"^0
Ph
125
Scheme 14. Products Obtained from the Reacfion of Thianthrene Cation Radical
with Benzaldehyde N-Benzoylhydrazone (96).
The following observations were made. The readion took place very
slowly. No product from oxidative cydoadditon to the solvent was detected (run
1. Table 5). Instead, intramolecular cyclization occurred (Scheme 14). The major
product was 2.5-diphenyl-1,3.4-oxadiazole (125) which was obtained in
moderate yield. No other produd was formed but a large amount of unreaded
hydrazone (51.9%) was recovered. However, when the reaction was carried out
in the presence of a pooriy nucleophilic base, 2,4-di-te/t-butyl-6-methylpyridine
(DTBMP), it took place rather rapidly (run 2, Table 5). Again the oxadiazole was
the major produd. but in higher yield. No unreaded hydrazone was recovered in
this case.
Thereafter, readions of two other N-acylhydrazones with thianthrene
cation radical were earned out in acetonitrile. These were phenylacetaldehyde
N-benzoylhydrazone (121) and trimethylacetaldehyde N-benzoylhydrazone
(123). Products and their yields are given in Table 5 (runs 3 and 4). Both the
reactions gave the corresponding oxadiazoles as the only produd. In the case of
121 no unreacted hydrazone was recovered but in the case of 123 a significant
amount (23.4%) of unreacted hydrazone was recovered.
84
Following these observations, reactions of Th"*"CI04" with a series of
aldehyde N-acylhydrazones were attempted in acetonitrile solution. With a
number of hydrazones. particularly those with higher molecular weight (e.g.,
hydrazones with a naphthyl group, 97-102), a problem of inadequate solubility in
acetonitrile was encountered. However, GC and GC-MS of the reaction mixtures
of these hydrazones showed that the cyclization produd oxadiazole had formed
but in small amounts. No cycloaddition produd was detected.
Without the proper solubility of the hydrazones, the reactions between the
hydrazones and the thianthrene cation radical cannot be expeded to go
smoothly to completion within a reasonable period of time. Therefore, switching
the solvent appeared to be the best alternative.
Dichloromethane seemed to be the proper choice on the basis that it
dissolved the hydrazones very well (much better than acetonitrile) and is inert in
cation radical readions. In addition, it has been reported66 that dichloromethane
was the solvent of choice for the lead tetraacetate induced oxidative cyclizations
of N-acylhydrazones leading to oxadiazoles.
Reactions of Aldehyde N-Acylhydrazones in
Dichloromethane
As a representative member of the acylhydrazones, benzaldehyde Nbenzoylhydrazone (96) was choosen to readfirstwith Th'*"CI04" to see whether
it maintained the same readivity pattern in dichloromethane as in acetonitrile.
Since there is no multiple bond present in dichloromethane, the question of
cycloaddition of the hydrazone to the solvent does not arise. Reactions were
carried out in the presence of DTBMP. Hydrazone 96 readed rapidly with
Th"^CI04-. The produds and their yields are listed in Table 6 (Run 1). In
addition to thianthrene (Th) (90.7%) and thianthrene 5-oxide (ThO) (3.0%), 2,5diphenyl-1,3,4-oxadiazole (125) was obtained as the major product in moderate
85
yield (70.6%). Unlike the reaction in acetonitrile a significant amount of
benzaldehyde (22.4%) was also obtained along with some unreacted hydrazone
(9.1%) (Table 6, run 1).
Thereafter, reactions of a series of aldehyde N-acylhydrazones were
carried out in dichloromethane in the presence of DTBMP. In each case the
acylhydrazone reacted rapidly with Th"*" CIO4'. Products obtained from these
reacfions are given in Scheme 15 and their respecfive yields are listed in Table
6. In almost all of the cases the cation radical induced oxidafive intramolecular
cyclization of the hydrazones occurred to give the corresponding 1,3,4oxadiazoles. In general, the oxadiazoles were the major products and were
obtained in excellent yields. However, there were a few exceptions in which an
aldehyde (RCHO) was obtained as the major product. The aldehyde
corresponded to the aldehydic part of the hydrazone molecule. For example, 4nitrobenzaldehyde [4-NO2C6H4CHO] was obtained from 4-nitrobenzaldehyde Nbenzoylhydrazone [4-N02C6H4CH=NNHCOC6H4] (115). In a good number of
cases some unreacted hydrazone was also recovered.
Table 6 lists thianthrene 5-oxide (ThO) as a by product, but its formation
is not related to the cyclization reaction. Instead, the ThO stems from the
reaction of thianthrene cation radical with water that was present in the
incompletely dried solvent and/or was added during the work-up procedure.
?1
R-CH=N-NH-C-R
150
2Th+
^
CH2CI2
N-N
^
X .
-^ f ^ ^ " 0 + Th + ThO
R^^O^^R'
161
Scheme 15. Products Obtained from the Reactions of Thianthrene Cation
Radical Perchlorate with Aldehyde N-Acydhydrazones in Dichloromethane.
86
Oxidation of the Aldehyde N-Acylhydrazone and Competitive
Formation of Aldehyde and Oxadiazole
An overview of the results obtained from all the reactions points to a
general trend regarding the relative yields of the oxadiazole and the aldehyde.
The formation of the oxadiazole and the aldehyde appears to be complementary
to each other. The reactions which gave higher yields of the aldehydes in turn
gave lower yields of the oxadiazoles and vice versa. This suggests that the
routes to the aldehyde and to the oxadiazole most probably start from the same
key intermediate (Scheme 16). The mechanisms for the formation of aldehyde
and oxadiazole will be discussed later.
0
II
R-CH=N—NH-C-R
150
Th+
R - C H - -N--NH—C—R
162
ReactionwithH20
Cydization
(Path A)
(Path B)
1f
0
II
R-C-H
N-N
A k
16;i
Scheme 16. Compefifive Formafion of Oxadiazole (161) and Aldehyde (RCHO)
from the Hydrazone Cation Radical (162).
87
Once formed, the hydrazone cation radical (162) can take either path A or
path B. Path A leads to oxadiazole (161) and path B leads to aldehyde (RCHO).
It appears that if R' increases the nudeophilidty of the carbonyl oxygen then
cyclization will be the predominant process and if cyclization is impeded then
formation of aldehyde becomes favored.The formation of the aldehyde can be
attributed to the reaction of the hydrazone cation radical (162) with water which
might be present in the incompletely dried solvent or added during workup. From
the results obtained from the reactions of thianthrene cation radical with
aldehyde N-acylhydrazones it appears that the formation of aldehyde and
oxadiazole are competitive.
Reactivity Patterns of the Aldehyde N-Acylhydrazones
In the reactions of thianthrene cation radical with aldehyde N-acyl
hydrazones the total recovery of the products (oxadiazole + aldehyde +
unreacted hydrazone) were poorer in some cases than in the others. For
example, run 3, Table 5 gave only 40.4% yield of the product oxadiazole
(oxadiazole was the only product recovered in this case). Similarly total
recoveries of the products from runs 3, 6, 10 and 12, Table 6 were 74.9%,
81.0%, 83.2%, 72.2%, respectively, of which 60.6%, 62.9%, 77.0% and 61.5%
were the yields of the respective oxadiazoles.
However, in some cases excellent yields of the oxadiazoles were
obtained where total recoveries were also very good. For example, runs 2, 5, 24
and 25 (Table 6) gave 91.4%, 93.5%, 97.5% and 96.4% yields of the
oxadiazoles where the total recoveries were 95.7%, 97.4%, 97.5% and 96.4%,
respectively.
And there are the cases where the recoveries of the oxadiazoles were not
too bad and the total recoveries were very good. For example, runs 7, 8, and 18
88
(Table 6) gave oxadiazoles in 86.7%, 84.9% and 78.9% yields, respectively, and
the respective total recoveries were 99^5%, 90.4% and 92.0%.
In some of the cases the formation of the aldehyde (RCHO) was a
problem. For example, runs 1, 4 and 9 (Table 6) gave aldehydes In 22.4%,
20.3% and 14.6%, respectively, where the total recoveries of the produds were
93.0%, 92.6% and 93.5%, respecfively.
Some of the hydrazones gave aldehydes as the main products in very
high yields. For example, runs 19 and 23 (Table 6) gave aldehydes in 88.5%
and 89.5% yields, respectively, where the total recoveries were 95.7% and
91.7%, respectively.
Effect of the R group on the Oxidizability of the
N-Acvlhvdrazone Molecule (RCH=NNHCOR')
Reaction of thianthrene cation radical with an aldehyde N-acylhydrazone
(RCH=NNNHCOR') would be expected to generate a hydrazone cafion radical,
CH3—0—/
\—CH=N-NH-C—/
y
106
Th+
O
CH3_
5iy
^c*H-N-NH-l!^
^
CH—N—NH-C
164
Scheme 17. Effect of the 4-Methoxyphenyl Group on the Stability of the
Hydrazone Cation Radical.
89
[RCH=NNHCOR']* by an initial one-electron transfer. The ease of this oxidation
would be dependent on the stability of the newly formed cation radical. It was
observed that where the R group of the hydrazone molecule (RCH=NNNHCOR')
stabilizes the initially formed hydrazone cation radical, all or most of the
substrate was used up^ For example, runs 5, 7 and 8 (Table 6) where the R
CH3-6-/
V-CH=:N-NH-C-/^
106
Th+
CH3-6>^i-C^H-N-NH-?-/
W
163
A
CH3—0=/
\=CH-N-NH-C—/
"^
164
Scheme 17. Effect of the 4-Methoxyphenyl Group on the Stability of the
Hydrazone Cation Radical.
groups were 2-naphthyl, 2-methoxyphenyl and 4-methoxyphenyl respectively,
did not give any unreaded hydrazone. All these three groups can be expeded to
stabilize the initially formed hydrazone cation radical very effectively and thus
facilitate the oxidation process. This effect is illustrated in the preceding scheme
using 4-methoxybenzaldehyde benzoylhydrazone as an example (Scheme 17).
On the other hand, when the R group is not a good stabilizer of the
hydrazone cation radical it discourages the oxidation of the acylhydrazone. For
90
example, runs 20 and 22, Table 6, where the R groups are 4-nitrophenyl and 3nitrophenyl gave unreacted hydrazones in 19.8% and 28.5% yields
respectively.This can be explained by the following scheme taking 4-nitrobenzaldehyde benzoylhydrazone as an example (Scheme 18). Positive charge
on the aldehydic aromatic ring destabilizes the cation radical and discourages its
formation.
II
CH=N—NH—C
^
/
\
/
115
Th+
O
+
.
II
CH—N—NH—C
165
A
'
o
,=,
CH—N—NH—C
166
\
/
Scheme 18. Effect of the 4-Nitrophenyl Group on the Stability of the Hydrazone
Cation Radical.
Hammerich and Parker48 studied the anodic oxidation of aldehyde
semicarbazones (RCH=NNHC0NH2). The ease of oxidafion of the
semicarbazones was found to be markedly dependent on the nature of the parasubstituent of the aryl group. The oxidation peak potential decreased steadily
from electron withdrawing to the highly electron donating group in the order p-CIC6H4>p-Me-C6H4>p-MeO-C6H4>p-Me2N-C6H4. It was suggested that the
91
resonance stabilization of the resulting cationic species was responsible for the
ease of oxidation of the semicarbazones. A similar resonance stabilizafion of the
aldehyde N-acylhydrazone cation radical is also possible.
Factors Affecting the Yield of Oxadiazole
An overview of the results in Tables 5 and 6 indicates that the good yield
of the oxadiazole is dependent on the combined properties of ready oxidizability
of the hydrazone molecule (RCH=NNHCOR') (i.e., hydrazone with a good R
group which would enhance its ready oxidation) and the propensity of the
hydrazone cation radical [RCH=NNHCOR']* to cydize (i.e., hydrazone with
^ y^CH—N-NH-C—/
y
Scheme 19. Effective Stabilization of the Hydrazone Cation Radical by the
Naphthyl group.
a good R' group which would stabilize the cyclic cationic charge and also
increase the nudeophilidty of the carbonyl oxygen. Scheme 19 shows the
effident stabilization of the hydrazone cation radical by the naphthyl group (a
good R group) which facilitates ready oxidation of the hydrazone molecule.
92
,j»»^^-;a**ei>
Once the cydization has taken place a good R' group (e.g., phenyl group)
can stabilize the cydic cationic charge as shown in the following scheme
(Scheme 20) enhancing the cyclization process.
/=.
N
N_
,^J^
Scheme 20. Stabilizafion of the Cyclic Cafionic Charge by the Phenyl Group (a
Good R' Group).
Aldehyde N-acylhydrazones with a good R' group can also increase the
nudeophilidty of the carbonyl oxygen. Increasing the nudeophilidty of the
carbonyl oxygen would enhance the attack on the azomethinyl carbon by the
carbonyl oxygen and thus increase the cyclization process. The following
scheme (Scheme 21) shows how a good R' group (e.g., phenyl group) can
increase the nudeophilidty of the carbonyl oxygen.
93
\
f/
//
00
\
-CH=N—NH—C
170
\
//
Scheme 21. Effect of the Phenyl Group (a good R' group) on the Nudeophilidty
of the Carbonyl Oxygen.
Competition Between the Formation of Aldehyde (RCHO)
and Oxadiazole
Regarding the competition between the formation of aldehyde and
oxadiazole, it appears that aldehyde formation occurs when the cyclization is not
enhanced. For example, runs 19, 21 and 23 (Table 6) gave high yields of the
aldehydes. An R' group that discourages the cyclization process, indirectly
encourages the reaction of the hydrazone cation radical with water which might
be present in the incompletely dried solvent. The following scheme (Scheme 22)
shows, for example, the lack of nudeophilidty on the part of the carbonyl oxygen
for attacking the azomethinyl carbon due to the presence of a P-NO2 group. Also,
once the cationic ring is formed it is destabilized by the presence of the positive
charge on the acyl aromaticringwhich the NO2 group helps develop. Under
these circumstances, trace amounts of water which might be present In the
system react with the hydrazone cation radical leading to the formation of an
aldehyde.
94
\
//
0
0
CH=N-NH-C—/ " ^ N ^
= /
^0^
116
Th+
CH—N—NH-C
\
//
171
etc.
Scheme 22. Effect of the p-Nitrophenyl Group (A Cation Destabilizing R' group)
on the Nudeophilidty of the Carbonyl Oxygen and the Cyclization of the
Hydrazone Cation Radical.
Mechanism for the Formation of Aldehydes (RCHO)
In the reactions of thianthrene cation radical with aldehyde Nacylhydrazones, an aldehyde was almost always formed as a by-produd. The
aldehyde, in general, was a minor produd, except in cases, where an eledron
withdrawing group was present on the acyl aromatic ring of the hydrazone
molecule. In addition to cation radical oxidation, aldehydes were reported to form
in other methods of oxidations of acylhydrazones too.8.72,74 How the aldehyde is
formed in the present work is not really understood. However, a mechanism for
the formation of aldehyde can be proposed as follows (Scheme 23).
95
il
R-CH=N-NH-C-R'
150
+
Th;
.
Th
+
.
II
R-CH-N-NH-C-R
162
(-e-, -H+)
.+
, "
i?
R-CH-N=N-C-R
174
H
i"!)
O
II
R-C-H
f
+
H20(-H+)
•*
0
II
HN=N-C-R
175
+
^
^
R_cH-N=N-C-R
173
u r.
H2O
»•
HN=NH
176
+
O
y
R-C-OH
177
Scheme 23. Mechanism for the Formation of Aldehyde from N-Acylhydrazone in
the Thianthrene Cation Radical Reaction.
An initial one-electron oxidation of the N-acylhydrazone (150) by
Th'''CI04" would give the cation radical of the hydrazone (162). If the situation is
such that the carbonyl oxygen is not nucleophilic enough for cyclization, an
additional oxidation of this intermediate (162) by another mole of Th'*'CI04"
would take place and simultaneous loss of a proton would produce the cationic
intermediate (173). The positively charged methine carbon of this intermediate
would undergo an attack by an water molecule leading to the hydrated
intermediate (174). Intermediate 174 then can undergo a carbon-nitrogen bond
cleavage and a simultaneous proton transfer would generate a molecule of
aldehyde and a molecule of acyldiimide (175). At this point the acyldiimide (175)
can undergo hydrolysis by the trace water present in the solvent to a diimide
(176) and a carboxylic acid (177).
96
The mechanism appears to be reasonable because some of the
hydrazones did produce carboxylic acids in the thianthrene cation radical
reactions. For example, 4-chlorobenzoic acid was detected by GC and GC-MS in
the reaction of 4-chlorobenzaldehyde 4-chlorobenzoylhydrazone. However,
attempts to measure the amount of acid in the readion mixture quantitatively
were not successful.
Oxadiazole from Two Routes (from RCH=NNHCOR'
and R'CH=NNHCOR)
Table 8 lists some of the oxadiazoles which were formed in the reactions
of thianthrene cation radical with acylhydrazones of the types RCH=NNHCOR'
and R'CH=NNHCOR as shown in Scheme 24. A trend that appears from this
table is that the benzoylhydrazones generally gave better yields of the
oxadiazoles. Switching the R and R' groups also had a significant effect on the
relative yields of the oxadiazoles. For example, hydrazone 117 gave 66.0% yield
of the oxadiazole whereas hydrazone 118 gave only 2.20% (Table 8). It appears
that when the NO2 group was present on the aroyI ring (in the case of 118) it
inhibited the cyclization process.
O
O
R-CH=N-NH-C-R
150
Th+
R—CH=N-NH-C-R
N—N
//
\\
''^^
Th+
Scheme 24. Formation of the Same Oxadiazole from Acylhydrazones
RCH=NNHCOR' and R'CH=NNHCOR.
97
Another pair of hydrazones which gave interesting results are
phenylacetaldehyde N-benzoylhydrazone (121) and benzaldehyde Nphenylacetylhydrazone (122). Hydrazone 121 gave oxadiazoles in 68.8% yield
whereas hydrazone 122 gave only 9.80% (Table 8). It appears that the cydic
cationic intermediate 179 obtained from 121 is resonance stabilized whereas
intermediate 180 which is obtained from 122 is not resonance stabilized
(Scheme 25). And that seems to be the reason for the hydrazone 121 giving
higher yields of the oxadiazole.
i
^ C H ,
Resonance Stabilized
N
N
W / J.^>LcH.-// ^
180
Not Resonance Stabilized
Scheme 25. Stabilized and Destabilized Cyclic Cationic Intermediates from
Hydrazones 121 and 122, respectively.
The results obtained from these reactions (runs 26 and 27, Table 6) are
similar to those reported by Chiba and Okimoto8 for the electrooxidative
cyclization of the N-acylhydrazones. In their investigations Chiba et al.8 found
that regardless of what the aldehyde part was, the benzoylhydrazones generally
gave higher yields of the oxadiazole than the acylhydrazones. However, they did
not offer any explanation for this reactivity pattern. In addition, it was reported by
98
other authors also that compared to aroy I hydrazones, acylhydrazones generally
gave lower yields of the oxadiazoles.®"^'^''
Mechanism for the Formation of 2.5-Disubstituted-1.3,41^1
Oxadiazoles
On the basis of the foregoing discussions and the results obtained from
the reactions, the following mechanism can be proposed for the formation of 2,5disubstituted-1,3,4-oxadiazole (Scheme 26).
0
II
R—CH=N—NH—C—R
150
+
N — NN
„ .
Th+
^ O ^ ^
^^^
r
^'*^P^^
\B
182
O
Thf
'^
^
Th
(s*®P^)
D
.,
..
N—N
/
\\
7^0^^
181
+
+
.
II
R—CH—N—NH—C—R
162
:B
r
_..+
-BH
(Step 2)
N—N^
H^
O^R'
162
I
-BH* (step 4)
(B = DTBMP)
161
Scheme 26. Mechanism for the formation of 2,5-Disubstituted-1,3,4-oxadiazoles
from Aldehyde N-Acylhydrazone in the Thianthrene Cation Radical.
99
The details of the mechanism follows: Atfirstthe N-acylhydrazone (150)
undergoes an initial one-electron oxidation by the thianthrene cation radical
generating a hydrazone cafion radical (162) (step 1). The carbonyl oxygen of the
new cation radical (162) then attacks the positively charged azomethine carbon
in a nucleophilic fashion, probably concerted with proton removal, to generate
the neutral radical 181. This radical is then further oxidized by another mole of
thianthrene cation radical which gives a cydic cafion (182) (step 3). In the final
step, which may also be concerted with oxidation, the cyclic cation can lose a
proton and restore the oxadiazole ring (161) (step 4).
This mechanism explains the key observations made during the course of
the present work. The reactions were faster when carried out in the presence of
base, DTBMP. If this fact is taken into account then step 2 appears to be
reversible. The effect of the added base (DTBMP) would be to enhance the
cyclization of 162 to 181 by removing the proton from the nitrogen atom in 162.
This would prevent the reversibility of step 2. Further, the effect of added
DTBMP may be to cause the almost simultaneous oxidation and deprotonation
of steps 3 and 4. That is, in the presence of DTBMP oxidation would go rapidly
in an apparent single two-electron step to 182. During the course of the reaction,
two protons need to be removed on two separate occasions. DTBMP most
probably does that and thus increases the rate of the reactions.
This mechanism also supports the observed effect of the electron
withdrawing and electron donating groups when present on the aldehydic or
aroyI aromatic rings. If the initially formed hydrazone cation radical is stabilized
then the oxadiazole is obtained in higher yields, and if destabilized then
aldehyde is obtained in lower yields.
100
Cydoaddition to Solvent RCN Versus Intramolecular
Cyclization
Results of the readions of aldehyde N-acylhydrazones with thianthrene
cation radical in acetonitrile (Table 5) indicate that the readions did not lead to
cycloaddition to the solvent. Instead, intramolecular cyclization took place
produdng 2,5-disubstituted-1,3,4-oxadiazoles as the major produd. Even though
aldehyde hydrazones (RCH=NNHR') were reported to undergo cydoaddition.
R—C H=:N—NH—C—R
Th+
O
+
•
II
R—CH—N—NH—C—R
150
+ Th
162
O
R—CH—N—NH—C—R
R—C H—N—NH—C—R'
K. ;t
N=C-Me
183
.,
N=C—Me
^
,N
O
II
C,
^;^ y"-R
N
184
Me
Scheme 27. Probability of 1,2,4-Triazole Formation from the Reaction of
Thianthrene Cation Radical with N-Acylhydrazone.
aldehyde N-acylhydrazones (RCH=NNHCOR') appeared to be unreactive toward
cycloaddition to the nitrile solvents. It is, in fact, a puzzle to us that the solvent
nitrile, present in so much molecular excess, does not attack the hydrazone
101
cafion radical intermediate. Yet H2O (in small concentration) does that in leading
to aldehyde. An attempt can be made to explain this observation by the following
scheme (Scheme 27). Attack of the nitrile groups nitrogen to the azomethinyl
carbon of the hydrazone cation radical (162) can lead to the complex 184. It
appears that the nitrogen atom of the amide group in 184 is not sufficiently
nucleophilic to attack the nitrile group's carbon atom. As a result cycloaddition
leading to 1,2,4-triazole 185 does not take place.
Regardless of mechanistic uncertainty, it is evident that the thianthrene
cation radical induced intramolecular cyclization of acylhydrazones provides a
useful method for synthesizing 1,3,4-oxadiazole in good yields. In some of the
cases the thianthrene cation radical route gave quite high yields of the
oxadiazoles and in some cases gave reasonably good yields. Thus, this method
provides an alternative to the conventional route to 2,5-disubstituted-1,3,4oxadiazoles.
Comparison of Conventional Versus Thianthrene
Cation Radical Routes to Oxadiazole
In this work oxadiazoles were prepared by three routes. Authentic
oxadiazoles were prepared by the oxidative cyclization of aldehyde Nacylhydrazones by lead tetraacetate [Pb(0Ac)4] and by the dehydration of 1,2diacylhydrazines by phosphorous oxychloride (POCl3)/phosphoric add (H3PO4).
Oxadiazoles and their yields are listed in Tables 3 and 4. Oxadiazoles were also
prepared by the reaction of thianthrene cation radical with aldehyde Nacylhydrazones. These are listed in Tables 5 and 6.
Preparations of some of the authentic oxadiazoles by the lead
tetraacetate method were not successful. Those were synthesized by the
phosphorous oxychloride/phosphoric acid method. If Tables 3, 4, 5 and 6 are
compared it becomes apparent that the conventional routes gave the better
102
0
R—CH=N—NH—C—R
150
Pb(0Ac)4
^
R—C—NH—NH—C—R
POCI3/A
185
or H3PO4/A
0
u
R—CH=N—NH—C—R
150
•
CH2CI2
Th+
CH3CNorCH2Cl2
161
Scheme 28. Preparafion of 2-R-5-R'-1,3,4-Oxadiazoles by Three Methods.
results, mostly even though several of the N-acylhydrazones gave very good
yields of the oxadiazole in the thianthrene cation radical route. For example,
runs 2,5, 11, 15, 24, 25 etc. (Table 6) gave very good yields of the oxadiazoles.
A pair of hydrazones gave better yields of the oxadiazoles in the thianthrene
cation radical method than the conventional methods. For example runs 26 and
28 (Table 6) gave oxadiazoles in 68.8% and 86.6% yields respectively, whereas
the conventional routes gave the corresponding oxadiazoles in 18.2 and 69.7%
yields respectively.
Another point to note here is that the conventional routes did not give any
aldehydes (RCHO) whereas a large number of N-acylhydrazones gave aldehyde
in the thianthrene cation radical method. Now it appears that the conventional
route does not go through a intermediate that can be attacked by water (H2O) to
cleave to RCHO.
103
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Table 2. List of Aldehyde N-Acylhydrazones (Synthesized According to the
Scheme Shown Below).
II
R-C-H
+
II
R—C—NH—NH2
^
•
II
R—CH=N—NH—C—R
MeOH
Hydrazone
Hydrazone
R
R'
Yield (%)
m. p. (OC)
96
Ph
Ph
58.0
205-207
97
1-Np
Ph
90.5
179-180
98
Ph
1-Np
84.0
228-229
99
1-Np
1-Np
93.4
238-240
100
2-Np
Ph
87.6
216-217
101
Ph
2-Np
75.6
215-216
102
2-Np
2-Np
82.0
232-234
103
2-MeO-Ph
Ph
95.0
196-197
104
Ph
2-MeO-Ph
83.7
175-176
105
2-MeO-Ph
2-MeO-Ph
91.0
149-150
106
4-MeO-Ph
Ph
87.6
56-157
107
Ph
4-MeO-Ph
80.0
196-198
108
4-MeO-Ph
4-MeO-Ph
97.0
174-175
109
4-Me-Ph
Ph
76.0
156-157
(Identity)
105
Table 2. (Continued)
R
R
Yield (%)
m. p. (OC)
110
Ph
4-Me-Ph
80.0
236-237
111
4-Me-Ph
4-Me-Ph
83.0
203-205
112
4-CI-Ph
Ph
78^0
176-177
113
Ph
4-CI-Ph
80.0
255-257
114
4-CI-Ph
4-CI-Ph
93.2
225-227
115
4-N02-Ph
Ph
94.0
249-250
116
Ph
4-N02-Ph
84.0
255-257
117
3-N02-Ph
Ph
86.1
197-198
118
Ph
3-N02-Ph
80.0
206-208
119
Ph-CH=CH
Ph
85.0
195-196
120
Me-CH=CH Ph
49.5
155-156
121
Ph
Ph-CH2
81.0
156-157
122
Ph-CH2
Ph
68.7
155-156
123
MesC
Ph
84.2
171-172
124
4-NMe2Ph
Ph
71.5
188-190
Hydrazone
(Identity)
106
Table 3. List of the Authentic 2-R-5-R'-1,3,4-Oxadiazoles (Synthesized
According to the Scheme Shown Below).
0
R—CH=N—NH—C—R
(A)
Pb(0Ac)4
•
CH2CI2
Aa
Bb
R
R
Yield (%)
m. p. (^C)
96
125
Ph
Ph
85.0
139-140
97
126
1-Np
Ph
91^0
120-121
99
127
1-Np
1-Np
95.5
179-181
100
128
2-Np
Ph
93.0
124-125
102
129
2-Np
2-Np
95.5
188-190
103
130
2-MeO-Ph
Ph
94.4
95-96
105
131
2-MeO-Ph
2-MeO-Ph
93.5
109-110
106
132
4-MeO-Ph
Ph
86.5
145-146
108
133
4-MeO-Ph
4-MeO-Ph
95.0
155-156
109
134
4-Me-Ph
Ph
85.3
126-127
111
135
4-Me-Ph
4-Me-Ph
81.8
175-176
112
136
4-CI-Ph
Ph
90.3
162-163
114
137
4-CI-Ph
4-CI-Ph
86.5
246-247
115
138
4-N02-Ph
Ph
92.4
207-209
107
Table 3. (Confinued)
Aa
Bb
R
R
Yield (%)
m. p. (OC)
117
139c
3-N02-Ph
Ph
89.0
153-154
118
139c
Ph
3-N02-Ph
90.7
153-154
121
142
Ph-CH2
Ph
18.2
99-100
123
143
(CH3)3C
Ph
69.7
^Identity of the aldehyde N-acylhydrazone (reactant). ^identity of the authentic 2R-5-R'-1,3,4-oxadiazole (product). cOxadiazole 139 was synthesized from both
hydrazones 117 and 118
Table 4. List of the Authenfic 2-R-5-R'-1,3,4-Oxadiazoles (Synthesized
According to the Scheme Shown Below).
N—N
O
0
POCI3/A
h
A
R-H-NH—NH—C-R
"
R ^ O ^ R '
1,2-Diacylhydrazone
or H3PO4/A
O
Oxadiazole
Oxadiazole^
R
R
Reagent
%Yield
m. p. (OC)
128-129
140
Ph-CH=CH
Ph
POCI3
96.8
141b
CH3-CH=CH
Ph
H3PO4
93.3
144
4-(CH3)2N-Ph
Ph
POCI3
96.8
143-144
aidentity of the authenfic 2-R-5-R'-1,3,4-oxadiazole. bQummy liquid. See
experimental section.
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Thianthrene Cation Radical with Aldehyde N-Acylhydrazones.
O
2Th4-
R—CH=N—NH—C—R
(A)
CH2CI2
A3
R
R'
Bb
Yield (%)
96
Ph
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70.6
97
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98
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99
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100
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101
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103
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104
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78.9
105
2-MeO-Ph
2-MeO-Ph
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77.0
106
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90.2
107
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132
61.5
108
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4-MeO-Ph
133
83.2
109
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134
76.6
115
Table 7 (Continued)
Aa
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110
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89.9
111
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4-Me-Ph
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112
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78.9
113
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78.9
114
4-CI-Ph
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137
7.18
115
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60.6
116
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117
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66.0
118
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2.20
119
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97.5
120
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96.4
121
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122
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9.80
123
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124
4-Me2N-Ph
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Bb
Yield (%)
^identity of the aldehyde N-acylhydrazone. ^identity of the 2-R-5-R'-1,3,4oxadiazole.
116
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118
CHAPTER IV
CONCLUSIONS
Reactions of thianthrene cation radical perchlorate with aldehyde
semicarbazones caused their oxidative, intramolecular cyclization into the
corresponding oxadiazoles as the major products, along with trace amounts of
triazolinones. The reactions were found to be slow and gave moderate yields of
the oxadiazoles. However, addition of a small amount of water or poorly
nucleophilic base 2,6-di-tert-butyl-4-methylpyridine (DTBMP) to the reaction
mixture enhanced the reactions and increased the yields of the oxadiazoles. The
oxadiazole isolated from the reaction of benzaldehyde C^oisemicarbazone with
thianthrene cation radical in the presence of added Hj^^O did not show any ^^O
enrichment in the product oxadiazole. On the other hand, the oxadiazole isolated
from the reaction of benzaldehyde C^oisemicarbazone with thianthrene cation
radical in the presence of added H2''®0 showed '^^O enrichment of the product
oxadiazole. These results indicate that hydrated nitriiiminium ion is not involved
in the oxadiazole formation and the roles of water and DTBMP appear to be that
of bases.
Reactions of thianthrene cation radical perchlorate with aldehyde Nacy I hydrazones in acetonitrile and dicloromethane led to the formation of 1,3,4oxadiazoles as major products. The oxadiazoles were formed by the cation
radical Induced oxidative intramolecular cyclization of the hydrazones. The
cyclization process appears to be a multi-step process. Any factor that stabilized
the initially formed hydrazone cation radical accelerated the oxidation of the
hydrazone. In these cases the total yields of the oxadiazole and the aldehyde
were always very high and very small amounts of hydrazones were recovered
unreacted. Any factor that Increased the nudeophilidty of the carbonyl oxygen
Increased the relative yields of the oxadiazoles. A good yield of the oxadiazole
119
was dependent on the combined effect of the ready oxidizability of the
hydrazone molecule and higher nudeophilidty of the carbonyl oxygen.
Aldehydes were obtained in higher yields for the cases where the hydrazone
cation radical was not stabilized.
Among comparisons of results from "switched" pairs of groups, i.e.,
RCH=NNHC0Ph and PhCH=NNHCOR, it appeared frequently that the better
yield of the oxadiazole was obtained from the N-benzoylhydrazone,
RCH=NNHCOPh. These reactions provide an alternative method for the
preparation of 1,3,4-oxadiazoles in moderate to very good yields.
120
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