Ligand-free Cu(ii)-mediated aerobic oxidations of aldehyde hydrazones leading to N,N′-diacylhydrazines and 1,3,4-oxadiazoles

Article abstract of DOI:10.1039/c7ob00042a

A Cu(ii)-mediated synthesis of N,N′-diacylhydrazines and 1,3,4-oxadiazoles from aldehyde hydrazones has been developed. This is the first time that the synthesis of N,N′-diacylhydrazines and 1,3,4-oxadiazoles using N,N-dimethylamides as the acylation reagent and O₂ in air as the oxidation reagent is reported. These reactions offered several advantages including simple workups, ligand-free inexpensive metal salts as mediators, high yields, and wide scope of substrates.

Full text of DOI:10.1039/c7ob00042a

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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ARTICLE
Ligand-free Cu(II)-mediated aerobic oxidations of aldehyde
hydrazones leading to N,N’-diacylhydrazines and 1,3,4-
oxadiazoles†
Received 00th January 20xx,
Accepted 00th January 20xx
Lei Liu*a and Suliu Fenga
DOI: 10.1039/x0xx00000x
A Cu(II)-mediated synthesis of N,N’-diacylhydrazines and 1,3,4-oxadiazoles from aldehyde hydrazones has been developed.
This is the first time in the synthesis of N,N’-diacylhydrazines and 1,3,4-oxadiazoles using N,N-dimethylamides as the
acylation reagent and O2 in air atmosphere as the oxidation reagent. These reactions offered several advantages including
simple workups, ligand-free inexpensive metal salt as a mediator, high yields and wide scope of substrates.
www.rsc.org/
These compounds could be synthesized through the acylation
of N-acylhydrazines with anhydrides (Scheme 1, path c).28
Photocatalyzed reaction of 2,5-disubstituted-2H-tetrazole is
Introduction
The N,N’-diacylhydrazines comprise an important structure
class as they find applications in the fields of pesticide
chemistry and pharmaceutical chemistry as shown in Fig. 1.
After discovered as ecdysone agonists by Wing et al, N,N’-
diacylhydrazines have become a class of novel insect growth
regulators and some of them have been commercialized.1,2
Working as nonsteroidal ecdysone agonists inducing
precocious molting and leading to death, they have several
advantages such as simple structure, unique action mechanism,
high insecticidal selectivity and low toxicity.3-7 And N,N’-
diacylhydrazines exhibit various bioactivities including
antitumor, antidiabetic, anti-inflammation, and anti-infection
properties and so on.8-14 They are also key intermediates for
the construction of 2,4-disubstituted-1,3,4-oxadiazoline-5-
ones and -thiones,15 1H-pyrazol-3(2H)-ones,16 thiazolo[2,3-
c][1,2,4]triazoles,17 and 4H-1,3,4-benzoxadiazines.18 Besides,
they have been used as electroluminescent analytical
reagents,19,20 selective recognition materials21 and liquid
crystal materials.22,23 All these broad application makes N,N’-
diacylhydrazines and the derivatives attractive for decades.
Due to myriad of applications of the N,N’-diacylhydrazines,
several methods are described in the literature as shown in
Scheme 1. These skeletons are synthesized by the nucleophilic
substitution of hydrazonoyl bromides toward various
nucleophiles acid radical ions (Scheme 1, path a).24 An
alternative route is via reactions of aldehyde hydrazones with
Pb(OAc)4,25 Tl(OAc)226 or PhI(OAc)227 (Scheme 1, path b, R3=Ac).
another method (Scheme 1, path d).29,30 Yet, many
disadvantages are associated with these methods which bind
them to a limited synthetic scope. In path a, the hydrazonoyl
bromides are obtained via reactions of aldehyde hydrazones
with Br2, and this method leads in some cases to hydrolysis
products or intramolecular nucleophilic substitution products.
In path b, the group R3 is limited acetyl group. In path c, when
group R3 becomes big, the reaction yield decreases sharply.
Herein we report direct access to the synthesis of N,N’-
diacylhydrazines via the reaction of aldehyde hydrazones with
N,N-dimethylamides mediated by CuBr2 in air atmosphere
(Scheme 1, path e). The yields are high and the reaction scope
is wide (R1, R2= alkyl or aryl; R3=H, alkyl or aryl).
Fig. 1 Representative examples of bioactive compounds possessing the N,N’-
diacylhydrazine skeleton.
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DOI: 10.1039/C7OB00042A
Scheme 2 Various methods for preparation of 1,3,4-oxadiazoles.
Scheme 1 Various strategies for preparation of N,N’-diacylhydrazines.
Results and Discussion
Table 1 Optimization of the reaction conditions using 1a as the examplea
Another type of products aimed in this research are five-
membered aromatic heterocycles 1,3,4-oxadiazoles, which
have been widely used in materials science, especially in
organic light emitting diodes (OLEDs), and medicinal
chemistry.31-36 1,3,4-Oxadiazoles display various biological
activities such as anticancer, antimicrobial, analgesic and so
on.37-44 Various methods have been reported, including direct
reaction of carboxylic acids or acyl chlorides with
acylhydrazines (Scheme 2, path a),45-47 electrophilic
substitution of 2-substituted-5-trimethylsilyl-1,3,4-oxadiazoles
(Scheme 2, path b),48 C–H alkylation of 2-substituted 1,3,4-
oxadiazoles with halohydrocarbons (Scheme 2, path c),49-53 the
oxidative cyclization of N-acylhydrazones (Scheme 2, path d),54-
59 the dehydrative cyclization of N,N’-diacylhydrazines (Scheme
2, path e)60-64 or reaction of orthoesters with acylhydrazines
(Scheme 2, path f).65,66 In the above methods a lot of expensive
and hazardous materials such as Pd(OAc)2,49 t-BuOLi,50
hypervalent iodines,54,55 chloramine T,56 tetravalent lead
reagents,57 sulfuric acid,60 PPA,61 or phosphorus oxychloride62
have been used. And the precursors 2-substituted 1,3,4-
oxadiazole or 2-substituted-5-trimethylsilyl-1,3,4-oxadiazole
are difficult to prepare. In addition, Patel’s group58 has
developed a method that 2,5-disubstituted 1,3,4-oxadiazoles
were synthesized via the imine C–H bond functionalisation of
N-arylidenearoylhydrazides or aroylhydrazone catalyzed by
Cu(OTf)2. In this method all the two counterparts should be
aromatic (R4, R5 = aryl), it is not successful in the preparation of
alkyl-substituted 1,3,4-oxadiazoles. So far rare methods have
been reported which is suitable for both the synthesis of 2-
substituted 1,3,4-oxadiazoles and 2,5-disubstituted 1,3,4-
oxadiazoles no matter the counterparts are aromatic or not.
We have achieved this goal via the reaction of N-tert-butyl
aldehyde hydrazones with N,N-dimethylamides mediated by
CuBr2 in air atmosphere (Scheme 2, path g). The method
tolerates a series of groups (R4 = alkyl or aryl; R5 = H, alkyl or
aryl) and has a simple workup, which is superior to the current
methods.
Metal Salt
(equiv)
DMF
(mL)
15
15
15
15
15
15
15
15
15
15
15
10
5
Entry T (oC)
t
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
100
100
100
100
100
100
80
160
160
160
160
160
160
FeCl3 (1.0)
ZnCl2 (1.0)
Cu(OAc)2 (1.0)
Cu(acac)2 (0.2)
CuCl2 (1.0)
CuBr2 (1.0)
CuBr2 (1.0)
CuBr2 (1.0)
CuBr2 (0.5)
CuBr2 (2.0)
CuBr2 (2.5)
CuBr2 (2.0)
CuBr2 (2.0)
1.0 h
1.0 h
1.0 h
1.0 h
1.0 h
NRc
NRc
NRc
NRc
32
49
43
75
33
95
92
95
81
1.0 h
1.0 h
0.50 h
0.67 h
5 min
5 min
5 min
10 min
aReaction conditions: (E)-1-benzylidene-2-phenylhydrazine (1, 1.5 mmol, 294
mg), DMF, metal salt in air atmosphere. bAll yields were isolated yields. NR:
c
No reaction.
At the beginning of our study, we chose (E)-1-
benzylidene-2-phenylhydrazine (
substrates to optimize the reaction conditions (Table 1).
Initially, a mixture of (E)-1-benzylidene-2-phenylhydrazine (
1) and DMF as the model
1
,
1.5 mmol, 294 mg) and DMF (15mL) was stirred at 100 °C in air
atmosphere and treated with a series of metal salts for 1.0 h.
No reaction took place with FeCl3 (Table 1, entry 1), ZnCl2
(Table 1, entry 2), Cu(OAc)2 (Table 1, entry 3), or Cu(acac)2
(Table 1, entry 4). Product 1a was obtained in 32% yield with
1.0 equiv of CuCl2 (Table 1, entry 5), 49% yield with 1.0 equiv
of CuBr2 (Table 1, entry 6). So CuBr2 was chosen. Then the
reaction temperature was investigated. At 80 °C, the yield of
1a was decreased to 43% (Table 1, entry 7). At the boiling
point (160 °C), the yield of 1a was increased to 75% and the
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reaction times decreased from 1.0 h to 0.5 h (Table 1, entry 8). higher the yield (Scheme 3, 1b vs 1c vs 1d
ARTICLE
,
1e vsVi1ewf)A.rAticnledOntlhinee
The reaction yield was the highest with 2.0 equiv of CuBr2 and yield was higher in the cases where theDeOlIe:c1t0r.1o0n3-9w/Cit7hOdBr0a0w04in2Ag
the reaction time decreased to 5 min (Table 1, entry 10). The group occupies o-position than that occupies m-position or p-
volume of DMF was also important for this reaction. The yields position (Scheme 3, 1c vs 1e vs 1h). The yield of 1g was 84%,
were the same with 15 mL or 10 mL DMF (Table 1, entries 10 the possible reason is the big steric hindrance with di-Cl in 2,6-
and 12). However, with 5 mL DMF, the yield was decreased to positions. Similarly substrates possessing electron-donating
81% (Table 1, entry 13). Based on these results, the optimized groups such as -Me, -OMe, tri-OMe also gave products in good
conditions are: (E)-1-benzylidene-2-phenylhydrazine (
1, 1.5 yields of 59% to 76% (Scheme 3, 1i-1m). Substrates originating
mmol), DMF (10 mL) and CuBr2 (2.0 equiv) at 160 °C in air from 1-naphthaldehyde and furfuraldehyde gave relatively low
atmosphere (Table 1, entry 12).
yields of the products 1n and 1o. Hydrazones derived from
aliphatic aldehydes gave N,N’-diacylhydrazines in excellent
yields which were higher than those derived from aromatic
Scheme
3 Formation of N,N’-diacylhydrazines via the reaction of N-
phenylhydrazones with DMFa
aldehydes (Scheme 3, 1p-1t).
Scheme 4 Formation of N,N’-diacylhydrazines via the reaction of hydrazones
derived from benzaldehyde with DMFa
aReaction conditions: substrate (1.5 mmol), DMF (10 mL) and CuBr2 (2.0
equiv) at 160 °C in air atmosphere. All yields were isolated yields.
Further application of the optimized conditions to
substrates derived from benzaldehyde and different
hydrazines also resulted in the desired N,N’-diacylhydrazines
(Scheme 4, 2a-
2k). Notably, when R2 adopted aryl groups,
these hydrazones could afford the corresponding N,N’-
diacylhydrazines in good yields of 74% to 91% (Scheme 4,
aReaction conditions: N-phenylhydrazone (1.5 mmol), DMF (10 mL) and
CuBr2 (2.0 equiv) at 160 °C in air atmosphere. All yields were isolated yields.
2a−2h). The similar phenomenon was observed here that
substrates bearing electron-withdrawing substrates gave
better yields compared with those bearing electron-donating
Under the optimized reaction conditions, we sought to groups. And when R2 adopted alkyl groups, the desired
examine the scope and generality of the method. Initially we products were obtained in slightly low yields (Scheme 4, 2i
extended substrates derived from a series of aldehydes and
Next, the scope of N,N-dimethylamides was studied using
phenylhydrazine. As shown in Scheme 3, this method is (E)-1-benzylidene-2-phenylhydrazine. As shown in Scheme 5,
compatible with variety of electron-donating and
the scope of N,N-dimethylamides ranged from aliphatic amide
-2k).
a
-
withdrawing groups. Hydrazones derived from aromatic to aromatic amides with electron-withdrawing or -donating
aldehydes possessing electron-withdrawing groups such as -F, groups and the yields ranged from 43% to 86% which were
-Cl, -Br, di-Cl gave N,N’-diacylhydrazines in excellent yields of lower than those using DMF as the acylation reagent. The
78% to 97% (Scheme 3, 1b
-1h). The stronger the electronic reason was that in the former reactions DMF was used not
withdrawing ability of the group on the aromatic ring, the only as acylation reagent but also as solvent. Herein the
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amides were used only as acylation reagent in 5.0 equivalent.
Journal Name
In the continuing expansion of the scope of VtiheweArreticalecOtinolinne,
DOI: 10.1039/C7OB00042A
Also we can see that substrates bearing electron-withdrawing using 1-benzylidene-2-tert-butylhydrazine and DMF as
groups gave better yields compared with those bearing substrates, the product was not N'-tert-butyl-N'-
electron-donating groups (Scheme 5, 3c vs 3b vs 3f vs 3h vs 3g). formylbenzohydrazide but 2-phenyl-1,3,4-oxadiazole. Then we
took N,N-dimethylbenzamide as the amide, 2,5-diphenyl-1,3,4-
Scheme 5 Formation of N,N’-diacylhydrazines via the reaction of compound
oxadiazole was obtained. Then we optimized the reaction
1 with various N,N-dimethylamidesa
conditions as shown in Table 2. First, a mixture of 1-
benzylidene-2-tert-butylhydrazine (
4, 1.5mmol, 264 mg) and
N,N-dimethylbenzamide ( , 1.0 equiv) was stirred at the
5
boiling point of chlorobenzene in air atmosphere and treated
with a series of metal salts. No reaction took place with CuCl
(Table 2, entry 1), Cu(OAc)2 (Table 2, entry 2), Cu(acac)2 (Table
2, entry 3). Product 6a was obtained in 32% yield with 1.0
equiv of CuCl2 (Table 2, entry 4), 12% yield with 1.0 equiv of
Cu(NO3)2 (Table 2, entry 5) and 37% yield with 1.0 equiv of
CuBr2 (Table 2, entry 6). Then the solvents were investigated.
Product 6a was obtained in 52% yield in o-xylene (Table 2,
entry 7) and 31% yield in 1,4-dioxane (Table 2, entry 11). And
No reaction took place in ethanol (Table 2, entry 8),
acetonitrile (Table 2, entry 9) or DMSO (Table 2, entry 10). So
o-xylene was chosen as the solvent. Then changing the amount
of CuBr2, the reaction yield was the highest with 1.0 equiv of
CuBr2 (Table 2, entry 7). The best yield was found to be with
5.0 equiv of
optimized
butylhydrazine (
(
5
(Table 2, entry 15). Based on these results, the
conditions were: 1-benzylidene-2-tert-
, 1.5 mmol, 264 mg), N,N-dimethylbenzamide
5, 5.0 equiv) and CuBr2 (1.0 equiv) in o-xylene refluxing in air
4
aReaction conditions: (E)-1-benzylidene-2-phenylhydrazine (1.5 mmol, 294
mg), N,N-dimethylamide (5.0 equiv), and CuBr2 (2.0 equiv) at 160 °C in o-
xylene in air atmosphere. All yields were isolated yields. bN,N-
dimethylacetamide (10 mL) acted as the acylation reagent and the solvent.
atmosphere (Table 2, entry 15).
Scheme 6 Formation of 1,3,4-oxadiazoles via the reaction of various N-tert-
butylhydrazones with N,N-dimethylamidesa
Table 2 Screening the reaction conditions using 6a as the examplea
5
(equiv)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
5.0
Metal Salt
(equiv)
CuCl (1.0)
Yieldb
(%)
NRc
NRc
NRc
32
Entry
Solvent
t (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Chlorobenzene
Chlorobenzene
2.0
2.0
2.0
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.0
1.0
0.75
0.5
Cu(OAc)2 (1.0)
Cu(acac)2 (0.2) Chlorobenzene
CuCl2 (1.0) Chlorobenzene
Cu(NO3)2 (1.0) Chlorobenzene
12
37
52
CuBr2 (1.0)
CuBr2 (1.0)
CuBr2 (1.0)
CuBr2 (1.0)
CuBr2 (1.0)
CuBr2 (1.0)
CuBr2 (0.5)
CuBr2 (1.5)
CuBr2 (1.0)
CuBr2 (1.0)
CuBr2 (1.0)
Chlorobenzene
o-Xylene
Ethanol
Acetonitrile
DMSO
1,4-Dioxane
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
NRc
NRc
NRc
31
26
50
73
85
10.0
62
aReaction conditions: N-tert-butylhydrazone (1.5 mmol), N,N-dimethylamide
(5.0 equiv), CuBr2 (1.0 equiv) at 150 °C in o-xylene in air atmosphere. All
yields were isolated yields. In the products: R4 on the left, R5 on the right.
bDMF was used as the solvent. cN,N-dimethylacetamide (DMA) was used as
the solvent.
aReaction conditions: 1-benzylidene-2-tert-butylhydrazine (4, 264 mg), N,N-
dimethylbenzamide (5), metal salt in air atmosphere at the boiling point of
the solvent. bAll yields were isolated yields. cNR: No reaction.
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Under the optimized conditions, various N,N- acylhydrazines as the reaction intermediates Vi(eSwcAhrteicmle eOnlin7e,
DOI: 10.1039/C7OB00042A
dimethylamides and N-tert-butylhydrazones derived from reaction (7)).
various aldehydes were subjected to the present reaction
Scheme 7 Mechanism studies for the synthesis of N,N’-diacylhydrazines a
conditions and the results are summarized in Scheme 6. When
N,N-dimethylbenzamide was used, N-tert-butylhydrazones
derived from aromatic aldehydes gave yields of 66% to 85%
(Scheme 6, 6a-6d). And substrates possessing stronger
electron withdrawing groups gave lower yields (Scheme 6, 6b
vs 6c). This was true when N,N-dimethyl-4-methylbenzamide
acted as the amide (Scheme 6, 6f vs 6g). And N-tert-butyl-N’-
cyclohexylmethylenehydrazine gave product 6e in a good yield
of 74% declaring this method is suitable for the synthesis of
alkyl-substituted 1,3,4-oxadiazoles (Scheme 6, 6e). Similarly,
the amides could be aromatic or alkylic and good yields of 67%
to 91% were obtained (Scheme 6, 6i-6m). And substrates
possessing stronger electron-donating groups gave higher
yields of the products (Scheme 6, 6i vs 6j vs 6c’ vs 6k). 2-
Phenyl-1,3,4-oxadiazole was obtained when DMF was used as
the amide declaring through this method 2-substituted 1,3,4-
oxadiazoles could be synthesized (Scheme 6, 6l). It is
interesting to mention that both 1-tert-butyl-2-(4-
chlorobenzylidene)hydrazine with N,N-dimethylbenzamide
and 1-benzylidene-2-tert-butylhydrazine with 4-chloro-N,N-
dimethylbenzamide gave 2-(4-chlorophenyl)-5-phenyl-1,3,4-
oxadiazole (6c and 6c’). The yield was superior by the former
approach. Compared to the methods in literature, our method
has offered a wider range of substrates. No matter the
counterparts were aromatic or not, it was not only suitable for
the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles but also
suitable for the synthesis of 2-substituted 1,3,4-oxadiazoles.
In order to gain insight into the mechanism in the
synthesis of N,N’-diacylhydrazines, several control experiments
were carried out (Scheme 7). The synthesis of 1a was operated
under N2 atmosphere or O2 atmosphere, the results that no
desired product was obtained under N2 atmosphere and a very
high yield was obtained under O2 atmosphere verified the
important of O2 (Scheme 7, reactions (1) and (2)). To further
confirm the source of oxygen atom 1, 5.0 equiv of H2O were
added to the reaction mixture, but no reaction occurred
(Scheme 7, reaction (3)). These experiments indicated that
oxygen atom 1 maybe come from O2 in air atmosphere.
aReaction conditions: DMA = N,N-dimethylacetamide.
Scheme
8 The probable mechanism for the synthesis of N,N-
diacylhydrazines
Subsequently, radical-trapping experiment was carried
out (Scheme 7, reaction (4)). The addition of TEMPO lowered
the reaction yield but did not stop it. The possible reason is
that the reaction is an intramolecular free radical reaction,
where intermolecular reaction with TEMPO does not dominate.
In order to confirm the reaction intermediates another three
reactions were carried out (Scheme 7, reactions (5)-(7)).
Without copper salts, no reaction occurred between (E)-1-
benzylidene-2-phenylhydrazine
reaction (5)). And under standard conditions, no reaction
occurred using (E)-N'-benzylidene-N-phenylacetohydrazide (
(1) and DMF (Scheme 7,
7)
as the substrate (Scheme 7, reaction (6)). These two reactions
indicated that N-acylhydrazones were not the reaction
intermediates. Then using N'-phenylbenzohydrazide (8) as the
substrate, no desired product was obtained, excluding N-
Based on these control experiments and the literature
reports,24-27,67-69 the probable reaction pathway is put forward
shown in Scheme 8. Firstly, hydrazone Ia coordinated with
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CuBr2 generating IIa which reacts with O2 producing free which is further aromatized to give the desired VpierwoAdruticcletOVnlIibne
.
radical intermediate IIIa; Through intramolecular addition to And Cu0 is oxidized by O2 giving CuII.
C=N bond, intermediate IIIa was transferred into IVa, then the
DOI: 10.1039/C7OB00042A
Scheme 10 The probable mechanism for the synthesis of 1,3,4-oxadiazoles
cleavage of O-O bond produced intermediate Va; Alkoxide Va
reacts with N,N-dimethylamide generating intermediate VIa
and releasing dimethylamide; Through tautomerization VIa is
transferred to VIIa and through intramolecular rearrangement
the desired product VIIIa is obtained. And a further detailed
mechanistic study is underway.
Similarly, to explore the mechanism in the synthesis of
1,3,4-oxadiazoles, several control experiments were carried
out (Scheme 9). We conducted the synthesis of 6a under N2
atmosphere or O2 atmosphere, both of them gave 6a in
different yields 68% and 83% indicating that O2 could only
influence the reaction yields but it is not the source of oxygen
atom
dimethylbenzamide (
(E)-N'-benzylidenebenzohydrazide (
2
and oxygen atom
) (Scheme 9, reactions (1) and (2)). Using
) as the substrate, a 22%
2 maybe come from N,N-
5
9
yield was obtain in o-xylene and a 47% yield was obtained in
DMF (Scheme 9, reactions (3) and (4)). Similarly, using (E)-N'-
benzylideneacetohydrazide (10) as the substrate, a 53% yield
was obtain in N,N-dimethylacetamide (Scheme 9, reaction (5)).
These reactions suggest that N-acylhydrazones are the
reaction intermediates.
Conclusions
In conclusion, we have for the first time developed a Cu(II)-
mediated method for the synthesis of N,N’-diacylhydrazines
and 1,3,4-oxadiazoles from hydrazones oxidized by O2 in air
atmosphere with N,N-dimethylamides as the acylation reagent.
In comparison to all methods documented in the literature,
this method offered several advantages including green
oxidization by O2 in air atmosphere, inexpensive metal salt as a
mediator under ligand-free conditions, simple workups, high
yields and wide scope of substrates.
Scheme 9 Mechanism studies for the synthesis of 1,3,4-oxadiazolesa
Experimental
General Experimental Information
All of the chemicals were obtained from commercial sources
or prepared according to standard methods. NMR spectra
1
were recorded with a 400 MHz spectrometer for H NMR, a
101 MHz spectrometer for 13C NMR. TMS was used as an
internal standard. Chemical shifts () were reported relative to
TMS (1H) or CDCl3 (13C). Multiplicities were reported as follows:
singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), dd
(doublet of doublets) and dt (doublet of triplets). Coupling
constants were reported in Hertz (Hz). Melting points were
recorded with a micro melting point apparatus. High resolution
mass spectra (HRMS) were recorded on a QTOF mass analyzer
with electrospray ionization (ESI).
General procedure using the preparation of N’-formyl-N’-
phenylbenzohydrazide (1a) as the example
aReaction conditions: DMA = N,N-dimethylacetamide.
(E)-1-Benzylidene-2-phenylhydrazine (1.5 mmol, 294 mg),
CuBr2 (2.0 equiv, 670mg) and N,N-dimethylformamide (10 mL)
were added to a 100 mL round-bottom flask. After the mixture
Based on these control experiments and the literature
reports,58,59 the probable reaction pathway is proposed shown
in Scheme 10. Firstly, N-t-butylhydrazone (Ib) mediated by
CuBr2 releases t-butyl cation and decomposes into anion IIb
which reacts with N,N-dimethylamide generating N-
o
was reflexed at 160 C in air atmosphere for 5 min and TLC
indicated the completion of the reaction. The DMF was then
distilled off. The residue was dissolved in ethyl acetate (20 mL)
and the insoluble residue was filtered. Then the filtrate was
acylhydrazone IIIb. Mediated by CuBr2, IIIb cyclizes to form Vb
,
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12 P. T. Witkowski, L. Schuenadel, J. Wiethaus, D. R. Bourquain,
washed with water (2 x 5 mL), and dried over Na2SO4. The
ethyl acetate was then evaporated and the product was
purified by column chromatography on silica gel (petroleum
ether/ethyl acetate=5:1) to give 1a (342 mg, 95%).
General procedure using the preparation of N’-benzoyl-N’-
phenylbenzohydrazide (3b) as the example
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o
845.
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