Synthesis and fluorescent behaviour of 2-aryl-4,5-dihydro-1H-1,2,4-triazoles

Article abstract of DOI:10.1021/acs.joc.6b02144

A series of new 4,5-dihydro-1H-1,2,4-triazoles was synthesized from amidrazones and acetylenedicarboxylic acid esters in the presence of pyridine in toluene. The synthesized compounds were characterized by 1H, 13C NMR, FT-IR spectral analyses and XRD data

Full text of DOI:10.1021/acs.joc.6b02144

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Article
Synthesis and Fluorescent Behaviour of 2-#ryl-4,5-Dihydro-1H-1,2,4-triazoles
Alexandra I. Eliseeva, Olga O. Nesterenko, Pavel A. Slepukhin, Enrico Benassi, and Nataliya P. Belskaya
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02144 • Publication Date (Web): 30 Nov 2016
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Synthesis and Fluorescent Behaviour of 2ꢀАrylꢀ4,5ꢀDihydroꢀ1Hꢀ
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1,2,4ꢀtriazoles
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Alexandra I. Eliseeva †, Olga O. Nesterenko †, Pavel A. Slepukhin ‡, Enrico Benassi §, *, Nataliya
P. Belskaya †, *
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†Ural Federal University, 19 Mira Street, Yekaterinburg 620002, Russia
‡I. Ya. Postovsky Institute of Organic Synthesis, 20 S. Kovalevskaya Street, Yekaterinburg
620219, Russia
§Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126 Pisa, Italy
*Eꢀmail: n.p.belskaya@urfu.ru
*Eꢀmail: enrico.benassi@sns.it
ABSTRACT
A series of new 4,5ꢀdihydroꢀ1Hꢀ1,2,4ꢀtriazoles was synthesized from amidrazones and
acetylenedicarboxylic acid esters in the presence of pyridine in toluene. The synthesized
compounds were characterized by 1H, 13C NMR, FTꢀIR spectral analyses and XRD data. Optical
studies revealed that most of the compounds reported here exhibited emission of blue or greenꢀ
yellow light upon irradiation in acetone and showed Stokes shifts in the region of 70ꢀ96 nm and
quantum yields of up to 45%. The interpretation of the experimental findings was supported by
stateꢀofꢀtheꢀart quantum mechanical calculations.
Keywords: 4,5ꢀDihydroꢀ1Hꢀ1,2,4ꢀtriazole, Amidrazone, Dimethyl acetylenedicarboxylate,
Stokes shift, Quantum yield, Fluorescence, TimeꢀDependent Density Functional Theory,
Polarizable Continuum Model
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INTRODUCTION
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1,2,4ꢀTriazole and its derivatives, an amide cisꢀbond isostere, can be used for both peptide
mimicry and drug design, where they can improve the pharmacological properties of the
corresponding lead compound.1 Type I 1,2,4ꢀtriazoles (Scheme 1) have also been extensively
studied as ligands for mononuclear and oligonuclear metal coordination, exhibiting interesting
physical and chemical properties.2 Nonꢀaromatic 1,2,4ꢀtriazoline (II, III) and –triazolidine (IV)
are lesser known and are relatively unstable.3 The most widely spread dihydroꢀ and
tetrahydrotriazoles usually include C=X exocyclic double bonds in their structures.3 Triazolines
and triazolidines, like their aromatic analogues, are readily hydrolysed in acidic media. 4,5ꢀ
Dihydroꢀ1Hꢀ1,2,4ꢀtriazoles II, III are famous for their ability to form stable carbenes, which are
applied as ligands and in organic catalysis.4
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Scheme 1. Known types of 1,2,4ꢀtriazoles, ꢀtriazolines and ꢀtriazolidines
The main method for the synthesis of 4,5ꢀdihydrotriazoles II is the 1,3ꢀdipolar cycloaddition
of nitrilimines to dipolarophiles bearing C=N bonds.5 However, this approach is unable to
provide a variety of substituents in the resulting triazoles because it is limited by the availability
of nitrilimines and appropriate reactive dipolarophiles. P. Frohberg and coauthors in their search
for new inhibitors of lypoxygenases, enzymes that are potent mediators of inflammatory and
allergic reactions in human, described the synthesis of 5,5ꢀdialkylꢀ4,5ꢀdihydrotriazoles II (R1 =
Ar, R2 = COMe, R3 = Alkyl, R4, R5 = Me) by cyclization of amidrazones with ketones.6 The
main disadvantage of these reactions was their limitation of the number of carbonyl compounds
(only acetone and methylethylketone) that can be used for this reaction. It worth noting that this
reaction proceeded only by refluxing amidrazone at a large excess of liquid ketone
.
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In this paper, we describe a new method for the synthesis of 4,5ꢀdihydrotriazoles II by the
cyclization of amidrazones with dimethylꢀ and diethylacetylene dicarboxylate (DMAD and
DEAD) and show the results of their photophysical properties.
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RESULTS AND DISCUSSION
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Synthesis and Characterization. Arylhydrazones with an amino functional group at the carbon
atom of the hydrazone group (usually referred to in the literature as ‘amidrazone’) were obtained
according to the procedure of nucleophilic substitution of the halogen atom of hydrazonoyl
сhlorides with amines.7 Access to hydrazonoyl chlorides could be realized via the Japp–
Klingemann reaction.8 Chlorinated dicarbonyl compounds, such as 3ꢀchloropentaneꢀ2,4ꢀdione 1a
or ethyl 2ꢀchloroꢀ3ꢀoxobutanoate 1b, were coupled with diazotized anilines 2aꢀg with
concomitant release of acetic acid (Scheme 2). Alkylꢀ, arylꢀ or hetarylaminocompounds 4aꢀh,
acting as nitrogen nucleophiles, were added readily to nitrile imines (the reactive species were
generated in situ from their corresponding hydrazonoyl chloride precursors 3aꢀh in the presence
of triethylamine) to give the respective amidrazone adducts 5aꢀr. This mode of nucleophilic
addition to 1,3ꢀdipoles has been well documented9 for various nucleophiles, and several adducts
related to 5 were obtained from the reaction of amines with hydrazonoyl chlorides.
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Scheme 2. Synthesis of amidrazones 5
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COR1
N
NHR2
COR1
Cl
COR1
Cl
NH2R2
ArN
2a-g
4a-h
2 Cl
H
H
N
N
Ar
Ar
N
MeOC
Dioxane
25 or 60 C
EtOH, H2O, NaOAc
5a-r
51-92%
3a-h
1a-b
90-95%
1
1
2
a
b
R = Me ( ), CO2Et ( )
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a
b
c
d
e
f
g
Ar = 4-MeC6H4 ( ), Ph ( ), 4-CNC6H4 ( ), (3,5-CF3)2C6H3 ( ), 2-ClC6H4 ( ), 2-CF3C6H4 ( ), 2-FC6H4 ( )
3 R1 = Me, Ar = 4-MeC6H4 (a); Ph (b); 4-CNC6H4 (c); 3,5-(CF3)2C6H3 (d); 2-ClC6H4 (e); 2-CF3C6H4 (f);
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2-FC6H4 ( ); R = OEt, Ar = 4-CNC6H4 ( )
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R = Me ( ), n-Bu( ), CH2CH2OMe ( ), cyclo-C6H11 ( ), Bn ( ), Ph ( ), 9-ethylcarbazole ( ),
h
C6H4-NH-Ph ( )
R1
R2
Ar
R1
Me
Me
Me
Me
Me
Me
Me
Me
R2
Ar
5
5
j
a
b
c
d
e
f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-MeC6H4
Ph
Ph
4-MeC6H4
4-CNC6H4
4-CNC6H4
4-CNC6H4
4-CNC6H4
4-CNC6H4
k
Ph
l
4-FC6H4
4-ClC6H4
4-CNC6H4
3,5-(CF3)2C6H3
2-FC6H4
2-ClC6H4
2-CF3C6H4
n-Bu
m
n
o
p
q
r
CH2CH2OMe
Bn
cyclo-C6H11
g
h
i
9-ethylcarbazole 4-CNC6H4
C6H4-NHPh
4-CNC6H4
4-CNC6H4
CO2Et Me
The newly synthesized compounds 5aꢀr were characterized by elemental analyses, MS and
NMR. These data, detailed in the Experimental part, are consistent with the suggested structures.
It should be mentioned that compounds 5i,r were isolated as a mixture of Zꢀ and Eꢀisomers. The
appearance of the additional isomer for the compounds 5i and r may be explained due to the
weakness of the Hꢀbond, which is the driving force for the stabilization of the one isomer
(usually Zꢀisomer). Spatial hindrance for compound 5i caused by the substituent in oꢀposition of
the aromatic ring (CF3) and lower acceptor property of the ester oxygen (COOEt) in comparison
with the Oꢀatom of the acyl group for compound 5r explain the presence of weakened hydrogen
bonds in these molecules. This phenomenon are wellꢀknown for the different types of
hydrazones, including amidrazones.7,9f
Reactions of binucleophiles with acetylene carboxylic acid (ACA) derivatives represent an
interesting field of heterocyclic chemistry both in the theoretical aspects and in the practical
applications of the obtained heterocyclic products.10 Reactions of ACA derivatives with
compounds bearing two or more nitrogenꢀcontaining nucleophilic centres have been employed as
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a route for generating a wide variety of heterocyclic compounds.9f,10ꢀ11 There is only one report
on the reaction of amidrazones with the latter reagents.11f For instance, the reaction between Nꢀ
acyl amidrazones 6 and DEAD leads to the formation of either 2Hꢀpyrrole or oxopyridine
depending on the reaction conditions and substitution pattern of amidrazone, thus giving either
2Hꢀpyrrolꢀ2ꢀones 7 or pyridinꢀ2ꢀones 8 (Scheme 3).
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Scheme 3. Reaction of amidrazones with DEAD
The amidrazones 5aꢀr are polyfunctionalized reagents bearing two nucleophilic and one
electrophilic centres. Thus, we can expect the formation of several heterocyclic compounds with
different types of azacyclic systems and different degrees of saturation in the products of their
interactions with DMAD. Concerning the amidrazones 5aꢀr, they could form at least three types
of heterocycles, 1ꢀarylꢀ4,5ꢀdihydroꢀ1Hꢀ1,2,4ꢀtriazoles 11, 4,5ꢀdihydroꢀ1,2,4ꢀtriazinꢀ6(1H)ꢀones
12 and 1,4ꢀdihydroꢀ7Hꢀ1,2,4ꢀtriazepinꢀ7ꢀones 13 (Scheme 4), via the initial attack of the amine
nitrogen to the carbon of the triple bond DMAD, followed by cyclization of intermediate 10 in
addition (A) or condensation (B, C) processes.
Scheme 4. Possible directions of the reaction of the amidrazones with ACA esters
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The presence of the rather active amino group of reagent 5 could afford amides 14 (according
to Scheme 3) and then 4,5ꢀdihydroꢀ1,2,4ꢀtriazinones 15 as the product of intramolecular
cyclization.
Initially, the reaction of amidrazone 5a with DMAD in the presence of diisopropyl ethylamine
(DIPEA) was investigated (Scheme 5). Interestingly, during refluxing of the starting reagents 5a
and 9a in chloroform in the presence of DIPEA for 17 h, only one product, 11a, was registered
by TLC. 4,5ꢀDihydrotriazole 11a was isolated from the reaction mixture by liquid column
chromatography.
Scheme 5. Reaction of amidrazone 5a with DMAD
The formation of 4,5ꢀdihydrotriazole 11a was indicated by its FTꢀIR spectrum, where the main
absorption bands were observed at 1738 cmꢀ1 due to the stretching of C=O bonds of two COOMe
groups and by the disappearance of the bands at 3263 and 3355 cmꢀ1 corresponding to the NꢀH
1
bonds of hydrazone and amine groups. The H NMR spectrum for compound 11a exhibited
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signals of all protonꢀcontaining groups. The main particularity of the structure of triazole 11a is
the presence of a C(5)ꢀasymmetric centre, which was induced during the cyclization step. Thus,
the signal of the two protons of the CH2ꢀgroup linked to this chiral C(5)ꢀatom was observed in
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the H NMR spectrum as an ABꢀsystem at 3.25 ppm. The 13С NMR spectrum displayed
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additional signals of carbon atoms of two Meꢀgroups from the CO2Meꢀfragments at 3.49 and
3.71 ppm, triplet of the CH2ꢀgroup at 34.1, quartet of triplets of the Cꢀ5ꢀring sp3ꢀatom at 88.0
ppm, and quartet and multiplet of the C=O groups at 167.5 and 167.7 ppm. Massꢀspectral and
elemental analysis data confirmed the structure of compound 11a. The mass spectrum of
compound 11a showed a molecular ion peak with small intensity (2.5%). The most abundant
was one, which corresponded to the elimination of one of the COOMe groups (288).
During the synthetic experiments, we found that the solutions of 4,5ꢀdihydrotriazole 11a
showed blue fluorescence. To obtain a series of these compounds for further detailed
investigation of their fluorescent properties, we carried out an optimization of the reaction
conditions for the first developed method (Scheme 5). For these purposes, the reaction of
amidrazone 5b and DMAD in the presence of a base and TsOH as a catalyst was selected as the
model reaction. The results of this investigation are summarized in Table 1.
Table 1. Optimization of the conditions for the reaction of amidrazone 5b with DMAD
entry X, (equiv.) catalyst Y, (equiv.)
solvent T, (°C) time, (min)
yield[a] of 11b, (%)
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2
3
4
5
6
7
8
9
2.0
2.0
1.5
2.0
2.0
2.0
2.0
1.0
1.0
2.0
ꢀ
ꢀ
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
110
110
110
110
110
110
110
110
110
110
1200
600
240
300
600
600
600
600
600
15
No reaction
TEA
DIPEA
DIPEA
NMM
DBU
DMAP
Py
2.0
1.0
2.0
2.0
2.0
2.0
1.0
2.0
2.0
74
60
88
Trace
Trace
Not completed[b]
Not completed[b]
Not completed[b]
95
Py
Py
10
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2.0
2.0
1.5
2.0
2.0
1.5
2.0
Py
Py
2.0
1.0
0.1
0.1
0.5
0.1
0.1
CHCl3
Toluene
Toluene
Toluene
Toluene
CHCl3
60
110
110
110
110
60
3600
180
450
600
450
320
720
Not completed[b]
66[c]
72
TsOH
TsOH
TsOH
TsOH
TsOH
74
59
50
90
CHCl3
60
9
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[a] – Isolated yield.
[b] ꢀ In the working conditions, the reaction did not complete during a long time. The
experiment was therefore interrupted and the product was not separated.
[c] – Byꢀproduct 16 (see Scheme 7) was isolated in 10% yield.
As important activating factors for the reaction, various types of bases (DIPEA, TEA, Nꢀ
methylmorpholine (NMM), 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀen (DBU), pyridine, Nꢀ
dimethylaminopyridine (DMAP)) and different ratios of the reagents in toluene or CHCl3 under
reflux were examined (Table 1). After a series of experiments, the optimal conditions were
identified as: reflux in toluene in the presence of 2 equiv. of pyridine and usage of 2 equiv. of
DMAD (Table 1, entry 10). The use other organic bases, such as TEA, DIPEA, NMM, DBU or
DMAP, was less successful (Table 1, entries 2–7). We can suggest that the main reason for the
differences in the influences of different organic bases on the investigated reaction might be the
spatial availability of the active electrophilic site in the zwitterions AꢀB, which generated an
ACA ester in situ under the action of an organic base (Scheme 6). These species could be formed
by the initial attack of the basic nitrogen atom onto the triple bond in DMAD. This assumption is
based on the known fact12 that for pyridine, this attack proceeds in transꢀmode and usually is
very fast, even at room temperature.
Scheme 6. Possible structures of the active intermediates generated by the interaction of
ACA esters with the catalysts
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The most accessible point for the next attack by amidine 5b is the electrophilic centre in
zwitterion A. It worth nothing that pyridine can react with a second molecule of DMAD to form
the product of 1,4ꢀdipolar cycloaddition ꢀ tetraethyl 1,3,4,9aꢀtetrahydroꢀ2Hꢀquinolizineꢀ1,2,3,4ꢀ
tetracarboxylate 16 (Scheme 7).13
Scheme 7. Reaction of pyridine with DMAD
Nevertheless, the implied conditions (Table 1, entry 10) provided an excellent yield of the
desired triazole 11b. This means that molecules of pyridine quickly reacted with DMAD to
generate zwitterion A, which then reacted with amidine 5b faster than cycloaddition with another
DMAD molecule. The experiment with an excess of DMAD (Table 1, entry 11), which was
preferable for the side reaction, generated the byꢀproduct 16 in a very small yield (10%).
The activation of the molecule DMAD with TsOH was usually realized by hydrogen bond
formation,14 and it might lead to the generation of complex D according to Scheme 6. This
complex is less active then zwitterion A due to the smaller positive charge located on the carbon
electrophilic centre (Table 1, entries 13ꢀ17). Increasing the concentration of the acid does not
improve the effectiveness of the reaction.
With the optimized reaction conditions on hand, the scope of the method was explored by
employing a variety of amidrazones 5aꢀr and dimethyl or diethyl esters 9a,b. As shown in Table
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2, various 1,2,4ꢀtriazoles 11 were obtained from moderate to high yields (52ꢀ95%). The reaction
was indifferent to the electronꢀwithdrawing or ꢀdonating character of groups in the aryl ring and
led to 4,5ꢀdihydroꢀ1Hꢀ1,2,4,ꢀtriazoles 11aꢀu at good or excellent yields (70ꢀ95%) within 10ꢀ60
min. An outlier is the reaction of compounds 5o,p with DMAD, which gave 11p,s at 52ꢀ56%
yields after 8 h. Furthermore, no product was detected when acetylene dicarboxylic acid or
monoꢀester of ACA ꢀ methyl propiolate were employed as reactants. Amidrazone 5r, which has
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an ethoxycarbonyl group (COR1
=
CO2Et), reacted with DMAD to afford 3ꢀ
ethoxycarbonyltriazoline 11u. However, this reaction was much longer (17 h) than for
amidrazones 5aꢀq with an acetyl moiety (COR1 = COMe) (Тable 2, entry 21).
Table 2. Reaction of amidrazones 5aꢀr with esters 9a,b under optimized conditions.
entry
compd
R1
time,
(min)
25
15
15
15
10
30
15
60
10
30
30
45
20
20
45
Yield
11, (%)
76
Ar
4ꢀMeC6H4
Ph
R2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
R3
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
11
11a
11b
11c
11d
11e
11f
11g
11h
11i
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
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17
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19
20
21
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OEt
95
76
89
92
86
92
75
78
70
72
95
89
76
64
56
96
4ꢀFC6H4
4ꢀClC6H4
4ꢀCNC6H4
3,5ꢀ(CF3)2C6H3
2ꢀClC6H4
2ꢀCF3C6H4
2ꢀFC6H4
4ꢀMeC6H4
Ph
11j
11k
11l
Et
Et
4ꢀCNC6H4
4ꢀCNC6H4
4ꢀCNC6H4
4ꢀCNC6H4
4ꢀCNC6H4
4ꢀMeC6H4
4ꢀCNC6H4
4ꢀCNC6H4
4ꢀCNC6H4
4ꢀCNC6H4
Me
nꢀBu
(CH2)2OMe
Me
Me
Me
Me
Me
Me
Me
Me
Et
11m
11n
11o
11p
11q
11r
11s
11t
Bn
Cy
Ph
Ph
480
45
60
480
60
1020
74
52
85
62
9ꢀEthylcarbazolꢀ3ꢀyl
NꢀPhenylanilinꢀ4ꢀyl
Me
11u
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The products 11aꢀu were stable bright yellowꢀorange solids or oils, and their structures were
3
4
5
1
fully characterized by IR, H and 13C NMR spectroscopy, massꢀspectrometry, and elemental
6
7
8
9
analysis (Experimental Section, Supporting Information). Additionally, ORTEP diagrams of
compounds 11d,e,g,q determined by singleꢀstructure XRD analysis are shown in Figures S45ꢀ
S48 (Supporting Information), which unambiguously confirm the structures and stereochemistry
of compounds 11.
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To check the stability of the obtained triazoles, we refluxed compounds 11b and 11l in
xylene, EtOH and EtOH with 1ꢀ3 equiv. HCl. It was found that both compounds were quite
stable for a long time (more than 30 h) under these conditions.
To compare the properties of triazolines 11 with previously synthesized 5,5ꢀdialkylꢀ4,5ꢀ
dihydrotriazoles, we reacted amidrazones 5 with large excess of acetone. The literature method6
for this condensation, which consisted of refluxing amidrazone in acetone in the presence of
TSA as a catalyst, was modified. To improve the yield of the desired compounds and to shorten
the time of conversion, we applied microwave irradiation. This allowed us to obtain a series of
new 5,5ꢀdimethylꢀ4,5ꢀdihydroꢀ1Hꢀ1,2,4ꢀtriazoles 17aꢀe as brightꢀyellow solids or oils at good
yields (Scheme 8).
Scheme 8. Synthesis of 4,5ꢀdihydrotriazoles in the reaction amidrazones with acetone
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In the FTꢀIR spectra of compounds 17aꢀe, the NHꢀstretching vibration observed for
amidrazones 5 disappeared and the intensity of the CꢀH bond stretching at 2990ꢀ2830 cmꢀ1
increased. 1H NMR spectra for compound 5 did not show the signals of NHꢀprotons (in contrast
to the spectra for the starting compounds), but a new singlet at 1.64ꢀ1.71 ppm belonging to the
six protons of the two Meꢀgroups appeared. Furthermore, 13C NMR, mass and elemental analysis
data support the proposed structure of the mentioned compound (Experimental section,
Supporting Information).
Photophysical properties of 4,5ꢀdihydroꢀ1Hꢀ1,2,4ꢀtriazoles. The UVꢀvisible properties,
fluorescence emission characteristics and photochemical parameters of the target compounds
(1×10ꢀ5 and 1×10ꢀ6 mol×Lꢀ1, correspondingly) are summarized in Table 3. The UV–vis spectra of
compounds 11aꢀu in acetone exhibited λmax at 377–405 nm (Figure 1). The molar extinction
coefficient values for most compounds indicated that the band through the π to π* transition gave
the largest contribution in the absorption. The replacement of electron–donating substituents by
electron–withdrawing substituents caused a smallꢀscale hypsochromic shift of the absorption
peak (blueꢀshift effect in 15 nm).
The fluorescence spectra of compounds 11aꢀu exhibited a maximum emission wavelength at
437–493 nm (acetone). The presence of the electronꢀwithdrawing group in the paraꢀor metaꢀ
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position of the aromatic ring in compounds 11aꢀf shifted the emission wavelength to a shorter
wavelength region (by 25 nm), i.e., caused a slight blue shift (Table 3, entries 1ꢀ6). The Stokes
shift of the synthesized compounds 11 was rather large and was in the range of 63ꢀ96 nm (3855ꢀ
5383 cm−1). The Stokes shift values indicated that there was little or no reꢀabsorption of the
emitted radiation. An increase of the fluorescence intensity (hyperchromic shift) in compounds
11aꢀf and 11jꢀl (Table 3, entries 1ꢀ6 and 10ꢀ12) along with an increase of the electronꢀ
withdrawing properties of the substituent in the aromatic ring were also observed. The quantum
yields of the derivatives were in the range of 0.01–0.45 and were strongly related to the structure
of the investigated compounds.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
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45
46
47
48
49
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52
53
54
55
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57
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59
60
Table 3. Photophysical Properties of compounds 11aꢀu in acetone.
UVꢀvisa
fluorescenceb
entry
compd
λabsmax,
(nm)
403
400
395
399
399
388
377
386
386
405
401
401
403
401
401
403
397
393
396
396
374
εmax
λemmax,
(nm)
490
482
481
479
473
465
473
465
472
493
485
474
473
476
472
473
478
462
no
Stokes shift,
(nm/cmꢀ1)
87/4406
82/4253
86/4526
80/4186
74/3921
77/4268
96/5383
79/4401
86/4720
88/4407
84/4319
73/3841
70/3672
75/3929
71/3751
70/3672
81/4268
69/3800
ꢀ
c
ФF
(Mꢀ1·cmꢀ1)
20600
14500
10700
10700
30200
7100
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
0.060
0.075
0.010
0.040
0.450
0.250
0.053
0.009
0.019
0.094
0.078
0.340
0.406
0.367
0.320
0.270
0.053
0.030
ꢀ
11a
11b
11c
11d
11e
11f
11g
11h
11i
4400
11900
10700
14200
10700
17600
14200
13200
16500
16100
13200
29900
15500
28700
26100
11j
11k
11l
11m
11n
11o
11p
11q
11r
11s
11t
no
437
ꢀ
ꢀ
0.020
63/3855
11u
aUVꢀvis absorption wavelengths at room temperature at a concentration of 1×10ꢀ5 M.
bFluorescence wavelengths at room temperature at a concentration of 1×10ꢀ6 M.
cFluorescence quantum yields measured using a 0.1 M H2SO4 solution of quinine sulphate (ΦF =
0.55) as a reference.15
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The electronic effect of substituents in the aromatic ring groups was obvious. The electronꢀ
withdrawing substituent (namely CNꢀgroup) decreased the Stokes shifts to 74 nm/3921 cmꢀ1 and
improved the quantum yields up to 0.45 for triazole 11e (Table 3 entry 5, Figure 1).
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a
b
Figure 1. Absorption (a) and emission spectra (b) of 4,5ꢀdihydroꢀ1,2,4ꢀtriazoles 11aꢀi,nꢀs in
acetone at room temperature.
The introduction of substituents at the orthoꢀposition of the aromatic ring of triazolines 11gꢀi
led to a hypsochromic shift of the absorption band due to the strong disruption of the conjugation
between the aromatic and 1,2,4ꢀtriazoline rings (Table 3 entries 7ꢀ9). From the XRD data
(Figures S45 and S46), the aromatic and 1,2,4ꢀtriazoline rings were more coplanar in the
structures of compounds 11 with the paraꢀsubstituted aromatic ring at the N(1)ꢀtriazole position
and more nonꢀplanar for the compounds with the orthoꢀsubstituted aromatic ring (Figure 47).
Replacement of the substituents at the C(3) and N(4) positions of azoles also influenced their
photophysical properties. Thus, triazolines 11e,mꢀp with alkyl substituents at the N(4) atom
showed good quantum yields (0.27ꢀ0.45) (Table 3, entries 5,13ꢀ16), while the aromatic ones, that
is, 11q,r, exhibited less fluorescence (Table 3, entries 17, 18). Moreover, triazole 11s bearing the
Nꢀethylcarbazole fragment (which showed blue fluorescence itself) and compound 11t with the
Nꢀphenylaniline substituent completely lost the fluorescent properties (Table 3, entries 19ꢀ20). It
should be mention that for carbazole derivative 11s and other compounds bearing R2 = Ar (viz.
11q, r, and t), conjugation of the aromatic cycle and triazoline ring in ground state is remarkably
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reduced as deducible from the large value of the torsion angle between these two cycles (see
XRD for the 11q in SI, Figure S48).
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9
The spectral characteristics (absorption, emission, molar extinction coefficient (ε) and quantum
yields (ФF)) for compounds 17aꢀe were measured in acetone, and the results are presented in
Table 4 and Figure 2.
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11
12
13
14
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17
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Table 4. UVꢀvis absorption and fluorescence emission properties of compounds 17aꢀe.
UVꢀvis
fluorescence
ФF
entry
compd
λabsmax,
εmax
(Mꢀ1·cmꢀ1)
13900
λemmax,
(nm)
499
498
494
Stokes shift,
(nm/cmꢀ1)
87/4231
81/3900
81/3900
(nm)
412
417
415
412
384
1
2
3
4
5
0.079
0.169
0.140
0.159
0.020
17a
17b
17c
17d
17e
22500
29800
27200
34000
495
455
83/4070
71/4064
a
b
Figure 2. Absorption (a) and emission (b) spectra of 4,5ꢀdihydroꢀ1,2,3ꢀtriazoles 17aꢀe in acetone
at room temperature.
Comparison of the photophysical properties of compounds 17aꢀe and 11aꢀu demonstrated a
slight red shift of the absorption λmax and emission λem by 10ꢀ14 and 15ꢀ26 nm, respectively.
Compound 17a showed the largest Stokes shift (87 nm/4231 cmꢀ1), while ester 17e had the
lowest Stokes shift (71 nm/4064 cmꢀ1). The fluorescence quantum yields for 4,5ꢀdihydrotriazoles
17aꢀe were 0.02ꢀ0.169. Thus, we can conclude that triazolines 17aꢀe exhibited a decrease of the
quantum yield but an increase of the Stokes shift value compared with triazolines 11aꢀu. An
improvement of quantum yields may be achieved by the elongation of the length of the
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substituent at the N(4) triazole atom. Most of compounds 17aꢀe exhibited greenꢀyellow
fluorescence (Supporting information, Figure S57).
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8
9
Quantum Mechanical Calculations. To better understand the electronic transition occurring in
4,5ꢀdihydrotriazoles 11 and 17 during the UVꢀvis absorption and fluorescence emission, further
investigation of the photophysical property via calculations at the Density Functional Theory
(DFT) level16 in vacuo and in acetone for the representative compounds 11aꢀg,i,l,m,o,r,u and
17aꢀe was conducted. The UVꢀvis absorption and fluorescence emission parameters for these
compounds were calculated by the TDꢀDFT method based on the optimized S0 and S1 state
geometries, respectively (Table 5). The wavelengths of the compounds, which corresponded to
the vertical excitation energies of absorption and fluorescence, аnd the corresponding Stokes’
shifts are compared with the experimental values in Tables 3 and 4. It should be noted that the
observed wavelengths are in very good agreement with the wavelengths calculated using TDꢀ
DFT with 6ꢀ311G (d,p).16
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11
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Table 5. Absorption and emission propertiesa of 4,5ꢀdihydrotriazoles 11aꢀe,g,i,l,m,o,r,u and
17aꢀe in implicit (IEFꢀPCM) solvated phase (acetone) obtained from quantum chemical
calculation.
entry compd
λa
f01
λe
f10
ꢁν
ꢀ0, D
ꢀ1v
ꢀ1r
θ0,1v
θ0,1r
1
2
3
4
5
6
7
8
9
10
11
12
13
15
16
17
18
403 0.2214 492 0.4330 4.49
401 0.2110 484 0.2981 4.28
395 0.2007 481 0.3957 4.53
398 0.2274 480 0.4471 4.29
399 0.3276 474 0.5689 3.97
378 0.2134 473 0.3120 5.31
387 0.1987 470 0.3144 4.56
402 0.3286 474 0.4951 3.78
403 0.2866 474 0.5738 3.72
401 0.5166 474 0.6083 3.84
395 0.6014 464 0.6963 3.76
5.3
5.0
4.6
4.6
6.9
6.3
6.2
7.1
7.7
8.8
9.9
10.6 13.5 15.1 111.7
10.1 10.1 17.5 109.0
11a
11b
11c
11d
11e
11g
11i
9.0
8.9
8.9
12.0 13.2
11.9 12.9
11.8 30.0
11.6 33.1
11.2 33.8
83.5
54.4
71.9
6.6
1.5
2.5
10.0
9.1
10.0
8.8
11.3 33.3 130.7
11l
9.0
7.3
17.2
36.3
26.0
59.7
94.0
44.6
40.3
33.1
11m
11o
11r
11u
17a
17b
17c
17d
17e
10.9 11.4 27.6
375 0.4967 436 0.5726 3.73 10.8 10.7 10.7 23.4
411 0.5379 500 0.5941 4.33
416 0.5379 500 0.6016 4.04
413 0.5804 496 0.6166 4.05
412 0.5378 496 0.6798 4.11
386 0.5992 456 0.6713 3.98
7.7
7.7
7.6
7.2
9.3
8.7
9.3
8.8
7.9
9.2
8.7
9.0
7.7
7.7
9.3
37.9
30.3
37.7 109.6
42.0 103.3
28.0
32.9
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[a] Computed absorption wavelength (λa, nm) and oscillator strength (f01), emission wavelength
(λe, nm) and oscillator strength (f10), Stokes’ shift (ꢁν, kK), modulus of the electric dipole
moments of the ground state (ꢀ0, D), of the vertical FC excited state (ꢀ1v, D), and of the relaxed
excited state (ꢀ1r, D), and angles formed by the dipole moment vectors (θ0,1v,((°) and θ0,1r (°)).
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The geometry of the optimized structures is depicted in Figures S49 and S50 (see
Supporting Information). It should be noted that the calculation and experimental data (XRD
data) for compounds 11d,e,g are in good agreement. A deviation between the experimental
(XRD) and calculated torsion angles between 4,5ꢀdihydrotriazole and the adjacent aromatic
cycle may be explained by the strong internal interactions, which arose in the crystal pattern.
The main important structure feature for the organic compounds, which can influence the
processes of absorption and emission, is the conjugation between opposite parts in a molecule.
Hence, we analysed the bond length and torsion angle between the aromatic and triazoline rings,
which are the most essential parts of the structures of compounds 11 and 17. The length of the
CArꢀNtriasole bond was in the range of 1.390ꢀ1.433 Å (Table S1, Supporting Information) at the
ground state and in most cases was less than the CArꢀN standard bond length (CArꢀN = 1.431 Å17)
and became shorter for compounds 11d,e, but longer for triazoline 11g in the excited state.
Shortening of this bridge bond was due to its partial doubleꢀbond character and indicated an
enhancement of the πꢀbonding interaction between these parts of molecules 11d,e. Moreover, the
structure of 11, especially for compounds 11l,m,o,r,u, bearing the CNꢀgroup at position 4 of the
aromatic cycle, became more planar with a significant decrease of the torsion angles after
photoexcitation. This phenomenon indicated an enhancement of the conjugation in the singletꢀ
excited state.
The nonꢀplanar geometry was predicted by calculation for compounds 11g,i with the
substituent in the orthoꢀposition of the aromatic cycle in both the ground and in excited states.
This was in accordance with the experimental data (XRD) for triazoline 11g (Figure S47). As a
result, the conjugation systems of these compounds were actually broken into two parts. This
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feature may explain the hypsochromic shifts of the longꢀwavelength bands in the absorption
spectra and the decrease of quantum yields (Table 3). It should be noted that the calculated
values of the oscillator strength for the adsorption (f01) and for fluorescent emission (f10), which
are characteristics of the electron transitions, were the smallest for compounds 11g,i (Table 5,
entries 6,7).
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The plots of the frontier molecular orbitals from HOMOꢀ1 to LUMO+1 in the ground and
excited states for representative compounds 11a,b,e,g and 17a are shown in Figure 3 (more
examples are presented in the Supporting information, Figures S51 and S52). The molecular
orbitals exhibited differences in the electron density distribution depending on the structure of
the investigated triazolines. The most important structural factors were the electronic nature and
position of the substituent within the N(1)ꢀaromatic ring. For example, an increase of the
electronꢀaccepting character of the substituent in the aromatic cycle in compounds 11aꢀe led to
an increase of HOMO and LUMO localization on the aromatic ring for both the ground and
excited states. This effect demonstrated the expansion of the HOMO and LUMO orbitals onto
the aromatic and triazoline rings at the ground and excited states and may cause compounds
11e,f,lꢀp to display the best quantum yields among the investigated compounds 11. This
phenomenon could be due to an enhancement in the probabilities of both the S0→S1 and S1→S0
transitions. Moreover, the oscillator strength for the emission (f10) was the largest for the same
compounds, and also predicted the better quantum yields.
An increase of conjugation between the two rings in the molecules of compounds 17, which
arose from the more planar structure, led to bathochromic shifts in the absorption and emission
spectra, as shown from the calculation data (Figure S54). A more uniform distribution of the
frontier molecular orbitals in the molecules of triazolines 17 allowed fluorescence to be retained,
although with lesser intensity in comparison with triazoles 11.
Ground state
Compound
HOMO–1
HOMO
LUMO
LUMO+1
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11e
11g
17a
Excited state
HOMO–1
HOMO
LUMO
LUMO+1
11a
11b
11e
11g
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Figure 3. Frontier Molecular Orbitals for triazolines 11a,b,e,g and 17a (MOs): HOMO–1,
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HOMO, LUMO, LUMO+1. (|Isovalue(MO)| = 0.02; |Isovalue(ρ)| = 0.0004.)
CONCLUSIONS
A novel method to synthesize 4,5ꢀdihydroꢀ1Hꢀtriazoles via nucleophilic addition/cyclization of
amidrazones with ACA esters in a sequence of reactions in a simple, atomꢀeconomical procedure
was proposed and was successand fully used for the preparation of a series of compounds with
good yields. All compounds were characterized by FTꢀIR, 1H and 13C NMR and UVꢀvis spectral
techniques.
Most of the compounds possessed a medium fluorescenceꢀemitting ability with quantum
yields up to 0.45 and displayed blue or yellowꢀgreen emission depending on the nature of the
whole molecule. The optimized geometrical parameters, vibrational frequencies, chemical shifts
and some physicochemical properties were calculated using the DFT/B3LYP method with the 6ꢀ
311 G(d,p) basis set. The theoretical results showed that the optimized geometries can well
reproduce the molecular structure of triazolines, and the calculated values of vibrational
frequencies showed good agreement with the experimental ones. An analysis of the
particularities in the electronic structures of triazoles 11 and 17 (obtained by the calculated
absorption and emission characteristics) and 3D patterns of HOMOꢀ1, HOMO, LUMO,
LUMO+1 allowed us to establish the relationships between the structure of the investigated
compounds and their photophysical properties.
It should be mentioned that stable smallꢀmolecule 4,5ꢀdihydroꢀ1,2,4ꢀtriazoline derivatives
with photoluminescence efficiency have not been reported earlier. Moreover, to date, the most
widely known fluorescent derivatives of 1,2,4ꢀtriazoles are their metalꢀcomplexes.2 Thus, we
found new fluorescent heterocyclic molecules, which are of interest in many application areas,
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such as emitters for electroluminescence devices, molecular probes for biochemical research,
fluorescent whitening agents and photoconducting materials.
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Further efforts in this work are directed towards the investigation of the fluorosolvatochromic
behaviour of 4,5ꢀ1Hꢀdihydrotriazoles, and the results will be reported in due course.
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EXPERIMENTAL SECTION
General. 3ꢀСhloropentaneꢀ2,4ꢀdione 1a and ethyl 2ꢀchloroꢀ3ꢀoxobutanoate 1b, were
commercially available. Hydrazonoyl chlorides were synthezised via the Japp–Klingemann
reaction as reported previously.8 Commercially available chemicals and solvents were used
without further purification. The products were purified by column chromatography on silica gel
(0.035–0.070, 60 Å) and reꢀcrystallized from ethanol.
Microwaveꢀheated reactions were carried out in an Anton Paar Monowave 300 microwave
synthesis reactor in sealed microwave Pyrex vessels (2ꢀ5 mL). The temperature was controlled
by external IR sensor. The pressure were monitored by an integrated hydraulic pressure sensor.
1Н NMR and 13C NMR spectra were recorded at 400 MHz for H and 100 MHz for 13C
1
spectrometer in DMSOꢀd6 or CDCl3. Chemical shifts (δ scale) are reported in parts per million
1
(ppm) relative to TMS in H NMR and to the residual solvent signals in 13C NMR spectra. The
13C NMR signal patterns for compound 11a were analysed by Gate and for all compounds by
APT (attached proton test) and are described as follows: + for secondary or quaternary carbon
atom (positive signal), ꢀ for primary or tertiary carbon atom (negative signal). The values of the
coupling constants (J) are given in Hertz (Hz). The signal splitting patterns are described as a
singlet (s), doublet (d), triplet (t), quartet (q), sextet (sext), quintet (quin), multiplet (m), broad
(br), doublet of doublets (dd), doublet of triplets (dt) or AA'XX' ꢀ spin system of paraꢀsubstituted
benzene with two different substituents. Mass spectra were recorded with a massꢀspectrometer
using the electron ionisation (EI) technique (40ꢀ200 °C, 70 eV). The abbreviation [M]+ refers to
the molecular ion. The IR spectra were obtained with a FTꢀIR ATR (attenuated total reflection,
ZnSe) spectrometer in the 4000ꢀ400 cmꢀ1 region. Elemental analysis was carried out using a
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CHNS/O analyser. Melting points were determined using a microscopic melting point meter
without correction. The reactions were monitored by analytical thinꢀlayer chromatography (TLC)
on aluminiumꢀbacked silicaꢀgel plates (Sorbfil UV–254). Visualization of the components was
accomplished by short wavelength UVꢀlight (254 nm).
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The absorption and emission spectra were recorded in acetone using 10.00ꢀmm quartz cells
at room temperature. The excitation wavelength was at the absorption maxima. Atmospheric
oxygen contained in the solutions was not removed. The concentrations of the compounds in
solution were 1.0 × 10ꢀ5 M and 1.0 × 10ꢀ6 M for absorption and fluorescence measurements,
respectively. The relative fluorescence quantum yields (ΦF) were determined using quinine
sulphate (1 × 10ꢀ5 M) in 0.1 M H2SO4 as a standard (ΦF = 0.546).15
Suitable single crystals of 4,5ꢀdihydroꢀ1,2,4ꢀtriazoles 11d,e,g,q for XRD structural analysis
were obtained by slow evaporation of a solution of the compounds in chloroform at room
temperature. XRD data were obtained on a CCD area detector diffractometer using the standard
procedure (MoKꢀirradiation, graphite monochromator, ωꢀscanning with 1o step, T = 295(2) K).
Empirical absorption correction was applied. Using Olex2,18 the structure was solved with the
Superflip19 structure solution program using Charge Flipping and refined with the ShelXL20
refinement package using Least Squares minimization in anisotropic approximation for nonꢀ
hydrogen atoms. The Hꢀatoms were added at the calculated position and refined in the “rider”
model. CCDC 1495198, 1495196, 1495197 and 1495508 for 11d,e,g,q contain the
supplementary data for this paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via link www.ccdc.cam.ac.uk/data_request/cif.
Computational Details. The ground state molecular geometry of the compounds under
investigation was fully optimized at the Density Functional Theory (DFT) level, both in vacuo
and in solvents (vide infra). The harmonic vibrational frequencies and thermochemicals were
computed. The ground state geometry optimization and harmonic vibrational frequencies
calculations were carried out using the hybrid Becke, threeꢀparameter, LeeꢀYangꢀParr exchangeꢀ
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correlation functional B3LYP,16a coupled with the 6−311++G** basis set. The D3 version of
Grimme’s dispersion with BeckeꢀJohnson damping16b was always used. Solvent effects were
taken into account by the implicit Polarizable Continuum Model in its Integral Equation
Formalism (IEF−PCM).21 The PCM molecular cavity was built according to the Universal Force
Field (UFF)22 radii, within the value used in the last implementation of the PCM (based on a
continuum surface charge formalism). Standard values for the dielectric constants and refractive
indexes were assumed. Both in vacuo and in solvents, the UVꢀvis spectra were also simulated
using TDꢀDFT by employing the longꢀrange corrected CAMꢀB3LYP16c hybrid functional level
coupled with the 6ꢀ311+G** basis set. S0 →Sn (n = 1 to 5) transitions were accounted for. In the
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case of the solvated phase, stateꢀspecific (SS)23 treatment of solvent effects was considered, both
within the nonꢀequilibrium (neq) and equilibrium (eq) solvation regimes.24 Electronic absorption
spectra were simulated by considering the first five singlet excited electronic states. The vibronic
progressions24a,25 of all nonꢀdark electronic transitions were also simulated, including
Duschinsky and Herzberg–Teller effects. The first singlet excited state S(π,π*) state geometry
was optimized using analytical gradients and the first transitions S1 → S0 of the emission
transition. Also in this case, SS (both eq and neq) treatment of solvent effects was considered and
the electronic emission band was simulated by accounting for the vibronic progressions, as done
in the absorption. The atomic charge population analysis, electric multiple moments and
electronic were also computed within the CHelpG procedure26 for both ground and S1 excited
(vertical and relaxed) states. The frontier Molecular Orbitals (MOs), were also computed and
plotted. All calculations were performed using the GAUSSIAN09 code.27
General procedure for the synthesis of amidrazones 5. A solution of arylhydrazonoyl chloride
(1 mmol), aromatic or aliphatic amine (1 mmol) and 0.17 ml (1 mmol) DIPEA in dioxane (20
o
ml) was stirring at 25ꢀ60 C for 2ꢀ8 h until the TLC analysis indicated the total consumption of
the starting arylhydrazonoyl chloride. The solution was poured into a mixture of water and
crushed ice. The precipitated solid was filtered, washed with water and dried.
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NꢀMethylꢀ2ꢀoxoꢀN'ꢀ(pꢀtolyl)propanehydrazonamide (5a). Yellow powder (172 mg, 84%). Rf
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= 0.62 (Hex/EtOAc, 1:1), 0.67 (Hex/CHCl3, 1:5); mp 100ꢀ101 ºC. IR (cmꢀ1): 3355, 3268 (NꢀH),
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2919, 2888, 2822 (CꢀH), 1658 (C=O). Н NMR (400 MHz, DMSOꢀd6): δ 2.25 (s, 3H), 2.38 (s,
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3H), 2.84 (d, J = 4.2 Hz, 3H), 5.06 (q, J = 4.2 Hz, 1H), 1H), 7.02 and 6.96 (АА'ХХ', J = 8.6 Hz,
4H), 8.86 (s, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ) 20.2, (ꢀ) 24.7, (ꢀ) 30.4, (ꢀ) 112.9, (+)
128.0, (ꢀ) 129.4, (+) 142.3, (+) 143.1, (+) 193.6. Anal. Calcd for C11H15N3O: C, 64.37; H, 7.37;
N, 20.47. Found: C, 64.13; H, 7.25; N, 20.22. EIMS (70 eV) m/z: M+ 205 (100).
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NꢀMethylꢀ2ꢀoxoꢀN'ꢀphenylpropanehydrazonamide (5b). Yellow powder (141 mg, 74%). Rf =
0.66 (Hex/EtOAc, 1:1), 0.60 (Hex/CHCl3, 1:5); mp 110ꢀ111 ºC. IR (cmꢀ1): 3374, 3308 (NꢀH),
3004, 2938, 2917 (CꢀH), 1658 (C=O). 1Н NMR (400 MHz, DMSOꢀd6): δ 2.40 (s, 3H), 2.85ꢀ2.87
(m, 3H), 5.20 (br. s, 1Н), 6.73 (t, J = 7.7 Hz, 1H), 7.19ꢀ7.08 (m, 4H), 8.97 (s, 1H). 13C NMR
(100 MHz, DMSOꢀd6): δ (ꢀ) 25.1, (ꢀ) 30.5, (ꢀ) 112.9, (ꢀ) 119.4, (ꢀ) 128.9, (+) 142.6, (+) 145.4, (+)
193.8. Anal. Calcd for C10H13N3O: C, 62.81; H, 6.85; N, 21.97. Found: C, 62.73; H, 6.71; N
21.87. EIMS (70 eV) m/z: M+ 191 (100).
N'ꢀ(4ꢀFluorophenyl)ꢀNꢀmethylꢀ2ꢀoxopropanehydrazonamide (5c). Yellow powder. (127 mg,
61%). Rf = 0.64 (Hex/EtOAc, 1:1), 0.51 (Hex/CHCl3, 1:5); mp 85ꢀ86 ºC. IR (cmꢀ1): 3389, 3313
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(NꢀH), 3035, 2993, 2938 (CꢀH), 1657 (C=O). Н NMR (400 MHz, DMSOꢀd6): δ 2.39 (s, 3Н),
2.84 (s, 3Н), 5.15 (br. s, 1Н), 6.93 (t, J = 8.8 Hz, 2Н), 7.08ꢀ7.14 (m, 2H), 9.00 (s, 1H). 13C NMR
(100 MHz, DMSOꢀd6): δ (ꢀ) 24.9, (ꢀ) 30.4, (ꢀ) 113.9 (d, JCꢀF = 7.5 Hz), (ꢀ) 115.4 (d, JCꢀF = 22.3
Hz), (+) 142.1 (d, JCꢀF = 1.5 Hz), (+) 142.7, (+) 156.2 (d, JCꢀF = 233.3 Hz), (+) 193.7. Anal. Calcd
for C10H12FN3O: C, 57.41; H, 5.78; N, 20.08. Found: C, 57.21; H, 5.88; N, 20.29. EIMS (70 eV)
m/z: M+ 209 (100).
N'ꢀ(4ꢀChlorophenyl)ꢀNꢀmethylꢀ2ꢀoxopropanehydrazonamide (5d). Yellow powder (171 mg,
76%). Rf = 0.66 (Hex/EtOAc, 1:1), 0.58 (Hex/CHCl3, 1:5); mp 100ꢀ101 ºC. IR (cmꢀ1): 3342,
3250 (NꢀH), 2884 (CꢀH), 1659 (C=O). 1Н NMR (400 MHz, DMSOꢀd6): δ 2.39 (c, 3Н), 2.87 (d, J
= 4.8 Hz, 3Н), 5.24 (q, J = 4.8 Hz, 1H), 7.13 and 7.49 (АА'ХХ', J = 9.2 Hz, 4H), 9.08 (s, 1H).
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13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ) 25.1, (ꢀ) 30.4, (ꢀ) 114.3, (+) 122.6, (ꢀ) 128.7, (+) 143.0,
(+) 144.4, (+) 193.9. Anal. Calcd for C10H12ClN3O: C, 53.22; H, 5.36; N, 18.62. Found: C,
52.95; H, 5.51; N, 18.44. EIMS (70 eV) m/z: M+ 225 (100).
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N'ꢀ(4ꢀCyanophenyl)ꢀNꢀmethylꢀ2ꢀoxopropanehydrazonamide (5e). Yellowꢀbrown powder
(149 mg, 69%). Rf = 0.44 (Hex/EtOAc, 1:1), 0.50 (Hex/CHCl3, 1:5); mp 150ꢀ151 ºC. IR (cmꢀ1):
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3385, 3251 (NꢀH), 2993, 2969, 2931 (CꢀH), 2213 (C≡N), 1677 (C=O). Н NMR (400 MHz,
DMSOꢀd6): δ 2.41 (s, 3Н), 2.89 (d, J = 5.0 Hz, 3Н), 5.70 (q, J = 5.0 Hz, 1Н), 7.19 and 7.61
(АА'ХХ', J = 8.6 Hz, 4H), 9.58 (s, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ) 25.5, (ꢀ) 30.4, (+)
99.6, (ꢀ) 112.8, (+) 120.0, (ꢀ) 133.4, (+) 144.1, (+) 148.9, (+) 194.4. Anal. Calcd for C11H12N4O:
C, 61.10; H, 5.59; N, 25.91. Found: C, 61.39; H, 5.69; N, 25.76. EIMS (70 eV) m/z: M+ 216
(76).
N'ꢀ(3,5ꢀBis(trifluoromethyl)phenyl)ꢀNꢀmethylꢀ2ꢀoxopropanehydrazonamide (5f). Paleꢀ
brown powder (275 mg, 84%). Rf = 0.63 (Hex/EtOAc, 1:1), 0.62 (Hex/CHCl3, 1:5); mp 104ꢀ105
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ºC. IR (cmꢀ1): 3331, 3297 (NꢀH), 2916, 2887, 2819 (CꢀH), 1672 (C=O). Н NMR (400 MHz,
DMSOꢀd6) δ: 2.42 (s, 3Н,), 2.90 (d, J = 5.2 Hz, 3Н), 5.50 (q, J = 4.8 Hz, 1Н), 7.17 (s, 1H), 7.56
(s, 2H), 9.57 (s, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ) 25.2, (ꢀ) 30.3, (ꢀ) 110.8, (ꢀ) 112.2,
(+) 123.4 (q, JCꢀF =271.1 Hz), (+) 131.0 (q, JCꢀF = 32.3 Hz), 1(+) 44.6, (+) 147.1, (+) 194.3. Anal.
Calcd for C12H11F6N3O: C, 44.05; H, 3.39; N, 12.84. Found: C, 44.26; H, 3.52; N, 12.62. EIMS
(70 eV) m/z: M+ 327 (53).
N'ꢀ(2ꢀFluorophenyl)ꢀNꢀmethylꢀ2ꢀoxopropanehydrazonamide (5g). Paleꢀbrown powder (146
mg, 70%). Rf = 0.58 (Hex/EtOAc, 1:1), 0.82 (Hex/CHCl3, 1:5); mp 66ꢀ67 ºC. IR (cmꢀ1): 3352,
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3300 (NꢀH), 2978, 2953, 2929 (CꢀH), 1671 (C=O). Н NMR (400 MHz, DMSOꢀd6): δ 2.42 (s,
3Н), 2.93 (d, J = 4.9 Hz, 3Н), 5.78 (br. s, 1Н), 6.71ꢀ6.77 (m, 1H), 6.98ꢀ7.08 (m, 2H), 7.46 (m,
1Н), 8.31 (s, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ) 25.9, (ꢀ) 30.4, (ꢀ) 114.7, (ꢀ) 114.9 (d, JCꢀ
F= 20.9 Hz), (ꢀ) 119.0 (d, JCꢀF= 6.7 Hz), (ꢀ) 124.8 (d, JCꢀF= 3.2 Hz), (+) 133.6 (d, JCꢀF= 9.7 Hz),
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(+) 143.6, (+) 149.9 (d, JCꢀF = 238.3 Hz), (+) 194.5. Anal. Calcd for C10H12FN3O: C, 57.41; H,
5.78; N, 20.08. Found: C, 57.24; H, 5.63; N, 20.31. EIMS (70 eV) m/z: M+ 209 (54).
N'ꢀ(2ꢀChlorophenyl)ꢀNꢀmethylꢀ2ꢀoxopropanehydrazonamide (5h). Yellow powder (196 mg,
87%). Rf = 0.69 (Hex/EtOAc, 1:1), 0.73 (Hex/CHCl3, 1:5); mp 67ꢀ68 ºC. IR (cmꢀ1): 3344 (NꢀH),
2925, 2883, 2877 (CꢀH), 1678 (C=O). 1Н NMR (400 MHz, DMSOꢀd6): δ 2.43 (s, 3Н), 2.92 (d, J
= 5.3 Hz, 3Н), 5.78 (br. s, 1Н), 6.81 (d, J = 7.8 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.28 (d, J = 7.3
Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ) 25.4, (ꢀ) 30.4, (ꢀ) 114.7,
(+) 117.4, (ꢀ) 120.3, (ꢀ) 128.0, (ꢀ) 129.1, (+) 141.3, (+) 144.3, (+) 194.4. Anal. Calcd for
C10H12ClN3O: C, 53.22; H, 5.36; N, 18.62. Found: C, 53.41; H, 5.50; N, 18.78. EIMS (70 eV)
m/z: M+ 225 (78).
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NꢀMethylꢀ2ꢀoxoꢀN'ꢀ(2ꢀ(trifluoromethyl)phenyl)propanehydrazonamide (5i). Paleꢀbrown
powder (223 mg, 86%). Rf = 0.64 (Hex/EtOAc, 1:1), 0.78 (Hex/CHCl3, 1:5); mp 83ꢀ84 ºC. IR
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(cmꢀ1): 3364 (NꢀH), 2972, 2950, 2917 (CꢀH), 1683 (C=O). Н NMR (400 MHz, DMSOꢀd6): δ
2.40 and 2.42 (two s, 3Н), 2.73 and 2.85 (two d, J = 5.0 Hz, 3Н), 5.63 and 5.98 (two br s, 1Н),
6.76 and 6.96 (two t, J = 7.6 Hz, 1Н), 7.36ꢀ7.46 and 7.47ꢀ7.56 (two m, 2H), 7.59ꢀ7.62 and 7.68ꢀ
7.72 (two m, 1H), 8.03 and 9.03 (two s, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ) 24.9, (ꢀ)
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30.3, (+) 112.5, (q, JCꢁF = 29.4 Hz), (ꢀ) 115.4, (ꢀ) 119.5, (+) 124.6 (q, JCꢁF = 270.6 Hz), (ꢀ)
126.1, (ꢀ) 133.6, (+) 142.4, (+) 145.0, (+) 194.2. Anal. Calcd for C11H12F3N3O: C, 50.97; H,
4.67; N, 16.21. Found: C, 50.74; H, 4.78; N, 16.52. EIMS (70 eV) m/z: M+ 259 (100). (Z,Eꢀ
isomers ꢀ 5:1).
2ꢀOxoꢀNꢀphenylꢀN'ꢀpꢀtolylpropanehydrazonamide (5j). Yellow powder (246 mg, 92%). Rf =
0.77 (Hex/EtOAc, 1:1), 0.67 (Hex/CHCl3, 1:5); mp 238ꢀ239 °С. IR (cmꢀ1): 3324, 3250 (NꢀH),
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3026, 2989, 2943 (CꢀH), 1670 (C=O). Н NMR (400 MHz, DMSOꢀd6): δ 2.28 (s, 3H), 2.50 (s,
3H), 6.56 (d, J = 7.7 Hz, m, 2Н), 6.75 (t, J = 7.2 Hz, 1Н), 7.03 (d, J = 7.8 Hz, 2Н), 7.10ꢀ7.16
(m, 4Н), 7.59 (s, 1Н), 9.26 (s, 1Н). 13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ) 20.3, (ꢀ) 24.7, (ꢀ)
113.9, (ꢀ) 115.6, (ꢀ) 118.9, (ꢀ) 128.5, (ꢀ) 129.5, (+) 129.8, (+) 135.6, (+) 141.5, (+) 142.6, (+)
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192.7. Anal. Calcd for C16H17N3O: C, 71.89; H, 6.41; N, 15.72. Found: C, 71.60; H, 6.62; N,
15.91. EIMS (70 eV) m/z: M+ 267 (88).
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N'ꢀ(4ꢀCyanophenyl)ꢀ2ꢀoxoꢀNꢀphenylpropanehydrazonamide (5k). Yellow powder (239 mg,
86%). Rf = 0.53 (Hex/EtOAc, 1:1), 0.55 (Hex/CHCl3, 1:5); mp 160ꢀ161 ºC. IR (cmꢀ1): 3331,
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3240 (NꢀH), 3001, 2967 (CꢀH), 2221 (C≡N), 1676 (C=O). Н NMR (400 MHz, DMSOꢀd6): δ
2.53 (s, 3Н), 6.60 (d, J = 7.8 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 7.14 (t, J = 7.8 Hz, 2H), 7.35 and
7.56 (АА'ХХ', J = 8.7 Hz, 4H), 8.18 (s, 1H), 9.88 (s, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ)
25.1, (+) 101.5, (ꢀ) 113.9, (ꢀ) 116.4, (ꢀ) 119.6, (+) 119.7, (ꢀ) 128.5, (ꢀ) 133.5, (+) 138.0, (+) 141.6,
(+) 147.7, (+) 193.4. Anal. Calcd for C16H14N4O: C, 69.05; H, 5.07; N, 20.13. Found: C, 69.32;
H, 5.25; N, 20.40. EIMS (70 eV) m/z: M+ 278 (24).
NꢀButylꢀN'ꢀ(4ꢀcyanophenyl)ꢀ2ꢀoxopropanehydrazonamide (5l). Brown oil (232 mg, 90%). Rf
= 0.65 (Hex/EtOAc, 1:1), 0.51 (Hex/CHCl3, 1:5). IR (cmꢀ1): 3333, 3321 (NꢀH), 2959, 2931, 2872
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(CꢀH), 2216 (C≡N), 1680 (C=O). Н NMR (400 MHz, DMSOꢀd6): δ 0.92 (t, J = 7.2 Hz, 3Н),
1.29ꢀ1.36 (m, 2H), 1.38ꢀ1.45 (m, 2H), 2.42 (s, 3Н), 3.30 (q, J = 6.8 Hz, 2H), 5.42 (t, J = 6.1 Hz,
1H), 7.18 and 7.50 (АА'ХХ', J = 8.8 Hz, 4H), 9.55 (s, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ
) 13.6, (+) 19.3, (ꢀ) 25.4, (+) 32.9, (+) 42.7, (ꢀ) 115.1, (+) 119.2, (ꢀ) 133.7, (+) 143.1, (+) 146.2,
(+) 148.9, (+) 194.5. Anal. Calcd for C14H18N4O: C, 65.09; H, 7.02; N, 21.69. Found: C, 65.29;
H, 7.33; N, 21.71. EIMS (70 eV) m/z: M+ 258 (69).
N'ꢀ(4ꢀCyanophenyl)ꢀNꢀ(2ꢀmethoxyethyl)ꢀ2ꢀoxopropanehydrazonamide
(5m).
Yellow
powder, (216 mg, 83%). Rf = 0.41 (Hex/EtOAc, 1:1), 0.38 (Hex/CHCl3, 1:5); m.p. 115ꢀ116 ºC.
IR (cmꢀ1): 3349, 3238 (NꢀH), 2938, 2929, 2901 (CꢀH), 2211 (C≡N), 1671 (C=O); 1Н NMR (400
MHz, DMSOꢀd6): δ 2.41 (s, 3Н), 3.33 (s, 3Н), 3.36ꢀ3ꢀ45 (m, 4Н), 5.62ꢀ5.67 (t, J = 6.0 Hz, 1Н),
7.16 and 7.50 (АА'ХХ', J = 8.7 Hz, 4H), 9.69 (s, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ)
25.4, (+) 42.4, (ꢀ) 58.0, (+) 72.4, (+) 99.7, (ꢀ) 112.8, (+) 119.9, (ꢀ) 133.5, (+) 143.2, (+) 148.7, (+)
194.3. Anal. Calcd for C13H16N4O2: C, 59.99; H, 6.20; N, 21.52. Found: C, 59.68; H, 6.34; N,
21.73. EIMS (70 eV) m/z: M+ 260 (49).
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NꢀBenzylꢀN'ꢀ(4ꢀcyanophenyl)ꢀ2ꢀoxopropanehydrazonamide (5n). Yellow powder (237 mg,
81%). Rf = 0.63 (Hex/EtOAc, 1:1), 0.53 (Hex/CHCl3, 1:5); mp 85ꢀ86 ºC. IR (cmꢀ1): 3351, 3290
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(NꢀH), 3065, 2965, 2920 (CꢀH), 2220 (C≡N), 1663 (C=O). Н NMR (400 MHz, DMSOꢀd6): δ
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2.35 (s, 3Н), 4.53 (d, J = 6.4 Hz, 2Н), 6.04 (t, J = 6.4 Hz, 1Н), 7.17 and 7.51 (АА'ХХ', J = 8.8
Hz, 4H), 7.21ꢀ7.32 (m, 5H), 9.68 (s, 1H). 13C NMR (100 MHz, DMSOꢀd6): δ (ꢀ) 25.6, (+) 46.5,
(+) 99.9, (ꢀ) 112.9, (+) 119.9, (ꢀ) 126.9, (ꢀ) 127.3, (ꢀ) 128.3, (ꢀ) 133.4, (+) 140.3, (+) 142.7, (+)
148.7, (+) 194.3. Anal. Calcd for C17H16N4O: C, 69.85; H, 5.52; N, 19.17. Found: C, 69.58; H,
5.69; N, 19.34. EIMS (70 eV) m/z: M+ 292 (11).
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N'ꢀ(4ꢀCyanophenyl)ꢀNꢀcyclohexylꢀ2ꢀoxopropanehydrazonamide (5o). Paleꢀyellow powder
(250 mg, 88%). Rf = 0.63 (Hex/EtOAc, 1:1), 0.69 (Hex/CHCl3, 1:5); mp 135ꢀ136 ºC. IR, (cmꢀ1):
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3319, 3221 (NꢀH), 2966, 2956, 2918 (CꢀH), 2218 (C≡N), 1687 (C=O). Н NMR (400 MHz,
DMSOꢀd6): δ 1.07ꢀ1.35 (m, 5H), 1.55ꢀ1.87 (m, 5H), 2.42 (s, 3Н), 3.36ꢀ3.75 (m, 1H), 5.11 (d, J =
8.9 Hz, 1Н), 7.20 and 7.51 (АА'ХХ', J = 8.7 Hz, 4H), 9.59 (s, 1H). 13C NMR (100 MHz, DMSOꢀ
d6): δ (+) 24.6, (+) 25.1, (ꢀ) 25.7, (+) 34.1, (ꢀ) 51.0, (+) 99.8, (ꢀ) 112.9, (+) 119.9, (ꢀ) 133.5, (+)
142.4, (+) 148.7, (+) 194.5. Anal. Calcd for C16H20N4O: C, 67.58; H, 7.09; N, 19.70. Found: C,
67.34; H, 7.21; N, 19.93. EIMS (70 eV) m/z: M+ 284 (60).
N'ꢀ(4ꢀCyanophenyl)ꢀNꢀ(9ꢀethylꢀ9Hꢀcarbazolꢀ2ꢀyl)ꢀ2ꢀoxopropanehydrazonamide (5p). Darkꢀ
brown powder (340 mg, 86%). Rf = 0.63 (Hex/EtOAc, 1:1), 0.51 (Hex/CHCl3, 1:5); mp 178ꢀ179
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ºC. IR (cmꢀ1): 3333 (NꢀH), 2972, 2931, 2913 (CꢀH), 2222 (C≡N), 1673 (C=O). Н NMR (400
MHz, DMSOꢀd6): δ 1.38 (t, J = 7.1 Hz, 3Н), 2.58 (s, 3Н), 4.38 (q, J = 7.1 Hz, 2Н), 6.92 (dd, J =
8.4, 2.0 Hz, 1Н), 7.09 (t, J = 7.2 Hz, 1Н), 7.28 and 7.53 (АА'ХХ', J = 8.8 Hz, 4H), 7.33ꢀ7.39 (m,
3H), 7.41ꢀ7.46 (m, 1H), 7.90ꢀ7.94 (m, 2H), 9.55 (s, 1H). 13C NMR (100 MHz, DMSOꢀd6,): δ (ꢀ)
13.7, (ꢀ) 25.4, (+) 36.9, (+) 101.4, (ꢀ) 109.4, (ꢀ) 114.1, (ꢀ) 118.4, (ꢀ) 118.6, (+) 120.3, (ꢀ) 120.7,
(+) 122.4, (+) 122.6, (ꢀ) 126.0, (+) 133.9, (ꢀ) 134.0, (+) 135.6, (+) 139.6, (+) 140.4, (+) 148.4,
(+) 193.7. Anal. Calcd for C24H21N5O: C, 72.89; H, 5.35; N, 17.71. Found: C, 72.60; H, 5.23; N,
17.91. EIMS (70 eV) m/z: M+ 395 (50).
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N'ꢀ(4ꢀCyanophenyl)ꢀ2ꢀoxoꢀNꢀ(4ꢀ(phenylamino)phenyl)propanehydrazonamide (5q). Darkꢀ
brown powder (317 mg, 86%) Rf = 0.61 (Hex/EtOAc, 1:1), 0.35 (Hex/CHCl3, 1:5); mp 135ꢀ136
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6.92 and 6.96 (АА'ХХ', J = 7.6 Hz, 4H), 7.12 (t, J = 7.2 Hz, 2Н), 7.31 and 7.56 (АА'ХХ', J = 8.8
Hz, 4H), 7.69 (s, 1H), 7.80 (s, 1H), 9.64 (s, 1H). 13C NMR (100 MHz, DMSOꢀd6,): δ (ꢀ) 25.2, (+)
101.1, (ꢀ) 113.7, (ꢀ) 114.9, (ꢀ) 118.2, (ꢀ) 119.3, (+) 119.8, (ꢀ) 129.0, (ꢀ) 133.5, (+) 134.8, (+ )
136.2, (+) 138.5, (+) 144.9, (+) 147.8, (+) 193.6. Anal. Calcd for C22H19N5O: C, 71.53; H, 5.18;
N, 18.96. Found: C, 71.31; H, 5.24; N, 18.71. EIMS (70 eV) m/z: M+ 369 (50).
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Ethyl 2ꢀ(2ꢀ(4ꢀcyanophenyl)hydrazono)ꢀ2ꢀ(methylamino)acetate (5r). Yellow powder (219
mg, 89%). Rf = 0.57 (Hex/EtOAc, 1:1), 0.51 (Hex/CHCl3, 1:5); mp 135ꢀ136 ºC. IR (cmꢀ1): 3394,
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3298 (NꢀH), 2983, 2946, 2936 (CꢀH), 2207 (C≡N), 1702, 1604 (C=O). Н NMR (400 MHz,
DMSOꢀd6): δ 1.32ꢀ1.41 (m, 3H), 2.72ꢀ2.76 and 2.86ꢀ2.90 (two m, 3Н), 4.27 and 4.35 (two q, J =
7.2 Hz, 2Н), 5.86 and 6.07 (two br s, 1Н), 7.00ꢀ7.08 (m, 2H), 7.40ꢀ7.49 (m, 2H), 9.17 and 10.40
(two s, 1H) (ratio of isomeres ꢀ 1:1.2). 13C NMR (100 MHz, DMSOꢀd6,): δ (ꢀ) 13.9/13.8, (ꢀ)
30.2/28.2, (+) 61.1/61.8, (+) 98.7/97.6, (+) 112.3/111.7, (ꢀ) 120.4/120.1, (ꢀ) 133.3/133.2, (+)
140.1/138.0, (+) 149.3/149.2, (+) 161.8/159.8. Anal. Calcd for C12H14N4O2: C, 58.53; H, 5.73;
N, 22.75. Found: C, 58.36; H, 5.53; N, 22.47. EIMS (70 eV) m/z: M+ 246 (59).
General Procedure (GP) for the synthesis of 4,5ꢀdihydroꢀ1Hꢀ1,2,4ꢀtriazoles 11aꢀu.
A solution containing 1.0 mmol of amidrazone 5, 0.16 mL (2 mmol) of pyridine and 2.0 mmol of
esters 5a or 5b in 20 ml of toluene was heated under reflux until the TLC analysis indicated total
consumption of the starting hydrazone. Toluene was evaporated, and the residue was purified by
liquid column chromatography (hexane/ethyl acetate 4:1 or 3:2).
Methyl 3ꢀacetylꢀ5ꢀ(2ꢀmethoxyꢀ2ꢀoxoethyl)ꢀ4ꢀmethylꢀ1ꢀpꢀtolylꢀ4,5ꢀdihydroꢀ1Hꢀ1,2,4ꢀtriazoleꢀ
5ꢀcarboxylate (11a). Bright yellow powder (243 mg, 70%). Rf = 0.26 (Hex/EtOAc, 4:1), 0.66
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(Hex/EtOAc, 1:1); mp 80ꢀ81 ºC. IR (cmꢀ1): 3010, 2979, 2954 (CꢀH), 1737, 1669 (C=O). Н
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