Derivatives of arylhydrazonic acids. Part 2: A facile approach to novel 4,5-dihydro-1H-1,2,4-triazoles via cyclization of amidrazones

Article abstract of DOI:10.1016/S0040-4020(02)00485-4

Starting from arylhydrazonoyl chlorides, the amide arylhydrazones (amidrazones) were obtained by nucleophilic substitution of the chloride function with ammonia, amines or anilines. Treatment of amidrazones with alkyl ketones under acidic catalysis led generally to 4,5-dihydro-1H-1,2,4-triazoles. In addition, with aldehydes 1H-1,2,4-triazoles or aryl condensed 4,5-dihydro-1H-1,3,4-triazepines were formed depending on substitution pattern of amidrazone moiety. The structures of the new products have been established by ¹H and ¹³C NMR studies.

Full text of DOI:10.1016/S0040-4020(02)00485-4

TETRAHEDRON
Pergamon
Tetrahedron 58 +2002) 5317±5326
Derivatives of arylhydrazonic acids. Part 2: A facile approach to
novel 4,5-dihydro-1H-1,2,4-triazoles
via cyclization of amidrazonesq
Guntram Drutkowski,p Christian Donner, Ingo Schulze and Petra Frohberg
È
Institute of Pharmaceutical Chemistry, Martin-Luther-Universitat Halle-Wittenberg, Wolfgang-Langenbeck-Straûe 4,
06120 Halle, Germany
Received 3 January2002; revised 11 April 2002; accepted 7 May2002
AbstractÐStarting from arylhydrazonoyl chlorides, the amide arylhydrazones +amidrazones) were obtained by nucleophilic substitution of
the chloride function with ammonia, amines or anilines. Treatment of amidrazones with alkyl ketones under acidic catalysis led generally to
4,5-dihydro-1H-1,2,4-triazoles. In addition, with aldehydes 1H-1,2,4-triazoles or aryl condensed 4,5-dihydro-1H-1,3,4-triazepines were
1
formed depending on substitution pattern of amidrazone moiety. The structures of the new products have been established by H and 13C
NMR studies. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
tion of a-carbonyl substituted amidrazones I to highly
substituted dihydrotriazoles II +Fig. 1).
In the recent past, derivatives of 4,5-dihydro-1H-1,2,4-tri-
azoles have been worthyof an increased note as a result of
their abilityto form stable carbenes, which are applied as
ligand in organometallic and inorganic chemistryas well
as in organic catalysis.2 Furthermore, Neugebauer and
Fischer could isolate stable 2,5-dihydro-1,2,4-triazol-2-yl
radicals, which have been prepared bydehydrogenation of
4,5-dihydro-1H-1,2,4-triazoles.3 The stabilityof these
radicals has made NMR and ESR studies and the
application in controlled radical polymerization processes
possible.3,4
Figure 1.
Various known 4,5-dihydro-1H-1,2,4-triazoles were synthe-
sized via 1,3-dipolar cycloaddition of nitrilimines with
dipolarophiles, but the substitution pattern is limited by
availabilityof nitrilimines and of appropriate reactive
dipolarophiles. Recently, the synthesis of 5-disubstituted
3-acetyl-4,5-dihydro-1H-1,2,4-triazoles has been described,
which were yielded by reaction of ketoximes with hydra-
zonoyl chlorides.5 However, this synthetic pathway
excludes the formation of 4-substituted derivatives. Alter-
natively, 1,3,4-trisubstituted 4,5-dihydro-1H-1,2,4-triazoles
can be prepared using amidrazones as intermediates.6 No
reports are found in literature concerning cyclization reac-
A wide range of various substituents of heterocylic systems
gains importance to construct combinatorial libraries for
medicinal chemistryprogram. Ccylic and open-chain
derivatives of amidrazones are known to exhibit
inhibitoryactivityagainst enzmy es of arachidonic acid
cascade which is responsible for the formation of
biological active metabolites.7 These substances are con-
sidered as potent mediators of in¯ammatoryand allergic
reactions in human.8 Our interest in amidrazones 1, their
properties and stabilityprompt us to investigate their
reactivity.
In this paper, we describe the synthesis of 5,5-dialkyl-1-
aryl-4,5-dihydro-1H-1,2,4-triazole-3-carboxanilides 2 besides
1H-1,2,4-triazoles 3 and aryl condensed 4,5-dihydro-1H-
1,3,4-triazepines 4 +for review on 1,3,4-triazepines, see Ref.
q See Ref. 1 for Part 1.
Keywords: amidrazones; heterocycles; structural assignment; triazoles;
benzotriazepines.
p
9) byccylization of amidrazones
compounds +Fig. 2).
1 with monocarbonyl
Corresponding author. Tel.: 149-345-5525178; fax: 149-345-5527027;
e-mail: guntram.drutkowski@epost.de
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+02)00485-4

5318
G. Drutkowski et al. / Tetrahedron 58 02002) 5317±5326
+synthesis of amidrazones 1m, 1p and 1q) required an
additional equimolar amount of triethylamine as proton
acceptor. Yields varied between 70 and 80%.
It is known that amidrazones cyclisize with monocarbonyl
compounds to give 4,5-dihydro-1H-1,2,4-triazoles as well
as 1,2,4-triazoles.11 The condensation of amidrazones with
aldehydes and ketones can yield 4,5-dihydro-1H-1,2,4-tri-
azoles.12 However, this method is limited bythe fact that the
product obtained from N1- or N2-unsubstituted amidrazones
is often the open-chain hydrazone rather than the tautomeric
dihydrotriazole.13
The not as yet described 5,5-dialkyl-1-aryl-4,5-dihydro-1H-
1,2,4-triazole-3-carboxanilides 2 were obtained from 1 and
alkyl ketones, which served themselves as solvent for the
reaction +Scheme 1, step B). Yields varied between 20 and
60%. Acidic conditions needed for cyclization were
achieved byaddition of catalyzing amounts of p-toluene
sulfonic acid. Attempts to increase the yields using other
acids for catalyzing +e.g. diluted or concentrated acetic acid
or hydrochloric acid, respectively) were unsuccessful and
led not onlyto the desired dihydrotriazoles but also to a lot
of byproducts in the reaction mixture. The ring closure
mostlyoccurred within 30 min. However, in some cases,
the reaction required about ®ve or more hours. Controlling
reaction progress byTLC was necessaryto ®nd out the
completion of the synthesis.
Figure 2.
2. Results and discussion
2.1. Synthesis
Oxaniloamide arylhydrazones 1 were prepared according to
known procedures,10 see Scheme 1 +step A). Nucleophilic
substitution of recently reported oxaniloarylhydrazonoyl
chlorides 51 was carried out with ammonia, amines or
anilines in dioxane and was promoted byan additional equi-
molar amount of base, ammonia or the corresponding
aliphatic amine, respectively. At a temperature between
40 and 458C, the reaction was complete usuallywithin
less than 12 h. The ammonia was applied as a methanolic
solution to suppress side reactions, which occurred in the
presence of water. However, anilines as nucleophiles
In addition to the affording 4,5-dihydro-1H-1,2,4-triazole-3-
carboxanilide 2i, a further product was formed bytreating
1p with acetone. Using TLC and comparing to the obtained
derivatives of triazepines 4 described below, it is conceiv-
able, that this product was the related 4,5-dihydro-1H-1,3,4-
benzotriazepine +analogous compound 4). Nevertheless, it
was not isolable.
Scheme 1.

G. Drutkowski et al. / Tetrahedron 58 02002) 5317±5326
5319
much higher than that of the corresponding open-chain
derivatives 1. No decomposition was discovered during
keeping the solid products at room temperature for some
months.
Under strong acidic conditions, the ring closure is reversible
which becomes visible byloss of ¯uorescence. It has been
proved byNMR experiments that in DMSO-d dihydro-
6
triazoles 2 slowlydecompose into the corresponding
amidrazones 1 in the presence of tri¯uoroacetic acid.
Scheme 2.
No reaction could be observed between amidrazones 1 and
alkyl aryl as well as diaryl substituted ketones, which is
attributed to lower carbonyl reactivity of aryl ketones.
However, the replacement bysubstituted a,a-dichloro-
methane should yield the cyclization.3
The treatment of amidrazones 1 +provided that R3ˆH, e.g.
1f or 1k) with formaldehyde instead of ketones in re¯uxing
ethanol led under acidic catalysis to 1-aryl-1H-1,2,4-tri-
azole-3-carboxanilides 3 +Scheme 2). The corresponding
dihydrotriazoles 2 were observed as intermediates and
detected in the reaction mixture byTLC. However, they
underwent a rapid oxidation to 1H-1,2,4-triazoles 3.14
Unlike the reaction with ketones, orthosubstituted N2-aryl-
amidrazones +e.g. 1f) gave a successful cyclization with
formaldehyde as well.
Scheme 3.
Amidrazones 1b, 1f, 1g and 1q were recovered unchanged
under the described conditions +Section 4). Onlya trace of
the 4,5-dihydrotriazole was detected by TLC in the reaction
mixtures because of the characteristic ¯uorescence. We
assume that ortho substitution of the arylhydrazone moiety
could result in a steric hindrance and a decreased reactivity.
On the other hand, the addition of formaldehyde or benzal-
dehyde to 1m, 1p or 1q +R3ˆaryl, reaction conditions like
that shown in Scheme 2) furnished aryl condensed dihydro-
triazepines 4, see Scheme 3. The preparation of similar
4-aryl-4,5-dihydro-1H-1,3,4-benzo[e]triazepines and the
assignment of its structure have previouslybeen
reported.15,16 Byanalogywith the referred reaction,
5,5-Dialkyl-1-aryl-4,5-dihydro-1H-1,2,4-triazole-3-carbox-
anilides 2 commonly form yellow colored crystals and are
soluble in alcohols with appearance of an intensive green±
yellow ¯uorescence. The stability of these compounds is
2-chlorooxanilo-N-+4-chlorophenyl)amide
phenylhydra-
zone +1p) and formaldehyde gave 4a; oxanilo-N-phenyl-
amide phenylhydrazone +1m) and benzaldehyde yielded
Table 1. Essential spectroscopic data of amidrazones 1
1H NMR spectroscopic data +DMSO-d6) d +ppm)
13C NMR spectroscopic data +DMSO-d6) d
+ppm)
IR spectroscopic data
+potassium bromide) n +cm21
)
NNH +s, 1H)
NH2/NH
CONH +s, 1H)
Ar-H
CvO +1C) CvN +1C)
Ar-C
CvO
NH
1b
1c
1d
1e
1f
8.25
8.80
8.54
8.79
8.02
6.44 +s, 2H)
6.12 +s, 2H)
6.01 +s, 2H)
6.21 +s, 2H)
6.71 +s, 2H)
6.55 +s, 2H)
6.25 +s, 2H)
9.80
9.83
9.75
9.96
9.96
9.71
9.97
6.7±7.8 +9H)
6.4±7.8 +9H)
7.0±7.8 +9H)
6.7±8.3 +9H)
6.8±8.2 +8H)
6.8±8.0 +8H)
6.7±8.2 +8H)
6.7±7.9 +8H)
6.7±7.8 +8H)
7.1±7.8 +8H)
6.7±8.0 +10H) 160.6
6.7±7.8 +15H) 160.8
7.0±7.7 +9H)
7.0±7.8 +9H)
6.6±8.2 +13H) 160.1
6.8±7.9 +15H) 160.8
160.2
160.1
159.9
159.4
159.6
159.6
159.5
160.4
160.0
160.2
138.0
136.7
138.1
134.3
137.7
137.7
136.2
136.7
137.1
137.8
140.4
132.4
139.7
142.7
130.1
133.9
115.6±150.9 +12C) 1654
104.2±164.9 +12C) 1648
113.4±158.0 +12C) 1646
112.0±145.6 +12C) 1675
114.6±142.0 +12C) 1691
3357, 3441
3440, 3361
3431, 3358
3368
3418, 3329
1ga 9.13
114.9±147.6 +12C) 1701, 1672 3460, 3356
1h
1i
1j
8.99
8.81
8.79
111.0±147.3 +12C) 1678
111.3±147.4 +12C) 1677
111.1±147.2 +12C) 1675
111.9±159.7 +12C) 1667
113.9±146.3 +12C) 1683
114.1±145.5 +18C) 1685
112.7±143.8 +12C) 1679
115.2±147.0 +12C) 1682
113.7±144.4 +18C) 1672
112.0±140.2 +22C) 1678
3324
3355
3359
3339, 3437
3331
3351
3403, 3336, 3284
3350
3335
6.13 +s, 2H) 10.01
6.12 +s, 2H)
6.10 +s, 2H)
5.73 +q, 1H)
9.99
9.92
9.94
1kb 8.83
1lc
8.51
1m 9.25
1nd 8.37
1oe 8.64
1p
1q
8.02 +s, 1H) 10.07
5.66 +q, 1H)
5.82 +q, 1H)
8.27 +s, 1H)
9.91
9.98
9.81
160.3
162.2
9.53
8.96
8.04 +s, 1H) 10.44
3345, 3307
a
Additional signals: 119.3 +1C, CuN).
Additional signals: 2.49 +s, 1H, CH3), 198.5 +1C, CvO), 26.8 +1C, CH3).
Additional signals: 2.93 +d, 3H, CH3), 30.3 +1C, CH3).
Additional signals: 2.19 +s, 3H, CH3), 2.91 +d, 3H, CH3), 20.3 +1C, CH3), 30.3 +1C, CH3).
Additional signals: 2.92 +d, 3H, CH3), 31.7 +1C, CH3).
b
c
d
e

Table 2. Essential spectroscopic data of cyclic compounds 2±4
1H NMR spectroscopic data +DMSO-d6) d +ppm)
13C NMR spectroscopic data +DMSO-d6) d +ppm)
IR spectroscopic data
+potassium bromide) n
+cm21
)
NH +s, 1H)
CONH +s, 1H)
CH3 +s)
Ar-H
CvO +1C)
CvN +1C)
C-5 +1C)
CH3
Ar-C
CvO
NH
2a
2ba
2c
7.34
±
7.55
±
10.24
10.15
10.06
10.11
10.19
10.05
9.54
9.48
9.81
9.73
10.26
10.24
10.22
10.07
10.65
10.11
9.78
1.57 +6H)
1.52 +6H)
1.60 +6H)
1.45 +6H)
1.53 +6H)
1.47 +6H)
1.56 +6H)
1.50 +3H)
1.51 +6H)
1.60 +6H)
1.59 +6H)
1.58 +6H)
1.58 +6H)
±
6.9±8.6 +10H)
6.9±7.7 +10H)
6.6±7.8 +9H)
7.1±7.8 +9H)
7.3±7.7 +9H)
7.0±7.8 +9H)
6.8±8.0 +9H)
6.8±8.0 +9H)
7.0±7.8 +13H)
6.7±7.8 +8H)
6.8±7.9 +8H)
6.8±7.8 +8H)
7.1±7.8 +8H)
7.2±8.0 +8H)
7.2±8.5 +8H)
6.9±8.3 +12H)
6.9±7.7 +19H)
7.2±8.1 +14H)
156.7
157.4
156.5
157.3
157.3
156.7
156.3
156.5
156.0
156.5
156.9
156.6
156.6
156.5
157.1
159.2
159.7
160.5
144.4
144.2
144.5
141.5
144.4
144.8
143.4
143.9
142.8
144.3
144.5
144.5
144.7
147.2
144.1
132.9
139.2
133.2
84.2
87.3
83.8
87.7
87.1
84.7
84.7
87.2
88.7
84.2
84.0
83.9
84.0
130.5
130.5
57.3
69.7
58.8
26.6 +2C)
22.1 +2C)
26.4 +2C)
22.2 +2C)
28.0 +2C)
26.5 +2C)
26.6 +2C)
25.4 +1C)
25.3 +2C)
26.5 +2C)
26.4 +2C)
26.5 +2C)
26.6 +2C)
±
116.7±143.9 +12C)
117.4±143.8 +12C)
102.4±165.4 +12C)
118.6±144.2 +12C)
118.4±142.6 +12C)
114.9±159.6 +12C)
116.3±143.8 +12C)
115.2±143.5 +12C)
118.2±142.5 +18C)
113.4±144.8 +12C)
113.4±144.9 +12C)
113.3±144.8 +12C)
114.9±160.9 +12C)
124.7±134.1 +12C)
115.2±138.4 +12C)
114.9±148.5 +18C)
116.8±149.4 +24C)
120.3±149.1 +22C)
1672
1678
1668
1679
1671
1679
1679
1679
1697
1697
1668
1674
1676
1703
1698
1685
1674
1685
3295, 3383
3331
3294
3436
3306
3381, 3325
3339
3351
3358
3358
3327
3317
3290
3346
3372
3327
3328
3442, 3337
2db
2ec
2f
±
7.30
7.38
7.40
±
7.69
7.43
7.58
7.53
±
2g
2hd
2i
2j
2k
2l
2me
3a
3bf
4a
4b
4c
±
±
±
±
±
±
±
±
±
9.29
8.90
9.09
10.12
a
Additional signals: 2.98 +s, 3H, CH3), 28.1 +1C, CH3).
Additional signals: 2.24 +s, 3H, CH3), 2.96 +s, 3H, CH3), 28.3 +1C, CH3), 20.4 +1C, CH3).
Additional signals: 2.98 +s, 3H, CH3), 22.1 +1C, CH3).
b
c
d
e
f
Additional signals: for R5: 0.85 +t, 3H, CH2CH3), 1.76 +m, 1H) and 2.17 +m, 1H, CH2CH3), 9.2 +1C, CH2CH3), 33.7 +1C, CH2CH3).
Additional signals: 2.57 +s, 3H, CH3), 26.8 +1C, CH3), 198.1 +1C, CvO).
Additional signals: 2.68 +s, 3H, CH3), 9.63 +s, 1H, NvCH±N); 26.9 +1C, CH3).

G. Drutkowski et al. / Tetrahedron 58 02002) 5317±5326
5321
4b; 3-chlorooxanilo-N-naphthylamide +2-chlorophenyl)-
hydrazone +1q) was converted with formaldehyde into 4c.
Furthermore, dihydrotriazoles, which were formed accord-
ing to above described cyclization mechanism +see Scheme
1, step B), were detected in reaction mixtures byTLC as
well but could not be isolated.
The structures of all compounds described herein were
con®rmed byanaltyical +Section 4) and spectroscopic
methods.
Scheme 4.
2.2. Establishment of structures
1H, 13C NMR and IR spectral data of considerable moieties
of amidrazones 1 are listed in Table 1. As expected, H
1
NMR spectra of these compounds in DMSO-d6 show
three characteristic signals: one singlet of the CONH
group at about 9±10 ppm, another singlet of the NNH
group in the region of 8±9 ppm and the signal of the NH2
or alkyl substituted NH group near 6 ppm or at about 8 ppm
in case of aryl substituted amide moiety, respectively. We
assigned the signal in the region of 8±9 ppm to the proton of
the NNH moietyusing 1H, 13C long range experiments. 13
C
NMR spectra exhibit two characteristic signals for the CvO
and the CvN moieties at about 160 and 137 ppm. The
signal of the hydrazone carbon is strongly in¯uenced by
the amide substituent of the amidrazone structure, see
1l±1q. Typical bands of CvO stretching at about
1650 cm21 and of NH stretching in the region of
3400 cm21 appear in the IR spectra.
Scheme 5.
The signal in the 13C NMR spectra of products 2 between 80
and 87 ppm +Table 2) was assigned to an aminal carbon and
proves the ring closure to 4,5-dihydro-1H-1,2,4-triazoles
consistent with literature data.6,11 In contrast, the 13C signal
of an imine carbon atom of open-chain isomer 2.B is
expected at 145±160 ppm.6,12
Essential 1H, 13C NMR and IR spectroscopic data of the new
synthesized heterocyclic compounds 2±4 are summarized in
1
Table 2. H NMR spectra of all carboxanilides displays a
Provided that R3ˆH, the dihydrotriazoles 2 can exist in
tautomeric form 2.A and 2.C as well +Scheme 5). NOE
experiments with derivative 2k +Section 4) revealed the
compounds to occur in tautomer 2.A. The irradiation in
frequencyof the methyl protons causes a NOE not onlyto
the aromatic ortho-protons, which could accord with both
tautomers but also to the cyclic NH proton, which excludes
structure 2k.C.
characteristic singlet in the range of 10 ppm. Considering
the spectral establishment of amidrazones 1 and the struc-
ture of triazole derivatives 3, the signal was assumed to be
that of the anilide proton. Accordingly, the signal near
7 ppm in the spectra of dihydrotriazoles 2 and about
9 ppm in the spectra of dihydrotriazepines 4 was assigned
to the heterocyclic NH moiety. NOE experiments with 2
1
+see below) as well as H, 13C long range experiments
with 4 con®rmed this assignment. Comparing to 13C NMR
spectra of open-chain derivatives 1, the chemical shift of the
CvO group of heterocycles 2 and 3 is deshielded for about
3 ppm up®eld and that of the CvN moietymostlymore than
7 ppm down®eld. The signals of the C-5 atom of dihydro-
triazoles 2 appear at about 85 ppm and around 58 ppm in
case of triazepines 4. The spectra of the triazoles 3 show the
signal of the C-5 atom in the region of aromatic carbon
atoms near 130 ppm. Typical bands of the CvO and NH
stretch in the region of 1680±1700 and 3290±3440 cm21 are
observed in IR spectra.
The acidic catalyzed reaction of amidrazone 1q and form-
aldehyde could lead to product 4c.A or the isomer 4c.B,
respectively+Scheme 6). 1H, 13C long range experiments
indicated that 4c.A was formed. There is no coupling
observed between the signal of C-5 and anyproton signal.
However, in case of product 4c.B a coupling should be
expected between the C-5 signal and the signal of the proton
in position 6.
3. Conclusion
The assignment of the 13C signal of the CvN group in both
the open-chain as well as the cyclic compounds was compli-
cated bythe similar chemical shift of the aromatic C-atom in
The described approach to 1,3,4,5,5-pentasubstituted 4,5-
dihydro-1H-1,2,4-triazoles is a facile method to obtain a
large scale of derivatives not onlyof dihydrotriazoles but
also of the isolated intermediate amidrazones. The con-
venient cyclization of amidrazones 1 to 4,5-dihydro-1H-
1,2,4-triazoles 2 we assume to be easytransfer to other
a-carbonyl substituted amidrazones. Considering combina-
torial libraries, 1,3,5-trisubstituted 1,2,4-triazoles were
1
a-position to the hydrazone moiety. H, 13C long range
experiments were used to distinguish between both.
The reaction of N1-unsubstituted amidrazones with ketones
could lead not onlyto the cyclic product 2.A but also to the
open-chain tautomer 2.B, see Scheme 4.

5322
G. Drutkowski et al. / Tetrahedron 58 02002) 5317±5326
arom. C), 163.4 +d, 1C, arom. CF, Jˆ242 Hz). IR
+potassium bromide):
n
3386, 3233 +NH), 1667
+CvO) cm21. MS m/z: 291 +[M]1, 72), 93 +100). Anal.
Calcd for C14H11N3OClF +291.7): C 57.65, H 3.80, N
14.40, Cl 12.15, F 6.51%. Found: C 57.82, H 3.78, N
14.30, Cl 12.06, F 6.52%.
4.2.2. N-/4-Fluorophenyl)-2-anilino-2-oxoethanehydra-
zonoyl chloride /5f). According to Ref. 1. Compound was
prepared from 4-¯uoroaniline +2.2 g, 20 mmol) and
2-chloro-N-phenyl-3-oxobutanamide +4.2 g, 20 mmol).
Crystallization from chloroform/heptane gave 2.3 g +82%)
1
of 5f as pale yellow platelets. Mp: 186±1888C. H NMR
+DMSO-d6): d 10.05 +s, 1H, NH), 10.32 +s, 1H, NH), 7.09±
7.71 +m, 9H, arom. H). 13C NMR +DMSO-d6): d 157.4 +1C,
CvO), 118.2 +1C, CvN), 115.5±139.6 +11C, arom. C),
157.8 +d, 1C, arom. CF, Jˆ238 Hz). IR +potassium
bromide): n 3385, 3231 +NH), 1667 +CvO) cm21. MS
m/z: 291 +[M]1, 52), 93 +100). Anal. Calcd for
C14H11N3OClF +291.7): C 57.65, H 3.80, N 14.40, Cl
12.15, F 6.51%. Found: C 57.78, H 3.90, N 14.45, Cl
12.03, F 6.38%.
Scheme 6.
recentlyobtained with dif®culties byoxidative cyclization
of substituted amidrazones.17 The side reaction, which we
observed bythe condensation of amidrazones with form-
aldehyde, is a known procedure to prepare 1,2,4-triazoles
from amidrazones and monocarbonyl compounds18 and
represents an alternative wayto the desired trisubstituted
1,2,4-triazoles.
4.2.3. N-/3-Acetylphenyl)-2-[/4-¯uorophenyl)amino]-2-
oxoethanehydrazonoyl chloride /5n). According to Ref.
1. Compound was prepared from 3-aminophenyl methyl
ketone +2.6 g, 20 mmol) and 2-chloro-N-+4-¯uorophenyl)-
3-oxobutanamide +4.6 g, 20 mmol) +synthesized following
Ref. 20). Crystallization from methanol gave 2.1 g +63%) of
5n as short dark yellow needles. Mp: 232±2348C. 1H NMR
+DMSO-d6): d 10.15 +s, 1H, NH), 10.32 +s, 1H, NH), 6.95±
7.78 +m, 8H, arom. H), 2.56 +s, 3H, CH3). 13C NMR
+DMSO-d6): d 157.7 +1C, CvO), 119.4 +1C, CvN),
114.4±160.9 +11C, arom. C), 158.5 +d, 1C, arom. CF,
Jˆ240 Hz), 26.8 +1C, COCH3), 197.8 +1C, COCH3). IR
4. Experimental
4.1. General
Melting points were determined with a Ko¯er hot-stage
apparatus and are uncorrected. NMR spectra were recorded
on a Gemini 2000 and Gemini 200, operating at 399.96 and
+potassium bromide):
n
3306, 3237 +NH), 1650
+CvO) cm21. MS m/z: 333 +[M]1, 100). Anal. Calcd for
C16H13N3O2ClF +333.7): C 57.58, H 3.92, N 12.59, Cl
10.62, F 5.69%. Found: C 57.70, H 4.02, N 12.51, Cl
10.59, F 5.78%.
1
199.95 MHz for H NMR and at 100.6 and 50.3 MHz for
13C NMR spectra. TMS was used as internal standard.
Chemical shifts are given in d units and refer to the center
of the signal. Mass spectra were obtained with an AMD 402
of the ®rm AMD INTEDRA +70 eV); IR spectra were
recorded on a Spectrum BX FT-IR from the ®rm Perkin±
Elmer. TLC was carried out with TLC aluminium sheets
Silica gel 60 F254 of the ®rm Merck developed in the solvent
chloroform: ether +7:3, v/v) and detected with ultraviolet
light +254 and 360 nm). For NMR and IR spectroscopic
data, see Tables 1 and 2.
4.3. Synthesis of 2-amino-N-aryl-2-arylhydrazono-
acetamides 1a±k, general procedure /GP 1)
A solution of arylhydrazonoyl chloride 5 +20 mmol) in
about 50 mL dioxane was added slowlyto 40 mmol
ammonia +5.7 mL of a 7N methanolic solution). After
stirring at 40±458C for 12 h the mixture was poured into
250 mL cold water. The solid was collected, thoroughly
washed with water, dried and recrystallized from the
given solvent.
4.2. Arylhydrazonoyl chlorides /5a±n)
Compounds were obtained in accordance to Ref. 19 +5a and
5d), Ref. 16 +5e) and Ref. 1 +5b and 5g±m).
2-Amino-N-phenyl-2-phenylhydrazonoacetamide 1a was
obtained starting from compound 5a according to published
procedure.16
4.2.1. N-/3-Fluorophenyl)-2-anilino-2-oxoethanehydra-
zonoyl chloride /5c). According to Ref. 1. Compound
was prepared from 3-¯uoroaniline +2.2 g, 20 mmol) and
2-chloro-N-phenyl-3-oxobutanamide +4.2 g, 20 mmol).
Crystallization from chloroform/heptane gave 2.3 g +82%)
4.3.1. 2-Amino-2-[/2-¯uorophenyl)hydrazono]-N-phenyl-
acetamide /1b). Compound was prepared from 2-anilino-N-
+2-¯uorophenyl)-2-oxoethanehydrazonoyl chloride 5b
+5.8 g, 20 mmol) following GP 1. Crystallization from
chloroform/heptane gave 2.8 g +52%) of 1b as yellow amor-
phous solid. Mp: 158±1608C. MS m/z: 272 +[M]1, 100).
1
of 5c as pale yellow needles. Mp: 168±1708C. H NMR
+DMSO-d6): d 10.11 +s, 1H, NH), 10.45 +s, 1H, NH),
6.73±7.70 +m, 9H, arom. H). 13C NMR +DMSO-d6): d
157.4 +1C, CvO), 119.6 +1C, CvN), 101.9±145.1 +11C,

G. Drutkowski et al. / Tetrahedron 58 02002) 5317±5326
5323
Anal. Calcd for C14H13N4OF +272.3): C 61.76, H 4.81, N
20.57, F 6.98%. Found: C 61.62, H 4.79, N 20.60, F 7.01%.
N-+3-chlorophenyl)-2-[+3-chlorophenyl)amino]-2-oxoethane-
hydrazonoyl chloride 5l +6.9 g, 20 mmol) following GP 1.
Crystallization ®rst from chloroform, then from methanol
gave 3.6 g +56%) of 1i as white amorphous solid. Mp: 148±
1508C. MS m/z: 322 +[M]1, 100). Anal. Calcd for
C14H12N4OCl2 +323.2): C 52.03, H 3.74, N 17.33, Cl
21.94%. Found: C 52.09, H 3.74, N 17.30, Cl 21.88%.
4.3.2. 2-Amino-2-[/3-¯uorophenyl)hydrazono]-N-phenyl-
acetamide /1c). Compound was prepared from 2-anilino-N-
+3-¯uorophenyl)-2-oxoethanehydrazonoyl chloride 5c
+5.8 g, 20 mmol) following GP 1. Crystallization from
chloroform/heptane gave 4.0 g +74%) of 1c as white amor-
phous solid. Mp: 175±1788C. MS m/z: 272 +[M]1, 100).
Anal. Calcd for C14H13N4OF +272.3): C 61.76, H 4.81, N
20.57, F 6.98%. Found: C 61.52, H 4.96, N 20.53, F 6.93%.
4.3.9. 2-Amino-N-/4-chlorophenyl)-2-[/3-chlorophenyl)-
hydrazono]acetamide /1j). Compound was prepared from
N-+3-chlorophenyl)-2-[+4-chlorophenyl)amino]-2-oxoethane-
hydrazonoyl chloride 5m +6.9 g, 20 mmol) following GP 1.
Crystallization from chloroform/heptane gave 4.8 g +74%)
of 1j as amorphous white solid. Mp: 188±1898C. MS m/z:
322 +[M]1, 100). Anal. Calcd for C14H12N4OCl2 +323.2): C
52.03, H 3.74, N 17.33, Cl 21.94%. Found: C 52.05, H 3.67,
N 17.01, Cl 21.37%.
4.3.3. 2-Amino-2-[/4-¯uorophenyl)hydrazono]-N-phenyl-
acetamide /1d). Compound was prepared from 2-anilino-N-
+4-¯uorophenyl)-2-oxoethanehydrazonoyl chloride 5f
+5.8 g, 20 mmol) following GP 1. Crystallization from
chloroform/heptane gave 4.2 g +77%) of 1d as yellow amor-
phous solid. Mp: 151±1538C. MS m/z: 272 +[M]1, 100).
Anal. Calcd for C14H13N4OF +272.3): C 61.76, H 4.81, N
20.57, F 6.98%. Found: C 61.68, H 4.87, N 20.49, F 7.09%.
4.3.10.
2-[/3-Acetylphenyl)hydrazono]-2-amino-N-/4-
¯uorophenyl)acetamide /1k). Compound was prepared
from N-+3-acetylphenyl)-2-[+4-¯uorophenyl)amino]-2-oxo-
ethanehydrazonoyl chloride 5n +6.7 g, 20 mmol) following
GP 1. Crystallization from chloroform/heptane gave 5.5 g
+87%) of 1k as yellow amorphous solid. Mp: 232±2348C.
MS m/z: 314 +[M]1, 100). Anal. Calcd for C16H15N4O2F
+314.3): C 61.14, H 4.81, N 17.82, F 6.04%. Found: C
60.96, H 4.86, N 17.60, F 6.22%.
4.3.4. 2-Amino-N-/2-chlorophenyl)-2-phenylhydrazono-
acetamide /1e). Compound was prepared from 2-[+2-
chlorophenyl)amino]-2-oxo-N-phenylethanehydrazonoyl
chloride 5g +6.2 g, 20 mmol) following GP 1. Crystalliza-
tion from methanol gave 4.2 g +72%) of 1e as long, yellow
needles. Mp: 155±1568C. MS m/z: 288 +[M]1, 89), 91 +100).
Anal. Calcd for C14H13N4OCl +288.7): C 58.24, H 4.54, N
19.40, Cl 12.28%. Found: C 58.19, H 4.55, N 19.48, Cl
12.26%.
4.4. Synthesis of N-substituted 2-amino-N-aryl-2-aryl-
hydrazonoacetamides 1l±1q, /GP2)
4.3.5. 2-Amino-N-/2-chlorophenyl)-2-[/2-chlorophenyl)-
hydrazono]acetamide /1f). Compound was prepared from
N-+2-chlorophenyl)-2-[+2-chlorophenyl)amino]-2-oxoethane-
hydrazonoyl chloride 5h +6.9 g, 20 mmol) following GP 1.
Crystallization from chloroform/heptane gave 4.8 g +75%)
of 1f as white needles. Mp: 172±1748C. MS m/z: 322 +[M]1,
100). Anal. Calcd for C14H12N4OCl2 +323.2): C 52.03, H
3.74, N 17.33, Cl 21.94%. Found: C 51.64, H 3.69, N
16.95, Cl 21.80%.
A solution of arylhydrazonoyl chloride 5 +20 mmol) in
about 50 mL dioxane was added dropwise to 40 mmol
methylamine +20 mL of 2 M methanolic solution) or
20 mmol aniline and 20 mmol triethylamine +2.7 mL),
respectively, in a few mL dioxane. After stirring at 40±
458C for at least 12 h +control of reaction progress by
TLC) the solvent was evaporated and the residue was
treated with cold water. The solid was collected, washed
with water, dried and recrystallized from the given solvent.
4.3.6. 2-Amino-N-/2-chlorophenyl)-2-[/2-cyanophenyl)-
hydrazono]acetamide /1g). Compound was prepared
from 2-[+2-chlorophenyl)amino]-N-+2-cyanophenyl)-2-oxo-
ethanehydrazonoyl chloride 5i +6.7 g, 20 mmol) following
GP 1. Crystallization from ethanol/chloroform gave 4.8 g
+76%) of 1g as amorphous pale yellow solid. Mp: 222±
2238C. MS m/z: 313 +[M]1, 10), 135 +100). Anal. Calcd
for C15H12N5OCl +313.7): C 57.43, H 3.85, N 22.32, Cl
11.30%. Found: C 57.22, H 3.71, N 21.94, Cl 11.16%.
4.4.1. 2-Methylamino-N-phenyl-2-phenylhydrazonoace-
tamide /1l). Compound was prepared from 2-anilino-2-
oxo-N-phenylethanehydrazonoyl chloride 5a +5.5 g,
20 mmol) and methylamine following GP 2. Crystallization
from heptane gave 3.9 g +72%) of 1l as yellow needles. Mp:
101±1038C. MS m/z: 268 +[M]1, 100). Anal. Calcd for
C15H16N4O +268.3): C 67.15, H 6.01, N 20.88%. Found: C
67.22, H 6.00, N 20.70%.
4.4.2. N-Phenyl-2-phenylamino-2-phenylhydrazonoacet-
amide /1m). Compound was prepared from 2-anilino-2-
oxo-N-phenylethanehydrazonoyl chloride 5a +5.5 g,
20 mmol) and aniline +1.9 g, 20 mmol) following GP 2.
Crystallization from chloroform/heptane gave 3.6 g +55%)
of 1m as dark yellow needles. Mp: 166±1688C. MS m/z: 330
+[M]1, 100). Anal. Calcd for C20H18N4O +330.4): C 72.71, H
5.49, N 16.96%. Found: C 72.64, H 5.55, N 16.98%.
4.3.7. 2-Amino-N-/2-chlorophenyl)-2-[/3-chlorophenyl)-
hydrazono]acetamide /1h). Compound was prepared
from
N-+3-chlorophenyl)-2-[+2-chlorophenyl)amino]-2-
oxoethanehydrazonoyl chloride 5j +6.9 g, 20 mmol) follow-
ing GP 1. Crystallization from chloroform gave 4.1 g +63%)
of 1h as amorphous yellow solid. Mp: 192±1948C. MS m/z:
322 +[M]1, 100). Anal. Calcd for C14H12N4OCl2 +323.2): C
52.03, H 3.74, N 17.33, Cl 21.94%. Found: C 52.10, H 3.71,
N 17.23, Cl 21.78%.
4.4.3. 2-Methylamino-2-[/4-methylphenyl)hydrazono]-
N-phenylacetamide /1n). Compound was prepared from
2-anilino-N-+4-methylphenyl)-2-oxoethanehydrazonoyl
chloride 5d +5.8 g, 20 mmol) and methylamine following
4.3.8. 2-Amino-N-/3-chlorophenyl)-2-[/3-chlorophenyl)-
hydrazono]acetamide /1i). Compound was prepared from

5324
G. Drutkowski et al. / Tetrahedron 58 02002) 5317±5326
GP 2. Crystallization from methanol gave 3.3 g +58%) of 1n
as dark yellow crystals. Mp: 106±1088C. MS m/z: 282
+[M]1, 100). Anal. Calcd for C16H18N4O +282.3): C 68.06,
H 6.43, N 19.84%. Found: C 68.05, H 6.46, N 19.93%.
crystals. Mp: 100±1028C. MS m/z: 308 +[M]1, 11), 292
+100). Anal. Calcd for C18H20N4O +308.4): C 70.11, H
6.53, N 18.16%. Found: C 69.79, H 6.40, N 17.95%.
4.5.3.
1-/3-Fluorophenyl)-5,5-dimethyl-N-phenyl-4,5-
4.4.4. 2-[/4-Chlorophenyl)hydrazono]-2-methylamino-
N-phenylacetamide /1o). Compound was prepared from
2-anilino-N-+4-chlorophenyl)-2-oxoethanehydrazonoyl
chloride 5e +6.2 g, 20 mmol) and methylamine following
GP 2. Crystallization from methanol gave 3.8 g +62%) of
1o as orange needles. Mp: 106±1088C. MS m/z: 302 +[M]1,
100). Anal. Calcd for C15H15N4OCl +302.8): C 59.51, H
4.99, N 18.51, Cl 11.71%. Found: C 59.64, H 5.01, N
18.46, Cl 11.68%.
dihydro-1H-1,2,4-triazole-3-carboxamide /2c). Com-
pound was prepared from 2-amino-2-[+3-¯uorophenyl)-
hydrazono]-N-phenylacetamide 1c +2.7 g, 10 mmol) and
acetone following GP 3. Crystallization from methanol
gave 2.3 g +73%) of 2c as yellow platelets. Mp: 172±
1758C. MS m/z: 312 +[M]1, 18), 204 +100). Anal. Calcd
for C17H17N4OF +312.3): C 65.37, H 5.48, N 17.93, F
6.08%. Found: C 65.27, H 5.59, N 17.91, F 6.22%.
4.5.4. 4,5,5-Trimethyl-1-/4-methylphenyl)-N-phenyl-4,5-
dihydro-1H-1,2,4-triazole-3-carboxamide /2d). Com-
pound was prepared from 2-methylamino-2-[+4-methyl-
phenyl)hydrazono]-N-phenylacetamide 1n +2.8 g, 10 mmol)
and acetone following GP 3. Crystallization from methanol
gave 2.4 g +75%) of 2d as yellow crystals. Mp: 106±1108C.
MS m/z: 322 +[M]1, 9), 307 +100). Anal. Calcd for
C19H22N4O +322.4): C 70.78, H 6.88, N 17.34%. Found: C
70.60, H 6.95, N 17.40%.
4.4.5. N-/2-Chlorophenyl)-2-[/4-chlorophenyl)amino]-2-
phenylhydrazonoacetamide /1p). Compound was
prepared from 2-[+2-chlorophenyl)amino]-2-oxo-N-phenyl-
ethanehydrazonoyl chloride 5g +6.2 g, 20 mmol) and
4-chloroaniline +2.6 g, 20 mmol) following GP 2. Crystal-
lization ®rst from chloroform/heptane, then from 2-propa-
nol gave 4.6 g +58%) of 1p as yellow crystals. Mp: 210±
2118C. MS m/z: 398 +[M]1, 14), 220 +100). Anal. Calcd for
C20H16N4OCl2 +399.3): C 60.17, H 4.04, N 14.03, Cl
17.76%. Found: C 60.14, H 4.09, N 13.74, Cl 17.32%.
4.5.5. 1-/4-Chlorophenyl)-4,5,5-trimethyl-N-phenyl-4,5-
dihydro-1H-1,2,4-triazole-3-carboxamide /2e). Com-
pound was prepared from 2-[+4-chlorophenyl)hydrazono]-
2-methylamino-N-phenylacetamide 1o +3.1 g, 10 mmol)
and acetone following GP 3. Crystallization from methanol
gave 1.2 g +35%) of 2e as yellow crystals. Mp: 120±1228C.
MS m/z: 342 +[M]1, 15), 327 +100). Anal. Calcd for
C18H19N4OCl +342.8): C 63.06, H 5.59, N 16.34, Cl
10.34%. Found: C 62.99, H 5.48, N 16.30, Cl 10.30%.
4.4.6.
N-/3-Chlorophenyl)-2-[/2-chlorophenyl)hydra-
zono]-2-/2-naphthylamino)acetamide /1q). Compound
was prepared from N-+2-chlorophenyl)-2-[+3-chlorophenyl)-
amino]-2-oxoethanehydrazonoyl chloride 5k +6.9 g,
20 mmol) and 2-naphthylamine +2.9 g, 20 mmol) following
GP 2. Crystallization ®rst from methanol, then from chloro-
form/heptane gave 6.0 g +67%) of 1q as small white needles.
Mp: 198±2008C. MS m/z: 448 +[M]1, 100). Anal. Calcd for
C24H18N4OCl2 +449.3): C 64.16, H 4.04, N 12.47, Cl
15.78%. Found: C 63.80, H 4.05, N 12.26, Cl 15.36%.
4.5.6.
1-/4-Fluorophenyl)-5,5-dimethyl-N-phenyl-4,5-
dihydro-1H-1,2,4-triazole-3-carboxamide /2f). Com-
pound was prepared from 2-amino-2-[+4-¯uorophenyl)-
hydrazono]-N-phenylacetamide 1d +2.7 g, 10 mmol) and
acetone following GP 3. Crystallization from heptane
gave 1.7 g +55%) of 2f as yellow crystals. Mp: 119±
1238C. MS m/z: 312 +[M]1, 18), 204 +100). Anal. Calcd
for C17H17N4OF +312.3): C 65.37, H 5.48, N 17.93, F
6.08%. Found: C 65.44, H 5.50, N 17.70, F 6.36%.
4.5. Synthesis of 5,5-dialkyl-1-aryl-4,5-dihydro-1H-1,2,4-
triazole-3-carboxamides 2a±m, general procedure
/GP 3)
The appropriate 2-amino-N-aryl-2-arylhydrazonoacetamide
1 +10 mmol) and 0.1 g p-toluene sulfonic acid dissolved in
approximately50 mL of the required ketone were re¯uxed
until the reaction was complete +controlling reaction
progress byTLC). The overabundant ketone was removed
byevaporation and the residue was crystallized from the
given solvent.
4.5.7.
N-/2-Chlorophenyl)-5,5-dimethyl-1-phenyl-4,5-
dihydro-1H-1,2,4-triazole-3-carboxamide /2g). Com-
pound was prepared from 2-amino-N-+2-chlorophenyl)-2-
phenylhydrazonoacetamide 1e +2.9 g, 10 mmol) and
acetone following GP 3. Crystallization from methanol
gave 2.0 g +60%) of 2g as yellow crystals. Mp: 139±
1418C. MS m/z: 328 +[M]1, 10), 186 +100). Anal. Calcd
for C17H17N4OCl +328.8): C 62.10, H 5.21, N 17.04, Cl
10.78%. Found: C 62.34, H 5.22, N 17.26, Cl 10.97%.
4.5.1. 5,5-Dimethyl-N,1-diphenyl-4,5-dihydro-1H-1,2,4-
triazole-3-carboxamide /2a). Compound was prepared
from 2-amino-N-phenyl-2-phenylhydrazonoacetamide 1a
+2.5 g, 10 mmol) and acetone following GP 3. Crystalliza-
tion from methanol gave 0.8 g +26%) of 2a as yellow
needles. Mp: 156±1598C. MS m/z: 294 +[M]1, 19), 186
+100). Anal. Calcd for C17H18N4O +294.4): C 69.37, H
6.16, N 19.03%. Found: C 69.59, H 6.25, N 19.03%.
4.5.8. N-/2-Chlorophenyl)-5-ethyl-5-methyl-1-phenyl-
4,5-dihydro-1H-1,2,4-triazole-3-carboxamide /2h). Com-
pound was prepared from 2-amino-N-+2-chlorophenyl)-2-
phenylhydrazonoacetamide 1e +2.9 g, 10 mmol) and ethyl
methyl ketone following GP 3. Crystallization from metha-
nol gave 1.5 g +45%) of 2h as orange yellow crystals. Mp:
143±1468C. MS m/z: 342 +[M]1, 9), 186 +100). Anal. Calcd
for C18H19N4OCl +342.8): C 63.07, H 5.58, N 16.34, Cl
10.34%. Found: C 62.95, H 5.57, N 16.30, Cl 10.16%.
4.5.2. 4,5,5-Trimethyl-N,1-diphenyl-4,5-dihydro-1H-1,2,
4-triazole-3-carboxamide /2b). Compound was prepared
from 2-methylamino-N-phenyl-2-phenylhydrazonoaceta-
mide 1l +2.7 g, 10 mmol) and acetone following GP 3. Crys-
tallization from methanol gave 1.3 g +43%) of 2b as yellow

G. Drutkowski et al. / Tetrahedron 58 02002) 5317±5326
5325
4.5.9. N-/2-Chlorophenyl)-4-/4-chlorophenyl)-5,5-dimethyl-
1-phenyl-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide
/2i). Compound was prepared from N-+2-chlorophenyl)-2-
[+4-chlorophenyl)amino]-2-phenylhydrazonoacetamide 1p
+4.0 g, 10 mmol) and acetone following GP 3. Crystalliza-
tion from 2-propanol gave 0.6 g +14%) of 2i as orange crys-
tals. Mp: 148±1518C. MS m/z: 438 +[M]1, 9), 423 +100).
Anal. Calcd for C23H20N4OCl2 +449.3): C 62.88, H 4.59, N
12.75, Cl 16.14%. Found: C 62.71, H 4.60, N 12.70, Cl
16.03%.
hyde +20 mmol) or 2.1 mL benzaldehyde +20 mmol) and
0.1 g p-toluene sulfonic acid were re¯uxed in approximately
50 mL ethanol. After the given time the mixture was cooled
to room temperature and the solvent was evaporated. The
solid product was collected and recrystallized.
4.6.1. N,1-Bis-/2-chlorophenyl)-1H-1,2,4-triazole-3-car-
boxamide /3a). Compound was prepared from 2-amino-
N-+2-chlorophenyl)-2-[+2-chlorophenyl)hydrazono]acetamide
1f +3.2 g, 10 mmol) and formaldehyde following GP 4.
Reaction was complete after 10 h. Recrystallization from
2-propanol gave 1.4 g +42%) of 3a as white amorphous
solid. Mp: 132±1348C. MS m/z: 332 +[M]1, 11), 297
+100). Anal. Calcd for C15H10N4OCl2 +333.2): C 54.08, H
3.11, N 16.81, Cl 21.28%. Found: C 53.66, H 3.14, N 16.99,
Cl 20.96%.
4.5.10. N-/2-Chlorophenyl)-1-/3-chlorophenyl)-5,5-di-
methyl-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide /2j).
Compound was prepared from 2-amino-N-+2-chlorophenyl)-
2-[+3-chlorophenyl)hydrazono]acetamide 1h +3.2 g, 10 mmol)
and acetone following GP 3. Crystallization from methanol
gave 2.6 g +71%) of 2j as dark yellow crystals. Mp: 146±
1498C. MS m/z: 362 +[M]1, 7), 220 +100). Anal. Calcd for
C17H16N4OCl2 +363.2): C 56.21, H 4.44, N 15.42, Cl 19.52%.
Found: C 56.32, H 4.48, N 15.72, Cl 19.45%.
4.6.2. 1-/3-Acetylphenyl)-N-/4-¯uorophenyl)-1H-1,2,4-
triazole-3-carboxamide /3b). Compound was prepared
from 2-[+3-acetylphenyl)hydrazono]-2-amino-N-+4-¯uoro-
phenyl)acetamide 1k +3.1 g, 10 mmol) and formaldehyde
following GP 4. Reaction was complete after 3 h.
Recrystallization from methanol gave 1.8 g +58%) of 3b
as ®ne white needles. Mp: 190±1928C. MS m/z: 324
+[M]1, 100). Anal. Calcd for C17H13N4O2F +324.3): C
62.96, H 4.04, N 17.27, F 5.86%. Found: C 63.26, H 3.99,
N 17.05, F 5.84%.
4.5.11. N,1-Bis-/3-chlorophenyl)-5,5-dimethyl-4,5-dihy-
dro-1H-1,2,4-triazole-3-carboxamide /2k). Compound
was prepared from 2-amino-N-+3-chlorophenyl)-2-[+3-
chlorophenyl)hydrazono]acetamide 1i +3.2 g, 10 mmol)
and acetone following GP 3. Crystallization from methanol
gave 1.7 g +48%) of 2k as yellow crystals. Mp: 160±1628C.
MS m/z: 362 +[M]1, 13), 220 +100). Anal. Calcd for
C17H16N4OCl2 +363.2): C 56.21, H 4.44, N 15.42, Cl
19.52%. Found: C 56.13, H 4.42, N 15.42, Cl 19.47%.
4.6.3.
7-Chloro-N-/2-chlorophenyl)-4-phenyl-4,5-di-
hydro-1H-1,3,4-benzo[e]triazepine-2-carboxamide /4a).
Compound was prepared from N-+2-chlorophenyl)-2-[+4-
chlorophenyl)amino]-2-phenylhydrazonoacetamide 1p +4.0 g,
10 mmol) and formaldehyde following GP 4. Reaction time
amounts to about 90 min. The product crystallized at
cooling to room temperature. Recrystallization from
methanol/chloroform gave 1.8 g +45%) of 4a as dark
orange needles. Mp: 190±1928C. MS m/z: 410 +[M]1,
100). Anal. Calcd for C21H16N4OCl2 +411.3): C 61.33, H
3.92, N 13.62, Cl 17.24%. Found: C 61.04, H 4.01, N
13.61, Cl 17.37%.
Data of the 1H NOE experiment +DMSO-d6). Frequencyof
irradiation: 795.07 Hz +1.59 ppmˆd CH3), NOE:
3786.41 Hz +7.58 ppmˆd NH), 3711.10 Hz +7.42 ppmˆd
H-Ar), 3571.28 Hz +7.14 ppmˆd H-Ar).
4.5.12. 1-/3-Chlorophenyl)-N-/4-chlorophenyl)-5,5-di-
methyl-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide /2l).
Compound was prepared from 2-amino-N-+4-chlorophenyl)-
2-[+3-chlorophenyl)hydrazono]acetamide 1j +3.2 g, 10 mmol)
and acetone following GP 3. Crystallization from methanol
gave 1.3 g +36%) of 2l as yellow crystals. Mp: 175±1778C.
MS m/z: 362 +[M]1, 9), 220 +64). Anal. Calcd for
C17H16N4OCl2 363.2): C 56.21, H 4.44, N 15.42, Cl
19.52%. Found: C 56.16, H 4.27, N 15.41, Cl 19.32%.
4.6.4. N,4,5-Triphenyl-4,5-dihydro-1H-1,3,4-benzo[e]-
triazepine-2-carboxamide /4b). Compound was prepared
from N-phenyl-2-phenylamino-2-phenylhydrazonoaceta-
mide 1m +3.3 g, 10 mmol) and benzaldehyde following
GP 4. Reaction time amounts to about 90 min. The product
crystallized at cooling to room temperature. Recrystalliza-
tion from methanol/2-isopronaol gave 1.0 g +25%) of 4b
as pale yellow needles. Mp: 186±1888C. MS m/z: 418
+[M]1, 34), 194 +100). Anal. Calcd for C27H22N4O
+418.5): C 77.49, H 5.30, N 13.39%. Found: C 77.45, H
5.34, N 13.34%.
4.5.13.
1-/3-Acetylphenyl)-N-/4-¯uorophenyl)-5,5-di-
methyl-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide /2m).
Compound was prepared from 2-[+3-acetylphenyl)hydrazono]-
2-amino-N-+4-¯uorophenyl)acetamide 1k +3.1 g, 10 mmol)
and acetone following GP 3. Crystallization from methanol
gave 1.8 g +50%) of 2m as yellow crystals. Mp: 146±1488C.
MS m/z: 354 +[M]1, 13), 228 +100). Anal. Calcd for
C19H19N4O2F +354.4): C 64.40, H 5.40, N 15.81, F 5.36%.
Found: C 64.23, H 5.43, N 15.73, F 5.38%.
4.6.5.
4-/2-Chlorophenyl)-N-/3-chlorophenyl)-4,5-di-
hydro-1H-1,3,4-naphtho[a,e]triazepine-2-carboxamide
/4c). Compound was prepared from N-+3-chlorophenyl)-2-
[+2-chlorophenyl)hydrazono]-2-+2-naphthylamino)aceta-
mide 1q +4.5 g, 10 mmol) within 10 h following GP 4.
Recrystallization from methanol/chloroform gave 2.0 g
+44%) of 4c as ®ne white yellow needles. Mp: 155±
1568C. MS m/z: 460 +[M]1, 100). Anal. Calcd for
C25H18N4OCl2 +461.4): C 65.09, H 3.93, N 12.14, Cl
15.37%. Found: C 64.76, H 3.81, N 12.12, Cl 15.25%.
4.6. Synthesis of 1-aryl-1H-1,2,4-triazole-3-carbox-
amides 3a,b and synthesis of aryl condensed 4-aryl-4,5-
dihydro-1H-1,3,4-triazepine-2-carboxamides 4a±c,
general procedure /GP 4)
The appropriate 2-amino-N-aryl-2-arylhydrazonoaceta-
mides 1 +10 mmol), 1.5 mL of a 37%-solution of formalde-

5326
G. Drutkowski et al. / Tetrahedron 58 02002) 5317±5326
10. Smith, R. F.; Johnson, D. S.; Abgott, R. A.; Madden, M. J.
J. Org. Chem. 1973, 38, 1344.
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