Synthesis of novel 3,5,7-triaryl-5,6-dihydro-4H-1,2,5-triazepines

Article abstract of DOI:10.1002/jhet.5570440121

(Chemical Equation Presented) Several hitherto unknown 3,5,7-triaryl-5,6- dihydro-4H-1,2,5-triazepines have been synthesised by cyclocondensation of N,N-bis(phenacyl)anilines with hydrazine hydrate in ethanol or ethyleneglycol under reflux condition. Incr

Full text of DOI:10.1002/jhet.5570440121

Jan-Feb 2007
133
Synthesis of Novel 3,5,7-Triaryl-5,6-dihydro-4H-1,2,5-triazepines
Gurusamy Ravindran, Shanmugam Muthusubramanian*, Sanguvan Selvaraj
and Subbu Perumal
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai - 625 021, India
Received April 6, 2006
X
X
X
X
N
N
NH2.NH2.H2O
p-TsOH
N
Y
N
O
O
EtOH or Ethanediol
reflux
1
2
Y
Several hitherto unknown 3,5,7-triaryl-5,6-dihydro-4H-1,2,5-triazepines have been synthesised by
cyclocondensation of N,N-bis(phenacyl)anilines with hydrazine hydrate in ethanol or ethyleneglycol under
reflux condition. Increased yields were obtained in the presence of p-toluenesulfonic acid compared to the
uncatalysed reaction.
J. Heterocyclic Chem., 44, 133 (2007).
INTRODUCTION
facilitates the cyclocondensation by increasing the electro-
philicity of the carbonyl groups. Reaction conditions
employed and the yields of 2 are summarized in Table 1.
The 1,2,5-triazepine system has received considerable
attention in recent times [1-3], though it is less significant
compared to the corresponding benzofused analogues
[4,5]. Besides being used as immunomodulating agents
[6], 1,2,5-triazepine derivatives are found to exhibit
antifungal [7], anti-inflammatory, analgesic [8] and
sedative activities [9]. This prompted us to synthesize
several novel 3,5,7-triaryl-5,6-dihydro-4H-1,2,5-triaze-
pines by a new route. Related 5-benzyl and 5-tosyl-3,7-
diaryl-4H-1,2,5-triazepines have been synthesized by a
different route from substituted ꢀ-bromoacetophenone
azine and respective amines [10].
Table 1:
Yield of the compound 2 in the presence and in the absence of catalyst
In the absence of
catalyst
In the presence of
Compound
p-TsOH
M. Pt
(°C)
Time
(min)
300
240
360
240
300
300
360
300
240
Yield
(%)
35
42
43
Time
(min)
15
Yield
(%)
40
2a
2b
2c
2d
2e
2f
>200
172
104a
154a
>200
168
146a
152a
142a
60
80
85
83
38
40
75
20
89
42
40
38
42
45
60
90
82
80
RESULTS AND DISCUSSION
2g
2h
2i
There are only a few reports [11,12] on the synthesis
and other studies of N,N-bis(phenacyl)anilines 1, the
precursors planned for the synthesis of the title
compounds. In the present method, compounds 1 were
obtained under solvent-free condition in good yields by
mixing anilines (1.25 mmol) with phenacyl bromides
(2.50 mmol) in the presence of potassium carbonate (1.25
mmol).
The reaction of 1 with hydrazine hydrate has been
carried out (Scheme 1) under reflux in ethanol or
ethyleneglycol. The products obtained were identified as
3,5,7-triaryl-5,6-dihydro-4H-1,2,5-triazepines 2. The
reaction has also been carried out in the presence of a
catalyst, viz., p-toluenesulfonic acid. Vastly improved
yields of 2 in most cases and significant reduction in
reaction time were observed by refluxing 1 with 1.5
equivalent of hydrazine hydrate in the presence of a
catalytic amount of p-toluenesulfonic acid compared to
the uncatalysed reaction (Table 1). Obviously, the catalyst
90
60
83
79
a decomposition occurs
All the new compounds 2 were characterized by their
NMR spectral data. The 1H NMR spectrum of a
representative compound, 3,7-bis(4-chlorophenyl)-5-
phenyl-5,6-dihydro-4H-1,2,5-triazepine (2b), showed a
broad signal at 4.18 ppm accounting for the four
methylene hydrogen atoms. This broad singlet indicates
that the methylene hydrogen atoms of the ring are not
equivalent and at room temperature there is a flipping
around these positions. Such a flipping around the 5
position has already been envisaged [13]. In the aromatic
region, multiplets were obtained in the following regions
(in ppm): 6.92-6.99 (m, 3H), 7.33-7.39 (m, 6H), 7.65-7.68
(m, 4H). The 13C NMR spectrum of 2b showed signals at
47.5, 115.6, 120.5, 128.4, 129.1, 129.7, 134.2, 136.6,
152.5, 160.0 ppm.

134
G.Ravindran, S.Muthusubramanian, S.Selvaraj and S.Perumal
Vol 44
General Procedure for the Preparation of Differently
Substituted N,N-Bis(phenacyl)anilines (1). N,N-Bis(phenacyl)-
anilines (1) were prepared by grinding a solventless mixture of
substituted phenacyl bromide, substituted aniline and potassium
carbonate in 2:1:1 molar ratio and leaving the reaction mixture
at room temperature for one hour. The reaction mixture was then
treated with chloroform and the chloroform extract was dried
over anhydrous sodium sulphate and evaporated. The crude
product was purified over silica column to give pure 1. The
conversion is in the range of 60-70 % for different 1.
The semi-empirical PM3 computations were performed
with Hyperchem (version 7.5) at the RHF level. It was
found that the total energy of 2a was E = –4948.6442
kcal/mol with Gradient 0.044. The theoretically optimized
geometry of 2a is shown in Figure 1.
Scheme 1
X
X
X
X
N
N
N,N-Bis(phenacyl)aniline (1a). This compound was obtained
as colorless crystals (dichloromethane), yield 62 %, mp 198 °C (
236-240 °C)[14]; H nmr (300 MHz, CDCl3): ꢀ 4.95 (s, 4H),
6.50-6.76 (m, 3H), 7.12-7.20 (m, 2H), 7.50-7.59 (m, 4H), 7.61-
7.68 (m, 2H), 8.01-8.04 (m, 4H); 13C nmr (75 MHz,
CDCl3): ꢀ 58.0, 112.6, 118.0, 127.8, 128.9, 129.2, 133.7, 140.7,
148.4, 196.5.
NH2.NH2.H2O
p-TsOH
N
N
1
O
O
EtOH or Ethanediol
reflux
Y
Y
1
2
N,N-Bis(4-chlorophenacyl)aniline (1b). This compound
was obtained as yellow crystals (ethanol), yield 70 %, mp 110
°C; H nmr (300 MHz, CDCl3): ꢀ 4.90 (s, 4H), 6.51- 6.79 (m,
1&2
X
Y
1
3H), 7.12-7.20 (m, 2H), 7.46-7.49 (m, 4H), 7.93-7.96 (m, 4H);
13C nmr (75 MHz, CDCl3): ꢀ 57.9, 112.7, 118.3, 129.2,
129.3, 130.3, 133.3, 140.3, 148.2, 195.4. Anal. Calcd. for
C22H17Cl2NO2: C, 66.34; H, 4.30; N, 3.52 %. Found: C, 66.32;
H, 4.29, N, 3.51 %.
a
b
c
d
e
f
g
h
i
H
Cl
Me
OMe
H
H
H
H
H
Me
Me
Me
Me
Cl
N,N-Bis(4-methylphenacyl)aniline (1c). This compound
was obtained as yellow crystals (ethanol), yield 64%, mp, 103
Me
OMe
Me
1
°C; H nmr (300 MHz, CDCl3): ꢀ 2.40 (s, 6H), 4.90 (s, 4H),
OMe
6.45-6.72 (m, 3H), 7.11-7.16 (m, 2H), 7.27-7.30 (m, 4H), 7.90-
7.93 (m, 4H); 13C nmr (75 MHz, CDCl3): ꢀ 21.7, 57.9, 112.5,
117.8, 129.0, 129.1, 129.5, 132.6, 144.6, 148.5, 196.1.
EXPERIMENTAL
Anal. Calcd. for C24H23NO2: C, 80.64; H, 6.49; N, 3.92 %.
Found: C, 80.62; H, 6.47, N, 3.91 %.
All chemicals were of reagent grade quality and used without
further purification. All melting points reported in this work
were measured in open capillaries and are uncorrected. 1H NMR
spectra were recorded on a Bruker 300 MHz (Ultrashield)
spectrometer. Chemical shifts are reported in ppm relative to
tetramethylsilane as an internal standard. The reactions were
routinely monitored by thin layer chromatography (TLC) on
silica gel plates.
N,N-Bis(4-methoxyphenacyl)aniline (1d). This compound
was obtained as yellow crystals (ethanol), yield 62 % mp, 152
°C; 1H nmr (300 MHz, CDCl3): ꢀ 3.9 (s, 6H), 4.84 (s, 4H), 6.50-
6.76 (m, 3H), 6.90-6.98 (m, 2H), 7.10-7.21 (m, 3H), 7.92-8.05
(m, 3H), 8.20-8.22 (m, 2H); 13C nmr (75 MHz, CDCl3): ꢀ 57.0,
58.1, 111.7, 112.7, 113.1, 118.5, 129.4, 129.5, 129.6, 133.8,
148.7, 160.4, 194.5. Anal. Calcd. for C24H23NO4: C, 74.02; H,
5.95; N, 3.60 %. Found: C, 74.06; H, 5.92, N, 3.58 %.
N,N-Bis(phenacyl)-p-toluidine (1e). This compound was
obtained as colorless crystals (dichloromethane), yield 63 %,
1
mp, 158 °C (255 °C)[15]; H nmr (300 MHz, CDCl3): ꢀ 2.21 (s,
3H), 4.90 (s, 4H), 6.52-6.58 (m, 3H), 6.96-7.03 (m, 3H), 7.36-
7.45 (m, 4H), 7.87-7.92 (m, 4H); 13C nmr (75 MHz, CDCl3): ꢀ
21.0, 58.0, 118.6, 128.2, 128.7, 129.5, 134.2, 141.2, 149.0,
197.2.
N,N-Bis(4-chlorophenacyl)-p-toluidine (1f). This compound
was obtained as yellow crystals (ethanol), yield 68 % mp, 140
1
°C; H nmr (300 MHz, CDCl3): ꢀ 2.20 (s, 3H), 4.86 (s, 4H),
6.45-6.48 (m, 2H), 6.95-6.98 (m, 2H), 7.45-7.49 (m, 4H), 7.92-
7.95 (m, 4H); 13C nmr (75 MHz, CDCl3): ꢀ 20.3, 56.2, 113.0,
130.0, 130.4, 131.0, 134.0, 141.2, 149.0, 196.2. Anal. Calcd. for
C23H19Cl2NO2: C, 67.00; H, 4.64; N, 3.40 %. Found: C, 67.05;
H, 4.62, N, 3.39 %.
N,N-Bis(4-methylphenacyl)-p-toluidine (1g). This compound
was obtained as yellow crystals (ethanol), yield 70% mp,128 °C;
1H nmr (300 MHz, CDCl3): ꢀ 2.04 (s, 3H), 2.20 (s, 6H), 4.91 (s,
4H), 6.49-6.50 (m, 2H), 6.90-7.00 (m, 2H), 7.28-7.35 (m, 4H),
7.90-7.95 (m, 4H); 13C nmr (75 MHz, CDCl3): ꢀ 20.6, 22.1,
58.5, 113.2, 127.4, 129.8, 130.1, 130.6, 133.1, 144.9, 146.7,
Figure: 1

Jan-Feb 2007
Synthesis of Novel 3,5,7-Triaryl-5,6-dihydro-4H-1,2,5-triazepines
135
196.8. Anal. Calcd. for C25H25NO2 : C, 80.83; H, 6.78; N, 3.77
%. Found: C, 80.85; H, 6.77, N, 3.74 %.
(s, 3H), 4.20 (bs, 4H), 6.85-6.88 (m, 3H), 7.14-7.20 (m, 4H),
7.32-7.40 (m,4H), 7.72-7.75 (m,3H); 13C nmr 75 MHz,
CDCl3): ꢁ 20.5, 47.8, 115.6, 127.1, 128.7, 129.5, 133.5, 135.6,
153.2, 159.6. Anal. Calcd. for C23H21N3: C, 81.38; H, 6.24; N,
12.38 %. Found: C, 81.33; H, 6.26, N, 12.41 %.
N,N-Bis(4-methoxyphenacyl)-p-toluidine (1h). This
compound was obtained as yellow crystals (ethanol), yield 68 %
ꢀ
1
mp,170 C; H nmr (300 MHz, CDCl3): ꢁ 2.20 (s, 3H), 3.90 (s,
6H), 4.80 (s, 4H), 6.40-6.47 (m, 2H), 6.93-6.98 (m, 4H), 7.95-
7.99 (m, 4H), 8.20-8.28 (m, 2H); 13C nmr (75 MHz, CDCl3): ꢁ
19.0, 54.5, 56.0, 109.2, 110.2, 111.0, 125.4, 127.0, 127.7, 131.3,
144.2, 158.0, 192.2. Anal. Calcd. for C25H25NO4: C, 74.42; H,
6.25; N, 3.47 %. Found: C, 74.44; H, 6.24, N, 3.45 %.
3,7-Bis(4-chlorophenyl)-5-(4-methylphenyl)-5,6-dihydro-
4H-1,2,5-triazepine (2f). This compound was obtained as
1
yellow crystals (ethanol), H nmr (300 MHz, CDCl3): ꢁ 2.30 (s,
3H), 4.13 (bs, 4H), 6.83-6.86 (m, 2H), 7.14-7.17 (m, 2H), 7.33-
7.35 (m, 4H), 7.64-7.67 (m, 4H); 13C nmr (75 MHz,
CDCl3): ꢁ 21.0, 48.2, 116.2, 128.8, 129.4, 130.5, 134.6, 136.8,
154.4, 160.8. ꢀnal. Calcd.for C23H19Cl2N3: C, 67.65; H, 4.67;
N, 10.29 %. Found: C, 67.61; H, 4.70; N, 10.32 %.
3,5,7-Tris(4-methylphenyl)-5,6-dihydro-4H-1,2,5-triazepine
(2g). This compound was obtained as yellow crystals (ethanol),
1H nmr (300 MHz, CDCl3): ꢁ 2.32 (s, 3H), 2.35 (s, 6H), 4.17
(bs, 4H), 6.83-6.86 (m, 2H), 7.13-7.19 (m, 6H), 7.62-7.65 (m,
4H); 13C nmr (75 MHz, CDCl3): ꢁ 20.8, 21.3, 47.7, 115.6, 127.0,
129.4, 129.9, 133.2, 140.4, 153.3, 161.3. Anal. Calcd. for
C25H25N3: C, 81.71; H, 6.86; N, 11.43 %. Found: C, 81.75; H,
6.85; N, 11.40 %.
N,N-Bis(4-methylphenacyl)- p-anisidine (1i). This compound
was obtained as pale yellow crystals (ethanol), yield 65 %, mp,
128 °C; 1H nmr (300 MHz, CDCl3): ꢁ 2.42 (s, 6H), 3.70 (s, 3H),
4.92 (s, 4H), 6.51-6.54 (m, 2H), 6.72-6.75 (m, 2H), 7.26-7.29
(m, 4H), 7.89-7.92 (m, 4H); 13C nmr (75 MHz, CDCl3): ꢁ 22.1,
56.1, 58.8, 114.9, 115.1, 128.4, 129.8, 133.1, 143.5, 144.9,
152.7, 197.0. Anal. Calcd. for C25H25NO3: C, 77.49; H, 6.50; N,
3.61 %. Found: C, 77.47; H, 6.48, N, 3.60 %.
General Procedure for the Preparation of 5,7-Triaryl-
5,6-dihydro-4H-1,2,5-triazepines (2). A mixture of 2-[(2-
oxo-2-arylethyl)anilino]-1-aryl-1-ethanone 1 (3 mmol) and
hydrazine hydrate (4.5 mmol) in ethanol or ethyleneglycol (8-
10 ml) was heated under reflux until the starting ethanone had
disappeared. The mixture was cooled to room temperature and
the resulting precipitate filtered and crystallized from an
appropriate solvent.
3,7-Bis(4-methoxyphenyl)-5-(4-methylphenyl)-5,6-dihydro-
4H-1,2,5-triazepine (2h). This compound was obtained as
1
yellow crystals (ethanol), H nmr (300 MHz, CDCl3) ꢁ: 2.32 (s,
3H), 3.82 (s, 6H), 4.14 (bs, 4H), 6.70-6.95 (m, 6H), 7.15-7.20
(m, 2H), 7.68-7.84 (m, 4H); 13C nmr (75 MHz, CDCl3): ꢁ 20.9,
48.0, 55.8, 114.3, 114.5, 116.0, 129.0, 130.4, 130.6, 153.5,
161.6. Anal. Calcd. for C25H25N3O2: C, 75.16; H, 6.31; N, 10.52.
Found: C, 75.20; H, 6.28; N, 10.51
The reaction was also carried out in the presence of p-
toluenesulfonic acid (5 mg) with other conditions being similar.
3,5,7-Triphenyl-5,6-dihydro-4H-1,2,5-triazepines (2a).
This compound was obtained as pale yellow crystals
3,7-Bis(4-methylphenyl)-5-(4-methoxyphenyl)-5,6-dihydro-
4H-1,2,5-triazepine (2i). This compound was obtained as
1
(Petroleum ether), mp > 200 °C; H nmr (300 MHz, CDCl3): ꢁ
1
4.24 (bs, 4H), 6.93-6.97 (m, 3H), 7.34-7.40 (m, 8H), 7.73-7.75
(m, 4H); 13C nmr (75 MHz, CDCl3): ꢁ 47.5, 115.4, 121.3,
127.1, 128.7, 129.6, 130.2, 136.0, 153.4, 159.6. Anal. Calcd.
for C22H19N3: C, 81.20; H, 5.89; N, 12.91 %. Found: C, 81.24;
H, 5.86; N, 12.90 %.
yellow crystals (ethanol), H nmr (300 MHz, CDCl3) ꢁ: 2.35 (s,
6H), 3.81 (s, 3H), 4.10 (bs, 4H), 6.88-6.92 (m, 4H), 7.15-7.25
(m, 4H), 7.60-7.62 (m, 4H); 13C nmr (75 MHz, CDCl3): ꢁ 21.7,
48.8, 56.0, 115.1, 117.9, 127.4, 129.8, 133.6, 140.7, 143.3,
153.7, 154.1. Anal. Calcd. for C25H25N3O: C, 78.30; H, 6.57; N,
10.96 %. Found: C, 78.35; H, 6.60; N, 10.94 %.
3,7-Bis(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,2,5-tri-
azepine (2b). This compound was obtained as yellow crystals
(ethanol), 1H nmr (300 MHz, CDCl3): ꢁ 4.18 (bs, 4H), 6.92-6.99
(m, 3H), 7.33-7.39 (m, 6H), 7.65-7.68 (m,4H); 13C nmr (75
MHz, CDCl3): ꢁ 47.5, 115.6, 120.5, 128.4, 129.1, 129.7, 134.2,
136.6, 152.5, 160.4. ꢀnal. Calcd. for C22H17Cl2N3: C,67.01; H,
4.35; N, 10.66 %. Found: C, 67.04; H, 4.33; N, 10.65 %.
3,7-Bis(4-methylphenyl)-5-phenyl-5,6-dihydro-4H-1,2,5-tri-
azepine (2c). This compound was obtained as yellow crystals
Acknowledgment. The authors thank DST-IRHPA NMR
facility at School of Chemistry, Madurai Kamaraj University,
for recording NMR spectra.
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1
(ethanol), H nmr (300 MHz, CDCl3) ꢁ 2.36 (s, 6H), 4.25 (bs,
4H), 6.89-6.95 (m, 3H), 7.15-7.23 (m, 4H), 7.30-7.37 (m, 2H),
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3,7-Bis(4-methoxyphenyl)-5-phenyl-5,6-dihydro-4H-1,2,5-
triazepine (2d). This compound was obtained as yellow
crystals (ethanol), H nmr (300 MHz, CDCl3): ꢁ 3.82 (s, 6H),
4.19 (bs, 4H), 6.87-6.98 (m, 8H), 7.32-7.37 (m, 2H), 7.69-7.72
(m, 3H); 13C nmr (75 Hz, CDCl3): ꢁ 47.6, 55.7, 114.5, 115.7,
120.2, 128.9, 129.0, 129.9, 148.8, 153.4, 161.6. Anal.Calcd.for
C24H23N3O2: C, 74.78; H,6.01; N, 10.90 %. Found: C, 74.81; H,
6.00; N, 10.88 %.
1
5-(4-Methylphenyl)-3,7-diphenyl-5,6-dihydro-4H-1,2,5-tri-
azepine(2e). This compound was obtained as Pale yellow
1
crystals (Petrolium ether), H nmr (300 MHz, CDCl3): ꢁ 2.30

136
G.Ravindran, S.Muthusubramanian, S.Selvaraj and S.Perumal
Vol 44
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