Synthesis of substituted 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepines

Article abstract of DOI:10.1023/B:COHC.0000040781.41929.9c

A one-pot synthetic approach to the novel 5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1,5]benzodiazepines by thermal cyclization of 4-acylhydrazino-2,3-dihydro- 1H-1,5-benzodiazepines is described.

Full text of DOI:10.1023/B:COHC.0000040781.41929.9c

Chemistry of Heterocyclic Compounds, Vol. 40, No. 6, 2004
SYNTHESIS OF SUBSTITUTED
5,6-DIHYDRO-4H-[1,2,4]TRIAZOLO-
[4,3-a][1,5]BENZODIAZEPINES
L. Kosychova, Z. Stumbreviciute, L. Pleckaitiene, R. Janciene, and B. D. Puodziunaite
A one-pot synthetic approach to the novel 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines
by thermal cyclization of 4-acylhydrazino-2,3-dihydro-1H-1,5-benzodiazepines is described.
Keywords: 4-acylhydrazino-2,3-dihydro-1H-1,5-benzodiazepines, 4H-[1,2,4]triazolo[4,3-a][1,5]benzo-
diazepines, cyclization.
Benzodiazepines and their polycyclic derivatives are important medicinal agents for the treatment of
CNS disturbances [1-4]. Moreover, some annulated benzodiazepines, e.g., naturally occurring pyrrolo[2,1-c]-
[1,4]benzodiazepines such as anthramycin [5], thiazolo[4,3-c][1,4]benzodiazepines [6] and substituted
chromeno[4,3-b][1,5]benzodiazepine stereoisomers [7] have been found to exhibit antitumor and antineoplastic
activities. The majority of these compounds have common general structures, comprising a tri- or tetracyclic
almost planar chromophore [8]. In view of these benefits and our interest in the study of novel compounds
bearing potential biological activity, our research group became interested in triazolo[4,3-a][1,5]benzodiazepine
derivatives. We report here the synthesis and the physicochemical properties of new compounds.
The preparation of some analogous target compounds was first reported by E. Szarvasi [9, 10] through
the one-step cyclocondensation procedure starting from the corresponding tetrahydro-1,5-benzodiazepine-2(1H)-
thiones and arylhydrazides. This procedure involved heating the reactants at 200°C or refluxing them in higher
boiling solvents (e.g., trimethylbenzene). However, this approach can be restricted by the lack of reactivity of the
thiolactams towards weak nucleophiles [11]. Besides, it was proved that the formation of the triazole ring in the
1,4-benzodiazepine series occurred through the intermediates obtained by phosphorylation with the moisture
sensitive di(4-morpholinyl)phosphinic chloride (commercially not available) of lactams and subsequent reaction
of an intermediate imine with hydrazides [2].
In the present work we used a procedure based on the thermal cyclization of 4-acylhydrazino-2,3-
dihydro-1H-1,5-benzodiazepines (1a-m) for the synthesis of the desired tricyclic compounds of the general
formula 2. The procedure herein reported was chosen after a number of experiments in order to obtain the
highest yields of the tricyclic derivatives. As a rule, the cyclization of 1 was achieved in refluxing anhydrous
ethanol or butanol. Dehydration of 4-methyl-substituted derivatives 1l,m was performed only at a higher
temperature by refluxing in xylene and removing the formed water. Generally, it was demonstrated that
cyclization of the starting materials proceeded within a separate time limit for each compound and depended on
its structure, as well as on the solubility in an appropriate solvent. An attempt to prepare triazole 2e from the
corresponding thiolactam [12] and an excess of the acetylhydrazine in refluxing tetrahydrofuran in the presence
of mercuric chloride [13] led to the mercury-benzodiazepine compound. The formation of a metal complex in
__________________________________________________________________________________________
Institute of Biochemistry, LT-2600 Vilnius, Lithuania; e-mail: apalaima@bchi.lt. Published in Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, 943-948, June, 2004. Original article submitted May 27, 2002.
0009-3122/04/4006-0811©2004 Plenum Publishing Corporation
811

the nucleophilic substitution reaction of tetrahydro-1,5-benzodiazepinethiones with amines was also observed
[14]. The key starting materials 1a-m were prepared from the corresponding 4-methylthio-2,3-dihydro-1H-1,5-
benzodiazepines and acetyl- or benzoylhydrazines, as previously described [15]. According to this procedure
compounds 1b,d,f,g,k,l have been obtained for the first time.
R3
N
NHNHCOR3
N
N
N
N
∆
R
R
N
R2
R1
R1
R2
1a–m
2a–m
R
R1
R2
R3
1, 2
H
H
H
H
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
H
H
CH2Ph
CH2Ph
H
H
Me
CH2Ph
CH2Ph
H
Me
Ph
Me
Ph
Me
Ph
Ph
Me
Ph
Me
Ph
Me
Ph
a
b
c
d
e
f
g
h
i
j
k
l
H
H
H
H
CH2Ph
CH2Ph
m
The structures of new compounds 1 and 2 were assigned by analytical and spectral data. For
triazolobenzodiazepines 2a-m, the IR spectra are characterized by C=N stretching absorption bands at
1600-1520 cm-1. The 1H NMR spectra of these compounds, registered in CDCl3, exhibit signals corresponding to
the diazepine skeleton protons. It can be noted that the C(1)–CH3 signals of 2a,c,e,h,j,l (R3 = CH3) appear as sharp
singlets at 2.45-2.51 ppm, thus indicating the formation of the triazole ring.
The in vitro anticancer activity of some newly synthesized tricyclic compounds has been tested at the
National Cancer Institute (NCI, USA). According to the NCI's Developmental Therapeutics Program the
compounds 2c,e,h,j,k have been evaluated in the 3-cell line, one dose primary anticancer assay. Only the
compound 2c which passed criteria for activity in this assay has been scheduled for testing against the full panel
of 60 human tumor cell lines. The compound 2c, bearing a lipophilic benzyl substituent at the N(6) atom of the
tricyclic heterosystem, exhibited noteworthy activity and remarkable selectivity for leukemia and breast cancer
cell lines.
EXPERIMENTAL
Melting points were determined in open glass capillaries and are not corrected. IR spectra were recorded
on a Specord IR-75 spectrometer. 1H NMR spectra were measured at 80 MHz on a Tesla BS-587A spectrometer
with TMS as an internal reference. TLC analyses were carried out on Silufol UV-254 silica gel plates in the
butanol–acetic acid–water, 4:2:1, system. Compounds 1a,c,e,h-j,m were synthesized following the reported
method [15].
812

TABLE 1. Physical and Analytical Data of the Newly Synthesized
Compounds
Found, %
Calculated, %
H
Empirical
formula
(MW)
——————
Com-
pound
Reaction
time, h
mp, °C
(solvent)
Yield*, %
C
N
1b
1d
—
—
C16H16N4O
(280.33)
68.34
68.55
5.59
5.75
20.23
19.98
199-200
(EtOH)
57
87
C23H22N4O
(370.45)
C17H18N4O
(294.36)
C18H20N4O
(308.38)
C17H18N4O
(294.36)
C24H24N4O
(384.48)
C11H12N4
(200.24)
C16H14N4
(262.32)
C18H18N4
(290.37)
C23H20N4
(352.44)
C12H14N4
(214.27)
C17H16N4
(276.34)
C18H18N4
(290.37)
C19H20N4
(304.40)
C24H22N4
(366.47)
C12H14N4
(214.27)
C17H16N4
(276.34)
C19H20N4
(304.40)
C24H22N4
(366.47)
74.69
74.57
5.81
5.99
15.22
15.12
206-208
(EtOH)
1f
—
—
—
—
7
69.51
69.37
6.26
6.16
19.23
19.03
166-168
(EtOH)
48
70
74
75
41
49
82
70
65
71
74
58
69
62
65
84
86
1g
1k
1l
70.18
70.11
6.36
6.54
18.21
18.17
192-195
(EtOH)
69.66
69.37
6.02
6.16
19.15
19.03
174-176
(EtOH)
75.12
74.98
6.17
6.29
14.42
14.57
178-181
(EtOH)
2a
2b
2c
2d
2e
2f
65.77
65.98
5.91
6.04
28.02
27.98
174-176
(EtOAc)
183-185*2
(EtOAc)
10
20
8
73.39
73.26
5.43
5.38
21.31
21.36
74.29
74.46
6.51
6.25
19.27
19.29
138-139
(EtOAc)
76.66
76.80
6.02
6.14
16.91
17.06
146-147
(EtOAc)
5
67.38
67.27
6.91
6.59
26.30
26.15
186-188
(EtOAc)
240-242*3
(EtOH)
8
74.12
73.89
6.01
5.84
20.39
20.27
2g
2h
2i
8
74.67
74.46
6.53
6.25
19.20
19.29
162-165
(Et2O)
28
15
25
18
6
74.95
74.97
6.93
6.62
18.59
18.40
120-122
(EtOAc)
78.74
78.66
6.17
6.05
15.42
15.29
174-176
(EtOAc)
2j
67.49
67.27
6.79
6.59
26.26
26.15
194-196
(EtOH)
2k
2l
73.61
73.89
6.12
5.84
19.93
20.27
134-136
(EtOH)
75.11
74.97
6.47
6.62
18.32
18.40
128-130
(EtOAc)
2m
16
78.53
78.66
6.00
6.05
15.20
15.29
190-193
(EtOAc)
_______
* Yields are based on purified products.
*2 Lit. [9] 183-185°C.
*3 Lit. [9] 239-240°C.
5,6-Dihydro-4-R-5-R'-6-R"-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines
(2a-m)
(General
Procedure). A suspension of the appropriate acylhydrazinobenzodiazepine 1a-m (5.0 mmol) in 60 ml of
anhydrous EtOH (for compounds 1a,b,h in 50 ml of anhydrous BuOH and for compounds 1l,m in 50 ml of
o-xylene employing Dean–Stark trap) was heated at reflux. After a while the reaction mixture became clear and
refluxing was continued. The reaction was monitored by TLC analysis. When the starting material was no
813

1
TABLE 2. IR and H NMR Spectral Data for the Newly Synthesized
Compounds
Com-
pound
IR (nujol), ν, cm-1
1H NMR, δ, ppm (J, Hz)*
1b
3350, 3180, 3135
(NH), 1660 (CO)
2.55 (2H, m, CH2); 3.50 (2H, m, CH2N); 5.40 (1H, s, NHCH2);
6.80-8.10 (9H, m, H–Ar); 8.35 (1H, br. s, NH); 9.98 (1H, br. s, NH)
1d
3280, 3185 (NH), 2.43 (2H, m, CH2); 3.34 (2H, m, CH2N); 4.32 (2H, s, CH2Ph);
1665 (CO)
6.85-8.10 (14H, m, H–Ar); 8.71 (1H, br. s, NH);
10.21 (1H, br. s, NH)
1f
1g
1k
1l
3325, 3220 (NH), 1.12 (3H, d, CH3); 2.30-3.80 (3H, m, CH2CH);
1655 (CO)
5.44 (1H, br. s, NHCH2); 6.80-8.05 (9H, m, H–Ar);
8.27 (1H, br. s, NH); 10.01 (1H, br. s, NH)
3300, 3220 (NH), 1.10 (3H, d, CH3CH); 2.30-3.80 (3H, m, CH2CH);
1660 (CO)
2.72 (2H, s, CH3); 6.85-8.05 (9H, m, H–Ar); 8.60 (1H, br. s, NH);
10.10 (1H, s, NH)
3270, 3175 (NH), 1.20 (3H, d, CH3); 2.00-2.60 (2H, m, CH2); 3.82 (1H, m, CH);
1660 (CO)
5.04 (1H, br. s, NHCH); 6.85-8.05 (9H, m, H–Ar);
10.21 (2H, br. s, NHNH)
3280, 3180, 3150
(NH), 1645 (CO)
1.01 (3H, d, CH3CH); 1.93 and 2.03 (3H, two s, CH3);
2.00-2.80 (2H, m, CH2); 3.67 (1H, m, CH);
4.26 (1H, AB-q, J = 15.2, CH2Ph); 4.37 (1H, AB-q,
J = 15.2, CH2Ph); 6.80-7.40 (9H, m, H–Ar);
8.34, 8.43, 9.58, 9.72 (2H, four br. s, NHNH)
2a
2b
2c
2d
2e
3260 (NH),
1600, 1585, 1550
2.51 (3H, s, CH3); 3.04 (2H, m, CH2); 3.49 (1H, br. s, NH);
3.72 (2H, m, CH2N); 6.85-7.50 (4H, m, H–Ar)
3300 (NH),
1600, 1580, 1525
3.11 (2H, m, CH2); 3.50 (1H, br. s, NH); 3.78 (2H, m, CH2N);
6.65-7.55 (9H, m, H–Ar)
1600, 1535
2.46 (3H, s, CH3); 2.88 (2H, m, CH2); 3.35 (2H, m, CH2N);
4.21 (2H, s, CH2Ph); 6.85-7.40 (9H, m, H–Ar)
3.03 (2H, m, CH2); 3.52 (2H, m, CH2N); 4.36 (2H, s, CH2Ph);
6.65-7.55 (14H, m, H–Ar)
1600, 1575, 1535
3255 (NH),
1605, 1535
1.49 (3H, d, CH3CH); 2.50 (3H, s, CH3); 3.00 (1H, br. s, NH);
3.06 (1H, m, CH); 3.15-3.85 (2H, m, CH2);
6.90-7.40 (4H, m, H–Ar)
2f
3250, 3175 (NH), 1.52 (3H, d, CH3CH); 2.95-3.90 (3H, m, CH2CH);
1660, 1520
3.81 (1H, br. s, NH); 6.65-7.50 (9H, m, H–Ar)
2g
2h
1600, 1535, 1525
1.53 (3H, d, CH3); 2.70-3.80 (3H, m, CH2CH); 2.86 (3H, s, CH3N);
6.60-7.45 (9H, m, H–Ar)
1600, 1535, 1525
1595, 1520
1.38 (3H, d, CH3CH); 2.51 (3H, s, CH3);
2.70-3.31 (3H, m, CH2CH); 4.07 (1H, AB-q, J = 14.8, CH2);
4.36 (1H, AB-q, J = 14.8, CH2); 6.95-7.30 (9H, m, H–Ar)
2i
1.49 (3H, d, CH3); 2.70-3.80 (3H, m, CH2CH);
4.18 (1H, AB-q, J = 14.8, CH2); 4.47 (1H, AB-q, J = 14.8, CH2);
6.60-7.50 (14H, m, H–Ar)
2j
2k
2l
3270 (NH),
1600, 1535
1.26 (3H, d, CH3CH); 2.48 (3H, s, CH3);
2.72 (1H, dd, J = 6.3, 14.5, CH2); 3.07 (1H, dd, J = 5.4, 14.5, CH2);
3.37 (1H, br. s, NH); 3.98 (1H, m, CH); 6.90-7.35 (4H, m, H–Ar)
1.27 (3H, d, CH3CH); 2.70 (1H, dd, J = 6.6, 14.6, CH2);
3.07 (1H, dd, J = 5.2, 14.6, CH2); 3.74 (1H, br. s, NH);
4.03 (1H, m, CH); 6.60-7.50 (9H, m, H–Ar)
3240 (NH),
1600, 1640
1600, 1545, 1530
1.14 (3H, d, CH3CH); 2.28 (1H, dd, J = 10.4, 14.3, CH2C=);
2.45 (3H, s, CH3); 3.24 (1H, dd, J = 6.8, 14.8, CH2C=);
3.87 (1H, m, CH); 4.17 (1H, AB-q, J = 15.2, CH2Ph);
4.35 (1H, AB-q, J = 15.2, CH2Ph); 6.70-7.40 (9H, m, H–Ar)
2m
1595, 1535
1.24 (3H, d, CH3CH); 2.40 (1H, dd, J = 11.2, 14.4, CH2C=);
3.38 (1H, dd, J = 6.0, 14.4, CH2C=); 3.98 (1H, m, CH);
4.24 (1H, AB-q, J = 14.4, CH2Ph);
4.54 (1H, AB-q, J = 14.4, CH2Ph); 6.70-7.40 (14H, m, H–Ar)
_______
* Solvents: compounds 1b,d,f,g,k,l recorded in DMSO-d6, 2a-m in CDCl3.
814

longer detectable (reaction time for each material is presented in Table 1) the work up of the reaction mixture for
the separate compound was performed differently. The mixture was concentrated by evaporation under reduced
pressure to 20 ml and left to cool. The precipitated product (2d,f,j) was filtered. In the case of compounds
2a,b,g-i,k the solvent was evaporated to dryness. The thick residue was triturated with diethyl ether and the
resultant product was filtered. After the reaction solvent was evaporated to dryness, the compounds 2l,m were
obtained as solids. The dark reaction mixture (compound 2c,e) after being cooled to room temperature was
filtered through a short plug of silica gel (Chemapol L 40/100, 8 g). After the column was eluted with ethanol
(20 ml), the combined organic fractions were evaporated to give a solid residue. Compounds 2a-m were
obtained as white or light yellow crystals by recrystallization from the proper solvent.
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