Synthesis of novel fused 4,5-dihydro-1,2,3-triazolo[1,5-a][1,4] benzodiazepine derivatives via four-component Ugi-Smiles-type reaction

Article abstract of DOI:10.1016/j.tet.2013.02.023

Using 2-azidobenzaldehyde and propargylamine in a Ugi-Smiles coupling gave easy access to 4,5-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepine derivatives. This novel approach is based on the reaction between 2-azidobenzaldehyde, propargylamine, isocyanides, and nitrophenols in methanol under reflux conditions without using additional reagents or catalysts.

Full text of DOI:10.1016/j.tet.2013.02.023

Accepted Manuscript
Synthesis of novel fused 4,5-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepine
derivatives via four-component Ugi-Smiles-type reaction
Mina Saeedi, Mohammad Mahdavi, Alireza Foroumadi, Abbas Shafiee
PII:
S0040-4020(13)00215-9
10.1016/j.tet.2013.02.023
TET 24018
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 October 2012
Revised Date: 13 January 2013
Accepted Date: 4 February 2013
Please cite this article as: Saeedi M, Mahdavi M, Foroumadi A, Shafiee A, Synthesis of novel fused
4,5-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepine derivatives via four-component Ugi-Smiles-type
reaction, Tetrahedron (2013), doi: 10.1016/j.tet.2013.02.023.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of novel fused
Leave this area blank for abstract info.
4,5-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepine
derivatives via four-component Ugi-Smiles-type reaction
Mina Saeedi, Mohammad Mahdavi, Alireza Foroumadi, Abbas Shafiee*
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, Tehran 14176, Iran
1

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Synthesis of novel fused 4,5-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepine
derivatives via four-component Ugi-Smiles-type reaction
Mina Saeedi a, Mohammad Mahdavi a, Alireza Foroumadi a,b, Abbas Shafiee a,
a
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical
Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176,
Iran
b
Drug Design & Development Research Center,Tehran University of Medicinal
Sciences, Tehran, Iran
Abstract Using 2-azidobenzaldehyde and propargylamine in a Ugi-Smiles coupling
gave easy access to 4,5-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepine derivatives.
This novel approach is based on the reaction between 2-azidobenzaldehyde,
propargylamine, isocyanides, and nitrophenols in methanol under reflux conditions
without using additional reagents or catalysts.
1. Introduction
After the introduction of novel multicomponent reactions by Passerini1 and
Ugi,2 the use of isocyanide-based multicomponent reactions (IMCRs) has attracted a
great deal of attention in medicinal chemistry3-6 owing to producing bifunctional
starting materials. Although the classical versions of the above reactions lead to
acyclic systems, development of IMCRs by replacing various bifunctional starting
Corresponding author. Tel.: +98-21-66406757; fax: +98-21-66461178; e-mail: ashafiee@ams.ac.ir
Keywords:
Ugi-Smiles
coupling,
4,5-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepines,
2-
azidobenzaldehyde, multicomponent reactions, heterocycles
2

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materials such as 2-azidobenzaldehyde7 allows researchers to develop efficient routes
to a range of functionalized heterocyclic scaffolds.8-10 Usually, these functional groups
lead to the intramolecular reactions11 and post-condensation or cyclizations12 to
produce new heterocyclic compounds.
One of the most important and efficient modifications of IMCRs was
investigated by El Kaïm et al.13 in which traditional carboxylic acids were replaced by
electron-deficient phenols as suitable surrogates in the Ugi reaction. The key step is
an irreversible Smiles rearrangement in the last step of these reactions. For this
reason, the reaction was termed Ugi-Smiles coupling.
Fused triazolo-benzodiazepines are of significant medical interests due to their
effective properties. Two common anxiolytic agents, Alprazolam (A) and Estazolam
(B) belong to this family of compounds (Fig. 1).14 Some triazolo-benzodiazepine
derivatives are known to bind weakly to the benzodiazepine receptor15 and also to
inhibit serine proteases.16 It seems the use of this class of compounds with useful
therapeutic purposes is of importance and designing libraries of fused triazolo-
benzodiazepines with maximum diversity is one of the major medicinal chemistry
researchers' goals.
Fig. 1. Alprazolam (A) and Estazolam (B).
Herein, as a continuation of our research into the synthesis of novel
heterocycles,17 especially promising bioactive compounds,18 we report a Ugi-Smiles
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reaction which provides an expedient route to novel and potentially bioactive fused
1,2,3-triazolo-1,4-benzodiazepine scaffolds 5 through a one step reaction (Scheme 1).
Scheme 1. Synthesis of 4,5-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepines 5.
2. Results and discussion
In this work, we used 2-azidobenzaldehyde 1 and propargylamine 2 as the
aldehyde and amine in the Ugi-Smiles coupling (Scheme 1). We found that
intramolecular cyclization happened spontaneously without the need for additional
reagents or catalysts to give the final compound 5. We first studied the reaction of 2-
azidobenzaldehyde (1 mmol), propargylamine (1 mmol), phenol (1 mmol) and
cyclohexylisocyanide (1 mmol) in MeOH as the solvent. As we expected, phenol did
not conduct the reaction due to lack of sufficient acidity. Thus, we utilized para and
different ortho-nitrophenols which are sufficiently acidic to take part in the reaction.
When a mixture of 2-azidobenzaldehyde (1 mmol), propargylamine (1 mmol), para-
nitrophenol (1 mmol) and cyclohexylisocyanide (1 mmol) in MeOH was heated at
reflux for 24 hours, the corresponding 4,5-dihydro-1,2,3-triazolo[1,5-
a][1,4]benzodiazepine derivative 5a was obtained in 50% yield. It was found that the
reaction did not go to completion when stoichiometric amounts of starting materials
were used. However, when 1.2 eq isocyanide was used the desired product 5a was
obtained in good yield (75%, Table 1, Entry 1).
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The combination of all analytical information confirmed the given structure
5a. The peak at 432 in mass spectrum is associated with the molecular ion and it is in
accordance with calculated mass for C23H24N6O3. Also the spectrum shows a strong
peak at 306 (M–126) which is related to elimination of –CONH–cyclohexyl group. A
fairly strong peak is observed at 278 resulting from loss of N2 from the M–126. The
strong peak at 232 indicates elimination of NO2 from the latter.
It should be noted that when meta-nitrophenols were used, there was no
reaction and we concluded that neither unsubstituted phenol nor m-nitrophenols are
suitable surrogates for carboxylic acids.
Table 1
Synthesis of 4,5-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepine derivatives 5
Entry
1
Nitrophenols
Isocyanides
Product
Yield (%)a
N
N
N
N
OH
H
N
NC
75
5a
O
NO2
NO2
N
N
N
N
OH
H
O2N
N
NC
2
3
80
85
5b
5c
O2N
O
N
N
N
N
OH
H
N
O2N
NC
O2N
O
NO2
NO2
N
N
N
OH
H
N
O2N
NO2
N
NC
4
88
5d
O
NO2
O2N
NO2
NO2
5

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N
N
N
OH
H
O2N
N
NC
N
5
6
85
80
5e
5f
O2N
O
F
F
N
N
N
OH
H
O2N
N
NC
N
O2N
O
N
N
N
OH
H
N
O2N
N
NC
7
8
85
85
5g
5h
O2N
O
NO2
NO2
N
N
N
OH
H
N
O2N
NC
N
O2N
O
F
F
a isolated yield
In spite of the fact that methanol usually is the solvent of choice for Ugi-type
multicomponent reactions,7b,12a,13a,13b,19 we screened other solvents such as toluene,
dichloromethane and ethanol in the reaction. Low yields and by-products resulted;
therefore, we continued our experiment using methanol.
Considering the results, we expanded the scope of this promising reaction by
using various nitrophenols and isocyanides. As can be seen in Table 1, they behaved
similarly in the Ugi-Smiles coupling. Ortho-nitrophenols, particularly the derivatives
with more electron-withdrawing groups, showed higher reactivity.
In the next step, we investigated the mechanism of reaction. A proposed
sequences, has been depicted schematically in Scheme 2. According to the literature,20
the first step in the Ugi reaction involves condensation of aldehyde 1 and amine 2 to
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form imine 6. Presence of azido group in imine 6 suggests that there are two possible
mechanisms for the reaction (routes 1 and 2 in Scheme 2).
O
N3
H
N
R2
R5
R4
R1
N
N3
O
N
HN R1
R5
R1
R3
N
Smiles
O
R2
N
R2
R5
R4
H
N3
R4
R3
R3
R1 N C
3
azide-alkyne cyclization
H
CH N
N
N
N
O
N
N3
HN R1
OH
R3
R2
R5
R2
R5
R4
4 route 1
R4
R3
5
CHO
N3
N
NH2
+
Smiles
N3
1
2
6
N
N
azide-alkyne cyclization route 2
N
N
N
R1
H
N
R5
N
O
N
N
R2
7
R4
OH
R3
R2
R5
4
R1
O
R4
R2
R5
R4
N
R3
H
H
N
N
R1 N C
R3
3
N
N
N
N
N
N
Scheme 2. Formation of 4,5-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepine
derivatives 5.
The first mechanism (route 1, Scheme 2) shows that the formation of Ugi
adduct takes place before azide-alkyne cyclization; while according to the second
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mechanism (route 2, Scheme 2), cyclization reaction and the formation of
benzodiazepine ring is prior to Ugi reaction. To distinguish between mechanisms, a
mixture of 2-azidobenzaldehyde 1 and propargylamine 2 in MeOH was heated at
reflux. After completion of reaction (checked by TLC), 4H-[1,2,3]triazolo[1,5-
a][1,4]benzodiazepine 7, the known compound reported by Alajarín et al.,21 was
obtained. Then, it was reacted with cyclohexylisocyanide 3a and 4-nitrophenol 4a
under the conditions described in section 4.2. The results revealed that 5a, the
corresponding product in one-pot four-component reaction (4.2.1) is the only product
and thus, the second mechanism (route 2, Scheme 2) is acceptable.
3. Conclusion
In conclusion, we have shown that 4,5-dihydro-1,2,3-triazolo[1,5-
a][1,4]benzodiazepine derivatives can be efficiently synthesized by modification of
the four-component Ugi-Smiles type reaction of 2-azidobenzaldehyde,
propargylamine, isocyanides, nitrophenols. The reaction was accomplished without
using additional reagents or catalysts. The ease of preparation of compounds and the
isolation of products, and the good chemical yields of the described transformation
are the remarkable synthetic aspects of this procedure for the synthesis of new 1,2,3-
triazolo-1,4-benzodiazepines.
4. Experimental Section
4.1. General
Melting points were taken on a Kofler hot stage apparatus and are uncorrected.
1H- and 13C-NMR spectra were recorded on Bruker FT-500, using TMS as an internal
standard. The IR spectra were obtained on a Nicolet Magna FTIR 550
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spectrophotometer (in KBr). Mass spectra were determined on an Agilent Technology
(HP) mass spectrometer operating at an ionization potential of 70 eV. The elemental
analysis was performed with an Elementar Analysensystem GmbH VarioEL CHNS
mode. All reagents and solvents were obtained from Merck and Aldrich and used
without any purification. Silica gel 60 (0.040-0.063 mm) were used for column
chromatography Thin layer chromatography (TLC) was performed using silica gel
60/Kieselguhr F254 precoated on Aluminum sheets (thickness 0.2 mm), commercially
available from Merck. Visualization of spots on TLC plate was accomplished with
UV light.
4.2. Synthesis of N-alkyl-4,5-dihydro-5-(substituted phenyl)-1,2,3-triazolo[1,5-
a][1,4]benzodiazepine-6-carboxamide 5; General Procedure
A mixture of 2-azidobenzaldehyde22 1 (1 mmol), propargylamine 2 (1 mmol),
isocyanides 3 (1.2 mmol) and nitrophenol 4 (1 mmol) in MeOH (10 mL) was heated
at reflux for 24 h. The solvent was then removed under reduced pressure and the
crude reaction mixture was purified by column chromatography on silica gel
(petroleum ether–ethyl acetate/6:1) to give pure products 5.
4.2.1.
N-Cyclohexyl-4,5-dihydro-5-(4-nitrophenyl)-1,2,3-triazolo[1,5-
a][1,4]benzodiazepine-6-carboxamide 5a. Yield: 75%; yellow crystals; mp 160-161
1
◦C; Rf value: 0.15. IR (KBr): 3367, 2930, 2854, 1660, 1593, 1497, 1389 cm-1. H
NMR (500 MHz, CDCl3): δ = 0.87-1.58 (m, 10 H, cyclohexyl), 3.45-3.47 (m, 1 H,
NCH), 4.19 (d, J = 13.5 Hz, 1 H, H4a), 5.01 (d, J = 13.5 Hz, 1 H, H4b), 5.38 (s, 1 H,
H6), 5.73 (d, J = 7.7 Hz, 1 H, NH), 6.94 (d, J = 9.1 Hz, 2 H, H2', H6'), 7.53 (t, J = 7.5
Hz, 1 H, H11), 7.56 (d, J = 7.5 Hz, 1 H, H12), 7.69 (t, J = 7.5 Hz, 1 H, H10), 7.85 (s, 1
9

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H, H3), 7.98 (d, J = 7.5 Hz, 1 H, H9), 8.21 (d, J = 9.1 Hz, 2 H, H3', H5'). 13C NMR
(125 MHz, CDCl3): δ = 24.2, 24.3, 24.7, 31.8, 32.2, 39.7, 48.2, 68.4, 112.9, 123.3,
125.6, 127.0, 129.6, 130.6, 130.8, 132.6, 132.9, 133.8, 139.8, 153.0, 166.2. MS: m/z
(%) = 432.19 [M]+ (1), 306 (95, M-CONHcyclohexyl), 278 (40), 232 (100), 129 (15),
103 (22), 77 (13), 76 (20), 55 (55). Anal. Calcd for C23H24N6O3: C, 63.88; H, 5.59; N,
19.43. Found: C, 64.05; H, 5.45; N, 19.21.
4.2.2.
N-Cyclohexyl-4,5-dihydro-5-(2-nitrophenyl)-1,2,3-triazolo[1,5-
a][1,4]benzodiazepine-6-carboxamide 5b. Yield: 80%; yellow crystals; mp 243-244
°C; Rf value: 0.18. IR (KBr): 3377, 2929, 2855, 1675, 1603, 1520, 1448, 1356 cm-1.
1H NMR (500 MHz, CDCl3): δ = 0.90-1.61 (m, 10 H, cyclohexyl), 3.37-3.43 (m, 1 H,
NCH), 3.87 (d, J = 13.5 Hz, 1 H, H4a), 4.48 (d, J = 13.5 Hz, 1 H, H4b), 4.91 (s, 1 H,
H6), 7.34 (d, J = 8.3 Hz, 1 H, NH), 7.42 (dt, J = 8.0, 1.0 Hz, 1 H, H4'), 7.53 (dd, J =
8.0, 1.0 Hz, 1 H, H6'), 7.60-7.69 (m, 4 H, H9, H10, H11, H12), 7.79 (s, 1 H, H3), 7.91-
7.94 (m, 2 H, H3', H5'). 13C NMR (125 MHz, CDCl3): δ = 24.2, 24.3, 24.8, 31.8, 31.9,
45.5, 47.8, 69.2, 123.3, 125.1, 125.8, 126.4, 128.3, 129.5, 130.1, 130.6, 131.8, 132.3,
134.1, 134.7, 144.1, 145.8, 166.9. MS: m/z (%) = 432.19 [M]+ (1), 332 (14), 306 (94,
M-CONHcyclohexyl), 278 (38), 260 (23), 231 (100), 205 (10), 151 (12), 129 (26),
102 (22), 77 (29), 55 (56). Anal. Calcd for C23H24N6O3: C, 63.88; H, 5.59; N, 19.43.
Found: C, 63.69; H, 5.65; N, 19.55.
4.2.3.
N-Cyclohexyl-4,5-dihydro-5-(2,4-dinitrophenyl)-1,2,3-triazolo[1,5-
a][1,4]benzodiazepine-6-carboxamide 5c. Yield: 85%; yellow crystals; mp 150-151
°C; Rf value: 0.15. IR (KBr): 3371, 2930, 2854, 1673, 1601, 1526, 1449, 1335 cm-1.
1H NMR (500 MHz, CDCl3): δ = 0.87-1.56 (m, 10 H, cyclohexyl), 3.40-3.43 (m, 1 H,
NCH), 4.12 (d, J = 13.5 Hz, 1 H, H4a), 4.38 (d, J = 13.5 Hz, 1 H, H4b), 5.26 (s, 1 H,
H6), 6.30 (d, J = 7.8 Hz, 1 H, NH), 7.55 (d, J = 9.1 Hz, 1 H, H6'), 7.65-7.75 (m, 3 H,
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H10, H11, H12), 7.77 (s, 1 H, H3), 7.98 (d, J = 7.8 Hz, 1 H, H9), 8.41 (dd, J = 9.1, 2.5
Hz, 1 H, H5'), 8.78 (d, J = 2.5 Hz, 1 H, H3'). 13C NMR (125 MHz, CDCl3): δ = 24.2,
24.7, 31.9, 32.0, 44.0, 48.3, 59.9, 67.8, 122.2, 123.4, 123.6, 126.6, 128.2, 129.9,
130.1, 131.0, 131.8, 132.8, 134.4, 141.1, 141.5, 148.0, 165.8. MS: m/z (%) = 477.18
[M]+ (1), 351 (8, M-CONHcyclohexyl), 318 (63), 290 (17), 260 (12), 243 (100), 216
(21), 190 (14), 155 (19), 129 (20), 102 (40), 76 (33), 55 (58). Anal. Calcd for
C23H23N7O5: C, 57.86; H, 4.86; N, 20.53. Found: C, 57.60; H, 4.72; N, 20.75.
4.2.4.
N-Cyclohexyl-4,5-dihydro-5-(2,4,6-trinitrophenyl)-1,2,3-triazolo[1,5-
a][1,4]benzodiazepine-6-carboxamide 5d. Yield: 88%; yellow crystals; mp 238-239
°C; Rf value: 0.21. IR (KBr): 3461, 2932, 2855, 1690, 1603, 1519, 1492, 1369 cm-1.
1H NMR (500 MHz, DMSO-d6): δ = 1.10-1.99 (m, 10 H, cyclohexyl), 2.95 (bs, 1 H,
NH), 3.59 (d, J = 13.4 Hz, 1 H, H4a), 4.01-4.03 (m, 1 H, NCH), 4.17 (d, J = 13.4 Hz,
1 H, H4b), 4.49 (s, 1 H, H6), 7.53-7.54 (m, 2 H, H9, H12), 7.77 (s, 1 H, H3), 7.82-7.87
(m, 2 H, H10, H11), 8.62 (s, 1 H, H3'), 8.73 (s, 1 H, H5'). 13C NMR (125 MHz, DMSO-
d6): δ = 24.8, 25.4, 28.2, 28.7, 37.7, 53.8, 59.7, 62.2, 118.3, 122.8, 128.1, 128.4,
128.5, 128.6, 128.9, 129.2, 132.0, 133.7, 135.7, 167.3. MS: m/z (%) = 522.16 [M]+
(1), 396 (1, M-CONHcyclohexyl), 391 (55), 270 (13), 242 (20), 215 (16), 185 (30),
155 (24), 129 (26), 102 (21), 83 (85), 55 (100). Anal. Calcd for C23H22N8O7: C, 52.87;
H, 4.24; N, 21.45. Found: C, 52.95; H, 4.44; N, 21.66.
4.2.5.
N-Cyclohexyl-4,5-dihydro-5-(5-fluoro-2-nitrophenyl)-1,2,3-triazolo[1,5-
a][1,4]benzodiazepine-6-carboxamide 5e. Yield: 85%; yellow crystals; mp 182-183
°C; Rf value: 0.22. IR (KBr): 3355, 2929, 2854, 1669, 1613, 1582, 1520, 1341 cm-1.
1H NMR (500 MHz, CDCl3): δ = 0.93-1.65 (m, 10 H, cyclohexyl), 3.41-3.43 (m, 1 H,
NCH), 3.87 (d, J = 13.5 Hz, 1 H, H4a), 4.49 (d, J = 13.5 Hz, 1 H, H4b), 4.95 (s, 1 H,
H6), 7.09 (ddd, J = 9.1, 8.0, 2.5 Hz, 1 H, H4'), 7.21 (dd, J = 9.2, 2.5 Hz, 1 H, H6'), 7.28
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(s, 1 H, NH), 7.65-7.71 (m, 3 H, H10, H11, H12), 7.81 (s, 1 H, H3), 7.95 (d, J = 7.6 Hz,
1 H, H9), 8.05 (dd, J = 9.1, 5.5 Hz, 1 H, H3'). 13C NMR (125 MHz, CDCl3): δ = 24.2,
2
2
24.3, 24.8, 31.8, 31.9, 45.2, 47.9, 69.0, 112.7 (d, JC-F = 23.1 Hz), 113.1 (d, JC-F
=
3
23.0 Hz), 123.5, 127.7, 128.2 (d, JC-F = 10.5 Hz), 129.7, 130.2, 130.4, 131.8, 132.5,
4
1
134.6, 141.2, 146.7 (d, JC-F = 9.8 Hz), 164.8 (d, JC-F = 258.8 Hz), 166.5. MS: m/z
(%) = 451.18 [M+1]+ (6), 324 (75, M-CONHcyclohexyl), 308 (16), 249 (100), 158
(12), 130 (14), 83 (28), 55 (65). Anal. Calcd for C23H23FN6O3: C, 61.32; H, 5.15; N,
18.66. Found: C, 61.55; H, 5.32; N, 18.50.
4.2.6.
N-tert-Butyl-4,5-dihydro-5-(2-nitrophenyl)-1,2,3-triazolo[1,5-
a][1,4]benzodiazepine-6-carboxamide 5f. Yield: 80%; yellow crystals; mp 221-223
°C; Rf value: 0.15. IR (KBr): 3353, 2966, 2829, 1678, 1602, 1521, 1476, 1361 cm-1.
1H NMR (500 MHz, CDCl3): δ = 1.10 (s, 9 H, t-butyl), 3.84 (d, J = 13.0 Hz, 1 H,
H4a), 4.52 (d, J = 13.0 Hz, 1 H, H4b), 4.86 (s, 1 H, H6), 7.32 (s, 1 H, NH), 7.42 (dt, J =
8.1, 1.0 Hz, 1 H, H4'), 7.55 (dd, J = 8.1, 1.0 Hz, 1 H, H6'), 7.61-7.69 (m, 4 H, H9, H10,
H11, H12), 7.83 (s, 1 H, H3), 7.92-7.95 (m, 2 H, H3', H5'). 13C NMR (125 MHz, CDCl3):
δ = 27.5, 45.4, 50.5, 70.1, 123.4, 125.1, 126.0, 126.4, 128.6, 129.4, 130.1, 130.6,
132.1, 132.3, 134.2, 134.6, 144.4, 145.8, 167.2. MS: m/z (%) = 406.18 [M]+ (1), 306
(42, M-CONHtertBu), 285 (12), 231 (77), 170 (10), 129 (21), 91 (100), 57 (61).
Anal. Calcd for C21H22N6O3: C, 62.06; H, 5.46; N, 20.68. Found: C, 62.22; H, 5.60;
N, 20.73.
4.2.7.
N-tert-Butyl-4,5-dihydro-5-(2,4-dinitrophenyl)-1,2,3-triazolo[1,5-
a][1,4]benzodiazepine-6-carboxamide 5g. Yield: 85%; yellow crystals; mp 130-132
1
°C; Rf value: 0.19. IR (KBr): 3372, 2969, 2829, 1678, 1601, 1527, 1389 cm-1. H
NMR (500 MHz, CDCl3): δ = 1.09 (s, 9 H, t-butyl), 4.05 (d, J = 14.0 Hz, 1 H, H4a),
4.42 (d, J = 14.0 Hz, 1 H, H4b), 5.18 (s, 1 H, H6), 6.44 (s, 1 H, NH), 7.59 (d, J = 9.0
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Hz, 1 H, H6'), 7.65-7.74 (m, 3 H, H10, H11, H12), 7.81 (s, 1 H, H3), 8.00 (d, J = 7.8 Hz,
1 H, H9), 8.45 (dd, J = 9.0, 2.5 Hz, 1 H, H5'), 8.80 (d, J = 2.5 Hz, 1 H, H3'). 13C NMR
(125 MHz, CDCl3): δ = 28.0, 44.6, 51.7, 69.1, 122.6, 124.1, 124.3, 127.4, 128.8,
130.3, 130.5, 131.4, 132.4, 133.3, 134.8, 142.1, 142.3, 148.8, 166.3. MS: m/z (%) =
451.16 [M]+ (1), 351 (20, M-CONHtertBu), 335 (14), 318 (18), 276 (21), 230 (79),
202 (16), 180 (10), 164 (14), 145 (30), 129 (29), 102 (45), 77 (52), 57 (100). Anal.
Calcd for C21H21N7O5: C, 55.87; H, 4.69; N, 21.72. Found: C, 55.70; H, 4.80; N,
21.90.
4.2.8.
N-tert-Butyl-4,5-dihydro-5-(5-fluoro-2-nitrophenyl)-1,2,3-triazolo[1,5-
a][1,4]benzodiazepine-6-carboxamide 5h. Yield: 85%; yellow crystals; mp 218-220
°C; Rf value: 0.20. IR (KBr): 3430, 2925, 2856, 1637, 1607, 1492, 1468, 1381 cm-1.
1H NMR (500 MHz, CDCl3): δ = 1.10 (s, 9 H, t-butyl), 3.83 (d, J = 13.0 Hz, 1 H,
H4a), 4.53 (d, J = 13.0 Hz, 1 H, H4b), 4.90 (s, 1 H, H6), 7.09 (ddd, J = 9.0, 8.0, 2.2 Hz,
1 H, H4'), 7.23 (dd, J = 9.2, 2.2 Hz, 1 H, H6'), 7.31 (s, 1 H, NH), 7.65-7.69 (m, 3 H,
H10, H11, H12), 7.85 (s, 1 H, H3), 7.95 (d, J = 7.6 Hz, 1 H, H9), 8.06 (dd, J = 9.0, 5.7
Hz, 1 H, H3'). 13C NMR (125 MHz, CDCl3): δ = 28.0, 45.5, 51.1, 70.2, 113.3 (d, 2JC-F
= 23.2 Hz), 113.7 (d, 2JC-F = 23.3 Hz), 124.0, 127.9, 128.4, 128.7 (d, 3JC-F = 10.6 Hz),
4
1
130.1, 130.8, 132.5, 132.9, 134.9, 141.7, 147.4 (d, JC-F = 9.5 Hz), 165.3 (d, JC-F
=
258.5 Hz), 167.3. MS: m/z (%) = 425.17 [M+1] + (11), 324 (86, M-CONHtertBu), 308
(25), 296 (20), 249 (100), 237 (24), 158 (15), 146 (16), 130 (20), 57 (95). Anal. Calcd
for C21H21FN6O3: C, 59.43; H, 4.99; N, 19.80. Found: C, 59.25; H, 5.10; N, 19.95.
4.2.9. 4H-[1,2,3]triazolo[1,5-a][1,4]benzodiazepine 7. Yield: 60%; yellow crystals;
1
mp 159-162 °C; Rf value: 0.15. H NMR (500 MHz, CDCl3): δ = 4.73 (s, 2 H, H4),
7.57-7.62 (m, 2 H, H8, H10), 7.68 (s, 1 H, H3), 7.72 (dt, J = 7.5, 2.1 Hz, 1 H, H9), 8.22
(d, J = 8.1 Hz, 1 H, H7), 8.48 (s, 1 H, H6). 13C NMR (125 MHz, CDCl3): δ = 43.5,
13

ACCEPTED MANUSCRIPT
122.5, 124.8, 128.5, 131.0, 131.6, 132.5, 134.7, 136.1, 163.2. Anal. Calcd for
C10H8N4: C, 65.21; H, 4.38; N, 30.42. Found: C, 64.95; H, 4.60; N, 30.20.
Acknowledgements
This research was supported by grants from the research council of Tehran
University of Medical Sciences and Iran National Science Foundation (INSF).
Supporting Information for this article is available online.
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