1,4-Benzodiazepine N-nitrosoamidines: Useful intermediates in the synthesis of tricyclic benzodiazepines

Article abstract of DOI:10.3390/11080583

1,4-Benzodiazepine N-nitrosoamidines have been used as scaffolds for the preparation of different tricyclic derivatives. Replacement of the N-nitrosoamidine moiety through treatment with the nucleophiles acetylhydrazine, aminoacetaldehyde dimethylacetal and 1-amino-2-propanol, followed by an acid-catalyzed cyclization step, afforded triazolo and imidazobenzodiazepines 1, 6, and 7, respectively, in good yields. When acetylhydrazine is used as a nucleophile, the overall process provides an alternative route to alprazolam (1b) and triazolam (1c), respectively.

Full text of DOI:10.3390/11080583

Molecules 2006, 11, 583-588
molecules
ISSN 1420-3049
http://www.mdpi.org
Communication
1,4-Benzodiazepine N-Nitrosoamidines: Useful Intermediates in
the Synthesis of Tricyclic Benzodiazepines
Santos Fustero 1,* Javier González 2 and Carlos del Pozo 1,*
1 Departamento de Química Orgánica, Universidad de Valencia, 46100-Burjassot, Valencia (Spain).
2 Departamento de Química Orgánica e Inorgánica, Universidad de Oviedo, Julián Clavería 8, 33006
Oviedo (Spain).
* Authors to whom correspondence should be addressed. E-mails: santos.fustero@uv.es,
carlos.pozo@uv.es
Received: 9 June 2006; in revised form: 31 July 2006 / Accepted: 1 August 2006 / Published: 9 August
2006
Abstract: 1,4-Benzodiazepine N-nitrosoamidines have been used as scaffolds for the
preparation of different tricyclic derivatives. Replacement of the N-nitrosoamidine
moiety through treatment with the nucleophiles acetylhydrazine, aminoacetaldehyde
dimethylacetal and 1-amino-2-propanol, followed by an acid-catalyzed cyclization step,
afforded triazolo and imidazobenzodiazepines 1, 6, and 7, respectively, in good yields.
When acetylhydrazine is used as a nucleophile, the overall process provides an
alternative route to alprazolam (1b) and triazolam (1c), respectively.
Keywords: N-Nitrosoamidines, 1,4-benzodiazepines, midazolam, alprazolam, triazolam
Introduction
The wide spectrum of pharmacological effects exhibited by benzodiazepines makes them one of the
most versatile classes of drugs used in psychopharmacology [1]. Among them, 1,4-benzodiazepines
fused to a five-membered heterocyclic ring are the most commonly prescribed group of drugs for the
treatment of CNS disturbances [2]. Triazolobenzodiazepines such as alprazolam (1b) or triazolam (1c)
and imidazobenzodiazepines such as midazolam (2) (Figure 1) see extensive clinical use as anxiolytic

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and anesthetic agents, respectively. Moreover, appropriate modifications of these systems have been
found to produce compounds with qualitatively different pharmacological profiles [3].
Figure 1
Me
Me
N
N
N
N
N
R1
Cl
N
N
R2
F
1b (R1=Cl, R2=H)
1c (R1=Cl, R2=Cl)
2
In the 1,4-benzodiazepine series chemical activation of cyclic secondary amides 3 via
transformation to N-nitrosoamidines 4 has been described as a useful approach to the functionalization
of position 2 of the bicyclic core of the heterocycle [4]. In this context, we have previously described
the use of these 1,4-benzodiazepine-derived N-nitrosoamidines 4 as synthetic equivalents of imidoyl
chlorides in their reaction with Tos-MIC to form 3-(4-tosyl)imidazo[1,5-a][1,4]benzodiazepines 5
(Scheme 1) [5].
Scheme 1
Me
N
Tos
N NO
Tos-MIC
H
O
N
N
N
R1
R1
R1
N
N
N
R2
R2
R2
3
4
5
As an extension of this previous work, we describe herein the use of this strategy for the
preparation of several tricyclic benzodiazepines with structures closely related to those of compounds
1b, 1c, and 2, using compounds 4 as starting materials.
Results and Discussion
Treatment of N-nitrosoamidines 4 [ 6 ] with aminoacetaldehyde dimethylacetal afforded the
corresponding amidines in an addition-elimination sequence. These amidine derivatives were heated in
toluene at 80º C in the presence of two equivalents of p-toluenesulfonic acid (TsOH) to furnish
imidazo[1,2-a][1,4]benzodiazepines 6 in very good yields (Scheme 2) [7]. The use of this methodology

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Molecules 2006, 11
in the preparation of imidazosugar derivatives, which show glycosidase inhibitor activity, has been
recently described [8].
Scheme 2
Me
N NO
1) H2NCH2CH(OMe)2
N
N
N
2) TsOH/Tol/∆
R1
R1
N
N
R2
R2
4a (R1=Cl, R2=F)
4b (R1=Cl, R2=H)
6a (R1=Cl, R2=F, 79%)
6b (R1=Cl, R2=H, 80%)
The N-nitrosoamidine functionality in compounds 4 can also be replaced through reaction with
1-amino-2-propanol. The hydroxyl functionality present in this newly created amidine was
subsequently oxidized to the corresponding methyl ketone through treatment with Jones’ reagent.
p-Toluenesulfonic acid-mediated cyclization under the conditions described above afforded tricyclic
benzodiazepines 7 in moderate yields (Scheme 3) [9].
Scheme 3
Me
Me
N NO
N
N
N
1) H2NCH2CH(OH)CH3
2) Jones'/acetone
3) TsOH/Tol/∆
R1
R1
N
N
R2
R2
4a (R1=Cl, R2=F)
4b (R1=Cl, R2=H)
4c (R1=Cl, R2=Cl)
7a (R1=Cl, R2=F, 50%)
7b (R1=Cl, R2=H, 48%)
7c (R1=Cl, R2=Cl, 52%)
Finally, treatment of N-nitrosoamidines 4 with acetylhydrazine gave rise to the corresponding
amidines, which were then cyclized upon heating in dimethylformamide (DMF) in the presence of
TsOH to afford triazole-fused 1,4-benzodiazepines 1 in very good yields (Scheme 1). Although this
reaction has previously been reported in the literature for the formation of the 4-oxide derivative of 1b
[4b], the final tricyclic system could not be isolated, but rather appeared together with another
uncyclized product. The use of TsOH in the cyclization step greatly increases the efficiency of this
process as it enables the complete conversion of the starting material, thereby improving the final yield.
The overall process constitutes an efficient alternative protocol for the preparation of alprazolam (1a)
and triazolam (1b) (Scheme 4).

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Molecules 2006, 11
Scheme 4
Me
Me
N
N NO
N
N
N
CH3CONHNH2
R1
R1
N
N
TsOH/∆
R2
R2
4a (R1=Cl, R2=F)
4b (R1=Cl, R2=H)
4c (R1=Cl, R2=Cl)
1a (R1=Cl, R2=F, 84%)
1b (R1=Cl, R2=H, 87%)
1c (R1=Cl, R2=Cl, 81%)
Conclusions
In summary, the syntheses of several tricyclic benzodiazepine derivatives through the reactions of
benzodiazepine N-nitrosoamidines with nitrogen nucleophiles are described. The initially formed
amidines were subsequently cyclized in the presence of TsOH to the corresponding triazolo- and
imidazo[1,2-a][1,4]benzodiazepines in good yields. Although these heterocyclic systems have been
previously described, the use of compounds 4 as precursors offers an efficient alternative for their
preparation.
Experimental
General
All reactions were carried out under argon or nitrogen atmospheres. Solvents were purified prior to
use: toluene was distilled from sodium; CH2Cl2 and DMF were distilled from calcium hydride. All
reagents were used as received. The reactions were monitored with the aid of thin-layer
chromatography (TLC) on 0.25-mm precoated silica gel plates. Visualization was carried out with UV
light and aqueous ceric ammonium molybdate solution or potassium permanganate stain. Flash column
chromatography was performed with the indicated solvents on silica gel 60 (particle size 0.040-0.063
1
mm). H- and 13C-NMR spectra were recorded on a 300 MHz Bruker AC300 spectrometer.
Compounds 1a-c [10], 5a,b [11] and 6a,b [10a-c] all showed NMR spectra identical to those
previously described in the literature.
General procedure for the preparation of triazolobenzodiazepines 1
A solution of N-nitrosoamidine 4 (2 mmol) and TsOH (0.19 g, 1 mmol) in DMF (10 mL) was
heated at 120º C for 1 h. The reaction was cooled to room temperature (r.t.), quenched with saturated
sodium bicarbonate (20 mL), and extracted with CH2Cl2. The combined organic layers were dried,
concentrated, and subjected to flash chromatography (4:1 EtOAc-MeOH) to afford the final products 1
in the yields shown in Scheme 4.

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Molecules 2006, 11
General procedure for the preparation of imidazobenzodiazepines 6
A solution of N-nitrosoamidine 4 (2 mmol) in aminoacetaldehyde dimethyl acetal (5 mL) was
stirred at r.t. for 24 h. The acetal, used as solvent, was evaporated in vacuo. The residue was dissolved
in toluene (10 mL), TsOH (0.76 g, 4 mmol) was added, and the resulting solution was heated at 80ºC
for 14 h. The reaction was quenched with aqueous sodium bicarbonate (20 mL) and extracted with
CH2Cl2 (3 x 20 mL); the combined organic layers were dried and concentrated in vacuo. Flash
chromatography of the crude mixture (EtOAc) afforded the desired tricyclic systems 6 in the yields
shown in Scheme 2.
General procedure for the preparation of imidazobenzodiazepines 7
A solution of N-nitrosoamidine 4 (2 mmol) in 1-amino-2-propanol (5 mL) was stirred at r.t. for 24
h. The reaction was then quenched with a saturated sodium bicarbonate solution (30 mL), extracted
with CH2Cl2 (3 x 20 mL) and the combined organic layers were washed with water (2 x 20 mL). The
residue was concentrated, dried, redissolved in acetone, and treated with Jones’ reagent (1 mL). The
reaction mixture was stirred at r.t. for 1 h and quenched with methanol (10 mL). Solvents were
eliminated in vacuo and the crude reaction mixture was dissolved in CH2Cl2 (30 mL), filtered through
a pad of Celite®, washed with aqueous sodium bicarbonate, dried, and concentrated in vacuo. The
residue was once again dissolved in toluene (20 mL), treated with TsOH (0.76 g, 4 mmol) and heated
at 80º C for 14 h. The reaction was cooled to r.t., quenched again with sodium bicarbonate, and after
aqueous workup and flash chromatography (4:1 EtOAc-MeOH), the final compounds 6 were obtained
in the overall yields shown in Scheme 3.
Acknowledgements
This research was supported by the European Community (Feder Project 1FD97-0869) and the
Generalitat Valenciana (GR03-193). C. P. expresses his gratitude for a Ramón y Cajal contract.
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6
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7
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9
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Sample availability: Not available.
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