Zinc montmorillonite as a reusable heterogeneous catalyst for the synthesis of 2,3-dihydro-1 H - 1,5-benzodiazepine derivatives

A novel approach for the synthesis of 2,3-dihydro-1 H -1,5-benzodiazepines from o -phenylene- diamines and structurally divergent ketones is described using zinc montmorillonite as catalyst at room temperature. The catalyst can be reused for at least three cycles with consistent activity


Introduction
1,5-Benzodiazepine derivatives have received significant attention, and the core is indeed a ''privileged scaffold'' found in compounds active against a variety of target types including peptide hormones (such as CCK), 1a interleukin converting enzymes (ICE) 1b and potassium blockers (I k ) 1c .More recently, the area of biological interest of 1,5-benzodiazepines has been extended to various diseases such as cancer, 2a viral infection (non-nucleoside inhibitors of HIV-1 reverse transcriptase), 2b,2e cardiovascular disorders.2c-d In addition, 1,5-benzodiazepines show antidepressive, antifungal, antibacterial, antifeedant, antiinflammatory, analgesic and anticonvulsant activities. 3Besides, these derivatives are also used as dyes for acrylic fibre 4 in photography.Moreover, 1,5-benzodiazepines are valuable synthons used for the preparation of other fused ring compounds such as triazolo-, oxadiazolo-, oxazino-, or furanobenzodiazepines. 5espite their importance from a pharmacological, industrial and synthetic point of view, comparatively few methods for their preparation are reported in the literature, a great number of which have appeared only very recently employing BF 3 •Et 2 O, 6a NaBH 4 , 6b polyphosphoric acid or SiO 2 , 6c MgO/POCl 3 , 6d Yb(OTf) 3 , 6e Al 2 O 3 /P 2 O 5 or AcOH under microwave conditions, 6f,g Amberlyst-15 in ionic liquid, 6h CeCl 3 .7H 2 O/NaI supported on silica gel, 6i InBr 3 , 6j 1-butyl-3methylimidazolium bromide ([bmim]Br), 6k Sc(OTf) 3 , 6l CAN, 6m ZnCl 2 under thermal conditions, 6n AgNO 3 , 6o sulfated zirconia, 6p InCl 3 6q as catalysts.However, many of these methods have some drawbacks such as low yields of the products, 6a,b high temperatures, 6c long reaction times, 6c and relatively expensive catalysts.6e,i,j,l,q Therefore, the search continues for a better catalyst for the synthesis of 1,5-benzodiazepines in terms of operational simplicity, reusability, economic viability.The increasing demand for cleaner processes promoted by stringent environment laws requires use of eco-friendly and selective catalysts.Use of inexpensive and non-polluting reagents is highly desirable in recent years and the use of clays as catalyst supports has received considerable attention. 7Academic and industrial interest has focused on the use of acid activated montmorillonite K10-supported zinc chloride (zinc montmorillonite, Zn 2+ -mont); use of this remarkable material has been first reported in 1989. 8Examples for Zn 2+ -mont-mediated organic reactions such as alkylation, preparation of 1,1-diacetates from aldehydes, hydroamination, 3-aza-Cope rearrangement etc. are well documented in the literature. 9n continuation of our interest in developing novel synthetic methodologies, particularly carbon-carbon, carbon-heteratom bond formations, 6m,10 and in the use of montmorillonites as environmentally friendly reagents for organic synthesis, we undertook a study of the utility of Zn 2+ -mont as catalyst for the synthesis of 2,3-dihydro-1H-1,5-benzodiazepines (Scheme 1).However, to the best of our knowledge, there are no earlier reports on the preparation of 2,3dihydro-1H-1,5-bezodiazepines using Zn 2+ -mont todate.

Results and Discussion
At first, we have evaluated the feasibility of the reaction of o-phenylenediamine (1a, 1 mmol) and acetophenone (2a, 2.2 mmol) using various zinc salts (Table 1) at ambient temperature to afford the corresponding 2,3-dihydro-1H-1,5-benzodiazepine 3a.Some of the examined zinc salts worked as reasonable catalysts, e.g., ZnBr 2 , ZnCl 2 , Zn(NO 3 ) 2 , etc., while some salts such as zinc hydroxyapatite, Zn metal (granulated), Zn dust and ZnSO 4 were not effective.Notably, Zn 2+ -mont (Table 1, entry 8) exhibited superior catalytic activity compared to the unsupported salts such as ZnBr 2 , ZnCl 2 in terms of regeneration and ease of disposal of the used catalyst.Furthermore, the corresponding homogeneous catalyst (e.g., ZnCl 2 ) is least preferred by the industry, because it generates problems such as environmental pollution, handling, safety, corrosion, and tedious work up.
Encouraged by these results, we studied different reaction parameters.The optimum product yield was obtained with a 1:2.2 ratio of o-phenylenediamines 1 to ketones 2. No reaction was observed when o-phenylenediamine 1a reacted with acetophenone 2a under similar conditions in the absence of Zn 2+ -mont as promotor even after stirring for 2 days,.
Electronically divergent acetophenones 2a-e were employed for the synthesis of 2,3dihydro-1H-1,5-benzodiazepines 3 in moderate to excellent yields (55-90%).Three new products 3ac, 3ad, and 3ae were characterized by IR, NMR, MS and elemental analyses (see Supporting Information).Benzodiazepines 3 were the only products isolated besides starting materials.The procedure was extended to four aliphatic ketones 2f-i.The reaction of o-phenylenediamines 1a-f with acetone (2f) was performed under similar conditions with good yields of the corresponding 2,3-dihydro-1H-1,5-benzodiazepines 3af-ff (62-80%).It is noteworthy that in the reaction with the unsymmetrical ketone 2-butanone (2g) ring formation occurred regioselectively forming a single product 3ag (78%).Cyclopentanone (2h) and cyclohexanone (2i) also reacted well affording moderate yields of the corresponding fused benzodiazepines 3ah and 3ai, respectively.The melting points observed for products 3ah and 3ai match those reported earlier 6b but not those given in a recent paper.6j The catalyst could be reused for at least three cycles after activation at 120 °C for 1 h; there was a slight decrease in activity after the third use in the reaction forming 3aa (78%).The mechanism of the reaction probably involves an intramolecular imine-enamine cyclization promoted by Zn 2+ -mont as already reported by Jung and coworkers when using polyphosphoric acid or silica.6c

Conclusions
A novel and efficient method for the synthesis of 2,3-dihydro-1H-1,5-benzodiazepines 3 is described using the solid acid catalyst Zn 2+ -mont at ambient temperature.The easy work-up procedure, inexpensive recyclable catalyst and good yields make this method a valid contribution to existing methodologies.

Experimental Section
Zn 2+ -mont was prepared according to the literature procedure.9d All reagents were obtained from commercial sources and used without further purification.Solvents for chromatography were distilled before use.

1 Table 1 .
Comparison of Zn salts as catalysts for the cyclocondensation reaction of o-phenylenediamine 1a with acetophenone 2a
1 H and 13 C NMR spectra of CDCl 3 solutions were recorded on VarianFT- 200 MHz (Gemini)and Bruker UXNMR FT-300 MHz (Avance) instruments.Electron-impact (EI) mass spectra were recorded on a VG 7070H Micromass mass spectrometer at 200 °C, 70 eV.Elemental analyses were performed by Elementar analyzer Vario EL.Melting points were recorded on an Electrothermal melting point apparatus.The IR spectra (using KBr pellets) were obtained with a Perkin Elmer 240-C instrument.The reactions were monitored by TLC using pre-coated plates (Merck, silica gel 60F-254 on glass).Column chromatography was performed using Acme silica gel (100-200 mesh).CAUTION: o-phenylenediamines are toxic to work with and hazardous to the environment.