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. 2011 May 14;2011:604348. doi: 10.5402/2011/604348

Bismuth (III) Salts Promoted and Ionic Liquid Assisted an Efficient and Environmentally Benign One-Pot Synthesis of 1,5-Benzodiazepine Derivatives

Atul Chaskar 1,*, Latika Patil 2, Kiran Phatangare 2, Vikas Padalkar 2, Santosh Takale 2
PMCID: PMC3767351  PMID: 24052827

Abstract

1,5-Benzodiazepine derivatives were synthesized by the condensation reactions of o-phenylenediamine and ketones catalyzed by bismuth (III) salts under mild conditions. This method is easy, efficient, environment and eco-friendly, free of toxic catalysts, and gives good to excellent yields of 1, 5-benzodiazepines.

1. Introduction

The synthesis of 1,5-benzodiazepines and their derivatives have attracted considerable attention of researchers, including pharmaceutical and organic synthetic chemists, in recent years because of their medicinal properties namely antianxiety, hypnotic, antidepressive, tranquilizing, antiinflammatory, anticonvulsant, antifeedant, antibacterial, and analgesic agents [1–4]. In addition, 1,5-benzodiazepines are valuable synthons used for the preparation of other fused ring compounds such as triazolo, oxazino or furano-benzodiazepines [5, 6]. Benzodiazepines derivatives are also used in industry as dyes for acrylic fibers in photography [7].

Due to their wide range of pharmacological activities and industrial and synthetic applications, the development of practical and green protocols continues to be a challenging endeavour in synthetic chemistry. In recent years, many methods for their preparation are reported in the literature. These include condensation reactions of o-phenylenediamine with α, β-unsaturated carbonyl compounds [8], β-haloketones [9], β-aminoketones [10] or ketones promoted by BF3·OEt2 [11], NaBH4 [12], polyphosphoric acid or SiO2 [13], ceric ammonium nitrate (CAN) [14], MgO/POCl3 [15], Yb(OTf)3 [16], Al2O3/P2O5 or AcOH under microwave conditions [17], Amberlyst-15 in ionic liquid [18], CeCl3/7H2O/NaI supported on silica gel [19], InBr3 [20], 1-butyl-3-methylimidazolium bromide ([bmim]Br) [21], Sc(OTf)3 [22], and Nb(Cl)3 [23]. However, many of these methodologies have one or more shortcomings, such as long reaction time, poor yields of the products, drastic reaction conditions, occurrence of several side products, expensive reagents, high catalyst loading, and tedious workup procedures.

Bismuth (III) salts have emerged in the recent years as “eco-friendly” reagents suitable for green chemistry. They have received considerable attention as mild Lewis acids [24–27] for an array of organic transformations because the catalysts are inexpensive, relatively nontoxic, moisture and air tolerant, environmentally benign, and commercially available. Ionic liquid is used as an alternative to traditional solvents for organic reactions particularly in the area of green chemistry.

Thus, considering the advantages and applications of bismuth (III) salts and ionic liquid, and as part of our ongoing project to explore the catalytic activities of bismuth (III) salts in organic transformations [28], we attempted the convenient and practical synthesis of 1,5 benzodiazepines using bismuth (III) salts (Scheme 1).

Scheme 1.

Scheme 1

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In order to investigate the catalytic efficiency of bismuth (III) salts and compare it with different acid catalysts, the condensation of o-phenylendiamine with acetone in presence of different catalysts at room temperature was investigated, and results are shown in Table 1.

Table 1.

Influence of catalysts on preparation of 1,5-benzodiazepines from o-phenylendiamine and acetonea.

Entry Catalyst Time Yieldb
1 — 20 h trace
2 HCl 3 h 79
3 SiO2 3 h 91
4 YbCl3 1.5 h 85
5 [HMIm]BF4 3 h 43
6 Amberlyst-15 3.5 h 90
7 Polyphosphoric acid 3 h 83
8 Bismuth (III) salts 1 h 95
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aReaction condition: o-phenylendiamine (0.01 mol), acetone (0.02 mol), Bismuth (III) salts (0.002 mol), Ionic liquid (2 mL), and room temperature. bIsolated Yield.

The results mentioned in Table 1 demonstrate the effective use of bismuth (III) salts and ionic liquid for the synthesis of 1,5-benzodiazepines.

Encouraged by the results obtained in the above reaction and in order to prove the generality and scope of this new protocol, a wide verity of ketones were evaluated and the results are summarised in Table 2. Aromatic, aliphatic, and cyclic ketones reacted with o-phenylenediamine, affording the corresponding 1,5-benzodiazepines in good to excellent yields. Cyclic ketones gave fused ring benzodiazepines. Products were characterized by 1H-NMR, 13C NMR, and Mass and physical constant. Physical and spectral data of known compounds are in good accordance with those reported in the literature.

Table 2.

Bismuth (III) salts catalysed condensation of o-phenylendiamine with different ketonesa.

graphic file with name ISRN.OC2011-604348.tab.001.jpg
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aReaction conditions: o-phenylenediamine (0.01 mol), ketones (0.02 mol), Bismuth (III) salts (0.002 mol), ionic liquid (2 mL), room temperature, and time 1 hr. bIsolated Yield.

Further, we extended this protocol to substituted o-phenylenediamine, and we have observed that the electron donating group increases the rate of reaction, whereas electron withdrawing group decreases the rate of reaction and yield of product.

2. Conclusion

In conclusion, we have demonstrated here a new and efficient procedure for the synthesis of 1,5-benzodiazepine derivatives catalyzed by bismuth (III) salts in ionic liquid. The advantages of our protocol are easy workup, fast reaction rate, and mild reaction condition with good yield, which make the method an attractive and a useful contribution to the present methodologies.

3. Experimental

All commercial reagents were used as received without purification, and all solvents were reagent grade. The reaction was monitored by TLC using on 0.25 mm E-Merck silica gel 60 F254 precoated plates, which were visualized with UV light. Melting points were taken in open capillaries. The IR spectra were recorded on a PerkinElmer 257 spectrometer using KBr discs. 1H NMR and 13C NMR spectra were recorded on a VXR-300 MHz instrument using TMS as an internal standard.

3.1. General Experimental Procedure

A mixture of o-phenylenediamine (0.01 mol), ketone (0.02 mol), and bismuth (III) salts (0.002 mol) in ionic liquid (2 mL) was stirred at room temperature for 1 hr. After completion of reaction, as monitored by TLC, the reaction mixture was extracted with ethyl acetate (2 × 10 mL). The combined organic extract were washed with distilled water, dried over Na2SO4, and removal of the solvent under reduced pressure furnished the crude product, which was loaded on the silica column and illute with Ethyl acetate-hexane (3 : 7) solvent system to get pure diazepine.

Representative Spectral Data for 2, 2,4-Trimethyl-2,3-dihydro-1H-1,5-benzodiazepine. —

IR (KBr) —

3290 (NH), 1642 (C=N), 1592 (Ar) cm−1;

1H NMR (300 MHz, CDCl3) —

δ 1.34 (s, 6H, 2CH3), 2.20 (s, 2H, CH2), 2.36 (s, 3H, CH3), 3.45 (brs, 1H, NH), 6.62–7.21 (m, 4H, Ar);

13C NMR (300 MHz, CDCl3) —

δ 171.6, 140.4, 138.0, 126.9, 125.3, 121.8, 121.6, 68.1, 45.4, 30.6, 29.5, 29.5;

GC/MS —

M+ 188. Mp 125 °C.

Acknowledgments

The authors greatly appreciate the financial support of University Grand Commission, New Delhi, and University of Mumbai. They are thankful to Dr. S. T. Gadade, Principal, C. K. Thakur College, for their generous support.

References

  • 1.Schutz H. Benzodiazepines. Heidelberg, Germany: Springer; 1982. [Google Scholar]
  • 2.Landquist JK. In: Comprehensive Heterocyclic Chemistry. Katritzky AR, Rees CW, editors. Vol. 1. Oxford, UK: Pergamon; 1984. p. 116. [Google Scholar]
  • 3.Randall LO, Kamal B. In: Benzodiazepines. Garattini S, Mussini E, Randall LO, editors. New York, NY, USA: Raven Press; 1973. p. 27. [Google Scholar]
  • 4.Baun JRD, Pallos FM, Baker DR. 5-furoyl-2,2,4-trimethyl-1,4-dihydro-1H-1,5-benzodiazepine as an anti-inflammatory agent. US patent no. 3,978,227, 1976; Chem. Abstr. 1977, 86, 5498d.
  • 5.Aversa MC, Ferlazzo A, Giannetto P, Kohnke FH. A convenient synthesis of novel [1,2,4]triazolo[4,3- a][1,5]benzodiazepine derivatives. Synthesis. 1986;3:230–231. [Google Scholar]
  • 6.Chimirri A, Grasso S, Ottana R, Romeo G, Zapala M. Synthesis and stereochemistry of Novel [1,2,4] oxadiazolo[4,5-][1,5]benzodiazepine aerivatives. Journal of Heterocyclic Chemistry. 1990;27(2):371–374. [Google Scholar]
  • 7.Haris RC, Straley JM. Cationic polymethine dyes for acrylic fibers. US patent no. 1,537,757, 1968; Chem. Abstr. 1970, 73, 100054w.
  • 8.Stahlofen P, Ried W. Über heterocyclische Siebenringsysteme, V. Umsetzung von o-Phenylendiamin mit, β-Ungesttigten Carbonylverbindungen. Chemische Berichte. 1957;90:815–824. [Google Scholar]
  • 9.Ried W, Torinus E. Über heterocyclische Siebenringsysteme, X. Synthesen kondensierter 5-, 7- und 8-gliedriger Heterocyclen mit 2 Stickstoffatomen. Chemische Berichte. 1959;92:2902–2916. [Google Scholar]
  • 10.Gheorghe R, Comanita E, Bogdan B. Synthesis and reactivity of mannich bases. XIV. Base-catalyzed cyclocondensation of β-aminoketones to 1,5-benzodiazepines and 1,4-naphthodiazepines. Acta Chimica Slovenica. 2002;49(3):575–585. [Google Scholar]
  • 11.Herbert JAL, Suschitzky H. Syntheses of heterocyclic compounds. Part XXIX. Substituted 2,3-dihydro-1H-1, 5-benzodiazepines. Journal of the Chemical Society, Perkin Transactions. 1974;1:2657–2661. [Google Scholar]
  • 12.Morales HR, Bulbarela A, Contreras R. New synthesis of dihydro-and tetrahydro-1,5-benzodiazepines by reductive condensation of o-phenylenediamine and ketones in the presence of sodium borohydride. Heterocycles. 1986;24(1):135–139. [Google Scholar]
  • 13.Jung DI, Choi TW, Kim YY, et al. Synthesis of 1,5-benzodiazepine derivatives. Synthetic Communications. 1999;29(11):1941–1951. [Google Scholar]
  • 14.Varala R, Enugala R, Nuvula S, Adapa SR. Ceric ammonium nitrate (CAN) promoted efficient synthesis of 1,5-benzodiazepine derivatives. Synlett. 2006;(7):1009–1014. [Google Scholar]
  • 15.Balakrishna MS, Kaboudin B. A simple and new method for the synthesis of 1,5-benzodiazepine derivatives on a solid surface. Tetrahedron Letters. 2001;42(6):1127–1129. [Google Scholar]
  • 16.Curini M, Epifano F, Marcotullio MC, Rosati O. Ytterbium triflate promoted synthesis of 1,5-benzodiazepine derivatives. Tetrahedron Letters. 2001;42(18):3193–3195. [Google Scholar]
  • 17.Pozarentzi M, Stephanidou-Stephanatou J, Tsoleridis CA. An efficient method for the synthesis of 1,5-benzodiazepine derivatives under microwave irradiation without solvent. Tetrahedron Letters. 2002;43(9):1755–1758. [Google Scholar]
  • 18.Yadav JS, Reddy BVS, Eshwaraiah B, Anuradha K. Amberlyst-15®: a novel and recyclable reagent for the synthesis of 1,5-benzodiazepines in ionic liquids. Green Chemistry. 2002;4(6):592–594. [Google Scholar]
  • 19.Sabitha G, Kiran Kumar Reddy GS, Bhaskar Reddy K, Mallikarjuna Reddy N, Yadav JS. A new, efficient and environmentally benign protocol for the synthesis of 1,5-benzodiazepines using cerium(III) chloride/sodium iodide supported on silica gel. Advanced Synthesis and Catalysis. 2004;346(8):921–923. [Google Scholar]
  • 20.Yadav JS, Reddy BVS, Praveenkumar S, Nagaiah K. Indium(III) bromide: a novel and efficient reagent for the rapid synthesis of 1,5-benzodiazepines under solvent-free conditions. Synthesis. 2005;(3):480–484. [Google Scholar]
  • 21.Jarikote DV, Siddiqui SA, Rajagopal R, Daniel T, Lahoti RJ, Srinivasan KV. Room temperature ionic liquid promoted synthesis of 1,5-benzodiazepine derivatives under ambient conditions. Tetrahedron Letters. 2003;44(9):1835–1838. [Google Scholar]
  • 22.De SK, Gibbs RA. Scandium(III) triflate as an efficient and reusable catalyst for synthesis of 1,5-benzodiazepine derivatives. Tetrahedron Letters. 2005;46(11):1811–1813. [Google Scholar]
  • 23.Gao ST, Liu WH, Ma JJ, Wang C, Liang Q. NbCl as an efficient catalyst for the synthesis of 1,5-benzodiazepine derivatives. Synthetic Communications. 2009;39(18):3278–3284. [Google Scholar]
  • 24.Sabitha G, Babu RS, Reddy EV, Yadav JS. A novel, efficient, and selective cleavage of acetals using bismuth(III) chloride. Chemistry Letters. 2000;(9):1074–1075. [Google Scholar]
  • 25.Firouzabadi H, Mohammadpoor-Baltork I, Kolagar S. A rapid, selective, and efficient method for deprotection of silyl ethers catalyzed by bismuth(III) salts. Synthetic Communications. 2001;31(6):905–909. [Google Scholar]
  • 26.Matano Y, Ikegami T. In: Organobismuth Chemistry. chapter 2. Suzuki H, Manato Y, editors. New York, NY, USA: Elsevier; 2001. pp. 21–245. [Google Scholar]
  • 27.Leonard NM, Wieland LC, Mohan RS. Applications of bismuth(III) compounds in organic synthesis. Tetrahedron. 2002;58(42):8373–8397. [Google Scholar]
  • 28.Chaskar AC, Langi BP, Deorukhkar A, Deokar H. Bismuth chloride-sodium nitrite: a novel reagent for chemoselective N-nitrosation. Synthetic Communications. 2009;39(4):604–612. [Google Scholar]

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