Various Approaches for Synthesis of 1, 5 -Benzodiazepines
Pandeya S. N.1 and Neha Rajput˛
1Department of Pharmaceutical Sciences, Saroj Institute of Technology & Management, Sultanpur Road, Lucknow-226002 (U.P.), India.
*Corresponding Author E-mail: nr.17neha@gmail.com
ABSTRACT:
Benzodiazepines and its derivatives constitute an important class of heterocyclic compounds which possess a wide range of therapeutic and pharmacological properties. This manuscript includes efficient synthesis of various derivatives of 1,5-benzodiazepines by different methods.
KEYWORDS: 1,5-benzodiazepines, heterocyclic, pharmacological properties
INTRODUCTION:
The benzodiazepines nucleus is a phamacophoric scaffold represents a class of heterocycles with a wide range of biological application.1
Many benzodiazepines are widely used as anticonvulsants, antianxiety, sedative, antidepressive, hypnotic and neuroleptic agents. Some heterocycles containing benzodiazepines moiety were reported to possess anti-inflammatory2, antiviral3, anti HIV4, antimicrobial5, antitumor6 activities. Other than their biological importance, benzodiazepines are valuable for the preparation of fused ring compounds, such as triazolo, thiazolo, imidazolo, and pyrimidobenzodiazepines.
Since the discovery of flurazepam, flunitrazepam, quazepam, halazepam and triflubazam, chemistry of banzodiazepines and allied compounds continues to draw attention of synthetic organic chemists due to their varied biological activity7.Benzodiazepines are valuable intermediates for the synthesis of fused ring compounds such as triazolo, oxadiazolo, oxazino, and furano-benzodiazepine.
This scaffold is also found use for synthesis of commercial type dye and acrylic fibres. Because of this unique position in synthetic as well as medicinal chemistry these have been intensive searches for their efficient and facile synthesis.
The chemical structure of the benzodiazepines seems at first sight to be unique among the various types of central depressants drugs.
The diazepines used today as anxiolytics, hypnotics or anticonvulsants are almost exclusively, 1,4-benzodiazepines (e.g diazepam). 1,5-diazepines have similar properties but considerably less sedative and hypnogenic activity (e.g clobazam).
SYNTHESIS OF 1, 5- BENZODIAZEPINES
1. SYNTHESIS OF 2,3-DIHYDRO-1H-1,5 BENZODIAZEPINES.
2,3-Dihydro-1H-1,5-Benzodiazepines are synthesized by the condensation of o-Phenylenediamine and various ketones in the presence of solid superacid catalyst ‘sulfated zirconia’ under solvent free conditions.8
Generally benzodiazepines are synthesized by the condensation of O-Phenylenediamines with α, β unsaturated carbonyl compounds, β-haloketones or with ketones. Many reagents have been reported in the literature for this condensation including BF3-etherate9, Polyphosphoric acid10, NaBH4 11, SiO2, MgO/POCl3 12, Yb(OTF)4 13 and acetic acid under microwave condition.14
Sulfated zirconia is one of the important agent that has attracted much attention recently because of its superacidity, non toxicity and low cost. Sulfated zirconia catalyzes many reactions under very mild condition in vapor as well as liquid phase.15
In this synthesis there is synthesis of 2,3-Dihydro-1H-1,5-Benzodiazepines by the condensation of O-Phenylenediamine with ketones under solvent free condition catalyzed by a solid super acid catalyst (SCHEME 1).15
O-Phenylenediamine ketone 2,3-Dihydro-1H-1,5-Benzodiazepine
SCHEME 1 : Synthesis of 2,3-Dihydro-1H-1,5- Benzodiazepine
2. SYNTHESIS OF AMINO-1,5-BENZODIAZEPINE FROM DIMEDONE
Synthesis of amine-1,5-benzodiazepines derivatives with a dimedone moiety is obtained by intramolecular cyclisation using cyanogenbromide of enaminone.16 (scheme 2).
SCHEME 2: Synthesis of amine 1,5-benzodiazepines
Various derivatives synthesized by intramolecular cyclisation using cyanogenbromide of enaminone are shown in table 1.
Table 1: Physico-chemical data of derivatives16
|
X |
Yields {%} |
Time (h) |
M. P. (0C) |
|
H |
45 |
4 |
274-276 |
|
CH3 |
49 |
4 |
280-282 |
|
Cl |
30 |
6 |
292-294 |
|
H |
86 |
1 |
180-182 |
|
CH3 |
77 |
1 |
190-192 |
|
Cl |
65 |
1 |
200-202 |
3. SYNTHESIS OF 1,5-BENZODIAZEPINE CATALYZED BY A TETRANITRILE-SILVER COMPLEX .
1,5-benzodiazepine synthesized by a tetranitrile-silver complex of dendritic tetranitrile ligand.17
The present catalyst eliminates the requirement of performed imines and enolates for obtaining good results.17
1. Preparation of ligand
The tetranitrile ligand (propylenediaminetetrapropionitrile) used here to prepare the catalyst. The ligand was derived from 1,3-diaminopropane and acrylonitrile. (SCHEME 3).
1,3-diaminopropane acrylonitrile propylenediamine tetrapropionitrile
SCHEME 3. SYNTHESIS OF THE LIGAND.
propylenediamine tetrapropionitrile propylenediamine tetranitrile-silver complex
SCHEME 4. SYNTHESIS OF THE CATALYST
o-phenylenediamine ketone 1,5-benzodiazepines
SCHEME 5. BENZODIAZEPINE SYNTHESIS CATALYZED BY THE SILVER COMPLEX.
Table 2. Benzodiazepine Synthesis Catalyzed by the Silver Complex17
|
S .NO. |
KETONE |
TIME |
% YIELD |
|
1 |
CH3COCH3 |
1 |
94 |
|
2 |
C6H5COCH3 |
1 |
91 |
|
3 |
C6H5COC6H5 |
2.5 |
90 |
|
4 |
C6H10 |
2 |
90 |
4. SYNTHESIS OF 1,5-BENZODIAZEPINES CATALYZED BY GaCl3.
1,5-benzodiazepine derivatives have been prepared from o-phenylenediamines and ketones using catalytic amount of GaCl₃ (5mol%) under solvent free conditions. This method affords 1,5-benzodiazepines in excellent yield.18 (SCHEME 6)
Recently the use of gallium is reported in some major reactions of organic chemistry like Reformatsky19, Barbeier20, Bromination of aromatics21.
o-phenylenediamine ketone 1,5-benzodiazepines
SCHEME 6: SYNTHESIS OF 1,5-BENZODIAZEPINES BY GaCl₃ (5MOL%) UNDER SOLVENT FREE CONDITIONS
Table 3: VARIOUS BENZODIAZEPINES SYNTHESIZED BY GaCl3 UNDER SOLVENT FREE CONDITIONS18
|
DIAMINE |
KETONE |
BENZODIAZEPINES |
TIME |
|
|
|
|
30 |
|
|
|
|
25 |
|
|
|
|
25 |
|
|
|
|
30 |
|
|
|
|
25 |
5. SYNTHESIS OF 7-CHOLRO -2- ALKYL/ ARYL- 4-ALKYL/ARYL-3-ARYLIDENE-3H-1,5- BENZODIAZEPINES
Various β-diketones(2) with appropriate araldehydes (1) in presence of piperidine has afforded 2-arylidene-1,3-diketones(3) which in turn on condensation with 4-chloro-1,2-phenylene diamine(4) in acidic medium give a series of 7-chloro -2-alkyl/aryl-4-alkyl/aryl-3-arylidene-3H-1.5-benzodiazepines(5).(SCHEME 7)
They are screened for their anti bacterial and antifungal activity.22
SCHEME 7: SYNTHESIS OF 7-CHOLRO -2-ALKYL/ARYL-4-ALKYL/ARYL-3- ARYLIDENE-3H-1,5-BENZODIAZEPINES
Table 4: VARIOUS GROUPS AT X,Rą.R˛ GIVES VARIOUS DERIVATIVES22
|
COMPOUND |
X |
R1 |
R2 |
|
A |
4-Cl |
Me |
Me |
|
B |
2-Cl |
Me |
Me |
|
C |
2-OCH3 |
Me |
Me |
|
D |
3,4,5-tri OCH3 |
Me |
Me |
|
E |
3-F |
Me |
Me |
|
F |
4-Cl |
Ph |
4-ClC6H4 |
|
G |
4-F |
Ph |
4-ClC6H4 |
|
H |
4-Cl |
Me |
4-ClC6H4 |
|
I |
4-F |
Me |
Ph |
|
J |
3,4-di F |
Me |
Ph |
6. SYNTHESIS OF 1,5-BENZODIAZEPINE DERIVATIVES CATALYZED BY TCT UNDER MILD CONDITIONS
Condensation reactions between 1,2-diamines and various enolizable ketones efficiently catalyzed by 2,4,6-Trichloro-1,3,5-triazine (TCT) to afford 1,5-benzodiazepines in good to
excellent yields23(scheme 8).
O-phenylenediamine and acetone were stirred at ambient temperature in dichloromethane with 4% TCT.
ketone 1,2-diamines 1,5-benzodiazepines
SCHEME 8: SYNTHESIS OF 1, 5-BENZODIAZEPINES BY TCT
ketones o-phenylenediamines 1,5-benzodiazepines
SCHEME 9; REACTION OF VARIOUS O-PHENYLENEDIAMINES WITH KETONES IN THE PRESENCE OF 4 MOL % OF TCT.
bisdiamine benzodiazepine
SCHEME 10: REACTION OF BISDIAMINE WITH ACETONE IN PRESENCE OF TCT.
Table 5. The results of the reaction of o-phenylenediamines with various ketones.23
|
R |
R1 |
R2 |
TIME |
YEILD |
|
CH3 |
Cl |
H |
2 |
99 |
|
C6H5 |
Cl |
H |
14 |
71 |
|
CH3 |
CH3 |
H |
2 |
99 |
|
C6H5 |
CH3 |
H |
14 |
70 |
|
CH3 |
CH3 |
CH3 |
2 |
99 |
|
C6H5 |
CH3 |
CH3 |
23 |
88 |
|
4-Cl-C6H4 |
CH3 |
CH3 |
5 |
76 |
|
CH3 |
Cl |
Cl |
7.5 |
72 |
|
C6H5 |
Cl |
Cl |
26 |
51 |
7. SYNTHESIS OF 1,5-BENZODIAZEPINE DERIVATIVES CATALYZED BY CdCl2.
CdCl₂, which is an inexpensive and common chemical, can efficiently catalyze this reaction.
2,3-Dihydro-1H-1,5-benzodiazepines have been synthesized by the condensation of O-phenyllenediamine and cyclic or acyclic ketones in the presence of CdCl₂ as catalyst at 80-85⁰c temperature . The reaction completes within 10-20 min.24 (SCHEME 11)
ketone 0-phenylenediamine 2,3-dihydro-1H-1,5- benzodiazepine
SCHEME 11: SYNTHESIS OF 1,5-BENZODIAZEPINE DERIVATIVES CATALYZED BY CdCl₂.
TABLE 6 : CONDENSATION OF O-PHENYLDIAMINE WITH ACYCLIC, CYCLIC AND AROMATIC KETONES (2) GIVING VARIOUS 1,5-BENZODIAZEPINES(3)24
|
Compd |
Ketones (2) |
Yeild(%) |
Product(3) |
|
1 |
|
94 |
|
|
2 |
|
80 |
|
|
3 |
|
92 |
|
|
4 |
|
70 |
|
8. SYNTHESIS OF 1,5-BENZODIAZEPINES CATALYZED BY [BPY]H2SO4 ACIDIC IONIC LIQUID UNDER MILD CONDITIONS
1-Butylpyridinium hydrogen sulphate ([BPy]H2SO4), an acidic room-temperature ionic liquid, found as a novel catalyst, was prepared and used in the synthesis of a series of 1,5-benzodiazepine derivatives by the reaction of o-phenylenediamine with chalcones under mild conditions.25(SCHEME 12)
This method is easy, efficient, environmentally friendly, economical, free of toxic catalysts, and has good yields for the formation of 1,5-benzodiazepines.25
Chalcone o-phenylenediamine 1,5-benzodiazepine
SCHEME12: SYNTHESIS OF 1,5-BENZODIAZEPINES FROM O-PHENYLENEDIAMINE AND CHALCONES.
SCHEME 13. ACIDIC IONIC LIQUIDS USED IN THE PRESENT WORK.25
10. THE SYNTHESIS OF NOVEL 1,5-BENZODIAZEPINES
It is a convenient, solvent-free, method described for the synthesis of novel 1,5-benzodiazepines by the reaction of ethylacetoacetate, aldehyde, and o-phenylenediamine without any catalyst at pH 7.26(SCHEME 15)
The synthesis involves microwave-assisted neat reaction technology, eradicating the use of any acid or catalyst.
1,5-benzodiazepines
SCHEME 15: ONE STEP SYNTHESIS
1,5-benzodiazepine is obtained as a side product in addition to desired product. This can be avoided by following 2 step synthesis rather than one 26(SCHEME 16).
Initially reaction made between ethylacetoacetate and aldehyde in equimolar ratio in erlenmeyer flask and irradiated for sufficient interval of time .Then o-phenylenediamine added ,which condenses with the intermediate and afforded the desired product.(SCHEME 16)
SCHEME 16: 2 STEP SYNTHESIS
TABLE 7: VARIOUS PRODUCT OBTAINED FROM DIFFERENT ALDEHYDES
|
ALDEHYDE |
PRODUCT |
YIELD(%) |
TIME (MIN) |
|
|
|
97 |
2.5 |
|
|
|
94 |
3 |
|
|
|
93 |
3 |
11. SYNTHESIS OF 1,5-BENZODIAZEPINE DERIVATIVES CATALYZED BY MONOAMMONIUM SALT OF 12-TUNGSTOPHOSPHORIC ACID
Monoammonium salt of 12-tungstophosphoric acid [(NH₄)H₂PW₁₂O₄₀] found to be a practical, inexpensive, reusable, and efficient heterogeneous catalyst for the preparation of 1,5-benzodiazepine derivatives of o-phenylenediamine and ketones.27(SCHEME 17)
The hetero poly acid-based catalyst has the advantages of simple workup procedure, water insolubility with good activity, and high-yielding reaction for the synthesis of 1,5-benzodiazepine derivatives.
The reaction involves o-phenylenediamine and ketone in 1,2-dichloroethane as solvent in presence of catalyst [(NH₄)H₂PW₁₂O₄₀] with stirring at reflux conditions for appropriate time.27
Acyclic and cyclic ketones such as acetone and cyclohexanone reacted effectively to produce the corresponding fused ring benzodiazepines. (TABLE 9)
o-phenylenediamine ketone 1,5-benzodiazepines
SCHEME 17: SYNTHESIS OF 1,5BENZODIAZEPINE DERIVATIVE IN PRESENCE OF [(NH₄)H₂ PW₁₂O₄₀].
Table 8. Fused ring benzodiazepines prepared from various acyclic and cyclic ketones
|
DIAMINE |
KETONE |
BENZODIAZEPINE |
TIME |
|
|
|
|
30 |
|
|
|
|
25 |
|
|
|
|
25 |
|
|
|
|
30 |
|
|
|
|
25 |
|
|
|
|
20 |
CONCLUSION:
In summary benzodiazepines are one of important basic moeity possessing various useful biological activity.There are various approaches for the efficient Synthesis of various derivatives of benzodiazepines with good activity as well as yeilds.
ACKNOWLEDGEMENT:
Authors are very thankful to CDRI library.
REFERENCES:
1. Randall L O. Psychopharmacological agents, edited by: M. Gordon, New York, Academic Press, 1974, 3, 175-281
2. Roma G, Grossi G C, Di Braccio M, Ghia M, Mattioli F. 1,5-benzodiazepines a new route to substituted 4H –[1,2,4] triazolo[4,3-a][1,5]benzodiazepine-5-amines with analgesic and anti inflammatory activity. Eur.J.Med.Chem.1991; 26 : 484-496.
3. Kavali J.R, badami B.V. 1,5-Benzodiazepines derivatives of 3-aryl-sydnones: synthesis and antimicrobial activity of 3-aryl-4-[2’-aryl-2’,4’,6’,7’,-tetrahydro-(1’H) -1’,5’,-benzodiazepine-4’-yl]sydnones. Farmaco, 2000 ; 55: 406-409.
4. Di Braccio M, Grossi G.C, Roma G, Vargiu L, Mura M, Morongiu M.E. 1,5-benzodiazepines. Part XII. Synthesis and biological evaluation of tricyclic and tetracyclic 1,5-benzodiazepine derivatives as nevirapine analogues. Eur.J.Med.Chem. 2001; 36:935-949.
5. Kumar R, Joshi Y.C, Synthesis, spectral studies and biological activity of 3H-1,5-benzodiazepine derivatives. Arkivoc 2007; 13: 142-149.
6. Kamal A, Shankaraiah N., Prabhakar S, Reddy C R, et al. solid phase synthesis of new pyrrolobenzodiazepine- chalcone conjugates: DNA-binding affinity and anticancer activity. Bioorg. Med. Chem. Lett. 2008; 18: 2434-2439.
7. Kelly T A and Patel U R, J Org Chem, 1995;60(6): 1875.
8. Reddy B M, and Pavani M. Sreekanth,Tetrahedron lett. 2003; 44: 4447-4449.
9. Herbert J A, Suschitzky H J. Chem. Soc., Perkin Trans. 1974; 1: 2657.
10. Jung D. I, Choi D. W, Kim Y. Y, Kim I. S, Park Y. M, Lee Y. G, Jung D. H. Synth. Commun. 1999; 29: 1941.
11. Morales H. R, Bulbarela A, Contreras R. Heterocycles 1986; 24: 135.
12. Balakrishna M. S, Kaboudin B. Tetrahedron Lett. 2001; 42: 1127.
13. Curini M, Epifano F, Marcotullio M C, Rosati O. Tetrahedron Lett. 2001; 42: 3193.
14. Pozarentzi, M.; Stephanatou, J. S.; Tsoleridis, C. A. Tetrahedron Lett. 2001; 43: 1755.
15. Benjaram M. Reddy and Pavani M. Sreekanth,Tetrahedron Lett. 2003; 44:4447-4449.
16. Norah Bennamane, Rachedine Kaoua, Lamouri Hammal, Nedjar-Kolli B, Synthesis of new amino 1,5-benzodiazepine and benzotriazole derivatives from dimedone, Org. Commun., 2008; 1:3, 62-68.
17. Panicker G K. Shreerekha R K and Krishnapillai Sreekumar. Three Component Mannich Reaction and 1,5-Benzodiazepine Synthesis Catalyzed by a Tetranitrile-Silver Complex. Letters in organic Chemistry, 2009; 6:17-21.
18. Sanjay kumar and Jagir S Sandhu. An efficient synthesis of 1,5-benzodiazepines catalysed by GaCl3 under solvent free condition. Ind J of Chem 2008; 47 B: 1463-1466.
19. Zhang X-L, Han Y, TaoW-T and Huang Y-Z, J Chem Soc, Perkin Trans 1995,1, 189.
20. Wang Z, Yuan S and Li C-J, Tetrahedron Lett,2002; 42: 5097.
21. Prajapati D, Gohain M and Gogoi B. J, Tetrahedron Lett. 2006; 47: 3535.
22. Vijai N Pathak; Rahul Joshi; and Neetu Gupta. Synthesis, spectral studies and antimicrobial activity of 7 chloro- 2-alkyl/aryl-4-alkyl/aryl-3-arylidene-3H-1,5-benzodiazepines. Indian Journal of chemistry. 2007; 46 B: 1191-1197.
23. Chun- Wei Kuo, Chun –chao Wang, Veerababurao Kavala, and Chung-Fa Yao. Efficient TCT-catalyzed Synthesis of 1,5-Benzodiazepine Derivatives under Mild Conditions .Molecules 2008; 13: 2313-2325.
24. Pasha M A and JayashanKara V P. An expeditious synthesis of 1,5-benzodiazepine derivatives catalyzed by CdCl2, Indian Journal of Chemistry. 2006; 45 B: 2716-2719.
25. Du Yuying, Tian, Fuli and Zhao, Wenzhi '[BPy]HSO4 Acidic Ionic Liquid as a Novel, Efficient, and Environmentally Benign Catalyst for Synthesis of 1,5-Benzodiazepines under Mild Conditions'. Synth Comm. 2006; 36: 12, 1661-1669.
26. Kidwai, Mazaahir and Mothsra, Poonam 'Neat Reaction Technology for the Synthesis of Novel 1,5-Benzodiazepines'. Synthetic Communications. 2006; 36: 6, 817 – 824.
27. Giri B Y, Prabavathi Devi B L A, Vijaya Lakshmi K, and Prasad R B N, Lingaiah N and Sai Prasad P S. Efficient Method for the Synthesis of 1,5-Benzodiazepine Derivatives Catalyzed by Monoammonium Salt of 12-Tungstophosphoric Acid. Synthetic Communications. 2006; 36:3797–3801, 2006
Received on 11.01.2011 Modified on 17.02.2011
Accepted on 28.02.2011 © AJRC All right reserved
Asian J. Research Chem. 4(6): June, 2011; Page 863-872