DOCSLIB.ORG

A Simplified Cadogan's Approach to Synthesis of New Isoxazolyl Indazoles

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Simplified Cadogan's Approach to Synthesis of New Isoxazolyl Indazoles Indian Journal of Chemistry Vol. 47B, October 2008, pp. 1591-1596 Note A simplified Cadogan’s approach to synthesis activity 13,14 was produced. The chemistry of these of new isoxazolyl indazoles linked bi-heterocycles has been the fascinating field of investigation in medicinal chemistry, as they have 15 E Rajanarendar*, A Siva Rami Reddy & Firoz been found to exhibit enhanced biological profile . Pasha Shaik Keeping in view the high potential of indiazoles Department of Chemistry, Kakatiya University, and isoxazoles as drug candidates, the synthesis of Warangal 506 009, India some novel analogs of isoxazolyl indazoles was E-mail: [email protected] undertaken, which are expected to be studied later for their medicinal properties. Received 21 May 2008; accepted (revised) 29 July 2008 The synthesis of a variety of nitrogen containing Isoxazolyl Schiff bases have been prepared from the heteocycles including indazoles, by de-oxygenative corresponding amines by reaction with 2-nitrobenzalde- cyclization of aromatic nitro compounds was reported hydes.These nitro compounds undergo de-oxygenative cyclization by Cadogan et al. 16,17 . The reaction requires heating to give indazoles via nitrenes on heating with triethyl phosphite in with excess of triethyl phosphite for several hours acetonitrile. Isoxazolyl indazoles have also been synthesized in a under N atmosphere. The reaction mechanism one-pot reaction. 2 involves the generation of a nitrene that is inserted to Keywords: Isoxazolyl indazoles, one-pot synthesis, form a new nitrogen containing ring. Another simplified Cadogan’s synthesis, de-oxygenative cyclization common route to the synthesis of indazole ring system is diazotisation of o-toluidines in acidic or The chemistry of heterocycles lies at the heart of drug neutral aqueous solution 18 . Recently, the synthesis of discovery 1. Many known active compounds contain pyrazolo [3,4-a] isoxazoles from 4-isoxazolyl heterocyclic cores, which are indispensable elements diazonium tetrafluoroborates has been reported under for bioactivity 2. Among aromatic heterocyles, the phase transfer conditions 19 . By adopting Cadogan isoxazole unit constitutes an easily accessible nucleus technique, de-oxygenative cyclization of 3-methyl-4- that is present in a number of natural and nitro-5-styrylisoxazole could not succeed in the pharmacological compounds 3. Additionally, construction of the pyrrole ring formation, as the isoxazoles display a wide range of organic reactivities reaction resulted in the cleavage of the most liable and could be used as an effective means of preparing nitroisoxazole on heating at high temperature 20 . In new molecular scaffolds 4. Isoxazoles have been view of this, the reaction has been planned in such a repeatedly shown as useful synthons in organic way, that the nitro group does not exist on the synthesis 5. isoxazole ring, so that, the de-oxygenative cyclization Substituted indazoles are a group of heterocycles of isoxazole Schiff bases derived from 2- gaining much importance in the recent research nitrobenzaldehyde could be conducted. The problem leading to discovery of potential drug candidates. of isoxazole ring undergoing cleavage on heating in Compounds derived from indazoles as basic moiety the presence of triethylphosphite 21 could be have been shown to possess a number of medicinal overcome, as the de-oxygenative cyclization was properties, which include, broad spectrum carried out under controlled heating conditions. As a antimicrobial 6,7 , DNA gyrase inhibitors 8, anti parasitic sequel to the interest in the synthesis of isoxazolyl activity 9, activation of soluble guanylate cyclase nitrogen heterocycles 22-25 , herein is reported the (Nitric oxide receptor) 10 , neuronal nitric synthesis of isoxazolyl indazoles for the first time via oxide synthase inhibitor 11 , selective Rho Kinase nitrenes. inhibitors 12 and anti cancer agents (kinase inhibitors) 12 . Results and Discussion Survey of literature revealed that when one The reaction of 4-amino-3,5-dimethylisoxazole 1 biodynamic heterocyclic system was coupled with with 2-nitrobenzaldehyde was carried out in methanol another, a molecule with enhanced biological in 2 hr. The product obtained was identified as 1592 INDIAN J. CHEM., SEC B, OCTOBER 2008 R OHC R H C NH N CH R N 3 2 H3C H3C N O2N (EtO) P 3 N O ethanol N O N N O 2 CH3CN O CH3 CH3 CH3 1 2 3 2a, R= H 3a, R=H 2b, 3b, R=Cl R= Cl Scheme I R OHC R N CH NH2 R N ON (EtO) P N N 2 3 H C O ethanol N ON CH CN N 3 H C O 2 3 O 3 H3C 4 5 6 5a, R= H 6a, R= H 5b, R= Cl 6b, R= Cl Scheme II isoxazole Schiff base 2 after purification by array of substituents on the benzene ring. To the best recrystallization from ethanol. of the knowledge, this report is the first of its kind to The nitro compounds 2 on heating while stirring in construct an indazole ring on isoxazole employing a the presence of triethyl phosphite in acetonitrile for 4 simplified hr underwent deoxygenative cyclization to give Cadogan reaction, as the reaction was carried out in isoxazolyl indazoles 3 in moderate to good yields, a one-pot method and without using N 2 atmosphere without using N 2 atmosphere, which is generally (Scheme II , Scheme III) . required in Cadogan’s approach. The reaction In conclusion, a new protocol has been successfully mechanism involves the generation of nitrenes that demonstrated for the synthesis of isoxazolyl indazoles underwent insertion to form indazoles through N-N by simplified Cadogan reaction in a one-pot method. bond formation (Scheme I) . In view of potential activity of isoxazoles and Synthesis of the isoxazolyl indazoles in a one-pot indazoles, it is predicted that the newly synthesized reaction could also be successfully completed. The isoxazolyl indazoles may be drug candidates and the two step Cadogan’s reaction for the synthesis of activity data will be published later. indoazoles was simplified to a one-pot reaction. For example, a mixture of 2-nitrobenzaldehyde, Experimental Section aminoisoxazole in equimolar ratio with excess of All the melting points were determined on a Cintex triethyl phosphite on heating while stirring in melting point apparatus and are uncorrected. acetonitrile resulted in the formation of indazole 3. Analytical TLC was performed on Merck precoated Finally, the results indicate that the current method 60 F 254 silica gel plates. Visualization was done by is compatible with various functional groups and the exposing to iodine vapour. IR spectra (KBr pellet) approach proved to be of general applicability as the were recorded on a Perkin-Elmer BX series FT-IR reaction was carried out on different isoxazoles. This spectrophotometer. 1H NMR spectra were recorded on synthetic strategy permits the introduction of a diverse a Varian Gemini 300 MHz spectrometer. Chemical NOTES 1593 R OHC R H C NH 3 2 H C N CH H C N ON 3 R 3 N 2 (EtO) P N 3 O N N Ar ethanol O ON CH3CN O CH CH St 2 St 7 8 9 8 , 9 St=CH CH Ar, R= H 8a, Ar = C H 6 5 9a, Ar = C6H5 8b, Ar = 4- CH C H 3 6 4 9b, Ar = 4- CH3C6H4 8c, Ar = 4- OCH C H 3 6 4 9c, Ar = 4- OCH3C6H4 8d, Ar = 4- ClC H 6 4 9d, Ar = 4- ClC6H4 8e, Ar = 2- ClC H 6 4 9e, Ar = 2- ClC6H4 8f, Ar =2- CH C H 9f, Ar = 2- CH C H 3 6 4 3 6 4 Scheme III shift values are given in ppm ( δ) with tetra- General procedure for the synthesis of N-(5- methylsilane as interal standard. Mass spectral methylisoxazol-3-yl)-N-(( E)-1-(2-nitrophenyl)met- measurements were carried out by EI method on a hylidene)amines , 5a ,b. A mixture of 3-amino-5- Jeol JMC-300 spectrometer at 70 eV. Elemental methyl-isoxazole 4 (0.01 mole) and 2-nitrobenzalde- analyses were performed on a Carlo Erba 106 Perkin- hyde (0.01 mole) were refluxed in ethanol (10 mL) Elmer model 240 analyser. for 2 hr. The resultant solution was cooled, the solid General procedure for the synthesis of N-(3,5- thus separated was filtered and purified by recrystal- dimethylisoxazol-4-yl)-N-(( E)-1-(nitrophenyl)met- lization from pet-ether. N N E hylidene) amines , 2a ,b. A mixture of 4-amino-3,5- -(5-Methylisoxazol-3-yl)- -(( )-1-(2-nitrophe- nyl)methylidene)amine , 5a . Yield: 85%. m.p. 52- dimethyl-isoxazole 1 (0.01 mole) and 2- -1 1 nitrobenzaldehyde (0.01 mole) were refluxed in 55°C; IR (KBr): 1635 (s), 1530 (s), 1360 (s) cm ; H δ ethanol (10 mL) for 2 hr. The resultant solution was NMR (200 MHz, CDCl 3): 2.4 (s, 3H, CH 3), 5.5 (s, 1H, isoxazole-H), 7.6-8.2 (m, 4H, Ar-H),10.4 (s, 1H, - cooled, the solid thus separated was filtered and + purified by recrystallization from pet-ether. N=CH); EI-MS: m/z 232 (M+H) . Anal. C 11 H9N3O3: Found C, 57.16; H, 3.84; N, 18.14. Calcd. C, 57.14; N N E -(3,5-Dimethylisoxazol-4-yl)- -(( )-1-(nitrophe- H, 3.89; N, 18.18%. nyl)methylidene)amine , 2a . Yellow colour comp- N-[( Z)-1-(5-Chloro-2-nitrophenyl)methylidene]- ound; Yield: 85%. m.p. 56-58°C; IR (KBr): 1615 (s), N -1 1 -(5-methyl-3-isoxazolyl)amine , 5b . Yield: 75%. 1515 (s), 1415(s) cm ; H NMR (200 MHz, CDCl 3): m.p. 97-100°C; IR (KBr): 1630 (s), 1540 (s), 1390 (s) δ 2.5 (s, 3H, CH 3), 2.6 (s, 3H, CH 3), 7.6-8.4 (m, 4H, -1 1 δ + cm ; H NMR (200 MHz, CDCl 3): 2.6 (s, 3H, CH 3), Ar-H), 9.0 (s, 1H, -N=CH-); EI-MS: m/z 245 (M ).
Load more

Recommended publications
  • Isoxazole—A Basic Aromatic Heterocycle : Synthesis, Reactivity and Biological Activity
    International Journal of ChemTech Research CODEN (USA): IJCRGG ISSN: 0974-4290 Vol.8, No.7, pp 297-317, 2015 Isoxazole—A Basic Aromatic Heterocycle : Synthesis, Reactivity And Biological Activity S.S.Rajput1*, Dr. S.N.Patel2, Nilesh B. Jadhav3 1Department of Chemistry, SVS’s Dadasaheb Rawal College Dondaicha 425408, Maharashtra, India. 2Department of Chemistry, S.P.D.M.College, Shirpur 425405, Maharashtra, India. 3Department of Chemistry, S.P.D.M. College, Shirpur425405, Maharashtra, India. Abstract: This review summarizes the synthetic method , reactions and biological application of isoxazoles and summarizes recent development in their derivatives such as chalcone, 5- isoxazole penicillins,shiff base etc.over the last years.The biological activities of isoxazoles is also briefly discussed .Formation of isoxazoles & fused heterocyclic isoxazoles derivatives constitute an interesting class of heterocycles which have diverse biological activities. Keywords: Isoxazoles, biological activity, 5-isoxazole penicillin. 1. Introduction Substituted Isoxazoles are important compounds of many drugs and drug candidates. It is one of the most fundamental objectives of organic and medicinal chemistry is the design and synthesis of molecules having value human therapeutic agents. The diversity of biological activities and pharmaceutical uses have been attributed to them, such as isoxazole is a part of many active molecule possessing activities such as Anti- tubercular[1], Analgesic[2], Antipyretic[2], Anti-inflammatory[2][3], Antiplatelet[4], Anti-HIV[4], Antagonist activity[4], CNS depressant[5], Antifungal[6][7], Antibacterial[6][7][8], Anti-oxidant[7], Anticancer[9][10] . The Substituted isoxazole moiety 1 appears as an interesting precursor of many biologically active of the above class compounds.
    [Show full text]
  • Isoxazoles: Molecules with Potential Medicinal Properties
    IJPCBS 2013, 3(2), 294-304 Jayaroopa et al. ISSN: 2249-9504 INTERNATIONAL JOURNAL OF PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL SCIENCES Available online at www.ijpcbs.com Research Article ISOXAZOLES: MOLECULES WITH POTENTIAL MEDICINAL PROPERTIES K. Ajay Kumar and P. Jayaroopa* Post Graduate Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysore-570 005, India. ABSTRACT Isoxazole is a five membered heterocyclic compound having various pharmacological actions. The great interest associated with isoxazoles and their derivatives is based on their versatility as synthetic building blocks, their latent functionalities as enaminones, 1,3-dicarbonyl compounds, γ-amino alcohols, and β-hydroxy nitriles have been widely exploited for the synthesis of other heterocycles and complex molecules. This review paper comprises of up to date information on isoxazole analogs. More emphasis was given to critical discussion on the synthetic strategy of isoxazole derivative, their utility as building blocks in their transformation to more biologically potent molecules. Results of isoxazole derivatives and their substitutions effect on diverse biological activities also presented. Keywords: Isoxazoles, antioxidant, antimicrobial, analgesic, anti-platelet, anti-HIV. INTRODUCTION sulfisoxazole, oxacillin, cycloserine and acivicin Nitrogen containing heterocycles with an have been in commercial use for many years. oxygen atom are considered as an important Cycloserine is the best known antibiotic drug class of compounds in medicinal chemistry that possess antitubercular, antibacterial because of their diversified biological activities and in treatment of leprosy. Acivicin is applications. The exploitation of a simple an antitumour, antileishmania drug, while molecule with different functionalities for the isoxaflutole is used as herbicidal drug. synthesis of heterocycles is a worthwhile Isoxazoles have illustrious history; their contribution in the chemistry of heterocycles.
    [Show full text]
  • Biological Evaluation of Newly Synthesized Isoxazole Derivatives Chandrashekara Raje Urs HR1, Sharath N1* and Jyothi K2 1 Department of P.G
    Available online at www.pelagiaresearchlibrary.com Pelagia Research Library Der Chemica Sinica, 2018, 9(1):581-587 ISSN : 0976-8505 CODEN (USA): CSHIA5 Biological Evaluation of Newly Synthesized Isoxazole Derivatives Chandrashekara Raje Urs HR1, Sharath N1* and Jyothi K2 1 Department of P.G. Studies and Research in Analytical Chemistry, Alva’s College, Moodbidre, Dakshina Kannada, Karnataka, India 2 Department of Studies of Chemistry, St. Joseph Engineering College, Vamanjoor, Mangalore Karnataka, India ABSTRACT A new bis-isoxazole derivative were synthesized and characterized by the spectral and analytical techniques. The compounds were prepared by the cyclo-addition reaction and comparatively studied by antimicrobial screening with different strains of gram positive and gram negative bacteria showed considerable against bacterial growth. The plasmid DNA interaction with compounds revealed the complete cleavage in 1c and 1d compounds, whereas in other compounds cleaved partially from supercoiled in to linear stranded DNA under UV-visible spectroscopic window. The differential DNA damage beside with H2O2 and light, compound exhibited cleavage in light. Keywords: Antimicrobial cleavage; Screening; Supercoiled; UV-visible INTRODUCTION The heterocyclic compounds results in enormous significance in the field of drug discovery process [1]. 1,3-Dipolar cycloaddition is a valuable route for the construction of pharmacological active five-membered isoxazoles. A good yields of isoxazoles is achieved by 1,3-Dipolar cyclisation of nitrile oxides with alkynes were reported [2-4]. Substituted oxazole, pyrazole, isoxazole and their analogues have been used as precursors for synthesis of various biologically dynamic molecules [5,6]. The heterocyclic moieties were found in the most of the natural products with more than one nitrogen, oxygen and sulphur atoms which are fused with unsaturated cyclic compounds.
    [Show full text]
  • Heterocyclic Chemistrychemistry
    HeterocyclicHeterocyclic ChemistryChemistry Professor J. Stephen Clark Room C4-04 Email: [email protected] 2011 –2012 1 http://www.chem.gla.ac.uk/staff/stephenc/UndergraduateTeaching.html Recommended Reading • Heterocyclic Chemistry – J. A. Joule, K. Mills and G. F. Smith • Heterocyclic Chemistry (Oxford Primer Series) – T. Gilchrist • Aromatic Heterocyclic Chemistry – D. T. Davies 2 Course Summary Introduction • Definition of terms and classification of heterocycles • Functional group chemistry: imines, enamines, acetals, enols, and sulfur-containing groups Intermediates used for the construction of aromatic heterocycles • Synthesis of aromatic heterocycles • Carbon–heteroatom bond formation and choice of oxidation state • Examples of commonly used strategies for heterocycle synthesis Pyridines • General properties, electronic structure • Synthesis of pyridines • Electrophilic substitution of pyridines • Nucleophilic substitution of pyridines • Metallation of pyridines Pyridine derivatives • Structure and reactivity of oxy-pyridines, alkyl pyridines, pyridinium salts, and pyridine N-oxides Quinolines and isoquinolines • General properties and reactivity compared to pyridine • Electrophilic and nucleophilic substitution quinolines and isoquinolines 3 • General methods used for the synthesis of quinolines and isoquinolines Course Summary (cont) Five-membered aromatic heterocycles • General properties, structure and reactivity of pyrroles, furans and thiophenes • Methods and strategies for the synthesis of five-membered heteroaromatics
    [Show full text]
  • Synthesis & Evaluation of Isoxazole for Their Antimicrobial Activity
    Original Research Article Synthesis & Evaluation of isoxazole for their antimicrobial activity Sagar Pol1,*, Vilasrao Kadam2, B. Ramesh3, Sachin S. Mali4, Vijay Patil5 1,2,5Bharati Vidyapeeth Institute of Pharmacy, CBD Belapur Navi Mumbai, Maharashtra, 3SAC College of Pharmacy, BG Nagara, Karnataka, 4Adarsh Institute of Pharmacy, Vita, Maharashtra *Corresponding Author: Email: [email protected], [email protected] Abstract Isoxazole is five membered heterocyclic ring having a broad spectrum of pharmacological activities like anti-tubercular, anti- cancer, anti-bacterial, anti-fungal, anti-HIV, anti-inflammatory and anti-hypertensive activities. In the present research work we reported the synthesis of some novel isoxazoles by using various different substituted chalcones and screened for their anti-microbial activity. Keyword: Isoxazole, Anti-microbial activity. Introduction investigation of chemical properties and in particular on Nitrogen containing heterocycles with an oxygen the peculiarities of the behaviour of isoxazole derivatives atom are considered as an important class of compounds and the elucidation of their physicochemical in medicinal chemistry because of their diversified characteristics. This enabled new datas to be obtained biological applications. The exploitation of a simple that were considerable importance. molecule with different functionalities for the synthesis of heterocycles is a worthwhile contribution in the Materials and Methods chemistry of heterocycles. All the melting points were determined on Micro- Isoxazole is a five membered heterocyclic controller based melting point apparatus CL 725/726 and compound containing oxygen and nitrogen atoms in the were uncorrected. Chloro and nitro benzaldehydes were 1, 2 positions, its partially saturated analogs are called purchased from Techno chemicals, Bangalore. Other isoxazolines and completely saturated analog is chemicals like hydroxyl amine hydrochloride & sodium isoxazolidine.
    [Show full text]
  • Chemotherapeutic Interventions Against Tuberculosis
    Pharmaceuticals 2012, 5, 690-718; doi:10.3390/ph5070690 OPEN ACCESS Pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review Chemotherapeutic Interventions Against Tuberculosis Neeraj Shakya 1, Gaurav Garg 2, Babita Agrawal 3 and Rakesh Kumar 1,* 1 Department of Laboratory Medicine and Pathology, 728-Heritage Medical Research Center, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada 2 Department of Pharmacy, Mangalayatan University, Beswan, Aligarh 202 145, India 3 Department of Surgery, 728-Heritage Medical Research Center, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada * Author to whom correspondence should be addressed; E-Mail: [email protected]. Received: 15 May 2012; in revised form: 12 June 2012 / Accepted: 21 June 2012 / Published: 28 June 2012 Abstract: Tuberculosis is the second leading cause of infectious deaths globally. Many effective conventional antimycobacterial drugs have been available, however, emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has overshadowed the effectiveness of the current first and second line drugs. Further, currently available agents are complicated by serious side effects, drug interactions and long-term administration. This has prompted urgent research efforts in the discovery and development of new anti-tuberculosis agent(s). Several families of compounds are currently being explored for the treatment of tuberculosis. This review article presents an account of the existing chemotherapeutics and highlights the therapeutic potential of emerging molecules that are at different stages of development for the management of tuberculosis disease. Keywords: tuberculosis chemotherapy; mycobacterium; drug-resistant tuberculosis; emerging TB drugs 1.
    [Show full text]
  • Design and Efficient Synthesis of Pyrazoline and Isoxazole Bridged
    www.nature.com/scientificreports There are amendments to this paper OPEN Design and efcient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents Priti Kumari1, Vishnu S. Mishra2, Chintam Narayana1, Ashish Khanna3, Anindita Chakrabarty2 & Ram Sagar1,3* C-glycosides are important class of molecules exhibit diverse biological activities and present as structural motif in many natural products. Two series of new pyrazoline and isoxazole bridged indole C-glycoside molecular hybrids (n = 36) were efciently synthesized starting from diverse indole 3-carboxaldehydes derived α, β-unsaturated ketone derivatives of β-D-glucosyl-propan-2-one, β-D-galactosyl-propan-2-one and β-D-mannosyl-propan-2-one, reacting with hydrazine hydrate and hydroxyl amine hydrochloride in shorter reaction time (15 min) under microwave assisted condition. Anticancer activity of these newly synthesized pyrazoline and isoxazole bridged indoles C-glycoside hybrids were determined in details through cellular assays against MCF-7, MDA-MB-453 and MDA-MB-231 cancer cell lines. The selected library members displayed low micromolar (IC50 = 0.67– 4.67 µM) and selective toxicity against breast cancer cell line (MCF-7). Whereas these compounds were nontoxic towards normal cell line (MCF-10A). Mechanistic studies showed that, active compounds inhibit COX-2 enzyme, which was also supported by molecular docking studies. These fndings are expected to provide new leads towards anticancer drug discovery. C-Glycosides are stable surrogates of O-glycosides and are ofen used as investigative tool in chemical biology and medicinal chemistry, in particular C-glycoside analogues are ofen used as substrate mimics for diferent enzymes involved in the carbohydrate metabolism1–10.
    [Show full text]
  • Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry
    Baran, Richter Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry 5 4 Deprotonation of N–H, Deprotonation of C–H, Deprotonation of Conjugate Acid 3 4 3 4 5 4 3 5 6 6 3 3 4 6 2 2 N 4 4 3 4 3 4 3 3 5 5 2 3 5 4 N HN 5 2 N N 7 2 7 N N 5 2 5 2 7 2 2 1 1 N NH H H 8 1 8 N 6 4 N 5 1 2 6 3 4 N 1 6 3 1 8 N 2-Pyrazoline Pyrazolidine H N 9 1 1 5 N 1 Quinazoline N 7 7 H Cinnoline 1 Pyrrolidine H 2 5 2 5 4 5 4 4 Isoindole 3H-Indole 6 Pyrazole N 3 4 Pyrimidine N pK : 11.3,44 Carbazole N 1 6 6 3 N 3 5 1 a N N 3 5 H 4 7 H pKa: 19.8, 35.9 N N pKa: 1.3 pKa: 19.9 8 3 Pyrrole 1 5 7 2 7 N 2 3 4 3 4 3 4 7 Indole 2 N 6 2 6 2 N N pK : 23.0, 39.5 2 8 1 8 1 N N a 6 pKa: 21.0, 38.1 1 1 2 5 2 5 2 5 6 N N 1 4 Pteridine 4 4 7 Phthalazine 1,2,4-Triazine 1,3,5-Triazine N 1 N 1 N 1 5 3 H N H H 3 5 pK : <0 pK : <0 3 5 Indoline H a a 3-Pyrroline 2H-Pyrrole 2-Pyrroline Indolizine 4 5 4 4 pKa: 4.9 2 6 N N 4 5 6 3 N 6 N 3 5 6 3 N 5 2 N 1 3 7 2 1 4 4 3 4 3 4 3 4 3 3 N 4 4 2 6 5 5 5 Pyrazine 7 2 6 Pyridazine 2 3 5 3 5 N 2 8 N 1 2 2 1 8 N 2 5 O 2 5 pKa: 0.6 H 1 1 N10 9 7 H pKa: 2.3 O 6 6 2 6 2 6 6 S Piperazine 1 O 1 O S 1 1 Quinoxaline 1H-Indazole 7 7 1 1 O1 7 Phenazine Furan Thiophene Benzofuran Isobenzofuran 2H-Pyran 4H-Pyran Benzo[b]thiophene Effects of Substitution on Pyridine Basicity: pKa: 35.6 pKa: 33.0 pKa: 33.2 pKa: 32.4 t 4 Me Bu NH2 NHAc OMe SMe Cl Ph vinyl CN NO2 CH(OH)2 4 8 5 4 9 1 3 2-position 6.0 5.8 6.9 4.1 3.3 3.6 0.7 4.5 4.8 –0.3 –2.6 3.8 6 3 3 5 7 4 8 2 3 5 2 3-position 5.7 5.9 6.1 4.5 4.9 4.4 2.8 4.8 4.8 1.4 0.6 3.8 4 2 6 7 7 3 N2 N 1 4-position
    [Show full text]
  • The Use of Α-Enone Derivative in the Preparation of Some New Heterocyclic Compounds with Expected Biological and Antitumor Activities
    1049 Advances in Environmental Biology, 7(6): 1049-1057, 2013 ISSN 1995-0756 This is a refereed journal and all articles are professionally screened and reviewed ORIGINAL ARTICLE The use of α-enone derivative in the preparation of some new heterocyclic compounds with expected biological and antitumor activities Zeinab H. Ismail Department of Chemistry, Faculty of Science, Al-Azhar University (Girls), Nasr City, Cairo, Egypt Zeinab H. Ismail: The use of α-enone derivative in the preparation of some new heterocyclic compounds with expected biological and antitumor activities ABSTRACT α-Enone 1, reacts with hydrazines, hydroxylamine hydrochloride, thiourea, diethylmalonate, malononitrile ethyl cyanoacetate to give the corresponding indazole, oxime, isoxazole, quinazoline, chromene and quinoline derivatives. The structures of all the synthesized compounds were confirmed by micro analytical and spectral data. The antimicrobial and the antitumor activities of some of the synthesized compounds were tested. Key words: α-enone, indazole, isoxazole, quinazoline, chromene and quinoline derivatives. Introduction hydrate in DMF to obtain the formohydrazide 4 has failed instead the parent indazole 2a was obtained. Indazole derivatives are reported to exhibit However reaction of 1 with hydroxylamine antibacterial [1,2], antifungal[1.2], antiproliferative hydrochloride in ethanol or pyridine gave the [3], antigiogenic [3], antiarrhythmic and analgesic corresponding oxime and isoxazole 5 and 6, [4] activities and antihypertensive properties [5], respectively. while quinazolines exhibit antitumor [6], Compound 1, was reduced and acetylated by antimicrobial [7] antitubercular [8], antiagonists [9], zinc dust in boiling acetic anhydride solution to give anticonvulsant [10] and analgesic[11] activities. compound (7). On the other hand quinolines exhibit antimalarial Reaction of 1 with indole gave compound 8, [12], antiplasmodial [13], antiproliferative [14], through condensation of 2 moles of indole with the antibacterial [15], antifungal [15].
    [Show full text]
  • The Microwave Spectrum of Oxazole II. Dipole Moment and Quadrupole Coupling Constants Anil Kumar, John Sheridan, and Otto L
    The Microwave Spectrum of Oxazole II. Dipole Moment and Quadrupole Coupling Constants Anil Kumar, John Sheridan, and Otto L. Stiefvater School of Physical and Molecular Sciences, University College of North Wales, Bangor LL57 2UW Gwynedd, U.K. Z. Naturforsch. 33a, 549—558 (1978); received February 11, 1978 The dipole moments and the quadrupole coupling constants of the normal and the three mono-deuterated species of oxazole have been measured. The dipole moment of 1.50 ± 0.03 D is found to deviate by 10.8° from the external bisector of the CNC angle towards the C(2) carbon atom. The principal values of the quadrupole coupling tensor are determined as Xzz = —4.04^ 0.02 MHz and %Xx — 1-66 =L 0.02 MHz along the axes in the molecular plane, so that the gradient perpendicular to this plane is %yy = 2.38 MHz. The direction of the largest gradient deviates by 5.7° from the external bisector of the CNC angle towards the carbon atom C(4). An attempt is made to correlate these results and the geometry of oxazole with the electron distribution in this molecule. I. Introduction which a crude sample of oxazole was obtained and purified by distillation: As a first part of the renewed investigation of r -i2- oxazole by microwave spectroscopy, we reported CuO - powder ^ 1 yr^ in a preceeding paper [1] the complete substitution Quinoline sulphate y±J>j(j structure of this compound as determined by DRM in quinoline ' techniques. With this work as a basis, valuable information concerning the electron distribution Deuterium substitution at the 2-position was in oxazole can be deduced by the traditional SEM obtained by direct exchange of oxazole with D2O, techniques from the magnitude and orientation of but the 4- and 5-positions could not be deuterated the dipole moment and of the electric field gradients in this simple way.
    [Show full text]
  • Amanita Muscaria: Chemistry, Biology, Toxicology, and Ethnomycology
    Mycol. Res. 107 (2): 131–146 (February 2003). f The British Mycological Society 131 DOI: 10.1017/S0953756203007305 Printed in the United Kingdom. Review Amanita muscaria: chemistry, biology, toxicology, and ethnomycology Didier MICHELOT1* and Leda Maria MELENDEZ-HOWELL2 1 Muse´um National d’Histoire Naturelle, Institut Re´gulation et De´veloppement, Diversite´ Mole´culaire, Chimie et Biochimie des Substances Naturelles, USM 502 UMR 8041 C.N.R.S., 63 rue de Buffon, F-75005 Paris, France. 2 Syste´matique et Evolution, USM 602, 12, rue Buffon, F-75005 Paris, France. E-mail: [email protected] Received 12 July 2002; accepted 14 January 2003. The fly agaric is a remarkable mushroom in many respects; these are its bearing, history, chemical components and the poisoning that it provokes when consumed. The ‘pantherina’ poisoning syndrome is characterized by central nervous system dysfunction. The main species responsible are Amanita muscaria and A. pantherina (Amanitaceae); however, some other species of the genus have been suspected for similar actions. Ibotenic acid and muscimol are the active components, and probably, some other substances detected in the latter species participate in the psychotropic effects. The use of the mushroom started in ancient times and is connected with mysticism. Current knowledge on the chemistry, toxicology, and biology relating to this mushroom is reviewed, together with distinctive features concerning this unique species. INTRODUCTION 50 cm diam and bright red, orange, or even orange or yellow, apart from the white fleck. Many species of the The fly agaric, Amanita muscaria, and the panther, A. muscaria complex bear so-called crassospores (Tul- A.
    [Show full text]
  • Downloaded 10/4/2021 1:16:42 PM
    ORGANIC CHEMISTRY FRONTIERS View Article Online REVIEW View Journal | View Issue Recent advances in metal catalyzed or mediated cyclization/functionalization of alkynes to Cite this: Org. Chem. Front., 2020, 7, 2325 construct isoxazoles Jianxiao Li, * Zidong Lin, Wanqing Wu and Huanfeng Jiang * Isoxazoles and their derivatives represent privileged heteroaromatic motifs, which exhibit remarkable bio- logical and pharmaceutical activities. Notably, metal catalyzed or mediated cyclization/functionalization of alkynes such as alkynone oxime ethers, acetylinic oximes, propargylic amino ethers, alkynyl nitrile oxides, and propargylic alcohols has recently attracted much attention from synthetic organic chemists because of their high efficiency in the assembly of structurally diverse isoxazole architectures under mild conditions with exceptional chemo-, stereo- and regioselectivities. In this review, a wide array of metal Received 19th May 2020, catalysts, such as palladium, copper, iron, gold, silver, and other metals, have been summarized and dis- Accepted 19th June 2020 cussed in detail. Moreover, we also highlight some representative synthetic strategies along with reaction DOI: 10.1039/d0qo00609b mechanisms involved during the reaction. And, the literature has been surveyed from 2010 until the rsc.li/frontiers-organic beginning of 2020. 1 Introduction chemistry.1 As one of the important five-membered heteroaro- matic ring scaffolds, isoxazoles exhibit significant biological Among the vibrant classes of aromatic heterocyclic com- and pharmaceutical activities in natural products, pharma- pounds, isoxazoles, discovered by Claisen in 1888, have always ceutical agents and preclinical candidates, including anti- been considered as a privileged class of molecules in organic cancer, antimicrobial, antibiotic, and anti-inflammatory activi- ties (Fig. 1).2 For example, valdecoxib has been established as 3 4 Published on 22 June 2020.
    [Show full text]