DOCSLIB.ORG

Reactions of Pyridazines and Pyridazine 1-Oxides with Nitrogen

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Reactions of Pyridazines and Pyridazine 1-Oxides with Nitrogen Reactionso fpyridazine san dpyridazin e1-oxide s withnitrogen-containin g nucleophiles 1185 Ditproefschrif tme tstellinge nva nDimb yEelc oKlinge , doctorandusi nd echemie ,gebore nt eGroot-Ammer so p4 jul i1942 , isgoedgekeur ddoo rd epromotor ,dr.H.C.va nde rPlas ,hoogleraa r ind eorganisch echemie . Derecto rmagnificu sva nd eLandbouwhogeschool , J.P.H.vande rWan t Wageningen,29maar t197 6 Y\n <9zo \ 6^2- D.E.Klinge Reactionso f pyridazinesan dpyridazin e 1-oxides with nitrogen-containing nucleophiles Proefschrift terverkrijgin gva nd egraa dva n doctori nd elandbouwwetenschappen , opgeza gva nd erecto rmagnificus , dr.ir.J.P.H.vande rWant ,hoogleraa ri nd evirologie , inhe topenbaa rt everdedige n opwoensda g2 jun i197 6de snamiddag st evie ruu r ind eaul ava nd eLandbouwhogeschoo lt eWageninge n fSrt *-/0¥'3l 'L-0 3 • ,rr,.rir... T: —* 7 A//J gz&/ 6s Ay Stellingen 1.D edoo rTurne re nCheesema ngegeve ngrafie kwaari nd e C-substituenteffee - tenva n2-gesubstitueerd e pyrazinenzij nuitgeze ttege ndi eva nmono-gesub - stitueerdebenzenen ,correleer tnie tme td edoo rhe ngemete nwaarden . C.J.Turner enG.W.H.Cheeseman , Org.Magn.Reson.6_ ,66 3 (1974). 2. Heti sonvoldoend ebeweze nda tnematicid ewerkin gka nworde ntoegeken daa nd e uitd eHeleniu mhybrid e "MoerheimBeauty "ge'isoleerd eve'rbindin g2,3-dihydro - -2-hydroxy-3-methyleen-6-methylbenzofuraan. F.J.Gommers,Proefschrift ,Groninge n1973 . 3.D eamino-dehalogenerin gva n2-chloor-3,6-difenylpyrazin e kanvolgen see nan - dermechanism everlope nda nvoorgestel dword tdoo rLon te tal . P.J.Lont,H.C.va nde rPla se nA.va nVeldhuizen , Recl.Trav.Chim.Pays-Ba s 92_,70 8 (1973). 4.O pgron dva nd evermeld e H-NMRgegeven si snie tt ebewijze nda t6-aryl-4,5 - dibenzyl-3-oxo-2,3,4,5-tetrahydropyridazinen gevormdworde ni nd ereacti eva n 6-aryl-2,3-dihydro-3-oxopyridazinen metbenzylmagnesiumchloride . F.G.Baddar,N.Lati fe nA.A.Nada , J.IndianChem .Soc . 1974,618 . 5.D econclusie sdi edoo rLevin ee nBieh lzij ngetrokke nui thu nexperimente n terbestuderin gva nhe teffec tva nd ealkalianione ni nd ereacti eva no-chloor - tolueenme talkaliamiden ,zij nonvoldoend egefundeerd . R.Levinee nE.R.Biehl , J.Org.Chem.40 ,183 5 (1975). 6.Bi jd everklarin gva nhe tverschi li nreductiesnelhei dva n 2-jood-nitrobenzeen en2-joodpyridin e door2-methylpiperidine ,word tte nonrecht ehe tverschi li n snelheidva nd eamino-dejoderin gbuite nbeschouwin ggelaten . E.Farina,L.Nucci ,G.Biggi ,F.De lCim ae nF.Pietra , TetrahedronLett .1974 ,3305 . 7.He tmechanism eva nd eautoxidati eva n 5-methyl-6,7-difenyl-5,6,7,8-tetrahydro- pterinevoorgestel ddoo rJongeja ne tal. ,i songeschik tal smode lvoo rd ebio - logischewerkin gva nd eco-facto r5-methyl-tetrahydro-foliumzuur . J.A.Jongejan,H.I.X.Mage r enW.Berends , Tetrahedron 31,53 3 (1975). 8.D egroeiend erelati eva nhe thoge rberoepsonderwij sto the twetenschappelij k onderwijsmoe tnie tal sargumen tgebruik tworde no m "lichamelijkeoefening " alsverplich talgemee nva kvoo rhe thoge rberoepsonderwij sa ft eschaffen ,maa r om "lichamelijkeoefening "al sverplich talgemee nva kvoo rhe twetenschappelij k onderwijsi nt evoeren . Wetsontwerpto twijzigin gva nartike l 16,derd eli d Weto phe tvoortgeze tonderwij s (Stb.1967 , 387). D.E.Kling e Reactionso fpyridazine san dpyridazin e 1-oxideswit hnitrogen-containin gnucleophile s Ternagedachteni saa nmij nvade r Aanmij nmoede r Ireen Michiele nDaa n Contents Introduction 7 PaperI :"Evidenc efo ra 4,5-didehydropyridazine inth eaminatio no f4-halogenopyridazine s withpotassiu mamid ei nliqui dammonia " 14 Paper II :"O nth eexistenc eo f4,5-didehydropyridazine " 17 Paper III :" H-NM Rinvestigation so na-adduc tformatio n ofpyridazine ,o fpyridazin e 1-oxidean dsom e ofit sderivative swit hammonia .A ne wsubsti ­ tutionmechanism " 20 Paper IV :" C-NMRdat ao fpyridazine san dsom eo fthei r covalentaminatio nproducts " 24 PaperV :"Conversio no f 4-amino-3-halogenopyridazines intopyrazole san do f 4-amino-3,6-dihalogeno- pyridazinesint o1,2,4-triazoles " 27 Discussion 31 Samenvatting 36 Introduction Therei sa prevailin g interest inth eLaborator yo fOrgani cChemistry , AgriculturalUniversit yWageningen ,i nth estud yo fth ebehaviou ro fhalogeno - 15-18 azaaromaticsi nreaction swit hnucleophile s (potassiumamid e 2-14 ammonia 19—22 23 Inth emonocycli csystem s lithiumpiperidid e ,potassiu mt-butanolat e ) especiallyth ereaction so fderivative so fpyridin e ,pyrimidin e and pyrazine withpotassiu mamid ei nliqui dammoni awer estudie dextensively . Fromthes estudie sth emechanisti cpictur ei semergin gtha ti ngenera lhalo - genopyridinesar emor eincline dt osubstitutio nreaction s without ringopenin g thanhalogenopyrimidine san dhalogenopyrazines ,whic hpreferentiall yunderg o substitutionsinvolvin ga nopen-chai ncompoun da sintermediate . Inprincipl eth enucleophili csubstitutio nreaction swhic har efoun dt o occurwhe nhalogenopyridine sar etreate dwit hpotassiu mamid ei nliqui dammoni a andwhic hd ono tinvolv ea nopen-chai nintermediat eca nb edivide d intothre e maincategorie s (seeSchem e 1): a.S IAEJ (theformatio no fa a-intermediat e byAdditio no fth eamid eio no nth erin gcarbo nato mbearin gth ehaloge natom , followedb yEliminatio no fth ehaloge n ion);b .S JAEJ-cinesubstitutio n (the attacko fth eamid eio ntake splac eo na rin gcarbo nato mt owhic hth ehaloge n atomi sno tattached ,followe db yprotonatio nan dth elos so fhydroge nhalide ) and£ .S (EAJ (abase-catalyse d Eliminationo fhydroge nhalid eformin gth e intermediarydidehydropyridin e followedb yAdditio no fammonia) .Fro mth e last-mentionedreactio na mixtur eo f3 -an d4-aminopyridin eresults . NH2 Therei sa ninterestin gdifferenc ei nth echemica lbehaviou ro fth ehalogeno - pyridinesan dth ehalogen oderivative so fth ediazines ,pyrimidin ean dpyrazine . Asalread yindicated ,th elatte rpreferentiall ysho wsubstitutio nwit hrin g openingo nreactio nwit hpotassiu mamid ei nliqui dammonia .Thi si sdu et oth e 24 facttha ti ngenera ldiazine seasil yfor ma-adduct s withth eamid eio na ta ringcarbo nato mwhic hi sno tsubstitute db ya haloge nato m (seefo rexampl e 8d 9ab 1 structurx. e (2,->)xi •n Schem „^ eo %2) .! „H-NM» m.T,R / » 0g,17,18" a an,d13 „C-NM„ m9Rc spectroscopy presentgoo devidenc efo rth eformatio no fthes eadducts .I ti so finteres tt o notetha tth eopen-chai nintermediat ewhic hi sforme dafte rrin gopenin gca n undergoa rin gclosur eleadin gt oth e same ringsyste ma si nth estartin g substance16'7'8'17. Experimentalevidenc efo rthes eso-calle ddegenerat erin gtransformation s wasobtaine db ya nextensiv estud yo fth e N-scramblingi nth ereactio npro - 15 duct^.4. sobtaine u. • * dwhe u nf | N«jl-halogenopyrimidine v,i •-.* • 7bcde,8,16b,17,2s 2 . anfl5d J|_ N j- lOcde halogenopyrazines aretreate dwit hpotassiu mamid ei nliqui dammonia . Seefo rexampl eth econversio no f4-chloro-6-phenylpyrimidin e (1)int o4-amino - 6-phenylpyrimidine (4)(Scheme2 )involvin ga nAdditio no fth eNucleophil e (at C(2)),Rin gOpenin g (into (3))an dRin gClosure .On erefer st othi ssubstitutio n mechanisma sa nS„(ANRORC)-mechanis m. TH II — H C X C6H5 H^^tf'^CeHs "X=N '^CeH s ^N^^BMS H2N » 12 3 4 SCHEME 2 Aver yimportan tfeatur eo ftnes ereaction si stha tafte radditio nan drin g openingb y fissiono fa carbon-carbo nbond ,a nopen-chai nintermediat ei sforme d which,i fappropriat esubstituent sar epresent ,ca nunderg oa rin gclosur elead ­ ingt oa different ringsyste mtha ntha to fth estartin gsubstanc e ' ' ' ' Forexampl e4-chloro-2-phenylpyrimidin e (5)react swit ha namid eio nt ogive , viath ea-adduc t (6),th eopen-chai nintermediat e (7).Rin gclosur ethroug ha n internalnucleophili cattac ko fth eamidine-nitroge no nth eunsubstitute dcarbo n atomo fth etripl ebon dresult si nth es-triazin e derivative (8)(Scheme3 ) 25-28 CH3 ^C=CH 21 *y H5C6 ^N=c' HSCS^N ^NH2 SCHEME 3 Carbon-carbonbon dfissio ni nth eazaheteroaren eha sals obee nobserve dwhen , besidesa haloge natom ,th eheterocycl econtain sa substituen twhic hca neasil y bedeprotonate db yth eamid eion ,fo rexampl ea namino -o rhydroxy 1group .I n thatcas eth eheterocycli crin gbecome snegativel ycharge dthroug hmesomeris m andtherefor emake sth erin gles ssusceptibl et onucleophili caddition . Interestingexample so freaction si nwhic hthi scarbon-carbo nbon d fissionoccur s 29 areth erin gcontractio no f3-amino-2-bromopyridin e (9)int o3-cyanopyrrol e (10) ando f5-amino-4-chloro-2-phenylpyrimidin e (11)int o 4(5)-cyano-2-phenylimidazole 30 (12) (Schem(Scheme 4)4). _ - ^ NH2 0 A NTH[Q* NH2 * Kll ©X-CN HC^H II N=C< Br oH 10 CI NH2 N^Sr H5CkJ6 ^^N HsCe SCHEME 4 11 12 Theexperience sobtaine di nth epyrimidin ean dpyrazin efiel dinduce du st o studyth echemica lbehaviou ro fth ethir drepresentativ eo f'th ediazine si.e . thepyridazin e .Ou rinteres twa sespeciall yconcentrate do nth eproble m whetherhalogenopyridazin ederivative si nreaction swit hpotassiu m amidei n liquidammoni aar emor eincline dt osubstitutio nreaction sb yS [AE] orS |EA] processeso rt oadditio nreaction sbein gfollowe db yrin gopening .Calculation s 32 usingth eExtende dHucke lTheor yindicat e that4,5-didehydropyridazin e (13)i s a farmor establ eintermediat etha nth ewell-establishe d 3,4-didehydropyridine, sotha ti tseeme dver ychallengin gt oestablis hth eoccurrenc eo fthi sdidehydro - pyridazine. Therear esevera lreaction sreporte di nth eliteratur ei nwhic hdidehydro - pyridazinesar eadvance dbu twher ethei rexistenc ei sno treall yproven . 33 .Kauffmanne tal . proposedth e "4,5-didehydropyridazine (14)"a sintermediat e inth ereactio no f l-methyl-2-phenyl-4-X (X=C1,Br) -an d-5- X (X=Br)-pyridazine- 3,6-dionewit hpiperidine .A nisomeri cmixtur eo f4 -an d 5-piperidinopyridazines wasobtained ,bu tsinc ethei rrati oi sno tindependen to fth enatur eo fth e 10 halogenatom ,a possibl esimultaneou soccurrenc eo fa nS [AEj-substitution anda nS j_AEJ-cinesubstitutio nca ncertainl yno tb eexcluded .
Load more

Recommended publications
  • [1,2,5]Thiadiazolo[3,4-D]Pyridazine As an Internal Acceptor in the DA-Π-A
    Article [1,2,5]Thiadiazolo[3,4-d]Pyridazine as an Internal Acceptor in the D-A-π-A Organic Sensitizers for Dye- Sensitized Solar Cells Timofey N. Chmovzh 1, Ekaterina A. Knyazeva 1,2, Ellie Tanaka 3, Vadim V. Popov 2, Ludmila V. Mikhalchenko 1, Neil Robertson 3,* and Oleg A. Rakitin 1,2,* 1 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia; [email protected] (O.A.R.); [email protected] (T.N.C.); [email protected] (E.A.K.); [email protected] (L.V.M.) 2 Nanotechnology Education and Research Center, South Ural State University, 454080 Chelyabinsk, Russia; [email protected] 3 EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh EH9 3FJ, UK; [email protected] * Correspondence: Correspondence: [email protected] (N.R.); [email protected] (O.A.R.); Tel.: +44-131-650-4755 (N.R.); +7-499-135-5327(O.A.R.) Academic Editor: Panayiotis A. Koutentis Received: 4 April 2019; Accepted: 19 April 2019; Published: 22 April 2019 Abstract: Four new D-A-π-A metal-free organic sensitizers for dye-sensitized solar cells (DSSCs), with [1,2,5]thiadiazolo[3 ,4-d]pyridazine as internal acceptor, thiophene unit as π-spacer and cyanoacrylate as anchoring electron acceptor, have been synthesized. The donor moiety was introduced into [1,2,5]thiadiazolo[3,4-d]pyridazine by nucleophilic aromatic substitution and Suzuki cross-coupling reactions, allowing design of D-A-π-A sensitizers with the donor attached to the internal heterocyclic acceptor not only by the carbon atom, as it is in a majority of DSSCs, but by the nitrogen atom also.
    [Show full text]
  • Heterocycles 2 Daniel Palleros
    Heterocycles 2 Daniel Palleros Heterocycles 1. Structures 2. Aromaticity and Basicity 2.1 Pyrrole 2.2 Imidazole 2.3 Pyridine 2.4 Pyrimidine 2.5 Purine 3. Π-excessive and Π-deficient Heterocycles 4. Electrophilic Aromatic Substitution 5. Oxidation-Reduction 6. DNA and RNA Bases 7. Tautomers 8. H-bond Formation 9. Absorption of UV Radiation 10. Reactions and Mutations Heterocycles 3 Daniel Palleros Heterocycles Heterocycles are cyclic compounds in which one or more atoms of the ring are heteroatoms: O, N, S, P, etc. They are present in many biologically important molecules such as amino acids, nucleic acids and hormones. They are also indispensable components of pharmaceuticals and therapeutic drugs. Caffeine, sildenafil (the active ingredient in Viagra), acyclovir (an antiviral agent), clopidogrel (an antiplatelet agent) and nicotine, they all have heterocyclic systems. O CH3 N HN O O N O CH 3 N H3C N N HN N OH O S O H N N N 2 N O N N O CH3 N CH3 caffeine sildenafil acyclovir Cl S N CH3 N N H COOCH3 nicotine (S)-clopidogrel Here we will discuss the chemistry of this important group of compounds beginning with the simplest rings and continuing to more complex systems such as those present in nucleic acids. Heterocycles 4 Daniel Palleros 1. Structures Some of the most important heterocycles are shown below. Note that they have five or six-membered rings such as pyrrole and pyridine or polycyclic ring systems such as quinoline and purine. Imidazole, pyrimidine and purine play a very important role in the chemistry of nucleic acids and are highlighted.
    [Show full text]
  • Construction of Unusual Indole-Based Heterocycles from Tetrahydro-1H-Pyridazino[3,4-B]Indoles
    molecules Article Construction of Unusual Indole-Based Heterocycles from Tetrahydro-1H-pyridazino[3,4-b]indoles Cecilia Ciccolini, Lucia De Crescentini, Fabio Mantellini, Giacomo Mari, Stefania Santeusanio and Gianfranco Favi * Department of Biomolecular Sciences, Section of Chemistry and Pharmaceutical Technologies, University of Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino, Italy; [email protected] (C.C.); [email protected] (L.D.C.); [email protected] (F.M.); [email protected] (G.M.); [email protected] (S.S.) * Correspondence: [email protected]; Tel.: +39-0722-303444 Academic Editor: Pascale Moreau Received: 27 August 2020; Accepted: 7 September 2020; Published: 9 September 2020 Abstract: Herein, we report the successful syntheses of scarcely represented indole-based heterocycles which have a structural connection with biologically active natural-like molecules. The selective oxidation of indoline nucleus to indole, hydrolysis of ester and carbamoyl residues followed by decarboxylation with concomitant aromatization of the pyridazine ring starting from tetrahydro-1H-pyridazino[3,4-b]indole derivatives lead to fused indole-pyridazine compounds. On the other hand, non-fused indole-pyrazol-5-one scaffolds are easily prepared by subjecting the same C2,C3-fused indoline tetrahydropyridazines to treatment with trifluoroacetic acid (TFA). These methods feature mild conditions, easy operation, high yields in most cases avoiding the chromatographic purification, and broad substrate scope. Interestingly, the formation of indole linked pyrazol-5-one system serves as a good example of the application of the umpolung strategy in the synthesis of C3-alkylated indoles. Keywords: indole-based heterocycles; C2-C3 indole oxidation; aromatization; ring-opening/ring-closing; umpolung 1.
    [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 of Novel Fused Heterocyclic Pyrazolo- Pyridazine Derivatives As
    Alam et al, 2015 Original Article TJPS The Thai Journal of Pharmaceutical Sciences 39 (3), July-September 2015: 76-82 Synthesis of novel fused heterocyclic pyrazolo- pyridazine derivatives as antimicrobial agents M. Alam1, M. S. Zaman2, M. M. Alam2, K. Arora2, A. Ahmad3, 4 2* S. A. Khan and A. Husain 1 Department of Pharmaceutical Science, Bhagwant University, Ajmer, Rajasthan 305004, India 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India 3Health Information Technology Department, Jeddah Community College, King Abdulaziz University, Jeddah 21589, Saudi Arabia 4Department of Pharmacy, Oman Medical College, Muscat, Sultanate of Oman Abstract A series of pyrazolo-pyridazine derivatives (4a-j) were synthesized and evaluated for their antimicrobial activities with an aim to obtain promising antimicrobial agents. In the first step, 6-substituted phenyl-2,3,4,5- tetrahydropyridazin-3-one (2a,b) was prepared by reacting 4-(4-methylphenyl)-4-oxobutanoic acid (1a) and 4-(4- chlorophenyl)-4-oxobutanoic acid (1b) with hydrazine hydrate. Then, aryl-aldehydes were reacted with 2 to furnish pyridazinones (3a-j). Finally, pyridazinones (3a-j) were reacted with hydrazine hydrate to furnish the title compounds (4a-j). The newly synthesized compounds were evaluated for their in vitro antibacterial and antifungal activities against six microbial strains. Compound 4i, 5-(4-Hydroxy-3-methoxyphenyl)-3-(4-chlorophenyl)- 3,3a,4,7-tetrahydro-2H-pyrazolo [3,4-c] pyridazine, was found to have significant action against Gram positive and Gram negative bacteria, whereas compound 4g, 3-(4-Bromophenyl)-5-(4-chlorophenyl)-3,3a,4,7-tetrahydro-2H- pyrazolo [3,4-c] pyridazine, exhibited potential antifungal activity.
    [Show full text]
  • Haloselectivity of Heterocycles Will Gutekunst
    Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst Background SN(ANRORC) Addition of Nuclophile, Ring Opening, Ring Closure Polysubstituted heterocycles represent some of the most important compounds in the realm of pharmaceutical and material sciences. New and more efficient ways to selectively produce these Br Br molecules are of great importance and one approach is though the use of polyhalo heterocycles. Br NaNH2 N N Consider: Ar N 3 Ar2 NH3(l), 90% NH2 3 Halogenations H NH2 H N CO2Me Ar H 3 Suzuki Couplings 1 N CO2Me - Br H Ar 3 Ar2 1 Triple Halogenation NH2 NH CO Me N N 2 Ar1 H 1 Triple Suzuki Coupling N CO2Me N NH H NH2 Ar H 3 Ar2 1 Triple C-H activation? CO Me N 2 Ar1 H N CO2Me Cross Coupling H Virtually all types of cross coupling have been utilized in regioselective cross coupling reactions: Nucleophilic Substitution Kumada, Negishi, Sonogashira, Stille, Suzuki, Hiyama, etc. SNAr or SN(AE) In all of these examples, the oxidative addition of the metal to the heterocycle is the selectivity determining steps and is frequently considered to be irreversible. This addition highly resembles a nucleophilic substitution and it frequently follows similar regioselectivities in traditional S Ar reactions. Nu N The regioselectivity of cross coupling reaction in polyhalo heterocycles do not always follow the BDE's Nu of the corresponding C-X bonds. N X N X N Nu 2nd 2nd Meisenheimer Complex 1st Br Br 88.9 83.2 S (EA) Br 88.9 N 87.3 Br O O via: st OMe 1 Br NaNH , t-BuONa 2 N N pyrrolidine + Merlic and Houk have determined that the oxidative addition in palladium catalyzed cross coupling N N THF, 40ºC N reactions is determined by the distortion energy of the C-X bond (related to BDE) and the interaction of N the LUMO of the heterocycle to the HOMO of the Pd species.
    [Show full text]
  • Dual Kinase Targeting in Leukemia
    cancers Review Dual Kinase Targeting in Leukemia Luca Mologni 1, Giovanni Marzaro 2 , Sara Redaelli 1 and Alfonso Zambon 3,* 1 Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; [email protected] (L.M.); [email protected] (S.R.) 2 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, I-35131 Padova, Italy; [email protected] 3 Department of Chemistry and Geological Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy * Correspondence: [email protected]; Tel.: +39-059-2058-640 Simple Summary: A new option to treat cancer is based on the use of so-called multi-targeting drugs. This strategy can replace the standard treatment based on the co-administration of several drugs. An increased and uncontrolled activity of kinases (enzymes devoted to the regulation of several cell pathways) is often seen in hematological malignancies. The development of multi-kinase inhibitors is having a great impact on the treatment of this kind of cancer. Here, we review the most recent findings on this novel class of drugs. Abstract: Pharmacological cancer therapy is often based on the concurrent inhibition of different survival pathways to improve treatment outcomes and to reduce the risk of relapses. While this strategy is traditionally pursued only through the co-administration of several drugs, the recent development of multi-targeting drugs (i.e., compounds intrinsically able to simultaneously target several macromolecules involved in cancer onset) has had a dramatic impact on cancer treatment. This review focuses on the most recent developments in dual-kinase inhibitors used in acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and lymphoid tumors, giving details on preclinical studies as well as ongoing clinical trials.
    [Show full text]
  • Exploring Potential, Synthetic Methods and General Chemistry of Pyridazine and Pyridazinone: a Brief Introduction
    International Journal of ChemTech Research CODEN( USA): IJCRGG ISSN : 0974-4290 Vol.2, No.2, pp 1112-1128, April-June 2010 Exploring Potential, Synthetic Methods and General Chemistry of Pyridazine and Pyridazinone: A Brief Introduction Mohammad Asif1* and Anita Singh2 1Department of Pharmacy, GRD(PG)IMT 214, Rajpur road Dehradun, (UK), 248901, India 2Devsthali Vidyapeeth, College of Pharmacy Rudrapur (UK) 263148 India *Corres. Author: [email protected] ABSTRACT: Pyridazin-3-one, a saturated or unsaturated form of pyridazine with carbonyl group on third carbon, has been considered as a magic moiety (wonder nucleus) which posses almost all types of biological activities. This diversity in the biological response profile has attracted the attention of many researchers to explore this skeleton to its multiple potential against several activities. Present article is sincere attempt to review chemistry, synthesis, spectral studies and applications of pyridazinone. Key words: Pyridazinone, pyridazine, biological activities. INTRODUCTION Pyridazine are diazine. The diazines are a group of compounds formally derived from benzene by the replacement of two of the ring carbon atom by nitrogen. Three isomeric diazines are possible with the nitrogen atoms in 1-2, 1-3, or 1-4 relationship, giving rise to the pyridazines (1) pyrimidine (2) & pyrazine (3) respectively. N N N N N N (1) (2) (3) Pyridazine (1,2-diazine) (1) & its benzo analogs cinnoline (1,2-diazanaphthalene) or benzo (C) pyridazine (4) & phthalazine benzo (d) pyridazine (5) have been known since the nineteen century. Although the basic synthetic principles and reactivity were investigated in the early years, interest in these compounds revived only during the past 35 years, when many of their derivatives found application as a result of their biological activities.
    [Show full text]
  • Heterocyclic Compounds
    Lecture note- 3 Organic Chemistry CHE 502 HETEROCYCLIC COMPOUNDS Co-Coordinator – Dr. Shalini Singh DEPARTMENT OF CHEMISTRY UTTARAKHAND OPEN UNIVERSITY UNIT 4: HETEROCYCLIC COMPOUNDS- I CONTENTS 4.1 Objectives 4.2 Introduction 4.3 Classification of heterocyclic compounds 4.4 Nomenclature of heterocyclic compounds 4.5 Molecular orbital picture 4.6 Structure and aromaticity of pyrrole, furan, thiophene and pyridine 4.7 Methods of synthesis properties and chemical reactions of Pyrrole, Furan, Thiophene and Pyridine 4.8 Comparison of basicity of Pyridine, Piperidine and Pyrrole 4.9 Summary 4.10 Terminal Question 4.1 OBJECTIVES In this unit learner will be able to • Know about the most important simple heterocyclic ring systems containing heteroatom and their systems of nomenclature and numbering. • Understand and discuss the reactivity and stability of hetero aromatic compounds. • Study the important synthetic routes and reactivity for five and six member hetero aromatic compounds. • Understand the important physical and chemical properties of five and six member hetero aromatic compounds. • Know about the applications of these hetero aromatic compounds in the synthesis of important industrial and pharmaceutical compounds 4.2 INTRODUCTION Heterocyclic compound is the class of cyclic organic compounds those having at least one hetero atom (i.e. atom other than carbon) in the cyclic ring system. The most common heteroatoms are nitrogen (N), oxygen (O) and sulphur (S). Heterocyclic compounds are frequently abundant in plants and animal products; and they are one of the important constituent of almost one half of the natural organic compounds known. Alkaloids, natural dyes, drugs, proteins, enzymes etc. are the some important class of natural heterocyclic compounds.
    [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]
  • Infrared Spectra of Pyrazine, Pyrimidine and Pyridazine in Solid Argon
    Journal of Molecular Structure 786 (2006) 193–206 www.elsevier.com/locate/molstruc Infrared spectra of pyrazine, pyrimidine and pyridazine in solid argon S. Breda a, I.D. Reva a, L. Lapinski a,b, M.J. Nowak b, R. Fausto a,* a Department of Chemistry, University of Coimbra, Coimbra P-3004-535, Portugal b Institute of Physics, Polish Academy of Sciences, Warsaw PL-02-668, Poland Received 17 August 2005; revised 8 September 2005; accepted 8 September 2005 Available online 25 October 2005 Abstract The vibrational spectra of monomeric diazines (pyrazine, pyrimidine and pyridazine) isolated in solid argon and of the neat crystalline phase of these compounds, at 10 K, are reported and discussed. Full assignment of the spectra is presented, providing evidence that the assignments of several bands previously undertaken for the compounds under other experimental conditions (e.g., gas phase, neat liquid or solution) shall be reconsidered. The interpretation of the experimental data is supported by extensive DFT calculations performed with the B3LYP functional and the 6-311CCG(d,p) basis set and by comparison with the anharmonic vibrational calculations reported by Boese and Martin [J.Phys.Chem. A, 108 (2004) 3085] and Berezin et al. [Russian J.Phys.Chem., 79 (2005) 425; Opt.Spectrosc., 97 (2004) 201]. Spectra/structure correlations were extracted from the data, enabling to conclude that, while the p-electron systems in both pyrazine and pyrimidine rings are strongly delocalized over all heavy-atoms, in pyridazine the canonical form with one CC and two CN double bonds strongly predominates. Finally, the UV-induced photoisomerization of matrix isolated monomeric pyrazine to pyrimidine is reported.
    [Show full text]
  • Synthesis and Evaluation of Aromaticity and Tautomerization of Pyrazolopyridazin(On)Es
    J. Chem. Sci. Vol. 129, No. 6, June 2017, pp. 741–752. © Indian Academy of Sciences. DOI 10.1007/s12039-017-1293-3 REGULAR ARTICLE Synthesis and evaluation of aromaticity and tautomerization of pyrazolopyridazin(on)es NURETTIN˙ MENGES∗ and ISHAK˙ BILD˙ IR˙ IC˙ I˙ Faculty of Pharmacy, Pharmaceutical Chemistry Section, Yuzuncu Yil University, 65090 Van, Turkey E-mail: [email protected] MS received 4 August 2016; revised 27 March 2017; accepted 24 April 2017 Abstract. Aromaticity of pyrazolopyridazin(on)es was investigated using NICS(0), NICS(1), NICSzz(1), FIPC-NICS and HOMA aromaticity indexes and it was observed that aromaticity of pyridazin(on)es was amenable to aromaticity of pyrazole and vice versa. Some tautomeric forms of pyridazinone were analyzed and the localized orbital locator maps, electron density maps, Fuzzy, Laplacian, and Mayer bond order methods showed dominant form. Different substituents, amine, chlorine, phenyl, methyl, hydrogen, substituted-phenyl, etc. on both the rings were chosen to search out the substituent effect. Aromaticity of pyrazolopyridazin(on)es was searched out in detail for the first time. Keywords. NICS; FIPC-NICS; Keto-enol tautomer; bond order; LOL map. 1. Introduction More recently, a new and widely used aromaticity index, the nucleus-independent chemical shift (NICS), has Pyrazolopyridazin(on)e is a bicyclic nitrogen-containing been proposed by Schleyer et al. 11 It has been reported structure and one of the important core of heterocyclic that the negative value of the absolute shielding was compounds (Figure 1). Their derivatives are applied as observed at a ring center or at some other interest- ligand for hedge hog signal cascade, 1 used for treatment ing points of the system.
    [Show full text]