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 . 34 Makie tal . suggestedth ebipolar"3,4-didehydropyridazin e (15)"ason eo f theintermediate si nth ebase-catalyse drin gcontractio nreactio no f4,5-di - chloro-2-phenyl-3(2H)-pyridazinoneint o 3-hydroxy-l-phenylpyrazole-5-carboxylic acid.I nthi scas eals oth eevidenc efo rth eintermediar y existenceo f (15)i s verypoo ran dit soccurrenc eseem shighl yspeculative ,sinc ei ti swell - 32 established thatth einteractio no fth enitroge nlon epai rwit hth eelectron s inth ecarbo norbital so fth eadjacen taryn ebon dlead st ostron gdestabilisa - tion.

^ .N rr ° ^N^ C6H5 ^hT C6H5 ^N^ CH3 13 U 15 16

FIGURE 1 Inorde rt oobtai nmor econclusiv eevidenc efo ra 4,5-didehydropyridazine asa nintermediate ,th ereactio no f3,6-disubstitute d 4-halogenopyridazines withpotassiu mamid ei nliqui dammoni awa sinvestigate d indetail .Th eresult s arepublishe di npaper sI andI I Extensiono fthi swor kle du st oa stud yo nadditio nreaction so fhalogeno - pyridazines.I twa salread yprove nb y H-NMRspectroscop ytha tth eparen t compoundpyridazin egive sa nanioni ca-adduc twit hth e strongly nucleophilic 37 amideio n ;thi sadditio ntake splac ea tC(4 )i.e . (16).I tseeme dtherefor e ofinteres tt ostud yth estructura lrequirement sfo radduc tformatio no f pyridazinederivative swit hth e weak nucleophileammonia .Fo rtha tpurpos ea 1 13 numbero fpyridazin ederivative swer esynthesize d andthei r H-an d C-NMR spectrawer emeasure di nliqui dammoni aan dmethanoli cammonia .Th eresult s 38 39 ofthes espectroscopi cmeasurement sar egive ni npaper sII I andI V 40 Finallyth epossibilit ywa sstudie do frin gcontractio nreaction s ofamino - halogeno-substitutedpyridazine sbase do nwha ti salread yknow no fth erin g 29 contractionso f3-amino-2-bromopyridin e and 5-amino-4-chloro-2-phenylpyrimi- dine .Th eresult so fou rinvestigatio no nrin gcontraction so f4-amino-3 - bromo(chloro)-an d4-amino-3,6-dibromo(chloro)pyridazine sar ereporte di n paperV 11

REFERENCES

1.Se efo ra survey : a)H.J.de nHerto gan dH.C.va nde rPla s"Advance si nHeterocycli cChemistry" , Ed.A.R.Katritzky ,Vol.4 ,Academi cPress ,Ne wYor k (1965). b)H.J.de nHerto gan dH.C.va nde rPla s "Chemistryo fAcetylenes" ,Ed .H.G . Viehe,Marce lDekker ,Ne wYor k (1969). c)A.J.Boulton ,G.B.Barli n "Aromatican dHeteroaromati cChemistry" ,Vol .I (1973),I I (1974),II I (1975),Th eChemica lSociety ,London . d)Th.Kauffmann ,Angew.Chem.Int.Ed . 10^,2 0 (1971). e)H.C.va nde rPla s "RingTransformation so fHeterocycles" ,Vol. 1an dII , AcademicPress ,Ne wYor k (1973). f)H.C.va nde rPla s "Lecturesi nHeterocycli cChemistry" ,Ed .R.N.Castl e andF.Elslager ,Vol .I I (1974). g)H.C.va nde rPla san dJ.W.Stree f "Aromatican dHeteroaromati cChemistry" , Vol.IV (1976),Th eChemica lSociety ,London . 2.L.va nde rDoe san dH.J.de nHertog ,Recl.Trav.Chim.Pays-Ba s91 , 1403 (1972). 3.H.J.de nHerto ge tal. ,Recl.Trav.Chim.Pays-Ba s 93_,19 5 (1974). 4.R.Peereboo man dH.J.de nHertog ,Recl.Trav.Chim.Pays-Ba s 93,28 1 (1974). 5.P.Vrijhof ,Thesis ,Wageninge n1974 . 6.H.W.va nMeetere nan dH.C.va nde rPlas ,Recl.Trav.Chim.Pays-Ba s 90,10 5 (1971) 7.a )J.d eVal kan dH.C.va nde rPlas ,Recl.Trav.Chim.Pays-Ba s 90,123 9 (1971); b)9J_ ,141 4 (1972);c )92_ ,14 5 (1973);d )J.d eValk ,H.C.va nde rPla san d J.W.A.deBode ,ibid .92 ,44 2 (1973);e )J.d eVal kan dH.C.va nde rPlas , ibid.92 ,47 1 (1973). 8.a )A.P.Kroo nan dH.C.va nde rPlas ,Recl.Trav.Chim.Pays-Ba s 92_,102 0 (1973); b)9_3 ,11 1 (1974);c )93_ ,22 7 (1974);d )A.P.Kroon ,H.C.va nde rPla san d G.vanGarderen ,ibid .93_ ,32 5 (1974). 9.a )J.P.Geerts ,H.C.va nde rPla san dA.va nVeldhuizen ,Recl.Trav.Chim . Pays-Bas92_ ,123 2 (1973);b )J.P.Geerts ,C.A.H.Rasmussen ,H.C.va nde rPla s andA.va nVeldhuizen ,ibid .93_ ,23 1 (1974);c )J.P.Geerts ,H.C.va nde rPla s andA.va nVeldhuizen ,Org.Magn.Reson . 1_,8 6 (1975). 10.a )P.J.Lont ,H.C.va nde rPla san dA.Koudijs ,Recl.Trav.Chim.Pays-Ba s 90,20 7 (1971);b )P.J.Lon tan dH.C.va nde rPlas ,ibid .9_1_ ,85 0 (1972);c )P.J.Lont , H.C.vande rPla san dA.J.Verbeek ,ibid .91_ ,94 9 (1972);d )P.J.Lont ,H.C . vande rPla san dE.Bosma ,ibid .9j^ ,135 2 (1972);e )P.J.Lon tan dH.C.va n derPlas ,ibid .92_ ,31 1 (1973);f )92 ,44 9 (1973);g )P.J.Lont ,H.C.va n derPla san dA.va nVeldhuizen ,ibid .92_ ,70 8 (1973). 11.a )H.J.de nHerto gan dD.J.Buurman ,Recl.Trav.Chim.Pays-Ba s 91,84 1 (1972); b)92 ,30 4 (1973). 12

12.a )G.M.Sanders ,M.va nDij kan dH.J.de nHertog ,Recl.Trav.Chim.Pays-Ba s93 , 198 (1974);b )93 ,27 3 (1974);c )93 ,29 8 (1974);d )G.M.Sanders ,M.va n Dijkan dH.J.de nHertog ,Tetrahedro nLett .1972 ,4717 . 13.A.Rykowsk ian dH.C.va nde rPlas ,Recl.Trav.Chim.Pays-Ba s 94,20 4 (1975). 14.a )J.Pomorsk ian dH.J.de nHertog ,Rocz.Ch .47 ,54 9 (1973);b )£7_ ,212 3 (1973). 15.H.C.va nde rPla se tal. ,Recl.Trav.Chim.Pays-Ba s 90_,124 6 (1971). 16.a )R.Peereboom ,H.C.va nde rPla san dA.Koudijs ,Recl.Trav.Chim.Pays-Ba s93 , 58 (1974);b )R.Peereboo man dH.C.va nde rPlas ,ibid .93_ ,27 7 (1974); c)93 ,28 4 (1974). 17.E.A.Oostveen,H.C.va nde rPla san dH.Jongejan ,Recl.Trav.Chim.Pays-Ba s93 , 114 (1974). 18.a )A.Nagel ,H.C.va nde rPla san dA.va nVeldhuizen ,Recl.Trav.Chim.Pays-Ba s 94,4 5 (1975);b )A.Nage lan dH.C.va nde rPlas ,Chem.Pharm.Bull .o fJapa n 23_,267 8 (1975). 19.H.C.va nde rPla san dA.Koudijs ,Recl.Trav.Chim.Pays-Ba s 89_,12 9 (1970). 20.a )H.N.M.va nde rLan san dH.J.de nHertog ,Recl.Trav.Chim.Pays-Ba s 87,54 9 (1968);b )H.N.M.va nde rLans ,H.J.de nHerto gan dA.va nVeldhuizen , TetrahedronLett .1971 ,1875 ;c )H.N.M.va nde rLan san dH.J.de nHertog , ibid.1973 ,1887 ;d )H.N.M.va nde rLans ,Thesis ,Wageninge n1973 . 21.D.A.d eBie ,H.C.va nde rPla san dG.Geurtsen ,Recl.Trav.Chim.Pays-Ba s90 , 594 (1971). 22.J.d eValk ,H.C.va nde rPlas ,F.Janse n andA.Koudijs ,Recl.Trav.Chim . Pays-Bas 92^,46 0 (1973). 23.a )W.J.va nZoes tan dH.J.de nHertog ,Recl.Trav.Chim.Pays-Ba s93 ,16 6 (1974); b)W.J.va nZoest ,Thesis ,Wageninge n1975 . 24.M.J.Strauss ,Chem.Rev .70_ ,66 2 (1970). 25.H.C.va nde rPla se tal ., Recl.Trav.Chim.Pays-Ba s 85_,110 1 (1966). 26.H.W.va nMeetere nan dH.C.va nde rPlas ,Recl.Trav.Chim.Pays-Ba s 86,1 5(1967 ) 27.H.C.va nde rPla san dB.Zuurdeeg ,Recl.Trav.Chim.Pays-Ba s 88_,42 6 (1969). 28.H.C.va nde rPla se tal. ,Recl.Trav.Chim.Pays-Ba s 88,115 6 (1969). 29.H.J.de nHerto ge tal.,Tetrahedro nLett .1966 ,4325 . 30.H.W.va nMeetere nan dH.C.va nde rPlas ,Tetrahedro nLett .1966 ,4517 . 31.Se efo ra surve yo npyridazin echemistry :a )M.Tisle ran dB.Stanovnik , "Advancesi nHeterocycli cChemistry" ,Ed .A.R.Katritzky ,A.J.Boulton ,Vol.9 , AcademicPress ,Ne wYor kan dLondo n (1968); b)Th.L.Jacob s"Heterocycli cCompounds" ,Ed .R.C.Elderfield ,Vol.6 ,Wiley - Interscience,Ne wYor k (1957); c)R.N.Castl e"Pyridazines" ,Th eChemistr yo fHeterocycli cCompounds , Vol.28 ,Wiley-Interscience ,Ne wYor k (1973). 13

32.W.Adam ,A.Grimiso nan dR.Hoffmann ,J.Amer.Chem.Soc .91_ ,259 0 (1969). 33.a )Th.Kauffman nan dA.Risberg ,Tetrahedro nLett .1963 ,145 9; b)Th.Kauffman ne tal. ,ibid .1964 ,3563 . 34.a )Y.Mak ian dM.Takaya ,Chem.Pharm.Bull .o fJapa n20_ ,74 7 (1972); b)Y.Mak ian dG.P.Beardsley ,Tetrahedro nLett .1971 ,1507 . 35.D.E.Klinge ,H.C.va nde rPla san dA.Koudijs ,Reel.Trav.Chim.Pays-Ba s93 ,201 , (1974). 36.D.E.Kling e andH.C.va nde rPlas ,Reel.Trav.Chim.Pays-Ba s95 ,3 4 (1976). 37.J.A.Zoltewicz ,L.S.Helmick ,J.Amer.Chem.Soc . 94_,68 2 (1972). 38.D.E.Kling e andH.C.va nde rPlas ,Reel.Trav.Chim.Pays-Ba s94 ,23 3 (1975). 39.D.E.Klinge ,H.C.va n derPla san dA.va nVeldhuizen ,Reel.Trav.Chim.Pays-Ba s 95,2 1 (1976). 40.H.Iget aan dT.Tsuchiya ,J.Synth.Org.Chem.Japa n 31_,86 7 (1973). 41.D.E.Klinge ,H.C.va nde rPlas ,G.Geurtse n andA.Koudijs ,Reel.Trav.Chim . Pays-Bas93 ,23 6 (1974). Recueil, Journal of the Royal Netherlands Chemical Society, 93/7,July 1974 14

Didehydrohetarenes (XXXIII)1 Evidence for a4,5-didehydropyridazin e in the amination of 4-halogenopyridazines with potassium ainide in liquid ammonia

D. E. Klinge, H. C van der Plas and A. Koudijs

Laboratory of Organic Chemistry, Agricultural University, Wageningen, The Netherlands (Received November 25th, 1973)

Abstract. 4-X-3-(methoxymethyl)-6-methylpyridazine (X = CI, Br, I) on treatment with potassium amide in liquid ammonia at —33° C givesa mixtur e of 4- and 5-amino-3-(methoxymethyl)-6-methyl- pyridazine (ratio 1:S) , which ratio is independent of the nature of the halogen atom. A 4,5-didehydro­ pyridazine ispropose d as intermediate.

1. Introduction hydropyridazine derivative is an intermediate. The ratio in which both amino compounds are present inth e reaction There is conclusive evidence forth e occurrence of 3,4- mixture must then beindependen t of the nature of the didehydropyridine (3,4-pyridyne) andit s derivatives in 4-halogen atom. strong basic media2 but not for its aza analogue the 4,5- didehydropyridazine (1)(4,5-pyridazyne) . The few dide- hydropyridazine derivatives advanced are the following: II. Synthesis of the 4-halogeno-3-(niethoxymethyl)-6-methyl- l-Methyl-2-phenyl-4,5-didehydropyridazine-3,6-dione (2)i s pyridazines postulated asintermediat e in the reaction of l-methyl-2- phenyl-4-X(X=Cl, Br)- and 5-X(X=Br)-pyridazine-3,6-dione 3,6-Bis(hydroxymethyl)-4-oxo-l,4-dihydropyridazine (4) - with piperidine in order to explain the formation of an 6,7 3 easily prepared from kojic acid and hydrazine - was isomeric mixture of4 - and 5-piperidinopyridazines ; the converted with thionyl chloride into the corresponding didehydro compound 3i s suggested as intermediate in the 3,6-bis(chloromethyl)-4-oxo-1,4-dihydropyridazine 5. base-catalysed ring contraction of 4,5-dichloro-2-phenyl- After treatment of5 with 1equiv . ofsodiu m methoxide anda 3(2H)-pyridazinone into 3-hydroxy-l-phenylpyrazole-5-car- 4 subsequent reduction ofth e resultant product with hydrogen, boxylic acid . using palladium-on-charcoal as a catalyst, 3-(methoxy- Recent calculations, using theextende d Hiickel theory, methyl)-6-methyl-4-oxo-l,4-dihydropyridazine (6;schem e 1) indicate3 that 4,5-didehydropyridazine (1)i s far more stable was obtained. than 3,4-didehydropyridine. Iti s also more stable than the isomeric 3,4-didehydropyridazine, since the last-mentioned 0 compound is strongly destabilized due to interaction of the CH2OH CH2CI NH2NH2. [I J] S0CJ2 nitrogen lone pair with the electrons in the carbon orbitals fa ' CH2OH HOHj(r\jj-'"' of the adjacent aryne bond. 0 H Since the symmetry in the 4,5-isomer 1 does not allow the observation oforientatio n effects, we synthesized an uri- CH2OCH] symmetrically substituted 4-halogenopyridazine i.e. 3-(me- thoxymethyiH>-methyl-4-X-pyridazine (X=C1, Br,I ) and studied its behaviour with potassium amide in liquid ammonia.

H" C6H5 I CH3

Scheme1 Excluding extremely different orientation effects of the methyl and the methoxymethyl groups generally, a mixture In order to establish that in these series of reactions 6wa s of two amino compounds should be formed ifa 4,5-dide- formed instead ofit sisome r 7, wemad eus eo fth e observation that in 3,6-dimethyl-4-oxo-l,4-dihydropyridazine (8) the GeorgineM. Sanders, M.van Dijk and H.J. denHertog, Reel. PMR signalo fth emethy lgrou p on position 6( 8 = 2.43ppm ) Trav. Chim. (Pays-Bas) 93, 198 (1974). hasa doublet structure (J = 0.6cps) ,th e H(5)-signal(8 = 6.46 H. J. den Hertog and H.C. van der Plas, Dehydrohetarenes, ppm) a quartet structure (J= 0.6 cps), while the methyl chapter 17 in "Chemistry of Acetylenes", Editor H.G . Viehe. group in position 3 (8 = 2.28 ppm) is unsplit. (Marcel Dekker, New York); Th.Kauffmann and R. Wirthwein, It iseviden t that inth e4-oxo-l,4-dihydropyridazin e8 ther e is Angew. Chem.interna l Edit 10,2 0 (1971). 1 coupling between the methyl group on position 6an d the 77t. Kauffmann and A. Risberg, Tetrahedron Lett. 1963, 1459; hydrogen on position 5, probably due to the considerable Th. Kauffmann, A. Risberg, J. Schulz and R. Weber, ibid. 1964, 3563. double bond character of the C(5)—C(6) bond. We observed Y.Mala and M. Takaya, Chem. Pharm. Bull, of Japan 20,74 7 (1972); Y.Mala, G.P. Beardsley,Tetrahedro n Lett. 1971, 1507. A. F. Thomas and A. Marxer, Helv.Chim . Acta 41, 1898 (1958). W. Adam,A. Grimison and R. Hoffmann, J.Amer . Chem. Soc. /. Ichimoto, K. Fujii and C. Tatsumi, Agr. Biol. Chem. 31, 979 91,2590(1969). (1967). 15 D. E. Klinge et al./ Didehydrohetarenes (XXXIII)

that also in the product obtained on treatment of 5 with so­ Table II dium methoxidean d subsequent reduction, the methyl group at 8= 2.48 ppm has a doublet structure (J=0.5 cps) and the Halogeno After amination: H(5)-signal (5=6.60 ppm) has the multiplicity of a quartet /a compound % compound pyridazine (J = 0.5cps) .Moreove r the methylene group (8 = 4.60 ppm) 13 14 has a singlet structure. 9 16.7 ± 1.6 83.3 ± 1.6 10 17.1 ± 1.7 82.9 ± 1.7 Table I PMR-dataof the 1,4-dihydro-4-oxopyridazines 6 and 8. 11 16.9 ± 1.6 83.1 ± 1.6

0 H H II |b |° a = 3.52 (s) ppm The identity of 13wa sprove d bycompariso n with an authen­ H s—^CH0CH2 b = 4.60(s) . „. tic specimen, prepared from 9 by a reaction with ammonia. 'I c = 6.60(q) ^ = 0.5 cps The isomeric compound 14 was identified by PMR, IR and *r Ni"" d = 2.48 (d) mass spectrometry. It was observed that compound 13 is Hd 6 much more volatile on the GLC column (filling 20% OV-17 on anakrom ABS 70/80 mesh; separation factor a,3/M =2.3) 0 H e = 2.28 (s) ppm very probably due to the occurrence of an intramolecular f = 6.46(q ) J, = 0.6 cps H g = 2.43 (d) hydrogen bridge between the hydrogen of the amino group Y and the electronegative oxygen ofth e ether linkage. H2C'Al ^ 1 H (PMRspectr a in D 0, H, 2 + 8 (CH3)3Si(CH2)3SOJNa asinterna l standard)

From these observations it is evident that the methyl group at 8 = 2.48 ppm is situated in position 6 and the methylene The independency of the composition of the reaction pro­ group (8 = 4.60ppm )i n position 3clearl y establishing that it ducts 13 and 14 on the nature of the halogeno substituent iscompoun d 6 and not 7 which isobtaine d from 5. conclusively indicates that the amination of the 4-halogeno- The 3-(methoxymethyl)-6-rnethyl-4-X-pyridazines 9 (X=C1), pyridazines 9, 10 and 11 proceeds via the 4,5-didehydro- 10 (X=Br), and 11 (X=I) were prepared by standard proce­ dures and are described in the experimental section. pyridazine 12 as intermediate. No indication for the occur­ The PMR spectra are in complete accordance with these rence an SN (AE-mechanism) is found. structures (see Table HI). It is worth mentioning that in the Considering thedirectin g effect ofbot h methyl and methoxy- mass spectrum all three of the compounds show a low inten­ methyl groups on the addition of the nucleophile to the sity M-peak, but a strong fragmentation (M-30)-peak electrophilic "triple bond", we are faced with the problem whether these groups are ionized in this strongly basic (M—CH 20). Similar observations have already been made 9 previously8. medium,or not; ample evidence is available in the literature on the deprotonation of methyl groups, amino and hydroxy groups, bound to pyridines in solution ofpotassiu m amide in liquid ammonia. We observed that the PMR spectrum of a solution of CH2CCH3 '^S\rCH2OCH3 3-(methoxymethyl)-6-methylpyridazine (15) in liquid am­ monia surprisingly does not change on addition of potassium H3C ^N. H amide, indicating that no ionisation takes place. Since the methoxymethylene group is more electron-attracting than 9 x = ci 12 10 X = Br the methyl group,w eca n expect that addition on position 5i s 11 X= I more favourable than addition on position 410. The proba­ bility that the methoxymethylene group also exerts a steric effect on the addition at position 4,canno t be excluded.

Experimental part

Melting points are uncorrected. The PMR spectra were recorded on a Jeol JNM C-60 H spectro­ meter. Tetramethylsilane (TMS, 6 = 0) was used as an internal standard whenth espectru m wasmeasure di nacetone-d 6o rCDC1 3; when the spectrum was taken in D20, sodium 3-{trimethylsilyl)- Scheme 2 propanesulfonate (8 = 0) was the internal standard. The IR spectra were recorded with a Hitachi, model EPI-G3,an d the mass spectra with an AEI MS90 2 instrument. III. Amination of the 4-halogeno-3-{niethoxymethyi)-6- Gas-liquid chromatographic analyses were carried out with a Becker Unigraph withflame ionisatio n detection, usinga n 1 m R.S. methylpyridazines column containing 20/i OV-17 on anakrom ABS 70/80 mesh (temperature 170°C, velocity nitrogen 50 ml/50sec) . The amination of compounds 9,10 and 11wa s carried out as described previously. After working-up and GLC analyses of the three reaction mixtures it was found that both the 4- and 8 Q. N. Porter and J. Baldos, "Mass spectrometry of heterocyclic 5-amino products 13 and 14 are present. The ratios of the compounds" Wiley Interscience, New York 1971,p . 299. amino compounds 13an d 14foun d in all three ofth e reaction 9 J.A. Zoltewicz and L.S. Helmick, J. Org. Chem. 38, 658(1973) . mixtures are given in Table II. This ratio is independent of 10 R.W. Hoffmann, "Dehydrobenzene and cycloalkynes", Aca­ the nature of the halogen atom. demic Press New York 1967. Recueil, Journalof the Royal Netherlands Chemical Society, 93/7,July 1974 16

1. Preparationo f thestartin gmaterial s by the same procedure as given for the conversion of 2-chloro- quinoxaline into 2-iodoquinoxaline". Yield 20%; m.p. 62-63°C a. 3,6-Bis(hydroxymethyl)-4-oxo-l,4-dihydropyridazine (4) and3fi- (after recrystallisation from petroleum ether (b.r. 40-60°C). For dimethyl-4-oxo-l,4-dihydropyridazine (8) its PMR data see Table HI. Analysis: C7H9IN20 (264.08); calc. C 31.84, H 3.44; found C 32.0, H 3.6. For the stability of the iodo Thesecompound swer eprepare d byth eprocedure sdescribe d inth e compound see the remark in section l.d. literature6. b. 3,6-Bis(chloromethyl)-4-oxo-l,4-dihydropyridazine(5 ) 2. General procedure for the reactions of the haiogenopyridazines After treating7. 0g (4 5mmoles )o f4 wit hS Om lo f6 NHC 1an devapo ­ 9,10 and 11wit h potassium amidei nliqui dammoni a ratingof f theexces so fth eaqueou shydrochlori c acid,a residuewa s Three mmoles of the halogeno compound were treated during \ h obtained, which was reacted with 20 ml of freshly distilled thionyl with a solution of a fourfold molar amount of potassium amidei n chloride at 0°C during 1-2 h. When the excess of thionyl chloride 50 ml liquid ammonia at -33°C ([KNH2] = 0.24). The reaction had been removed by shaking with petroleum ether (b.r.60-80°C) , wasterminate d byadditio n ofammoniu m chloride,afte r which the the residue was mixed with sodium bicarbonate. This mixture was ammonia was evaporated. After extraction with chloroform and extracted with boiling ethyl acetate. This extraction was repeated evaporation of the solvent,a crude residue wasobtained , which on several times, each time using fresh ethyl acetate. The combined GLC showed only peaks of the two amino compounds 13 and 14; extracts were dried over MgS04, after which the solvent was eva­ also in the PMR spectrum of this crude residue, signals were porated. A yellow coloured solid with a characteristic odour observed which could only be ascribed to the two amino isomers. remained. Yield 3,8g (45%) ;m.p .206° C (lit.6: m.p.206°C) . Sincen oorgani cmateria l remained inth eresidu efro m theevapora ­ tion of ammonia, these results indicate a complete and exclusive formation ofth etw oamin oproducts ;n obyproduct swer eobserved . c. 3-(Methoxymethyl)-6-methyl-4-oxo-l,4-dihydropyridazine(6 ) The ratioo f the two amino isomers was determined by comparing 1.9g (1 0mmoles )o f5 wer ereacte dwit h 1 equiv.o fsodiu mmethoxid e the peak area of the methylene group at 8 4.78 ppm in 13an d at in absolute methanol during 24 h at 20°C. The solvent was then 5 4.55 ppm in 14. removed and theresidu edissolve d in4 5m lo faceti caci d and 45 ml The amino compounds 13 and 14 were separated by preparative ofethanol .Thi s solution wasmixe d with 3g o fsodiu m acetate and GLC. We observed in the mass spectrum of both amino isomers a then reduced withhydroge n using25 0m go fpalladium-on-charcoa l strong fragmentation (M-30)-peak just as in the mass spectra of catalyst. When hydrogen was no longer taken up the catalyst was compounds 9,10an d 11 described insectio n III. filtered off,th e solvent removed and the residueextracte d withethy l acetate. The combined extracts were dried over MgS04 and after 4-Amino-3-(methoxymethyl)-6-methylpyridazine (13) has a m.p. of evaporating the solvent, 1.4g (90% )o fa colourless solid remained, 133-135°C. It wasfoun d to be identical in all respects(m.p. ,mixe d 1 m.p. 179-180°C (subl.); v C=0: 1623cm" (in CHC13).Analysis : m.p., IR, PMR and mass spectra) with an authentic specimen (see C7H10N2O2 (154.17); Calc.C 54.53,H 6.54 ;foun d C54.7 ,H 6.6 . section 3). For its PMR data see Table III. Analysis: C7H,,N30 (153.18)calc .C 54.88,H 7.24; found C 54.6,H 7.2.NH 2 stretching l d. 4-CMoro-3-(methoxymethyl)-6-methylpyridazine(9 ) vibrations 3490cm" and 3380cm"' ; NH2 deformation frequency at 1618cm" ' (in CHC1 ). 1.0 g (6.5 mmoles) of 6 was refluxed with 15 ml of phosphorus 3 oxychloride for 45 min.Th e excesso f phosphorus oxychloride was 5-Amino-3-l'methoxymethyl)-6-methylpyridazine (14) has a m.p. of removed in vacuo and the residue, after having been cooled, was 85-87°C. For its PMR data see Table III. Analysis: C H,,N30 poured on to ice.Thereupo n the solution was made alkaline with 7 (153.18)calc .C 54.88,H 7.24;foun d C 54.5 H 7.3.NH 2 stretching ammonia and extracted with chloroform. The chloroform extracts 1 1 vibrations 3492cm" and 3400cm" ; NH2 deformation frequency weredrie d over MgS04, after which the solvent wasdistille d off. A 1 residue wasobtained , which after recrystallisation from petroleum at 1622 cm" (in CHC13). ether (b.r. 40-60°C) gave 0.83 g (73%) of colourless crystals; m.p. 47-48°C. See Table III for its PMR data. Analysis: C7H9C1N20 3. 4-Amiiio-3-(inetBoxv»erhylH-memylpyriaarine(13 ) (172.62);calc .C 48.70 ,H 5.26;foun d C48.2 ,H 5.2 . Thechlor ocompoun d 9,lik eth ebrom ocompoun d 10an d theiod o compound 11, was found to be unstable on standing in the dry 100m g(0. 6mmoles )o f9 an d 10m lo fethanoli cammonia ,saturate d state; it was stored in a solution of petroleum ether (b.r.40-60°C) . at 0°C,wer eheate d ina sealed tubea t 130°Cfo r 20h .Th ereactio n mixture was evaporated to dryness and the residue was extracted with chloroform. By preparative GLC 61 mg of 13( = 67% ) were e. 4-Bromo-3-(methoxymethyl)-6-methylpyridazine(10 ) isolated; m.p. 133-135°C. 1.0 g (6.5 mmoles) of 6 and 4.0 g of phosphorus oxybromide were Itwa si nal lrespect s(m.p. ,mixe dmeltin gpoint ,GL Cdata ,IR ,PM R heatedtogethe ra t30-40° Cfo r 1 h,whil ethi smixtur ewa sintensivel y and mass spectrum) identical with one of the amino compounds shaken.Afte r havingbee ncooled ,th ereactio nmixtur ewa sadde di n obtained by aminationo fth ehalogenopyridazin e 9,10o r11 . small portions at a time to ice-water, after which the solution was made alkaline with ammonia and worked up as already described 4. 3-(Metnoxymethyr>6-methylpyridazine (IS) in section l.d. Yield 0.27 g(20%) ;m.p . 58-60°C; seeTabl e III for 840m g(4. 8mmoles )o f9,2. 0g o fsodiu macetat e in3 0m lo fethano l its PMR data. Analysis: C7H,BrN20 (217.07); calc. C 38.73, H4.18 ;foun d C39.1 ,H 3.9 . Forth estabilit yo fth ebrom ocompoun d and 30 ml of acetic acid were reduced by hydrogen using a 0.5 g see the remark in section l.d. palladium-on-charcoal catalyst.Whe n the take up of hydrogen ceased thecatalys t wasfiltere d off and the solution wasevaporate d to dryness.Compoun d ISwa sisolate d bycolum n chromatography f. 4-lodo-3'(methoxymethyl) -6-methylpyridazine (11 ) through silicagel using chloroform as eluent. 346m go fa n oil were This compound was prepared from the chloro compound 9 by a obtained PMR data: 80CH3 = 3.47, 8CH2 = 4.73,8CH 3 = 2,72, reaction with sodium iodidei n ethyl methyl ketonei n acid medium 8H(4) = 7.50 (dX SH(5) = 7.73 (d), J4.} = 8.25 cps.

Table III Chemical shifts of the protons (expressedin 6) of the Acknowledgement 4-and 5-substituted 3-(methoxymethyl )-6-methylpyridazines. We are indebted to Drs. C. A. Landheer for mass spectro­ Com­ scopicdata ,t o Mr. W, P.Combe for carrying out the micro­ CH Haro m C// solvent pound OCH3 2 3 analyses,t o Mr. A. vanVeldhuizen for measuring PMR and IR spectra and to Mr.W. Ch. Melgerfo r adviceo n the GLC 9 3.50pp m 4.87 ppm 7.45 ppm 2.75 ppm CDC13 analyses. 10 3.50 4.90 7.67 2.73 CDC13 11 3.51 4.85 7.95 2.70 CDC13 13 3.38 4.78 6.76 2.46 acetone-d6 11 14 3.40 4.55 6.87 2.53 acetone-d6 P.J. Lontan d H. C. van derPlas, Reel.Trav . Chim. (Pays-Bas) 91, 850(1972) . 17 D.E. Klingeet al. / Didehydrohetarenes (XXXVII). On the existenceof 45-didehydropyridazine Didehydrohetarenes (XXXVII)1. On the existence of 4,5-didehydropyridazine2 D. E. Klinge and H.C . van der Plas

Laboratoryof Organic Chemistry, Agricultural University, Wageningen, TheNetherlands (ReceivedOctober 13th, 1975)

Abstract. Reaction of 4-chloro-3,6-diphenylpyridazine with potassium amide in liquid ammonia gives 4-amino-3,6-diphenylpyridazine and imino-4,4'-bis(3,6-diphenylpyridazine). Starting with 4-chloro-3,6-diphenylpyridazine-[5-l3C], it was proved by quantitative 13C-NMR measurements that both products are formed via the intermediacy of 4,5-didehydro-3,6-diphenylpyridazine.

1. Introductionan d amination reaction NMR spectroscopy the distribution of the 13C-label over the carbon atoms C(4)an d Q5) in the formed 4-amino-3,6- A reliable test for the formation of 1,2-didehydrobenzene diphenylpyridazine( 7*). Fromth ethre edifferen t routesgive n [benzyne (1)], its two diaza analogues 2,3-didehydro- inSchem e1 fo rnucleophili cdisplacement si ti seviden ttha ta pyrazine (2)an d 4,5-didehydropyridazine(3 ,R = H)an d its quantitative determination of the distribution of the Re­ tetraaza analogue 5,6-didehydro-l,2,3,4-tetrazine (4)a spos ­ label over the positions 4 and 5 of the pyridazine ring sible transient intermediates in the reactions of halogeno- provides us with an excellent method for establishing the benzenes or the corresponding halogenoazaaromatics, re­ actualpathwa y for thisaminatio n reaction sinceth e normal , , spectively,wit hpotassiu mamid ei nliqui dammonia ,involve s SN[A(4)E] substitution gives7 T_C t5)],th e SN[A(5)E] cine- theintroductio n ofa labelle dato m aton erin gato m position substitution process gives 7"[C1(4)] while the hetaryne in the starting halogeno compound. In 1953 a definite proof SN(EA) reaction distributes the label equally over the two wasobtaine d by thisapproac hfo r theformatio n ofbenzyn e positions 4 and 5 giving a 1:1 mixture of 7*[C1(5)] and inth ereactio no fl-halogenobenzene-[l- 14C]wit hpotassiu m 7«[CK4)]. amide in liquid ammonia yielding an almost 1:1mixtur eo f 1-an d 2-aminobenzene-[l-14C]3. Using the same approach C*H5 CtH5 we established some years ago that the amination of 2- SN[*»>E; >4 chloroquinoxaline-[2- C] with potassium amide in liquid HsC. ammonia yields only 2-aminoquinoxaline-[2-14C], unequi­ vocally proving that in this amination the symmetrical 2,3- didehydroquinoxaline (5) could not be involved as inter­ 4 C5H5 HjN mediate . CsHs CtH5 SN[A(5)E[ H"

HSCJ

7*(C-(4))

SNM ^ If 7*(C*(5))+r1c*(*)) Fig.l HsCj (1:1) 3* (R^CjHs) Recently,w eobtaine d someevidenc efo r theintermediac y of 3-(methoxymethyl)-6-methyl-4,5-didehydropyridazinei n the Scheme 1 reactiono f4-X-3-(methoxymethyl)-6-methylpyridazin e( X = CI, Br, I) with potassium amide in liquid ammonia5. This 2. Synthesis of 4-chJoro-3,6-dipbenyIpyrkiazine-(5-13C) (6*) conclusion was based on the fact that the ratio of the two isomeric 4- and 5-amino-3-(methoxymethyl)-6-rnethylpyri- The reaction which wasfoun d to be useful for the synthesis dazines(1:5 )wa sfoun d tob eindependen to fth enatur eo fth e of 6* was the well-known Diels Alder reaction7'8 of 1,1- halogenatom .Th egrea tdifferenc e inth eratio o fbot h amino diethoxyethene with 3,6-diphenyltetrazine. It leads to an isomers was supposed to bedetermine d by the difference in orientation effects of both substituents combined with a hydrogen bondingphenomen a between theincomin gamin o Part XXXVII in the series on Didehydrohetarenes from this group and the methoxymethylene group. In order to cancel laboratory. Previouspape r inthi sseries :Georgine M. Sanders, M.van Dijk andH. J. den Hertog, Reel. Trav.Chim . (Pays-Bas) out the different orientation effects due to different substi­ 95,3 1 (1976). tuents located at the 3-an d 6-position of a 4,5-didehydro­ : Part Vo n Pyridazines from this laboratory. See for part IV pyridazine derivative, we have studied the reaction of 4- D. E. Klinge,H. C. van der Plas an d A.van Veldhuizen,Reel .Trav . chloro-3,6-diphenylpyridazine (6) with potassium amide in Chim. (Pays-Bas) 95,21 (1976). liquid ammonia J. D. Roberts,H. E. Simmons,L. A.Carlsmith an dC .W. Vaughan, This reaction led to the formation of two products which J. Amer.Chem . Soc.75 ,329 0 (1953). were identified by their spectroanalytical data as 4-amino- P.J.Lont, H.Cvander Plas an dA. J. Verbeek,Reel .Trav .Chim . 3,6-diphenylpyridazine (7) and imino-4,4'-bis(diphenylpyri- (Pays-Bas)91,949(1972) : dazine) (15)(vide Experimental). D. E. Klinge,H. C. vander Plas an d A.Koudijs, Reel .Trav . Chim. (Pays-Bas) 93,20 1 (1974): It iseviden t from what has been pointed out above that the In this paper all the labelled compounds are indicated bya n occurrence of 3,6-diphenyl-4,5-didehydropyridazine (3,R = asterisk, the corresponding unlabelled compounds are given C6HS) as a possible intermediate in this reaction can be withouta nasterisk . detected when we use the halide 4-cnloro-3,6-diphenyl- J.Sauer, A. Mielert, D. Lang andD. Peter, Bet. 98, 143S (1965). pyridazine-[5-13C] (6*)6 and study by quantitative 13C- J. Sauer and G. Heinrichs, Tetrahedron Lett 1966, 4979. Recueil, Journalof the Royal Netherlands ChemicalSociety, 95/2,february 1976 18 adduct whicheasil ylose snitroge n and subsequently ethanol this dimer isthu s 8.0% This means that each pyridazine yielding 4-ethoxy-3,6-diphenylpyridazine. The synthesiso f nucleus contains 4.0%o f13 C-enrichment The 13C-labeli s l,l-diethoxyethene-[2-I3C] (12*) required forth e prepara­ thus equally distributed over the positions 4,4'an d 5,5'.Th e tiono f6*wa sperforme d asfollows :acetonitrile-[2- 13C](9* ) several mechanisms whichlea d to thisequa ldistributio n are which was prepared from methyl-[l3C] iodide (8*) by re- summarizedi nSchem e3 .Thre epossibilitie sfo rth eoperatio n fluxing with a mixture ofpotassiu m cyanide and glycerol, ofth ereactio n mayb econsidered ,(a )rout e A,(b )rout eB o r was converted into triethyl orthoacetate-[2-i3C] (10*) by (c)a simultaneou soperatio no fa combinatio no froute sA an d an acid-catalysed reaction with ethanol. From this com­ B. The result ofth e 13C-distribution incompoun d 15* is pound the triethyl 2-bromoorthoacetate-[2-13C] (11*) was considered to bea goo d indication for theintermediacy ofa obtainedb ya reactio n withbromin ea tlo wtemperatur e The 4^-didehydropyridazine (3* R= C6H5), since itseem s less conversion into 12*wa s performed byrefluxin g 11* with probable that the reactions given in route B are also com­ powdered sodium in benzene. Reaction of 12* with 3,6- peting atexactl y the same rate. diphenyltetrazine in benzene gave 3,6-diphenyl-4-ethoxy- 13 pyridazine-[5- C] (13*% This was converted by treatment C$H5 H CsHs with hydrochloric acid into the 4-oxo compound14* . r/ TTT» 1*1, ^N Transformation of14 *int o4-chloro-3,6-diphenylpyridazine - 7*(C»(5)) • 7'IC'HII 13 [5- C] (6*) was achieved by refluxing with phosphoryl (1:1) chloride (Scheme 2\ CeHs C6Hs 1s•(c•(^),c•(5),c•(V),c»(s•))

*CH I — *CH3CN — *CH3C(0C2H )3 — *CH BrC(OC Hsfo — H C*=C (OC Hs> 3 5 2 2 2 2 2 SN[A«)E] 15»(C*(5),C*(5-)) 25%

7*[Cm (5)) SN[A(5)E] 15*(C*(5),C»W)) 25% (1:1) I SN[W)E] OC2H5 0 CI * 15«(C»H),C*(5')) 25% *•«:•(*)) SN[A(5)E] # J » 16*(C (4),C*(V)) 25% HsCif V ««. *V-" wiV tehr*

13* Scheme 3 Scheme2 Calculationsusin gth eextende d Huckeltheor ypredict 1' that the 4,5-didehydropyridazine should befa r more stable than the widely accepted andwel l established 3,4-didehydro- 3. Calculation of13 C-distribution using quantitative pyridine.I ti sremarkabl e that after thediscover y of the3,4 - 13C-NMR spectroscopy9. Discussion ofreactio n didehydropyridine12 it took nearly fifteen years before the mechanism existenceo f4,5-didehydropyridazin ecoul db eprove nclearly . The quantitative 13C-NMR measurements in 6* were carried out by comparison ofth e peak area ofC(5 ) of the Experimentalpar t unlabelled chlorocompoun d 6wit htha t ofth e I3C-enriched chloro compound 6*. Both spectra were taken with exactly The carbon spectra were obtained with a Varian CFT-20. The thesam econcentration san dwit hth esam eparameter so fth e spectrometer was equipped with a 16K computer. The spectral NMR records. Since,unde r these conditions, the total peak widthwa s400 0 Hz, pulsewidt h 12(is , pulsedela y0. 6s ,acquisitio n area ofth e carbon atoms of the two phenyl groups inth e time1.02 3s . Numbero ftransients :fo rth echlor ocompoun d6 *an d record of the unlabelled and the labelled chloro compound thecouplin gproduc t 15*2500 ,fo r theamin ocompoun d7 *25000 . areth esame ,fro m thequotien t ofth epea k areaso fC(5 )i n6 Theconcentration so fth esolution sfo r "C-NMRrecord swer efo r 13 thechlor ocompound :0.5 3M (CDC13);amin ocompoun d0.1 0 M and C*(5) in 6*a reasonable value for the C-enrichment (DMSO-i/ ); coupling product: 0.07 M (CDC1 ). could be calculated: chloro compound 6*: quotient C*(5)/ 6 3 Q5) =5 4.6; this means that 4.6 x 1.1% (being the natural abundance of13 C inC(5 )o fth e unlabelled compound)= 1. Synthesiso f4-chloro-3,6-dipbenylpyridazine-|5- 13C](6* ) 5.1% 13C is present in the C*(5)o f the labelled compound The enrichment intha t position isthu s 5.1-1.1= 4.0%i0. a Acetonitrile-[2-,3CJ(9* ) By thesam e method thelabe l distribution and thetota l 3 13 13 40.0g (28 0mmoles )o fmethyl-[ ' C]iodid e( 8* )(about 3. 8ato m % percentageo f C-enrichment in the amino product 7*wa s 13C)wer emixe dwit h2 5 ml ofdr yglycero lan d 18.2g (33 0mmoles ) calculated: amino product 7*: quotient C*(4)/C(4) = 27; ofpotassiu mcyanid e wereadde d Duringth estirrin go fthi shetero ­ enrichmenti s(2. 7 x 1.1%) - 1.1%= 1.9%;quotien tC*(5) / geneous system at25 ° an exothermic reaction occurs. After 4 h, C(5)= 27;enrichmen t (27 x 1.1%) - 1.1%= 1.9%. Total enrichment 3.8% 10. Theseexperimenta l resultsshowe dtha tafte r amination of6 * 9 We gratefully acknowledgeth ehel po fDr .M. J. A. de Bie, Drs. the label distribution in 7*ove r Q4) and C(5)i s 1:1. From N.J. Koole and Ir.T. Spoormaker(NM Rsectio no fth elabora ­ thisresul t theconclusio n isdraw n that inthi saminatio n the tory of Organic Chemistry of the University, Croesestraat 79, 13 aminocompoun d isforme d bya SN(EA) process.Th e simul­ Utrecht)fo rth equantitativ e C-NMRmeasurements . 10 taneous occurrence oftw o mechanisms i.e. SN[A(4)E] and Anapproximatio no fth edeviatio ni nth ecalculate dvalue sbase d SN[A(5)E] both ofwhic h should compete for exactly 50% onth eerro ri nth ecalculatio no fth epea kare aa sbein gth emos t importantsourc eo ferror si sabou t 10%. cannot definitively beexcluded , butseem s very unlikely. 11 Measurement of the label distribution in the coupling pro­ W. Adam,A Grimison an dR. Hoffmann, J . Amer. Chem. Soc 91, 2590(1969 ) duct imino-4,4'-bis(3,6-diphenylpyridazine) (15*) gaveth e 12 following result: inth e coupling product 15*th e quotient M.J. Pieterse, Thesis, Amsterdam 1962; M.J. Pieterse and H.J. denHertog, Reel .Trav . Chim.(Pays-Bas )80,137 6(1961) . C*(4)C*(4')/C(4)C(4') is 28; enrichment (28x2.2%)- 13 5.0g ofmethyl-[ 13C]iodide ,abou t6 1 atom % 13Cwa s diluted 22% = 4.0%;quotien t C*(5)C*(5')/C(5)C(5') = 2.8;enrich ­ 10 with unlabelled methyl iodide to80. 0g (56 0 mmoles, about ment (28 x 22%) - 22% = 4.0% . Total enrichmenti n 3.8ato m % l3C\ 19 D.E. Klinge et al. / Didehydrohetarenes(XXXVII). Onthe existence of4J-didehydropyridazine

9* was slowly distilled from the reaction mixture using an oil bath amide in 250 ml of liquid ammonia at —33°([KNH J = 0.23) in which was heated to a final temperature of 180°. Yield 10.3 g of small portions during6 h. The reaction mixturewa s then stirred for 9*(90%) . another hour after which the reaction was terminated byadditio n of ammonium chloride. The ammonia was evaporated and the residue b. Triethyl orthoacetate-[2-l3C] (10*) was extracted with ten portions of 75 ml of boiling benzene each. After cooling, all the precipitates were collected and recrystallized 14 The procedure was followed as given in the literature for the from ethyl acetate. Yield 190m go f4-amino-3,6-diphenylpyridazine - one-step acid-catalysed conversion of nitriles into ortho esters. [4,5-13C] (7*)(2 1%) . M.p. 290-295°. It seemed necessary for continuation of the reaction to allow the 13 'H-NMR data: phenyl groups 7.35-8.10 ppm, H(5) 7.24 ppm; C- reaction temperature to rise to 40° during the passing through of 20 NMR data : C(3) 151.2ppm , C(4) 146.9 ppm, Q5) 108.6ppm , Q6) dry hydrogen chloride. Starting with 10.3 g (252 mmoles) of aceto- l J 159.5ppm ;N— Hstretchin g vibrationa t 3475cm" and 3285 cm" ; nitrile-[2-13C] (9*), 11.6gof 10*(28%)wa sobtained . B.p. 144-145°. parent peak in the mass spectrum 247;analysi s C, H N (247.29): (Lit. »* 59-78% , b.p. 70-80°/60 on) 6 13 3 15 calc. C 77.71, H 5.30;foun d C 77.3,H 5.3.Th e compound was in all "C-NMR data : C(l) 114.3 ppm, C(2) 20.7 ppm, OCH2CH3 respects identical (IR, NMR spectra and melting point) with the 57.5 ppm, OCH2CH3 15.6 ppm. compound obtained in section 3.

13 From the filtrates of the ten benzene portions a second product was c. Triethyl 2-bromoorthoacetaie-[2- C] (11 *) isolated by evaporation of the benzene, which afforded 200 mg of 11.5 g (72 mmoles) of bromine were added in 2 h, with stirring, to imino-4,4'-bis(3,6-diphenylpyridazine) (15*) (10%). M.p. 258-260°. 1 11.6 g (72 mmoles) of triethyl orthoacetate-[2-13C] (10*). The H-NM R data: phenyl groups 7.34-7.64 ppm (6H), 8.02-8.16 ppm 13 20 reaction temperature waskep t between0-5° . After addition of 10m l (4H), H(5) 7.86 ppm; C-NMR data : C(3) 152.2 ppm, C(4) of dry ether, the reaction mixture was vigorously stirred at room 137.8 ppm, Q5) 108.8 ppm, C(6) 158.3 ppm; -NH- stretching 1 + temperature for about 15 min. The working-up procedure was vibration at 3410 cm" ; M = 477; analysis C32H23N5 (477.54): carried out as described in the literature17. Yield 8.7 g of 11*(50%). calc. C 80.48, H 4.85;foun d C 80.6, H 5.0. B.p. 88-92°/20 mm (Lit. 17 72%, b.p. 77-79°/9 mm). 3. 4-Amino-3,6-diphenylpyridazine (7) d. l,l-Diethoxyethene-[2-t3CJ (12*) The dehydrobromination of 11* wa s performed as described in the 0.5 g (1.9 mmoles) of 4-chloro-3,6-diphenylpyridazine(6 )wa s mixed literature18 andcarrie d out ina nitroge natmosphere . The powdered with a little phenol and anhydrous cupric sulfate and refluxed for sodium was prepared in refluxing toluene, but for the reaction ben­ 4 h while ammonia was led into this mixture. The solution was zene was used. After termination of the reaction, 12* was not acidified to pH ~ 3 with dilute hydrochloric acid. The phenol was isolated but, after filtration of the coloured material, the remaining removed by steam distillation and the residue was extracted with clear reaction mixture was immediately used for the coupling dilute aqueous hydrochloric acid. The combined acidic aqueous reaction with 3,6-diphenyltetrazine. layers were made alkaline with ammonia, the precipitate was filtered off and recrystallized from ethanol: 0.28 g of 7 (60% )wa s e. 3,6-Diphenyl-4-ethoxypyridazine-[5-13C] (13* ) obtained. M.p. 292-295°. The Diels-Alder reaction was carried out in a nitrogen atmosphere using benzene as a solvent7,8 (see section d) Since the quantity of 1,1-diethoxyethene-[2 -• 3 C]wa sno tdetermine d (seesectio n d),smal l Acknowledgement portions of 3,6-diphenyltetrazine were added to the refluxing reaction mixture till the characteristic violet colour of the tetrazine We are indebted to Drs, C. A. Landheer for mass spectro- compound failed to disappear. The reaction rate is slow, so it took metric data, to Mr. A. van Veldhuizen for measuring *H- two days before the ketene acetal (12* )wa s completely consumed. NMR, 13C-NMR and IR spectra and to Mr. W. P. Combe for The solvent was thenevaporate d in vacuo andth eexces s ofth e tetra­ carrying out the microanalyses. zine compound was removed by several washings of the residue with petroleum ether (b.r. 40-60°). By this procedure the residue changed in colour from violet to pale-yellow. Yield 3.0 g of 13* (30% from 11* > M.p. 102-104° (Lit.7 m.p. 100-104°). Note added in proof f. 3,6-Diphenylpyridazin-4-one-[5-'3 C] (14* ) Since our paper was accepted, a publication has appeared21 describing the generation of 3,6-diphenyl-4,5-didehydro- 3.0 g (10.9 mmoles) of 13*wer e distributed over six Carius tubes. To each one 10 ml of concentrated hydrochloric acid were added, pyridazine by oxidation of l-amino-4,7-diphenyltriazolo- then the tubes were sealed and heated at 150°fo r 6 h.Afte r the reac­ [4,5-d]pyridazine with lead tetra-acetate at room tempera­ tion, the acidic solution was evaporated to dryness, water was ture. The intermediacy of this aryne was proven by inter­ added and the solution was neutralized with sodium bicarbonate. ception with tetracyclone, yielding 1,4,5,6,7,8-hexaphenyl- The precipitate formed was isolated, yielding 25 g of 14*(92%) . phthalazine, or with furan giving 5,8-epoxy-5,8-dihydro-l,4- 19 M.p. > 300°(Lit. m.p. 330°> Analysiso fth eunlabelle d compound diphenylphthalazine C,6H12N20 (248.27); calc. C 77.40, H 4.87; found C 77.3, H 5.1. g. 4-Chloro-3,6-diphenylpyridazine-[5-i3C] (6*) 14 R.H. DeWolfe, Synthesis 1974, 153. 2.5 g (9.4mmoles) of 14*wer e refluxed with 20m l offreshl y distilled 15 Interpretation of the 13C-NMR spectrum is based on the results phosphoryl chloride for 2 h. The excess of phosphoryl chloride was of 13C-measurements mentioned in the literature16 and on a removed in vacuo and the residue, after having been cooled, was comparison of the '3 C-spectra of the unlabelled and the labelled poured on to ice.Th esolutio n was then made neutral with ammonia compound. keeping the temperature below 20°. The precipitate of 6* was fil­ 16 P. C. Lauterbur, Ann. N.Y. Acad. Sci. 70, 841 (1958). tered off and recrystallized from ethanoL Yield 2.3 g of 6* (85%). 17 19 F. Beyerstedt and S.M. McElvain, J. Amer. Chem. Soc 59, 1273 M.p. 135-136° (Lit. rap. 138°). Analysis of the unlabelled com­ (1937). pound C H„C1N (266.72): calc. C 72.05, H 4.16; found C 71.9, 18 16 2 Ph.M. Walters and S.M. McElvain,J .Amer .Che m Soc 62,1482 H 4.3. 13C-NMR data20: C(3) 158.4 ppm, C(4) 134.9 ppm, C(5) (1940). 124.8 ppm, C(6) 158.0 ppm 19 T. Aiello, V.Spiro and G. C. Vaccaro,Gazz . chim. ital. 89, 2232 (1959). 20 Interpretation of the 13C-NMR spectrum is based on the results 2. Animation of 4-chk>ro-3,6-diphenylpyridazine-|5-"C| (6*) of 13C-measurements in literature2 and on comparison of the 13C-spectra of the unlabelled and the labelled compound. 1.0 g (3.8 mmoles) of 4-chloro-3,6-diphenylpyridazine-[5-I3C) (6*) 21 Th.L Gilchrist, G.E. Gymer and Ch. W. Rees, J. Chem. Soc. was added to a solution of a fifteenfold molar amount of potassium Perkin I, 1975, 1747. Recueil, Journal of the Royal Netherlands Chemical Society, 94/11, novemher 1975 20 NMR studies on cx-adductso f heterocyclic systems with nucleophiles (Part VII)1. 'H-NMR investigations on a-adduct formation of pyridazine, of pyridazine 1-oxide and some of its derivatives with ammonia. A new substitution mechanism2

D.E . Klinge and H. C. van der Plas Laboratory of Organic Chemistry, Agricultural University, Wageningen, The Netherlands (ReceivedJune 16th, 1975)

Abstract. In the reaction of 6-chloro-3-methoxy-4-nitropyridazine 1-oxide with methanolic am­ monia and with liquid ammonia, amino-demethoxylation occurs. By using 'H-NMR spectroscopy weobserve d that with ammonia a a-adduct at C(5) is formed. The unusual substitution reaction at C(3)i spropose d totak e place in this a-adduct. This newsubstitutio n mechanism isdiscussed .

Introduction Reaction of 6-chloro-3-roethoxy-4-nitropyridazine1-oxid e(8 ) with methanolicammoni a Recent 'H- and 13C-NMR studies have shown that diazines and several substituted diazines when dissolved in liquid On reacting 6-chloro-3-methoxy-4-nitropyridazine 1-oxide ammonia containing potassium amide, form anionic a- (8) with methanolic ammonia at 0°C for 1 h, amino-de­ adducts.I nthi slaborator y itwa srecentl yestablishe d thatth e methoxylation takes place leading to the corresponding a-adducts 1-4 are formed with 2-chloro-3,6-diphenylpyra- 3-amino compound (9)i n good yield. The structure assign­ 3 4 5 zine , 4-R-5-bromopyrimidines , 2-X-4-phenylpyrimidines mento f9 wa sbase don :(i). the 'H-NMR spectrum(CDC1 3) and 4-chloro-2-R-pyrimidines6, respectively. Also in liquid showing a singlet at 8 = 8.50 (1H); (ii). the IR spectrum ammonia, beingfre efro m amideions ,a-adduc t formation is (KBr) featuring at 3430 cm-1 and at 3265 cm"1 the NH- 7 stretching vibration absorptions and at 1306 cm"1 the observed: pteridine gives the adduct 5 or 6 (depending on + the temperature) and with N-methylpyrimidinium salts8 the stretching vibration of the N —O" group; (Hi), the mass adduct 7i sforme d spectrum showing the molecular peaks at m/e= 190-192, fragmentation peaks at m/e = 174-176 (M-16, loss of the + C6H5 oxygen of the N -0" function) and (to), the elemental H5C6v^Ji\,CI analyses.Chemica l evidence wasobtaine d by reduction of9 H. with hydrogen - using a mixture of Raney nickel and pal­ H2N C6H5 ladium oncharcoa l asa catalys t- to3,4-diaminopyridazine , its hydrochloride being identical with an authentic speci­ men10, with respect to its melting point, IR spectrum and •H-NMR spectrum (D20) 5 = 6.91 (d) and 8 = 8.30 (d) (J = 6.0 Hz). Until now amino-demethoxylation in com­ pound 8ha s not been observed11; usually reaction of8 wit h H2N' K nucleophilessuc ha sth emethoxy ,mercapt o orazid oanio n - j alsoi nmethano l assolven t- leadst osubstitutio n atQ4 )an d CH3 only in one case, with benzylamine, has substitution of the chlorine atom at C(6) been reported12. This interesting Fig. 1 reactivity at Q3)i n8 induce d ust ostud y theconversio n of8 into 9 in more detail. We observed that in the 'H-NMR spectrum of a solution of 8 in methanolic ammonia the Our recent work on the formation of didehydro interme­ 9 2 proton at C(5)i sconsiderabl y shifted upfield (about 3.5ppm ) diates and ring transformations in reactions of halogeno- as compared with the chemical shift of H(5) in 8 in the pyridazines with potassium amide in liquid ammonia 13 solvent CDC13 (seeTabl eI) .Base do nthi sobservatio n and induced us to study the reaction of pyridazine derivatives, on those obtained inearlie r studies3-6 in our laboratory,w e containing different leaving groups at different positions of havet o conclude that in methanolic ammonia a a-adduct is thering .I nthi spape rw erepor to nth ereactio no f6-chloro-3 - formed; structure 10 was assigned to this adduct As an methoxy-4-nitropyridazine 1-oxide (8)wit h methanolic am­ monia and with liquid ammonia

E. A. Oostveen, H.C. van der Plas and H. Jongejan, RecL Trav. See part VI in these series: J. P. Geerts, H.C. van der Plas and Chim. Pays-Bas 93, 114 (1974) A. van Veldhuizen,Org . Maga Reson7, 86(1975). Part I on pyridazines: D.E. Klinge, H.C. van der Plas and Part III on pyridazinesfro m thislaboratory . Seefo r part II: D. E. A. Koudijs, Reel. Trav. Chim. Pays-Bas 93, 201 (1974). Klinge, H. C.van der Plas, G. Gewtsen and A. Koudijs, Reel. Trav. W.D. Guither, D.G. Clark and R. N. Castle, J. Heterocycl. Chem. Chim. Pays-Bas 93, 236(1974) . 2, 67 (1965) P. J. Lont, H.C. van der Plas and A. van Veldhuizen, Reel. Trav. The replacement of an alkoxy group at C(3) in pyridazine Chim. Pays-Bas 92, 708 (1973) 1-oxides has also been found to take place in reactions of 3- J. P. Geerts, C. A. H. Rasmussen, H. C. van der Plas and A. van alkoxy-4-nitro- (and4,6-dinitro)pyridazin e 1-oxides withamines . Veldhuizen,Ree l Trav. Chim.*Pays-Ba s 93, 231 (1974). See: M. Yanai, T. Kinoshita, S. Takeda and H. Sadaki, Chem. A. P. Kroon, H. C. van der Plas and G.van Garderen, RecL Trav. Pharm. Bull 20, 166 (1972) Chim. Pays-Bas 93, 325(1974) . T. Novinson, R. K. Robins and D. E.O'Brien, J. Heterocycl. Chem. J. P. Geerts, H.C. vander Plas and A. van Veldhuizen, Reel. Trav. 10, 835 (1973) Chim. Pays-Bas 92, 1232 (1973) Iti sknown 3,6, that theinfluenc e on thechemica l shifts of protons A. Nagel, H. C. van der Plas and A. van Veldhuizen, RecL Trav. of aza-aromatics, on changing the solvent from CDC13 to liquid Chim. Pays-Bas 94, 45 (1975) ammonia, is very small. 21 D. E.Klinge et al. /NMR studies ono-adducts ofheterocyclic systems with nucleophiles (Part VII) interesting contrast we observed, using 'H-NMR spectro­ Reactiono f6-chloro-3-inethoxy-4-nitropyridazin e1-oxid e (8) scopy,tha t ina solutio no f8 i nmethanol ,containin g sodium and of 3-aniino-6-cliloro-4-nitropyridaziiie 1-oxide (9) with azide, an adduct of type 10(replacemen t of NH2 by N3) is liquidammoni a notformed . Based on thisremarkabl e difference wepropos e that amino-demethoxylation takes place in theprimarily When 6-chloro-3-methoxy-4-nitropyridazine 1-oxide(8 )wa s formed covalent adduct 10*^10b14, but that the azido- dissolved inliqui d ammoniaa t - 33°C,i twa sals oconverte d denitration takesplac ei n8 itsel f via theusua lMeisenheime r intoth e3-amin ocompoun d (9).Th ereactio ndoe sno tsto pa t adduct at C(4> In 10*± ?10 bth e nitrovinylether moiety can thisstage ,bu tcontinue swit hth eformatio n oftw one wcom ­ easily undergo addition by the ammonia yielding the inter­ pounds to which we assigned the structure of 6-chloro-3,5- mediate 11 which finally gives 9. diamino-4-nitropyridazine 1-oxide (16) (15%) and of the deoxygenatedcompoun d 17a sa mino rproduc t(Schem e 2).

N02

H2NS^?\,NH2

NO2 NO? NOJ 0CH3 H^"\0CH3 NH2

00 e NO2 "V

N02 N02 NH2 is

10b o© (OH 14. Scheme 1 Scheme2 Itmigh tb eo fimportanc et opoin tou ttha tth eexplanatio ngive nfo r the replacement reaction in 8 - i.e the amino-demethoxylation The structure assignment of 16wa s based on: (i). the 1H- occursi n theadduc t 10- isdifferen t from theproposa l givenpre ­ viously for the mechanism of the slowly occurring amination of NMR spectrum (DMSO-d6) showing no absorption in the 2-chloro-3,6-diphenylpyrazine into 2-amino-3,6-diphenylpyrazine3 aromatic region, but only a broad absorption of amino withpotassiu mamid em liquidammoni aa t —33° GAlthoug hals o groups; (ii). the IR spectrum (KBr)wit h characteristic NH- in this reaction there is excellent evidence for theformatio n ofa stretching vibrations at 3455cm -1, 3435cm -1, 3340 cm-1 rather stablea-adduc t- U. 1 - itwa ssuggeste di n that studytha t and 3285 cm"', and with the stretching vibration of the thereplacemen to fth echlorin eato mb yth eamin ogrou pdoe s not + -1 occuri n1 , buti n2-chloro-3,6-diphenylpyrazin eitsel fbein gpresen t N —O" group at 1290 cm ; (Hi), the mass spectrum, inlo wconcentratio ndu et oth eequilibriu m with1 lyingfa rove rt o showing parent peaks at m/e = 205-207 and fragmentation the left However, the result mentioned in this paper makes this peaksa t 189-191 (M-16,los so fth eoxyge nfro m the N+-0" explanation doubtful, since it cannot be excluded that anamino - function); and (iv). theexac t massdeterminatio n (C H 35C1 dehalogenation takes place leading to 2-amino-3,6-diphenylpyra- 4 4 zineals oi nadduc t 1 (orit sprotonate d form). It is clear thatmor e N503) calc. 205.0003,foun d 205.0002 The structure assign­ work is necessary to settle this interesting problem. ment of 17 was based on: (i). the XH-NMR spectrum (DMSO-dgXn o aromatic protons but only a broad absorp­ Asuggestio n whyadduc tformatio n atC(5 )i n8 b y ammonia tion ofamin o groups; (ii). theI R spectrum (KBr)whic h did not show the characteristic stretching vibration of the ispreferre d toadduc tformatio n atC(4 )i n8 b yth eazid eanio n + might be the stabilisation of adduct 10 due to hydrogen N —O"grou pa tabou t 1300cm "* ; (Hi), themas sspectru m bridge formation13 between the incoming amino group and whichgav eparen tpeak sa tm/e 189-191 butn ofragmentatio n peaks at M-16; and (iv) the exact mass determination the nitro group. 35 (C4H4 ClN502)calc. 189.0033,foun d 189.0054.Reductio n of the reaction mixture obtained on amination of 9, with hydrogen, using the "mixed" catalyst (see above), yielded OCHj 3,4,5-triaminopyridazine. The structure assignment was based on the 'H-NMR spectrum of its hydrochloride [S = 8.00 (DMSO-

Table I Chemical shifts ofthe ring protons (expressed in 0) ofpyridazine and ofpyridazine 1-oxide and some ofits derivatives.

a = CDCI3 b - DMSO-^j liquid NH3 NH3+ CD3OD H(3), H(4), H(5), H(6) H(3), H(4), H(5), H(6) H(5)

pyridazine (14)*' 9.40 8.00 8.00 9.40 9.34 7.84 7.84 9.34 pyridazine 1-oxide(15)* d 8.50 7.17 7.75 8.25 8.67 7.40 8.05 8.50 4-nitropyridazine 1-oxide (13)b•' 9.50 AB-centre at 8.60 8.03 4.55 6.65 3-methoxypyridazine 1-oxide(18)* >f 6.79 7.77 8.09 7.08 8.01 8.30 6-chloro-3-methoxypyridazine 1-oxide(19)*' * 6.72 7.70 7.17 8.38 6-chloro-3-methoxy-4-nitropyridazine 1-oxide(8) * 8.53 4.82 5.06 3-amino-6-chloro-4-nitropyridazine 1-oxide (9)b 8.60 4.68 5.00 6-chloro-3-hydroxy-4-nitropyridazine 1-oxide (I2f 8.85 8.55

b 27,28 29 i Solvent CDC13; solvent DMSO-d6; ' the spectrum consists of two symmetrical triplets of an A2X2 type in both solvents ; all the coupling 29 constants measured in liquid ammonia are in good agreement with those given in literature using CDC13 as solvent; * 'H-NMR data of 13 measured in 29 CDCl, are given in literature , in liquid ammonia: J3i = ~1.0 Hz; J56 = 5.3 Hz; ' coupling constants measured in CDC13 as solvent are given in 29 29 literature , in liquid ammonia: J4,5 = 9.0 Hz; Js>6 = 6.6 Hz; • J4,5 = 8.8 Hz (CDCI3) ; J4,5 = 8.8 Hz (NH3).

may be concluded therefore that the conversion of 9 into 16 a. Thefollowing compounds wereprepared byprocedures given in the and 17 also starts with the formation of an adduct. By loss literature ofa hydride ion or bya n oxidation process aromatisation can Pyridazine 1-oxide (15)22; 4-nitropyridazine 1-oxide (13)22; 3- take place leading to 16; by loss of water - as indicated in methoxypyridazine 1-oxide(18) 23;6-chloro-3-methoxy-4-nitropyri - Scheme 2- the deoxygenated compound 17ca n be formed. dazine 1-oxide (8)24 and 6-chloro-3-hydroxy-4-nitropyridazine 1-oxide(12) 24.

Structural requirements for adduct formation of pyridazine b. 6-Chloro-3-methoxypyridazine 1-oxide (19) derivatives with liquid ammonia Thiscompoun d beingth estartin gsubstanc efo r thepreparatio no f8 , was obtained from 6-chloro-3-methoxypyridazine using permaleic As already pointed out, adduct formation of9 with ammonia acid in CHC13 according to the procedure described for the pre­ has not been established previously and this induced us to paration of4-chloro-6-methylpyrimidin e1-oxide 25.Yiel d93% , mp. 2 investigate which structural requirements have to be ful­ 16

D. E. Klinge, H.C . van der Plas and A. van VeMhuizen

Laboratory of Organic Chemistry, Agricultural University Wageningen, The Netherlands (ReceivedJuly 8th, 1975)

Abstract 13C-NMR data of several 3-mono-an d 3,6-di-substituted pyridazines, 3-,4 -an d 6-mono- and 3,6-di-substituted pyridazine 1-oxides and 4-nitro-3,6-disubstituted pyridazine 1-oxides are reported. 13C substituenteffect s ofsom esubstituent si nth e3- ,4 -an d 6-position ofth epyridazin e ring and that of the iv*-oxide function are calculated. The "C-NMR spectra of the a-adducts of 4-nitro- 3,6-disubstituted pyridazine 1-oxides with liquid ammonia are described.

Introduction From these data the 13C substituent effects of several sub- stitutents in the 3-,4 - and 6-position of the pyridazine ring In our study on nucleophilic displacement reactions in and that of the Af-oxidefunctio n have been calculated. pyridazines,w epostulate d that the amino-demethoxylation in 6-chloro-3-methoxy-4-nitropyridazine 1-oxide (1) - this reaction occurs with liquid ammonia aswel l aswit h metha- nolicammoni a- takesplac ei nth einitiall yforme d a-adduct Resultan ddiscussio n 22.Sinc et oth ebes to fou rknowledg en oexampl eo fa nucleo ­ philicsubstitutio n in heteroaromatics has been presented in 1. 13C* shieldingand deshielding effects in 3-mono- and which covalent amination precedes displacement it seemed 3,6-di-substitutedpyridazines of interest to obtain a more profound understanding of this 13 unusual behaviour. For that purposew estarte d a 13C-NMR The C-NMR data of several 3-mono- and 3,6-di-substi­ studyo f1 andit sadduc t 1 Thestud yo nth ecarbon-shieldin g tuted pyridazinederivative sar egive ni nTabl eI .Mos t ofth e effects in azine aromatics has been concentrated mainly on pyridine derivatives3-4, pyrimidine derivatives5 and mono- 6 I3 TableI Carbon-13 shifts (ppm) andcoupling constants substituted pyrazines whereas C-NMR spectroscopy of 1J(CH)(Hz) ofpyridazine and some ofits derivatives. pyridazines and their a-adducts has never been carried out Hence it seemed useful to extend our study to other pyrida­ zine derivatives. In this paper j.3C-NMR data on several substituent 0(3) 'ACHr 0(4) V(CHr Q5) VfCHf Q6) V(CH)T

3-mono- and 3,6-di-substituted pyridazines, 3-, 4- and 6- none* 151.9 180 126.6 168 126.6 168 151.9 180 mono- and 3,6-di-substituted pyridazine 1-oxides, and 4- 3-CV 157.4 128.9* 173 128.6* 178 1507 185 nitro-3,6-disubstituted pyridazine 1-oxidesar ereported . J-OCH3- 165.5 117.3 170 129.1 170 147.5 183 3-C.H,- 159.4 123.9 168 126.9 167 150.1 189 3,Mi-Cr 156.3 130.9 180 130.9 180 156.3 3,6-di-OCH,* 1624 121.4 165 121.4 165 1624

N02 6-Cl-3-OCH3" 164.7 120.4 170 131.0 175 151.3

OCHj 6-NH2-3-Cl» 145.3 129.1 175 117.8 170 1605

l CDCI,; » DMSO-

NH2 \ if — — HT >H2 spectra are taken in CDC13, some in DMSO-d6 depending oe oe on the solubility of the compounds. The difference of the 13 NOj C chemical shift in these solvents isgenerall yfoun d to be H. OCHs small (max. 1.0 ppm) as appears, for example, from the H2N' spectra of 4-nitropyridazine 1-oxide and of 3-methox.y- pyridazine 1-oxidetake n in both solvents (see Table III). oe Spectral assignment ofth e 13C resonances in the pyridazine 2b derivatives, such as in the 3-substituted pyridazines (3)wa s performed by measuring the proton-decoupled, proton- Scheme 1 coupled and selectively proton-decoupled 13C spectrum.

NOT See for part VIIi n these series:D. E. Klinge and H.C. van der Plan, Reel Trav. Chim.Pays-Ba s94 , 233 (1975). Part IV on pyridazines from this laboratory. Seefo r part III, ^"' ,^N reference1 . o© H. L Retcofskyan dK .A Friedel, J . Phys. Chem. 71,3592(1967) ; 72,29 a 2619 (1968) 3 8 H. L. Retcofsky and F.R. McDonald, Tetrahedron Lett 1968, 2575. Fig.l J.P. Geerts,H. C. van der Plas an d A.van Veldhuizen,Org . Magn. Res. 7, 86 (1975). a. In the proton-decoupled spectrum, Q3) is distinguish­ C.J. Turner and G.W. H. Cheeseman, Org Magn. Res. 6, 663 ablefro m Q4),Q5 )an d Q6)b yit ssmal lsignal ,base do nth e (1974) 25 D.E. Klinge et al. / NMR studies on a-adducts ofheterocyclic systems with nucleopkiles (Part VIII)

Table II Carbon-13substituent effects ofsubstituted pyridazines inppm.

Direct effect Ortho effect Meta effect Fora effect

3-X- 2-X- 2-X- 3-X- 2-X- 2-X- 3-X- 2-X- 2-X- 3-X- 2-X- 2-X- pyn- benzene pyn- pyra- pyn- benzene pyri- pyra- pyn- benzene pyn- pyra- pyn- benzene pyn- pyra- dazine dine zine dazine dine zine dazine dine zine dazine dine zine

Substituent OCH,' + 13.6 + 31.4 + 14.2 + 15.6 - 9.3 -14.4 -13.1 - 3.4 + 15 + 1.0 + 1.8 +0.8 - 4.4 -7.7 - 7.6 - 14 dM + 5.5 + 6.2 + 1.4 + 4.7 + 12 + 0.4 + 0.3 + 0.3 + Z1 + 1.3 + 3.0 -07 - 1.2 -1.9 - 0.8 - 14 b NH2 + 9.8 + 18.0 + 9.8 + 13.6 -10.9 -13.3 -15.0 -10.4 +03 +09 + 1.7 -1.4 -12.1 -9.8 -10.5 -11.4 C6H5'« + 7.5 + 13.1 - - - Z7 - 1.1 - - +03 +0.4 - - - 1.8 -1.2 - -

9 CDC1, " DMSO-4,; • direct effect in 4-X-pyrimidine : CI = +4.0, C,H5 - +6.9. known phenomenon7,8 thata carbon atom being substituted i.e. the amino group - indicating that this para effect is has a longer relaxation time in comparison with the one probably strongly related with the mesomeric effect of the bearing a protoa substituent b. In the proton-coupled spectrum, Q3) showing no multi­ 13 plicity can be easily assigned; C(6)9 can be distinguished 2. The C shielding of the N*—0~ function in pyridazine from C(4) and Q5) by the one-bond carbon to hydrogen 1-oxide derivatives coupling constant ['J(CH)] since the lJ(CH) of a carbon The 13C-NMR data of pyridazine 1-oxide and some of its adjacent to the ring nitrogen is known to be larger than the mono- and di-substituted derivatives are given in Table III. 1J(CH ) of carbons in more remote positions from the ring nitrogen7,8. Table III Carbon-13 shifts (ppm)and coupling constants 1J(CH)° (Hz) ofpyridazine 1-oxide and someof its derivatives. c. Selective proton decoupling experiments enabled us to 3 assignth e * Cresonance sdefinitively . Onirradiatio no fvH(4 ) substituent CO) •J(CH) C<4) •J(CH) Q5) V(CH) Q6) •J(CH) the doublet assigned toQ4 )collapse sint oa singlet;th esam e occurs with the doublets assigned to Q5) and Q6) on irra­ none* 150.9 183 116.6 175 134.9 174 134.4 190 3-C1* 1S3.6 117.8 180 135.7 176 132.9 200 diation of vH(5) and vH(6), respectively. 6-C1* 1488 188 116.5 180 135.0 178 138.6 3-OCHj* 165.7 107.2 176 135.9 170 127.7 193 13 From the C resonances of pyridazine and those of some 3-OCH," 165.4 106.6 182 136.6 175 127.8 194 monosubstituted pyridazines, we calculated the substituent 4-NOj* 146.0 196 _•* * 128.5 186 134.5 200 135.4 184 135.0 204 effects of a chloro, methoxy and phenyl substituent at posi­ 4-N02* 146.2 198 129.5 13 6^1-3-OCHj' 164.2 109.0 179 136.0 175 130.9 tion C(3). From the difference in chemical shifts of the C 6-NH,-3-Cl» 146.3 1201 178 118.5 172 137.0 resonances of 3-chloropyridazine and 3-amino-6-chloro- pyridazine we calculated the substituent effect of an amino • CDCIj; * DMSO-4,; • V(CH) i i one-bond carbon to hydrogen coupling group at C(3). The sign and the magnitude of the effects of constant different substituents on 13C resonances of C(3) (direct *** No signal due to low solubility. effect), Q4) (ortho effect). C(5) (meta effect) and Q6) (para By comparison ofthes e datawit h those ofth e corresponding effect) are summarised in Table II. deoxygenated compounds, we calculated the influence of the + For comparison, the corresponding substituent effects in N —O" function on the chemical shift of the ring-carbon benzene7,8, pyridines3,4 and pyrazines6 are included in atoms (Table IV) Thedat asho w that thecarbo n atoms ortho Table IL An important conclusion which can be drawn by Table IV Carbon-13 substituent effect (ppm) of the N-oxide comparison of these results is that the magnitude of the function by comparison ofsome pyridazines and their ti( 1)-oxides. direct shielding increment, specially that of the amino and methoxy groups, is much less in pyridazine than in benzene. Apparently, the ring nitrogens compete for the available electronic charge with the electron attracting substituent at Q3) leading to lesselectroni c charge removal from C(3) than C(3) C(4) Q5) Q6) h the corresponding position in benzene. The direct substi­ tuenteffect s parallel theone sfoun d in2-substitute d pyridines and might beconsidere d as an indication that the additional ring nitrogen has little influence in controlling this direct Ri=R*=H -1.0 -10.0 +8.3 -17.5 effect on Q3). A similar conclusion has been reached for R'-Cl, R2=H -3.8 -11.0 +7.0 -17.8 6 R'=H,R*=C 1 -1.9 -122 +6.2 -18.8 monosubstituted pyrazines . The para substituent effect has 2 thegreates t valuefo r thepowerfu l electron-donatinggrou p - R'=OCH3,R =H +0.2 -10.1 +6.8 -19.8

and para to the N+—O" function i.e.Q6 ) and C(4), respec­ J. B. Stothersi n "Organic Chemistry" (A.T. Blomquist and tively, undergo a shielding effect, the meta carbon atom i.e. H. Wasserman Ed), Vol 24, Carbon-13 NMR Spectroscopy, Q5) a deshielding effect, while the influence of the N+-0~ Academic Press, N.Y. (1972* function especially at Q3) shows a relatively important G. C. Levyan d G. L. Nelson, Carbon-13 Nuclear MagneticRe ­ variation depending on the substituent The interesting ob­ sonance for Organic Chemist Wiley-Interscience N.Y. 1972. servation was made that the set of substituent effects of the In case of 3-X-pyridazine 1-oxide the C(6) assignment could N+-0" function obtained from the 13C-NMR data of also be based on the fact that due to a magnetic anisotropic effect10 theC(6 )double ti na tota l protoncouple d l3Cspectru m 6-amino-3-chloropyridazine and 6-amino-3-chloropyrida- isalway spresen ta stw obroa dsignals .Th eC(4 )an dC(S )doublet s zine 1-oxide- on Q3) + 1.0,o n Q4)- 9.0,o n C(5) + 0.7 and areo nth econtrar y sharpan dalway ssho wa smal l2 J(CH). on Q6) - 23.5- considerably deviates- especially on C(5) - M.J. Cookan d A. R.Katritzky, Adv.Heterocyc LChem. , Vol 17 from the average value of these effects calculated from Table (1974). IV: i.e.o n Q3) -1.6, on Q4) -10.8, on Q5) +7.1, and on Recueil,Journal of the Royal Netherlands ChemicalSociety, 95/1,January 1976 26

TableV. Carbon-13 shifts of4-nitropyridazine 1-oxide derivatives in the solvents DMSO-d6 andliquid ammonia, respectively.

3 13 substituent C-NMRdat ai n ppm(DMSCW 6) C-NMR datai npp m(liqui dNH 3) Q3) Q4) C(5) Q6) Q3) Q4) Q5) C(6) none(4 ) 146.2 135.6 129.8 135.0 147.7 115.8 45.0 121.4 6-CI-3-OCH3 (1) 156.6 127.2 131.8 131.8 160.2 104.6 53.2 1212 6-C1-3-NH,(5 ) 152.7 126.2 131.2 122.4 155.2 106.6 51.4 117.4 6-C1-3-OH(6 ) 157.7 127.2 1314 129.0 161.0 120.6* 131.2 129.2*

* Ori nopposition .

C(6) —18.5. Justa si nth epyridazine sw eobserve dtha ti n the good agreement with the 13C shielding difference of about pyridazine 1-oxidederivative s the difference in magnitude of 90 ppm observed on adduct formation in pyrimidines. Also 1J(CH )i sdependen t on thepositio n ofth ering-carbo n atom. in accordance with this phenomenon of o-adduct formation The 'J(CH )o fcarbon si n a-positiont oth eN + —O" function is the significant change of 'J(CH). Whereas in the com­ is around 190-200 Hz, of carbons in (J-an d y-position of the pounds 1,4,5 a *J[Q5)H ] is observed of around 180 Hz, in N+—O" function 170-180 Hz and of carbons in 8-position theCT-adduct o f these compounds the tetrahedral Q5) gives of the N+—O" function (thus a of the other ring nitrogen) a iJ[C(5)H ] of about 150 Hz (Table VI). 180-190 Hz (see Table III). These relatively large differences Parallel to the upfield shift of Q5) is that of the carbon may have diagnostic value and may be very useful for atoms C(4)an d Q6), neighbouring thesp 3 carbon atom; this spectral assignments upfield shift is much smaller (about 20 ppm for C(4), 5-14 The ortho substituent effect of a nitro group at C(4) is ppmfo r C(6)>Whethe rthis shieldin geffec t hast ob eascribe d calculatedfro mth e 13C-NMRdat ao fpyridazin e 1-oxidean d to the presence ofa negative charge in thering, t o the hybri­ 4-nitropyridazine 1-oxide: on C(3)-4-9 and on Q5)-6.4. Its disation change of Q5) or to both influences, is unknown. meta substituent effect is, in agreement with meta effects of Dissolving 6-chloro-3-hydroxy-4-nitropyridazine 1-oxide (6) other substituents, very small (+0.1) inliqui dammoni a theinterestin gobservatio n wasmad etha t Q5) undergoes an upfield shift of only 1.2 ppm, and that 3. 13C-NMR spectra of 3,6-disubstituted 4-nitropyridazine 'J[Q5)H] is not significantly changed. The explanation we 1-oxides andof their a-adducts with liquid ammonia advance is that compound 6 with ammonia does not form a o-adduct but undergoes proton abstraction, leading to a For the results of the measurements of 13C-resonances in negatively charged ion in which a nucleophilic addition is several 3,6-disubstituted-4-nitropyridazine 1-oxide deriva­ strongly hindered.Th eobserve d shift onC(4) ,whe n changing tives using DMSO-d6 as solvent, see Table V. In order to be the solvent from DMSO-

11 A. Nagel, H.C. van derPlas and A van Veldhuizen, RecLTrav . This considerable upfield shift must be ascribed to rehybri- China. Pays-Bas 94, 45(1975) . disation ofC(5 )(sp 2 -» sp3) duet oth eformatio n ofa covalen t 12 R.N. Castle, Pyridazines. The Chemistry of HeterocyclicCom ­ o-adduct at Q5) (see Scheme 1).Thi s upfield shift value is in pounds Vol 28, Wiley-Interscience N.Y. 1973. 27

Ring transformations in reactions of heterocyclic halogeno compounds with nucleophiles (XXXVI)1 Conversion of 4-amino-3-halogenopyridazines into pyrazoles and of 4-amino-3,6-dihalogenopyridazines into 1,2,4-triazoles2

D. E. Klinge, H. C. van der Plas, G. Geurtsen and A. Koudijs

Laboratory of Organic Chemistry, Agricultural University, Wageningen, The Netherlands (Received February 27th, 1974)

Abstract. On treatment of 4-amino-3-X-pyridazine (X=C1, Br) with potassium amide in liquid ammonia 4-cyanopyrazole is formed. Under the same reaction conditions 4-amino-3,6-di-X-pyrida- zine (X=C1, Br) undergoes a ring contraction into 3-(cyanomethyl)-l,2,4-triazole. The mechanism of both ring contractions is discussed.

I. Introduction NH2

In this laboratory it has been found that aza- and diaza- aromatics which contain a halogen substituent on a carbon - o atom in an a-position to the ring nitrogen, as well as an 1 X=CI amino group in the P-position, undergo ring contraction on 2 X-Br treatment with potassium amide in liquid ammonia3. Examples of these ring contractions are the conversions of Scheme I 3-amino-2-bromopyridine into 3-cyanopyrrole4, of 3-amino- 2-bromoquinoline into 3-cyanoindole5, and of 5-amino-4- chloro-2-phenylpyrimidine into 4(5)-cyano-2-phenylimida- The same ring contraction was also observed with 4-amino- zole6.A characteristi c feature ofal l these reactions istha t the 3-X-pyridazine (2, X=Br); the yield of 3 was somewhat novel heterocyclic ring which is formed on ring contraction enhanced. Both reactions provide us with novel interesting contains the same number of ring nitrogen atoms as the examples of a potassium amide catalysed ring contraction starting substance (pyridine -» pyrrole, quinoline -»indole, and underline the general reaction pattern, which has been pyrimidine -* imidazole). In our study on reactions of discussed above with other azines. halogenopyridazines with potassium amide, we became Although there are several base-catalysed ring contractions 8 interested to find out whether 4-aminohalogenopyridazines of JV-substituted pyridazines known in literature e.g.: the also would undergo ring contraction on treatment with conversion of 3,5-dichloro (and 4,5-dichloro)-l-phenyl-6- potassium amide. (l//)-pyridazone into the 3-hydroxy-l-phenylpyrazole-5-

Previous paper in these series:H.J. den Hertog, H. Boer, J. W. II. Treatment of 4-amino-3-halogenopyridazines with potas­ Streef, F. C. A. Vekemans and W. J.v. Zoest,Reel . Trav. Chim. (Pays-Bas) 93, 195(1974). sium amide Part II on pyridazines from this laboratory. See for part I: D. E. Klinge,H. C. vander Plas an d A. Koudijs, Reel.Trav .Chim . Treatment of 4-amino-3-X-pyridazine (1, X=C1) with a (Pays-Bas)93 ,20 1 (1974). sixfold molar amount of potassium amide in liquid am­ For a review on ring transformations ofazine sse eH. C. van der monia at —33°C , yields a compound A of which the IR Plas, Lectures in Heterocyclic Chem, Vol. II,S-8 3 1974. spectrum features at 3250 cm-1 a NH-stretching vibration H.J. denHertog, R.J. Martens, H.C. van derPlas and J. Bon, absorption and at 2230 cm-1 the stretching vibration of a Tetrahedron Lett. 1966, 4325. CN group;th e PMR spectrum ofa solution ofA (acetone-d6) H.J. den Hertogan d D.J. Buurman, Tetrahedron Lett 1967, shows a singlet at 8 = 8.26 ppm (2H)an d a broad absorption 3657. 7 H. W.van Meeteren and H.C. vander Plas, Tetrahedron Lett. at8= 6.86 ppm (1H); in the mass spectrum the parent peak 1966, 4517. was observed at m/e=93 and a fragmentation peak at m/e= We are indebted to Mrs. P. Cohen-Fernandes of the Gorlaeus 66 (loss of HCN). Based on these data, the structure of 4- Laboratory at Leiden for providing with the IR spectrum and cyanopyrazole (3) was assigned to compound A. This the PMR spectrum of 4-cyanopyrazole. structure assignment wasprove d to becorrec t on comparison H.C. van der Plas, "Ring transformations of Heterocycles" with an authentic specimen (Scheme 1). Vol.2 .Academi c Press (London and New York)1973 . Recueil, Journal of the Royal Netherlands Chemical Society, 93/8, august 1974 28 carboxylic acid9 (a recent report suggests a pyridazyne as intermediate10 X the ring transformation of 4,5-dibromo-l- phenyl-6(l//)-pyridazoneint o the4-hydroxypyrazol e deriva­ tive11 and the conversion of 4-hydroxy-2-methyl-l-phenyl- ^6 tetrahydropyridazine-3,6-dione into the 5-pyrazolone-3- carboxylic acid12, the ring contraction of pyridazines, in 10 which no group is attached to the nitrogen, into pyrazoles is without precedent. CN

S \ X III. Treatment of 4-amino-3,6-dihaIogenopyridazines with /" N. li potassium amide 13

When reacting 4-amino-3,6-dichloropyridazine (4) or 4- Scheme 3 amino-3,6-dibromopyridazine (5) with potassium amide in liquid ammonia, from both reaction mixtures a compound These ring contractions can only occur when the pyridazine could be isolated to which we assigned the structure of ring is substituted at position 4 with a group containing two 3-(cyanomethyl)-1,2,4-triazole (6). The structure evidence hydrogens easily split off in this strong basic medium (e.g.a n for6 i sbase d on:a it sI R spectrum which showed absorptions -1 -1 NH2 group). This has been proved by studying the reaction at 3250 cm (NH) and at 2265 cm (CN); b its PMR of 3,6-dichloro-4-(methylamino)pyridazine (14) with po­ spectrum (acetone-d6) which revealed a singlet at 6 = 8.4 tassium amide. No ring contraction reaction was observed ppm (1H),a singlet at 5 = 4.0pp m (2H)an d an unsharp NH- even when an extremely high potassium amide concen­ absorption at 8 = 11.5 ppm; c its mass spectrum which tration was used. Only 6-amino-3-chloro-4-(methylamino)- showed a parent peak at m/e = 108 and a fragmentation pyridazine (15) was formed. peak at m/e = 81 (loss of HCN); d mixed melting point determination with an authentic specimen - prepared from 3-(chloromethyl)-l,2,4-triazole (7) with potassium cyanide - showing no depression (Scheme 2). The conversion of a pyridazine ring into a triazole is un­ precedented and is very unusual since it is in fact the first example of a potassium amide catalysed ring contraction in which the number of ring nitrogen atoms in the product formed is increased in comparison with that of the starting material. That 15 and not the isomeric 3-amino-6-chloro-4-(methyl- amino)pyridazine was obtained was proved by dehalogena- NH2 tion with hydrogen and palladium-on-charcoal yielding CH2C=N CHjCI compound 16. Structure 16 was identified by PMR-spec- — / ( troscopy, showing two doublets at 8 = 7.97 ppm (H(3)) and N i, u. at 5 = 5.85 ppm (H(5)), both with coupling constant of 2.6 cps, clearly a meta-coupling13(Schem e 4). 4 x-ci 5 X-Br Scheme 2 V. Syntheses of the starting substances 1, 2, 4 and 5

The amino compounds 1 and 2 were prepared as given in IV. Discussion Scheme 5. 18 as well as 19, obtained on treatment of the 4-chloro-3-pyridazone (17) with phosphorus pentachloride Considering the mechanism of the ring contraction reactions or phosphorus pentabromide, respectively, are rather un­ the interesting question arises why in case of 1 and 2 a stable compounds; they were not isolated but immediately pyrazole ring, in case of 4 and 5 a 1,2,4-triazole ring, is converted into 1o r 2, respectively, by heating with ethanolic produced. ammonia. Following previous suggestions we assume that in the ring contraction of the pyridazine ring into the 1,2,4-triazole ring the first step is the base-catalysed deprotonation of the NH2 amino group into the anion 8, being possibly in equilibrium with its C-conjugated acid 9. A further deprotonation of the NH imino group with subsequent fission of the C(3)—C(4) bond and loss of a halogen anion yields the (cyanoketenimino)- 17 18 x-ci 1 X-CI imidoyl halogenide 10. This highly reactive imidoyl halo- 19 X- Br 2 X-Br genide is converted into the amidrazone 11whic h can easily cyclise into 6 by addition of the amino group across the Scheme 5 azomethine bond in the ketenimino group. This mechanism can explain why the 4-amino-3-halogeno compounds 1 and 2 do not give a 1,2,4-triazole, but a pyrazole. The ring cleavage of 12 cannot lead to an intermediate with a keteni- T. Takahashi, N. Furukawa and Y.Maki, Yakugak u Zasshi 86, mine structure but gives the carbanion 13.Th e ring cyclisa- 867(1966) . tion occurs now by a nucleophilic attack of this carbanion V. Maki and G. P. Beardsley, Tetrahedron 1971,1507 . moiety to the imidoyl halogenide function leading to a F. Kuhelj, B. Stanovnik and M. Tisler, Croat. Chem. Acta,38 , pyrazole; it must be concluded that the ring cyclisation oc­ 299(1966). curs at a faster rate than replacement of the halogen atom by J. Druey, K. Meier and A. Staehelin, Pharm. Acta Helv.38 , 498 an amino group (Scheme 3). (1963); K. Dury, Angew. Chem. 77,28 2(1965) . K. Torian d M.Ogata, Chem.Pharm .Bull .12,27 2(1964) . 29 D.E. Klinge etal. j Ringtransformations in reactionsof heterocyclic halogenocompounds withnucleophiles (XXXVI)

It was found that the 4-amino-3-bromopyridazine (2) is not Howeverth ecompoun dwa sno tpur e(m.p . 114-118°C),abou t10 % quite pure, but contains according to the mass spectrum of 3-amino-4-chloropyridazine was present (see section V). The about 10%o fa namino-chloropyridazine ,probabl y 3-amino- reaction with potassium amide was studied with this somewhat 4-chloropyridazine. This was proved by reduction of the impure product. reaction mixture by hydrogen and palladium-on-charcoal: besides 4-aminopyridazine, about 10% of 3-aminopyrida- d) 3.6-Dibromo-4-chhropyridazine(21 ) zine wasshow n tob epresen t inth ereactio n mixture by PMR 20.0 g (136 mmoles) of 4-chloro-3,6-pyridazinedione19 and 40.0 g spectroscopy. Attempts to synthesize compound 2 by (93 mmoles) of phosphorus pentabromide were well mixed and bromination of 4-aminopyridazine with HBr and H202, heated on thestea m bathfo r 8h .Th e reaction mixturewa scoole d using the same procedure14 as given in the literature for the to - 10°C and added in small portions at a time to a mixture of chlorination of 3-aminopyridine to 3-amino-2-chloropyri- ammonia (2N)an d ice.Th e pH was kept at about 8an d thetem ­ peraturewa sno tallowe d toris eabov e0°C .Th ecrud eproduc twa s dine, failed. A compound was formed which according to its filtered off and washed successively with 25 ml of UV-sodium PMR, IR and mass spectrum was 4-amino-5-bromopyri- hydroxidesolutio na t0°C ,an dwit hcol dwater .Th eprecipitat ewa s dazine (22). intensively dried in vacuo over phosphorus pentoxide, followed by In the PMR spectrum of 22 we did not observe a coupling extraction in a Soxhlet apparatus for 2 days with petroleum ether constant between H(3) and H(6). In the literature divergent (b.r. 60-80°C). The solvent was removed and the residue was 15 1316 distilleda t 140°C/3 mm. Yieldo f21,27. 7g (74%) ,m.p .62.5-64°C . values for J3 6 are reported (1.38 cps and 3.5 cps ). In Analysis: C4HBr2ClN2 (272.35) calc. C 17.64, H 0.37, N 10.29; order to evaluate the influence of an 4-amino group on the foundC 17.9,H 0.8 ,N 10.3 . magnitude of the J3 6 we prepared the reference compound 4-amino-5-chloropyfidazine in the same way as described in e) 3,4,6-Tribromopyridazine(20 ) the literature17. A compound18 was obtained, m.p. 120°C (lit.17 73°CX m.p. picrate 212°C (lit.17 212°C), the PMR 15.0g (102 mmoles) of4-chloro-3,6-pyridazinedione 19 wereheate d spectrum of which also showed no coupling between H(3) during3 h a t140° Cwit h65. 0g (22 6mmoles )o fphosphory lbromide . and H(6). After cooling to0°C ,th ereactio nmixtur ewa scarefull y pouredou t on to ice and made alkaline with an 28% aqueous solution of Compound 5 was obtained by heating 3,4,6-tribromo- ammonia. The precipitate was collected, washed with water and pyridazine (20) or 3,6-dibromo-4-chloropyridazine (21) with distilled with steam. The crystals werefiltered of f and dried over ethanolic ammonia at about 100°C; the same procedure anhydrous magnesium sulfate. Yield 18.0 g of 20(56%) , m.p. 95- was used for the preparation of 4 from 3,4,6-trichloro- 96°C. Analysis:C 4HBr3N2 (316.81) calc. C 15.16, H0.32 , N 8.84; pyridazine19. foundC15.5,H0.6,N8.8. 0 4-Amino-3fi-dibromopyridazine(5 ) 1) 1.0g (3. 1 mmoles) of 3,4,6-tribromopyridazine(20 )an d 15m lo f Experimental part ethanolic ammonia,saturate d at0°C ,wer eheate d ina sealedtub e at 100°Cfo r 2h .Th econtent s ofth etub e wereevaporate d todry ­ ness in vacuo. Theresidu ewa srecrystallize d fromaqueou sethanol . Meltingpoint sar e uncorrected.Th ePM Rspectr awer erecorde do n Yield 0.5 g of 5 (64%), m.p. 225-226°C. Analysis: C4H3Br2N3 aJeo lJN MC-6 0H spectrometer .Th espectr awer etake ni nacetone - (252.92)calc .C 18.99 ,H 1.20 ,N 16.62;foun dC 19.3 ,H 1.1 ,N 16.4. d6 or CDC13 using tetramethylsilane (TMS, 8 = 0) as an internal standard;whe nth espectru mi stake ni nD 20, sodium 3-(trimethyl- 2) 1.0 g (3.7 mmoles) of 3,6-dibromo-4-chloropyridazine (21) was silyl)propane-l-sulfonate (8 = 0)wa s the internal standard (seefo r submitted to the same procedure as described in section lf-1; the PMR datasectio n 5).Th e IRspectr a wererecorde d witha Hitach i reaction time was 5 h instead of 2 h. After recrystallization from modelEPI-G3,an dth emas sspectr awit ha nAE I MS90 2instrument . aqueousethano lth eyiel do f5 wa s0.5 5g (60%) ,m.p .225-226°C . g) 3-(Cyanomethyl)-12,4-triazole(6) 1. Preparation of thestartin g andreferenc e compounds 3.0 g (25.5 mmoles) of 3-(chloromethyl)-l,2,4-triazole (7)24 were dissolvedi n2 0m lo f96 %ethano lan dadde ddropwis et oa solutio n a) The following compounds were prepared by the procedures of 2.5 g (39 mmoles) of potassium cyanide in 30 ml of water.Thi s given in the literature: solution wasrefluxe d for2 h .Afte rdilutio n with5 0m lo fwater , the 4-amino-3,6-dichloropyridazine (4)20, and 3,6-dichloro-4-(methyl- solution obtained was neutralized with concentrated sulfuric acid amino)pyridazine (14)2'. and continuously extracted with ether during4 days.Th eetherea l solution was dried over anhydrous magnesium sulfate. After b) 4-Amino-3-chloropyridazine (1) evaporation of the solvent 1.18 g (40%) of 6 remained, m.p. 137- 22 139°C (from toluene). Analysis: C4H4N4 (108.10) calc. C 44.44, 1.0g (6. 7mmoles )o f3,4-dichloropyridazin e(18) wasdissolve di n H 3.73; found C 44.2, H 3.5. 12m l of absolute ethanol. Thissolutio n wassaturate d at0° Cwit h ammonia and then heated in a sealed tube for 6 h at 125°C.Th e solvent was removed and the residue was extracted with boiling ethyl acetate. After evaporation of the solvent the residue was 14 O. von Schickh, A. Binz undA. Schulz, Ber.69,259 3(1936) . purified by column chromatography through silica gel using a 15 mixtureo fethy l acetatean dmethano l(10:1 )a seluent ,yieldin g45 0 V.M.S. Gil an d A.J. L. Pinto, Mol .Phys .16,62 3(1969) ;Physica l mg of 1 (52%), m.p. 140-142°C (lit" 141-142.5-C). Analysis: Methods in heterocyclic chemistry A.R. Katritzky, Vol. IV, Academic Press (New York and London) 1971. C4H4C1N3 (129.55)calc .C 37.08 ,H 3.11;foun dC 36.5,H 3.1. 16 Applications of nuclear magnetic resonance spectroscopy in c) 4-Amino-3-bromopyridazine(2 ) organic chemistry. L.M. Jackmann and S.Sternhell, Pergamon Press 2nd Edition 1969. 1.0 g (7.7 mmoles) of 4-chloro-3-pyridazone (17)22 and 1.66 g(3. 8 17 T. Kuraishi and R.N. Castle, J. of Heterocyclic Chem. 1, 42 mmoles) of phosphorus pentabromide were intensively mixed at (1964). 18 100°Cdurin g3 h .Afte r cooling, thereactio n mixturewa sadde di n Analysis: C4H4C1N3 (129.55) calc. C 37.08, H 3.11; found small portions at a time to crushed ice. This solution was made C37.2 , H 3.2. alkaline with 2JV-ammoniawhil e the temperature was kept below 19 R.H. Mizzoni and P. E.Spoerri, J. Amer. Chem. Soc. 76,220 1 5°C.Th ealkalin e aqueoussolutio n wasextracte d withchloroform . (1954). After drying over anhydrous magnesium sulfate, the chloroform 20 T. Kuraishi,Chem .Pharm .Bull .4,13 7(1956) . was removed and 1.1 g of crude 19remained . 21 R.Schonbeck und E.Kloimstein, Monatsh. Chem 99, 15 (1968). This compound was very unstable and was used immediately for 22 Af. Yanai and T. Kinoshita, Yakugaku Zasshi 8$ 344(1965) . itsconversio n to4-amino-3-bromopyridazin e(2) .Th ereactio nan d 23 M. Yanai and T. Kinoshita, Yakugaku Zasshi 82, 857 (1962). the purification was carried out according to the same procedure 24 R.G. Jonesan d C. Ainsworth, J. Amer. Chem. Soc. 77, 1538 as given in section lb. The yield of product obtained was 280mg . (1955)- Recueil, Journal ofthe Royal Netherlands ChemicalSociety, 93/8, august 1974 30

2. Reactionso fth ehajogenopyridazine s1 ,2,4, 5 and1 4wit h potas­ 3. 3-Amino-5-(methylamino)pyridazine (16) sium amide • liquid ammonia To 117m g (0.74 mmoles)o f IS in 4.5 ml of ethanol and 4.5 ml of aceticaci d wereadde d 300m go fsodiu m acetate.Thi ssolutio n was a) 4-Amino-3-chloropyridazine(1 ) reduced by hydrogen using 25 mg of palladium-on-charcoal as 130m g( 1mmole )o f 1wer e treated during 11h with a solution of catalyst. To complete the reduction, after 1 h a second amount of potassium amide in SO ml of liquid ammonia ([KNH2] = 0.12) 25m go f catalyst wasadded . When the hydrogen-taken up ceased, at - 33°C.Th e reaction wasterminate d by addition of ammonium the catalyst was filtered off and the solution was evaporated to chloride and the ammonia was evaporated. The residue was ex­ dryness. Extraction of the residue afforded 57m go f 16 (62%),m.p . tracted with ethyl acetate, dried over anhydrous magnesium 205-206°C. Analysis: C5HgN4 (124.15) calc. C 48.37, H 6.50; sulfate and the solvent was removed. Yield: 47 mg of 4-cyano- found C 48.3, H 6.7. pyrazole(3 )(50%) .Afte r sublimation m.p.89-90° C(lit ." 91-92°C). 4. 4-Amino-5-bromopyridazine(22 ) b) 4-Amino-3-bromopyridazine(2 ) To a solution of 475 mg (5 mmoles) of 4-aminopyridazine20 in 15 mlo f47-50 % hydrobromic acid wereadde d slowly 7m lo f15 % 174 mg (1 mmole) of 2 were treated with potassium amide as hydrogen peroxide at 80°C. After 1^ h at 80°C, the solution was described insectio n 2a,excep t that thereactio n timewa s6 h instea d made alkaline with sodium hydrogen sulfite, followed by dilute of1 1 h.Yield :6 2m go f4-cyanopyrazol e(3 )(67%) .Afte r sublimation, ammonia. This mixture was extracted with ethyl acetate. The m.p.89-90° C(li t " 91-92°C). solvent wasremoved , yielding 330m go f2 2(38%) ,m.p .134-136° C (from benzene); m.p. picrate 216-217°C. Analysis: C10H7BrN6O7 c) 4-Amino-3j6-dichloropyridazine(4 ) (403.12)calc .C 29.79,H 1.75; found C 30.5,H 2.1. 164m g (1 mmole) of 4 were treated during 18h at -33°C with a 5. Table Chemicalshifts of the ring protons (expressedin S)of some solutiono fpotassiu mamid ei n7 5m lo fliqui dammoni a([KNH 2] = di- andtri-substituted pyridazines. 0.16)a t —33°C .Afte r working upa susua l theresidu ewa sextracte d five times with 100 ml of boiling ether. The ether was distilled off in vacuo. Yield 26 mg of 3-(cyanomethyl)-l,2,4-triazole (6)(24%) , Pyridazine derivative H(3) H(4) H(5) H(6) J in cps m.p. 137-139°C (from toluene). This melting point was not de­ 4-CI-3-one<17y 7.66(d) 7.84(d) •/»..- « pressed when mixed with an authentic specimen of 6 (section lg). b 3,4-di-Cl (18) 7.69(d) 9.09(d) K* - 5.1 Also the IR and PMR spectra were identical with those of com­ 4-NH,-3-Cl(ir 6.97(d) 8.60(d) '... » 5.5 pound 6. 4-NH2-3-Br (If 7.00(d) 8.60(d) J,., - 5.5 4-NH -5-Br(22r Analysis: C4H4N4 (108.10); calc. C 44.44, H 3.73; found: C 44.7, 2 8.79» 8.84* H 3.5. 4-NH2-5-Cr' 8.65* 8.73* ** 4-Cl-3.6-dione' 7.09 4-a-3,6sU-Br(2t)b 7.84 b d) 4-Amino-3,6-dibromopyridazine(5 ) 3,4,6-tri-Br (20) 8.00 4-NH2-3,6-di-Br[Sf 7.09 253 mg (1 mmole) of 5 were treated with potassium amide as de­ 3,4,6-lri-a1 8.18 scribedi nsectio n2c ,excep t that thepotassiu mamid econcentratio n 4-NH2-3,6-di-Cl W 6.94 was 0.12 instead of 0.16, and that the reaction time was only 5 h. 3,6-di-CI-4-NHCHj(14) - 6.81 Yield 63 mg of 3-(cyanomethyl)-l,2,4-triazole (6)(60%) ,m.p . 137- 3-a-4-NHCH,-6-NH2 (15C 597 139°C (from toluene). 3-NH2-5-NHCHj(16T S.8S (d) 7.97 (d) ./..«-26

* Solvent acetone-d6. e) 3fi-Dichioro-4'(methylamino) pyridazine (14 ) * Solvent CDClj. * Solvent D20. 178m g( 1mmole )o f 14wer e treated during 28h at —33° Cwit h a * Tbe assignment of the proton chemical shift was based on the reasonable assumption solutiono fpotassiu mamid ei n2 0m lo fliqui dammonia .([KNH 2] = that the H(3)-atom,bein g adjacent to the aminogroup ,appear s ata higherfiel d than the 0.65)a t —33° CAfte rterminatio no fth ereactio nan devaporatio no f H(6)-atom. the ammonia, the residue was extracted extensively with 50 ml of *• In the PMR spectrum of4-NH 2-5-Cl-pyridazine recorded ona Varian XL-100(acetone - dry ether in a Soxhlet apparatus. The ether was removed in vacuo. d6Xw eobserve d a small coupling constant:J 36 = 0.65cps . Yield 100m g of 6-amino-3-chloro-4-(methylamino)pyridazine (15) (63%), m.p. 190-191°C (from benzene). Analysis: C5H7C1N4 (158.60); calc. C 37.86, H 4.45; found C 37.7, H 4.5. PMR data: Acknowledgement 8H(5) = 5.97 ppm (s), 8N-CH3 = 2.85 ppm (d,J = 5 cps), 6NH2 and 8NH = 5.5 ppm (broad). We are indebted to Drs. C.A. Landheer for mass spectros­ copic data, to Mr. W. P. Combe for carrying out the micro­ analyses, to Mr. A. van Veldhuizen for measuring PMR and IR spectra and to Mr. N. Rensen for taking part insom eo f the S. Trofimenko, J.Org .Chem . 28, 2755 (1963). experiments. 31 Discussion

Asalread ypointe dou ti nth eintroduction ,a tth estar to fou rwor kconclu ­ siveevidenc efo rth eintermediac yo fa 4,5-didehydropyridazin eha sneve rbee n 12 presented '. I nthi sthesi sexperiment sar edescribe dprovin gunequivocall y thetransien texistenc eo fa 4,5-didehydropyridazine .Thi sevidenc ei sbase d onth eresult so ftw oinvestigations : a.Aminatio no f4-X-3-(methoxymethyl)-6-methylpyridazin e (X=Cl,Br,I)give s anisomeri cmixtur eo f4 -an d5-amino-3-(methoxymethyl)-6-methylpyridazin e in arati oo f 1: 5 ,whic hrati oi sfoun dt ob e independent ofth enatur eo fth e halogenatom .Thi sca nonl yb eexplaine di fa 3-(methoxymethyl)-6-methyl-4,5 - didehydropyridazine (1)occur sa sintermediate .Th efavoure dadditio no fth e 3 amideio nt oC(5 )i n (1)i sdu et oth estronge relectron-attractin g character 4 ofth emethoxymethy lgrou pa scompare dt otha to fth emethy lgrou p (PaperI ). 13 b.Aminatio no f4-chloro-3,6-diphenylpyridazine-5 - Cgive stw oproduct s 13 i.e.4-amino-3,6-diphenylpyridazine-(4,5) - Can dimino-4,4'-bis(3,6-dipheny1 - 13 13 pyridazine^-(4,4')(5,5') - C.Usin gquantitativ e C-NMRspectroscopy ,th e distributiono fth e C-labelove rth eposition s4 an d5 i nth e4-amin ocompoun d andove rth eposition s 4,4' and 5,5' inth ecouple dproduc twa scalculated . Sincei nbot hcompound sa nexac t 1: 1 distributio n overthes eposition swa s foundth eresul twa sconsidere da ssoun devidenc efo rth eexistenc eo fa 4,5 - didehydropyridazine i.e.3,6-diphenyl-4,5-didehydropyridazin e (2)(Paper II). CeH5 C6H5 Cfrt

CH2OCH3 C6H5

C H H5C6 6 5 C6H5 C6H5 CeHs

1 2 J

FIGURE 1 7 Whenou rwor kwa scompleted ,i twa sreporte d thatth etherma lfragmentatio n reactiono f4,5,8-triphenylpyridazin o |4,5-dJ triazineals olead st oth einter ­ mediary 3,6-diphenyl-4,5-didehydropyridazine (2).Thi swa sprove nb yinter ­ ceptiono fthi sintermediat ewit htetracyclon ean dwit hfura nyieldin g respectively,afte rCO-evolution ,1,4,5,6,7,8-hexaphenylphthalazin e (3)an d 5,8-epoxy-5,8-dihydro-l,4-diphenylphthalazine(4) . Fromthes eresult si ti seviden ttha tth e4-chloropyridazine sreac ttoward s potassiumamid ei nliqui dammoni aquit esimila rt oth e3 -an d4-chloropyridines . 32

Thislead st oth econclusio ntha ti n4-chloropyridazine sth edehydrohalogena - tioni sthu sstrongl yfavoure dabov eadditio nreactions ,whic har echaracteristi c forth e4-chloropyrimidine san dth e2-chloropyrazines .Th ehig hacidit yo f position4(5 )o fth epyridazin erin g inccompariso nwit htha to fth epositio n 3(6)i si nagreemen twit hthi sconclusion .

9 Thestud yo fth ea-adduc tformatio n betweenpyridazin ederivative san d Weaknucleophile s (liquidammoni aan dmethanoli cammonia )ha sindicate dtha t thepresenc eo fa nitr ogrou pi nth epyridazin erin gi sa necessar y structural requirement. Datao nth epositio no fadduc tformatio nwer efurnishe db yusin g H-NMR (PaperIII ) and C-NMRspectroscop y (PaperIV ) .Fro mthes edat ai ti s cleartha tth eattac ko fammoni atake splac ea tC(5) ,se estructur e (5). This isi nagreemen twit hth epositio no fadduc tformatio nbetwee nth eparen t 12 compoundpyridazin ean dth estron gnucleophil epotassiu mamid e .Th eassign ­ mentsar eessentiall ybase do nth eimportan tupfiel d shifto fth eH(5 )proto n absorption (A6^ 4ppm )an do fth eC(5 )carbo nabsorptio n (A5 X80 ppm). Bot h 2 3 shiftsar edu et oth echang eo fhybridisatio no fC(5 )(s p-* •s p) whe nth eadduc t isformed .Base do nthi sspectroscopi cmetho d4-nitropyridazin e 1-oxidewa s observedt ogiv ea nadduct ,unlik epyridazin ean dpyridazin e 1-oxide.Apparent ­ lyth epyridazin erin gneed sth ehighl yelectron-attractin g nitrogrou pt omak e therin gsusceptibl efo rattac kwit hwea knucleophile s .Hydroge nbridg e formationbetwee nth enitr ogrou pa tC(4 )an dth eincomin gamin ogrou pi s certainlyon eo fth eimportan tfactor swhic hdetermine sth epositio no fattac k ofth enucleophile . Furthermorei twa sprove ntha tadditio na tC(5 )als ooccur swhe n6-chloro - 3-methoxy-4-nitropyridazine 1-oxidei sdissolve d inliqui dammoni ao ri nmetha ­ nolicammonia .A surprisin gfac ti sobserve dwhe nthes esolution swer ekep tfo r 1h a t0 .A nucleophili cdisplacemen toccur si nwhic hno tth enitr ogrou pi s replaced,a si susuall yobserve di nreaction so fthi scompoun dwit hothe rnucleo ­ philes (methoxy,mercapt oo razid o ion),bu tth emethox ygroup ,yieldin gth e newcompoun d 3-amino-6-chloro-4-nitropyridazine 1-oxide.Fro mth espectroscopi c dataan dth estructur eo fth eaminatio nproduc ti twa ssuggeste dtha tthi s amino-demethoxylationmus ttak eplac e in thea-adduc t (6)vi ath ediadduc t(7) . Exampleso fthi styp eo fnucleophili c substitutionhav eneve rbee nobserve d before.Thi sne wmechanis mcertainl ydeserve sgrea tattentio nan dneed st ob e investigatedi nmor edetai lt odetermin eit spotentiall ybroa d scopean dit s generalapplicabilit y inhighl yactivate dsystems . 1 13 Applicationo f H-an d C-NMRspectroscop y furnishesth eevidenc eo fth e presenceo fth ea-adduc t (8)i na solutio no f 3-amino-6-chloro-4-nitropyridazine 33

1-oxidei nbot hliqui dammoni aan di nmethanoli cammonia .Thi sadduc tslowl y convertsint o6-chloro-3,5-diamino-4-nitropyridazin e 1-oxidean dint o6-chloro - 3,5-diamino-4-nitropyridazine. Itwa sobserve db yth esam etechnique,however , that6-chloro-3-hydroxy-4-nitropyridazin e 1-oxidedoe sno tgiv ea c-adduct , butundergoe sdeprotonatio no fit shydroxy lgroup ,yieldin gth eanio n (9)whic h providesth enucleu swit ha nelectro ndensit ystrongl yinhibitin gth eaddition s ofnucleophile s (PapersII Ian dIV ) ' NOj NO2 Ncf

H2Nl ^] H2Nl ^1 HjT\ ]SH2

0© 00 0© 5 6 7

N02

NH2 H2NT ^J

8 FIGURE 2 Finallyth eoccurrenc eo ftw one wrin gcontraction s ofpyridazine swa s observedi nreaction swit hth eamid eion . a.Treatmen to f4-amino-3-bromo(chloro)pyridazin e bypotassiu mamid eyield s 4-cyanopyrazole.Th emechanis mo fthi srin gcontractio ni ssomewha tsimila rt o theon ealread ygive ni nth eintroductio nfo rth econversio no f 3-amino-2-bromo- 17 pyridineint o3-cyanopyrrol e ando f5-amino-4-chloro-2-phenylpyrimidin e into 18 4(5)-cyano-2-phenylimidazole b. Theconversio no f4-amino-3,6-dibromo(chloro)pyridazin e into3-(cyano - methyl)-l,2,4-triazole.Thi srin gcontractio ni snove lan dunprecedente dan d hasth einterestin gfeatur etha ti nth erin gcontractio nproduc tth enumbe ro f ringnitroge natoms ,i ncompariso nwit htha to fth estartin gsubstance ,ha s increased.Thi si si ncontras tt oal lth epreviousl yreporte dexample so frin g contractions,i nwhic hth enumbe ro frin gnitroge natom si nstartin gsubstanc e andrin gcontractio nproduc ti sth esame . Themechanism so fbot hrin gcontraction shav ebee ndiscusse dextensivel yi n 19 paperV .I twa sprove n thata substituen twit h two acid-labilehydroge natom s (NH„group )i sa necessar y structuralrequiremen tfo rth eoccurrenc eo fthes e ringcontractions ;n orin gcontractio nwa sobserve dwhe na methylamin ogrou p ispresen tinstea do fth eamin ogroup .I ntha tcas eonl ywit ha nextremel yhig h 34

concentrationo fpotassiu mamide ,a substitutio no fth echlor oato ma tC(6 ) slowlyoccurred .Thi sunusuall ylo wreactivit yo fth echlor oato ma tpositio n 20-22 3(6)toward spotassiu mamid ei sobserve d inman y 3-chloro-6-X-pyridazines

(X=H,CI ,OCH, ,C..H C)an di squit esurprisin gcompare dt oth ehig hreactivit y 23-25 of2-chloropyridine ,4-chloropyrimidin ean d2-chloropyrazin e .A reaso n forthi sdeviatin gbehaviou r isno tquit eclea ran dcertainl yneed smor estudy . 2 Apossibl eexplanatio nma yb etha tth elone-pai rnitroge ns p-orbital sinter - 32 6 act,leadin gt oa decrease dreactivit ya tpositio n 3(6) ' .Alternativel yi t cannotb eexclude dtha trin gdeprotonatio nb ypotassiu mamid eoccurs ,yieldin g ananio nwhic hmake sa nucleophili cattac kunfavourable .However ,n oproo fo f 1 13 thispossibilit ycoul db eobtaine db y H-NMRo r C-NMRmeasurements .

REFERENCES

1.a )Th.Kauffman nan dA.Risberg ,Tetrahedro nLett .1963 ,1459 ; b)Th.Kauffman ne tal. ,ibid .1964 ,3563 . 2.a )Y.Mak ian dM.Takaya ,Chem.Pharm.Bull.o fJapa n20 ,74 7 (1972); b)Y.Maki ,G.P.Beardsley ,Tetrahedro nLett .1971 ,1507 . 3.R.W.Hoffman n "Dehydrobenzenean dcycloalkynes" ,Academi cPress ,Ne wYor k (1967). 4.D.E.Klinge ,H.C.va nde rPla san dA.Koudijs ,Recl.Trav.Chim.Pays-Ba s93 ,20 1 (1974). 5.J.D.Roberts ,H.E.Simmons ,L.A.Carlsmit han dC.W.Vaughan ,J.Amer.Chem.Soc . 75,329 0 (1953). 6.D.E.Kling e andH.C.va nde rPlas ,Recl.Trav.Chim.Pays-Ba s95 ,3 4 (1976). 7.Th.L.Gilchrist ,G.E.Gyme ran dCh.W.Rees ,J.Chem.Soc.Perki nI 1975 ,1747 . 8.J.A.Zoltewicz ,G.Grah ean dC.L.Smith ,J.Amer.Chem.Soc . 91_,550 1 (1969). 9.M.J.Strauss ,Chem.Rev .7£ ,66 2 (1970). 10.D.E.Kling e andH.C.va nde rPlas ,Recl.Trav.Chim.Pays-Ba s 94_,23 3 (1975). 11.D.E.Klinge ,H.C.va nde rPla san dA.va nVeldhuizen ,Recl.Trav.Chim.Pays-Ba s 95,2 1 (1976). 12.J.A.Zoltewicz ,L.S.Helmick ,J.Amer.Chem.Soc .94 ,68 2 (1972). 13.G.Illuminat i"Advance si nHeterocycli cChemistry" ,Ed .A.R.Katritzky ,Vol.3 , AcademicPress ,Ne wYor k (1964). 14.C.A.Fyfe ,Tetrahedro nLett .1968 ,659 . 15.P.Bemporad ,G.Illuminat i andF.Stegel ,J.Amer.Chem.Soc . 91_,674 2 (1969). 16.H.Iget aan dT.Tsuchiya ,J.Synth.Org.Chem.Japa n31_ ,86 7 (1973). 17.H.J.de nHerto ge tal. ,Tetrahedro nLett .1966 ,4325 . 18.H.W.va nMeetere nan dH.C.va nde rPlas ,Tetrahedro nLett .1966 ,4517 . 35

19.D.E.Klinge ,H.C.va nde rPlas ,G.Geurtse n andA.Koudijs ,Recl.Trav.Chim . Pays-Bas93_ ,23 6 (1974). 20.D.E.Klinge ,Unpublishe dresults . 21.E.A.Steck ,J.Org.Chem .24_ ,159 7 (1959). 22.W.E.Taft ,J.Adam s andW.V.Curran ,J.Org.Chem . 26_,60 5 (1961). 23.H.C.va nde rPla s "RingTransformation so fHeterocycles" ,Vol. 1an dII , AcademicPress ,Ne wYor k (1973). 24.H.C.va nde rPla s "Lecturesi nHeterocycli cChemistry" ,Ed .R.N.Castl ean d E.F.Elslager,Vol.1 1 (1974). 25.H.C.va nde rPla san dJ.W.Stree f "Aromatican dHeteroaromati cChemistry" , Vol.IV (1976),Th eChemica lSociety ,London . 26.S.F.Mason ,Chem.Soc.Specia lPubl .No.1 2 (1958). 36 Samenvatting

Indi tproefschrif ti see norienteren donderzoe kbeschreve nnaa rhe tche - mischgedra gva nhalogeen-pyridazine ne nhalogeen-pyridazine-N-oxide nme tka - liumamidei nvloeibar eammoniak ,me tmethanolisch eammonia ke nme tvloeibar e ammoniak.Di tonderzoe khang tnau wsame nme tuitvoerig estudie sove rd ereac - tiviteitva npyridinen ,pyrimidine ne npyrazinen ,di ed eafgelope njare ni n hetlaboratoriu mvoo rOrganisch eChemi et eWageninge nzij nverricht . Deresultate nva nhe tdoo ron suitgevoerd eonderzoe k zijni nee nvijfta lpu - blikatiesverwerk te nlate nzic hal svolg tsamenvatten :

Publikatie I:4-X-3-(methoxymethyl)-6-methylpyridazin e (X=C1,Br ,I )geef t naaminerin gee nmengse lva n4 -an d5-amino-3-(methoxymethyl) - 6-methylpyridazine (verhouding 1: 5) ; heti sgebleke nda tdez e verhoudingonafhankelij k isva nd eaar dva nhe thalogee natoom . Daaromword tal sintermediai r indez ereacti ehe t 3-(methoxy- methy1)-6-methyl-4,5-didehydropyridazineaangenomen .

Publikatie II:D ereacti eva n4-chloor-3,6-difenylpyridazin e metkaliumamid e invloeibar eammonia klever ttwe eprodukte nop ,namelij k4 - amino-3,6-difenylpyridazine enimino-4,4'-bis(3,6-difenylpyrida - zine).Uitgaand eva n4-chloor-3,6-difenylpyridazine - \5- CJ 13 werd,doo rmidde lva nquantitatiev e C-NMRspectrometrie ,va n beideaminoverbindinge naangetoon dda tzi jgevorm dzij nvi ahe t symmetrischintermediai r3,6-difenyl-4,5-didehydropyridazine .

Deresultate nvermel di nI e nI Igeve nvoo rhe teers tzee rgefundeerd eaan - wijzingenvoo rhe tbestaa nva nee nintermediai r 3,6-digesubstitueerd 4,5-dide­ hydropyridazine inreactie sva n3,6-digesubstitueerd e 4-halogeenpyridazinen metkaliumamid ei nvloeibar eammoniak .

PublikatieIII :I nd ereacti eva n6-chloor-3-methoxy-4-nitropyridazin e 1-oxide metmethanolisch eammonia ke nme tvloeibar eammonia ktreed t amino-demethoxyleringop .Me tbehul pva n H-NMRmetinge nko n wordenaangetoon dda tdez esubstituti eo pee nzee rongewon e wijzeverloopt ,n.l . in heto pC(5 )gevormd eMeisenheime rcom ­ plex. 37

PublikatieIV :Vei nverschillend e3-mono -e n3,6-digesubstitueerd epyridazinen , 3-,4 -e n6-mono -e n3,6-digesubstitueerd epyridazin e1-oxide n en4-nitro-3,6-digesubstitueerd epyridazin e1-oxide nzij nd e 13 13 C-absorptiesbepaald .Hierui twerde nd e C-substituenteffee - ten vansubstituente ni nd e3- ,4 -e n6-positi eva nd epyrida ­ zinerin ge ndi eva nd eN-oxid efuncti eberekend .Doo rtoepas - singva ndez esubstituen teffecte nkonde nd e C-NMRspectr a vand ea-adducte nva n4-nitro-3,6-digesubstitueerd epyridazin e 1-oxidenme tvloeibar eammonia kworde ngeinterpreteerd . 1 13 Uitd eresultate nva nd e H-NMRe n C-NMRmetinge nvermel di nII Ie nI V konzee rduidelij kworde nvastgestel dda t3-methoxy-4-nitropyridazin e1-oxide n eennucleofiel esubstituti eo pC(3 )kunne nondergaa nvolgen see nmechanisme , datto tn uto enie teerde ri nd eliteratuu ri sbeschreven .

PublikatieV :Bi jd ebehandelin gva n4-amino-3-X-pyridazin e (X=C1,Br )me t kaliumamidei nvloeibar eammonia kword t4-cyaanpyrazoo lgevormd . Onderdezelfd ereacti eomstandighede nondergaa t4-amino-3,6-di - X-pyridazine (X=C1,Br )ee nringcontracti eto t3-(cyaanmethyl) - 1,2,4-triazool.

Dei nV beschreve nringcontracti eto t4-cyaanpyrazoo lka nworde nbeschouw d alsee nnieu wvoorbeel dva nee nreactie ,di ereed si nander eringsysteme nbe ­ schrevenis .D ei nV beschreve nringcontracti eto t3-(cyaanmethyl)-l,2,4 - triazooli sechte rhe teerst evoorbeel dva nee ndoo rkaliumamid egekatalyseer - deringcontractie ,waarbi jhe tgevormd evijfringsystee m meev stikstofatomenbe - vatda nhe toorspronkelijk ezesringsysteem . 39

Bijhe tverschijne nva ndi tproefschrif tgaa tmij ndan kui tnaa rmij npromoto r Prof.Dr.H.C.vande rPla svoo rzij nstimulerend einvloe de nenthousiast ebege - leiding; naarmevrou wM.Snel le nd ehee rA.Schuchhar dvoo rhe tverzorge nva nhe tmanus ­ cript; ennaa rall elede nva nd evakgroe pOrganisch eChemi evoo rd eprettig esamen - werking. 40 Curriculum vitae

Nahe tbehale nva nhe tdiplom aHBS- Bt eUtrech ti n1961 ,he bi kd emilitai - redienstplich tvervuld .I n196 3bego ni kme td escheikund estudi eaa nd eRijks - universiteitt eUtrecht .He tkandidaatsexame n (letterg )wer dafgeleg di napri l 1968;he tdoctoraalexamen ,onde rleidin gva nProf.Dr.J.F.Aren s (hoofdvak:orga- nischechemie )e nProf.Dr.Ir.P.M.Heertje s (bijvakrchemischetechnologie ,Tech - nischeHogeschoo lDelft )i njun i1970 . VanSeptembe r 1970to taugustu s 1975be ni kal swetenschappelij kmedewerke r verbondengewees taa nhe tLaboratoriu mvoo rOrganisch eChemi eva nd eLandbouw - hogeschoolt eWageningen ,waa ronde rleidin gva nProf.Dr.H.C.va nde rPla she t onderzoekvoo rdi tproefschrif twer dverricht . Sindsaugustu s 1975be ni kal sdocen tschei -e nnatuurkund everbonde naa n de "Opleidingvoo rmiddelbaa re nhoge rlaboratoriumpersonee lSTOVA "t e Wageningen.