The Synthesis and Reactions of Some Bicyclic Nitrogen Heterocycles

TEE ST-I{EI{ESIS Al{D RTACTIoNS 0X' Sol[E BrcTcLIc'

I

NITROGnI HETMOCTCI,ES

A THESIS - PRESB¡'TED FOR TIIE DæREE OF

DOCTOR 0F PHIIrOS0PHf

1n the

UNIV .SIrÏ 0F AÐE AIDD

by

D.3. PAUIr¡ B.So.

Departnent of Organio ChenistrY

Typewritt€h llloo

, 1966 -VI^.z /^L J l.lqJ /4r^lvz/W

LAr*¿/ûJ.l- .+rc -+-^-etÅ+¿ /'(úÆ¿/ ÅÆ'f^!â

Cu^ P¿^o/,a/ec) J'tryMM 4*¿,n;o' THE SYNTHESTS AND REACTIONS OF SOMX BTCYCTIC

NITRoGIÎ{ HE'ImoCYCLE coNTu{rs

SUMMARÏ )

STATU[ST[

ACKNOÏILÐGEtr\IB{T

TNERODUCTION 1

RESUI,TS AI{D DISCUSSION

PTRIDOI CHAPTM 1 S ST]'ITIIESIS AI'ID PHTSIçAIJ PROPMTTES OA 2' 3-4]-

PTTTDAzTNE Al{D rrnrm[ 3'4-g]PrRrDAzrNE çr RemovaÌ of subgtituent groups 24 a{. (\¿" Preparat ion of p¡mitLlnæg-d icarboxalcl'ehyd'ee 43 ç 49 e'l PÌ¡Yeical ProPerties

t PTIIDOPT-R'IDAZINES ì CHAPIffi 2¡ REACI]ONS OF I i I I I lheoret ioal consideratlons 74 I i of p¡"rid'o[ Zr ¡:È]p¡æld'azine 79 Attempted nitration I Bromination 81 i i I Amination 88 i

¡ Reaction of p¡rricLo[ Z, ¡-g] pyrid-azine wlth ]¡¡rochlorous I I acld 9o I 0xid.ation 96 I N-OxÍtlation 101 cIIAP[trR ]: REACTToNS 0F pnIDo[ z, 3-¿]prnrDAzINE ÐBIV\AIIVES

5-P¡rrido[ 2, 3:È] p¡æid.azlnone ancl 8-p¡rridof 21 3-g] - p¡æÍd.azinone 113

5- and. 8-chlorop¡r¡id.o[ 2, 3-g] pqrid.azLne 127 P¡rrtd,o-g-t ri azol o[ 4 r 3€] pfryi d.azÍnes 133

CIIAPIB {r N.M.R. ANÐ u.v. spæTRA oa pmrDopIRrDAzrND

DERIVATTVES

N.tû.f. .''t': s¡lectra 139

llltravlolet speotra 141

FJ(PMIUUMAÍJ

Gene¡a1 153 ïÍork clescribed in chapter 1 154 Work descrlbecL in cha¡rter 2 177 tJfork d.esorÍbed. 1n chapter 3 æo

ÌVork d.escribed. fn chapter { 225

RU'MBTCES 228 SUMMARÏ

pfri¿ol 2, 3-g] pyrid.azine and pyrid.o[ 314-g] p¡pid.azine have been prepared. for the first time either by removal of chloror û¡ercapto or

Ïqrd.razino groups from substituted. d.erivatives or Uy conaánsation of the requisite p¡rrid-ine-g-d.icarboxald.eÌ¡yd.es with byct¡azine lSrd'rate. The nechanisms of the condensation of heterocyclic o-d.initriles with hydrazíne and of the dehydrazinatÍon of the resulting d.ihyd'razino , compounds have been stud-ied- and d'iscueÐêd'.

The basic strengths and- ultravÍolet and. infrared. spectra of the pyrid.op¡rrj-d.azines have been d.etermined. and correlated. with those of similar heterocycles. The n.rrorr spectra were analysed. in d.etail

an¿ long-range spin couplings were detected. and assigned.. By comparison of the chemical shifts with those of naphthalener absolute l(-electron d.ensitios of the parent p¡mid.op¡æid.azines were obtained.. Potentiometric titrations and ultraviolet spectra ind.lcated. that the pyridop¡æid.azines

and. their cations dld. not undergo covalent hyd,ratlon to any significant

d.egree. Attempted nitration of p¡rrid.oler¡-g]p¡æid.azine gave only an

oxidation prod.uct and. attempted brominations in acÍd'io med.la'a1so failed. Sromination to give tbe l-bromo tl.erivative was achieved. by d.ecornposition of the ilperbromid.eil by various methods. Amination of pyri¿of213-g]pyridazinê gave a monoanìino derivatÍve which was presumed. to be the 2-isomer. Reaction of an aqueous solution of pyri¿olZr¡-g]- pyrid.azine with chlorine produced. p¡rrid-o-2¡3-d'iald'ehyd'e. Qxid'ation of the pyrid.opyridazines by potassiurn permanganatê was stud-ied' over a range of reaction times in both acÍd.ic and. aLkaline media' N-oxid.ation of p¡rrido[ 213-g]pyridazine proceeded. best in peracetic prepare acid- to give a mixture of the 6- and. ?-oxid.es. Attempts to the 1-oxide by an alternative route \ffere unsucceseful' The results

and. signifj-cance of the above reactions have been d-iscussed' in relatlon'to those of similar heterocycles and. the d.irection of attack by various reagents rational-ised.. æ-EIectron d.ensitiest bond lengths¡

n-bond. orders and. free valence numbers of the pyridopyrfdazinss were

d_etermined and. theoretical predictions frorn these calculations were

in agreement with experimental results' to give a 5rB-Dich-1oropyrÍdol Z,¡-¿]p¡rrid-azine rvas hy¿rolysed- mixture of chlorop¡rrid.o[ 213-g]pyrid.azinones which were separated and' methods' dehaJ-ogenated. to the pyri¿ol er¡-g]p¡r-rid.azinones by several

unambiguous syntheses of the latter compounds were achieved' via picol 2-hydroxymethyl nicot i nic acitl ]act one and 3-hyd'roxymet hyI inic acid. Iactone. Nicotinic acid' 3-ald-ehyd'e r¡ras synthesised for the first time. The pyrúd.ol 213-g]pyridazinones r/vere converted into the chl'oro

compounds which were also prepared' from the chloro-hydrazÍno d'erivatives' the substitution reactions of the !- and' B-obl-oro cornpound's with

v,rater, ammonia and. hydrazine were stud'ied'. fhe 5- an¿ B-hyarazino derivatives weTe cyclised with formic or acetic acid-s to new heterocycles which were used to determine the constitution of the mixtures obtained" from slmíIar cyclisations of the 5rB-d.ihyarazino

compound.. Dehytlrazination has been extensively empl.oyed. in this work and. mercurlc oxide has been sbown to be the reagent of choice for this process. Raney nickel has been shown to be a general reagent i I i for the cleavage of N-N bonds of hydrazino derivativês. I The n.m.t. ârd. ul.traviolet speetra of nar¡y p¡rrid-op¡rrld'azine I

i tabulated, and. correlations I d.erivatlves have been analysed. anô ! I t I series have been made. Tbe existencê of various tautonelrio t within the I I has been postulatetl. from ! forns of 5t8-p¡rridol 2r3-g]p¡rridazined.ione t,

I Ì spectra determíned. in clifferent Êo1vents. !

l

T

I

1 i , t, i

É t I ! I T

r ) f tÈ I :'I Ë I t I t I t f ) i È. t" i i ; I I I ( i 3TÀTBIBIÍT

fhe work d.escribeci in this thesis incorporates no naterial prevlouely eubmltted for a degree in any Universlty¡ ancl to the best of ny knowlecLge ancl belief¡ contains no ¡naterLal prevlously published or written by another pergon exoept where due referenee in nacle in the textr ACicüoVif., ÐGTilIUüIS

I am indebtecl to Ðr. H.J. Rod'da for his guid-ance and' for constructive d.fscussions'tlr:ring his, supervision of this study. I also wish to express my gratituôe to DT. Í0.M. Spotswood- for d.etermining nany of the n'm'r' spectra¡ assistance in their interpretation and- for d.iscusslon of the physical aspects of this project. I an also ind.ebtetl. to h¡. R.A. Jones for performÍng the potentiometrlc titrations for ns determinatlons¡ Mr. B. Roney for zç-electron density caloulations ancl to Dr. !Í.L.F. Armarego for an authentlo specinen of Lnethylp¡pido-

I z, ¡-g] p¡rrÍd-azÍne. This research wag carried out d.uling the ten¡.¡re of a

cornnonwealth Post-Gra.duate Besearoh Awartl for whioh I am .most

grat eful. àt ol Hl E{l ()l Þl Êl ol Frl e.l zl t-r I . ._ _ . . -* .,"_Ì.:_.- , .'. I i ! I i \ '..; I

INTRODUCTÏON

It has recently been estÍmated- that over a third- of the i

-1 knov¡n organic compound.s are heterocyclÍc.' Although an immense i

i

number of such ring structures are possible, with fe,,v exceptions i

I

most of the simpler mono- and- bicyclic systems Ìrave been thoroughly i

I The pyrid.opyrid.azine series¡ has¡ however¡ received investigated. i

ì scant attention and- this fact has prompted- the present stud-y. A i i

knowled.ge of the fundamental chemistry of d.iazine ring systems in general i i

is therefore required as a basis for such an investigation. i

I i (u) DrÄzrI{ES : i

i The parent members of the three possible monocyclic d-iazÍnes i i (¡ are p¡rrimid.ine, (l ) , p¡trazine¡ (z) an¿ pyrid-azine, ) . irlthough i t these compounds have not been as extensively stud.ied. as p¡rrid.ine, several reviews of their chemistry have appeared in recent y"u"".2-4 llumerous important natural products such as purines, pterid.ines and nucleic acid.s are derived from pyrimid-ine whioh is the best known

member of the group. fhe 1 22- and' 1 ¡ -ùi-azines are not wid-ely d,istributed. in nature, however, and these ring systems have accord.Íngly received- less attention. X-Ray crystallographic determinations of bond. tengths5-9

ind-icate that the d.iazÍnes are aromatic and. the electronic structures

of these compounds must therefore closely resemble that of pyríd.ine.

Valence bond. theory supports these conclusions and. the cu,nonical forms -2- for pyrid.azínø are shown in structyres (3a-3f). As the nitrogen atoms are more el-ectronegative than carbon the ionic structr'res should- contribute significantly to the resulting hybrid'. ÐipoIe moments of 1.9 D for pyrid-azLne aað' 2.4Ð for pyrimid-ine confirm this theory.lo-14 pyrazine, hovrever, possesses a symmetrical mofecule and confirmatory evidence from d,ipole monent d.ata is therefore preclud.ed-. [lhe Tesonance energy of, both pyrimid.ine and. p¡rrazine has been cäf.cul-ated- to be 33 k'cals/mole but for pyrj-d'azine the vaÌue that is only ZZ k,cal=/mo1e.10 Theoretical consid-erations ind.icate the two Kelculé structures of pyridazine¡ which should make the greatest contribution to the resonance hybrid-, are not equivalent. structt're (ja) tas been predicted. to be Less stable than (:l¡,10r15 ¡,rtr experimental attempts to relate this fact to the d-ifferences in resonance energies of the diazines have faiI"¿'16 The experimentally determined- values of the sesonance energies in fact bear little 6 resemblanoe to those calcuLated. theoretical-Iy.1

N

() il |'t

fi) (2) (3a) (3b)

N N N T I + N N 't 't (3c) (3d) (3e) (3f) -3-

Several v¡orkers have determined n-electron d.ensity d-istributiond for the d.iazires.1 4'17-19 Thu"" calculations must be regarded_ as approximations as the results depend on the parameters chosen and the assumptions that are made. The charge d.ensÍtÍes shor,vn in diagrams (¿r)-(+a)¡ hovrever¡ rvêrê compiled. by 7 use of the same method. of calculationl und. val,id. predictions may therefore be mad.e concerning ar\y one structr¡re in qelation to the others.

0.94 0,9 3 0,88 0.94 t.l3 0'97 IT N N 1.20 1.1 9 (4a) (4 b) (¿,cl (4d )

it is apparent that the combined. elect¡on rvithdrawing effect on the carbon atoms of the diazine nuclei by the nitrogen atoms is greater than for pyrid.ine and this is reflected in the substitution reactions of these compounds. All attempts to carry out nitrationt sulphonation or tr'ried.el-Orafts reactions on the parent diazines have been unsuccessful .2-4t20t21 ?yrazine has, hor,vever, been ihl-orinated- 23 in the vapour phase at high temperatur.r22' ¡,rt a free rad-ica1 meohaníÈm is probably involvod- in this case. Ð-ectrophilic substitution of the diazines has been achieved. when electron donating substituents are present in the rings. The oarbon atom !n the l-position of pyrimÍdine may be read.ily nitrated-r24 htlogentted-25 and. sulphontted'26 -4-

^r ^o and will. al-so take part in d.iazo-coupling.ltTz

have been achieved lvith the díazines as the electron deficient carbon :r;heoretieally atcit.;, of the nucLel are aotivatëcl to suth åri attaek. .rmin¿rtions of pyra rinu32'33 rtd. sorne pJma rín.34'35 u,^d- pyrimid-i-ne36 derivatives have been reporied- but the only d-irect nucleophilic achieved- with pyridazine is the reaction substitution ',vhich has been ).f v¡ith lithium butyl to form l-butylpyridazine.Jr Pyrimid-ine al-so reacts readily with organolithium compouncls'38t39 The nucfeophilic substitution of halogen atoms has, by contrastt been extensively employed. IIalogens in the a- and- Y-positions to nitrogen atoms are activated- tov¡ards such an attaci< because the electron attracting properties of the halogen and ring-nitrogen atoms'combine toprod.uceahig'herpositivenettchargein.tlresepositions.Such activated- halogen atoms may be replaced nucLeophilically by alkoxylt phenoxyì-, hydroxyl, amino¡ mercapto and cyano groups '4o'42 The replacement of cr- and. Y-hyd.roxyÌ groups by halogen43-45 has aLso been

claimed to d-epend on the low el-ectron density of the carbon atom to Àâ. v¡hich the hyd,roxyl group is attachod'e' -5-

Free-radical substitution of the d.iazines has received- little concerns attention and. the only investigation which has been reported the phenylation of pyri¿azine. A, 26/" yield- of 4-phenylpyrid-azine was obtained-.70 A fr,uther consequence of the eleotron attracting ability of the hetero nitrogen Ís the activation of methyl groups in the o- t exemplified by the ancr y-positions to such atoms ,40'42'47 '48 rhis is methyl groups in the 3- and. {-positions of the pyrid.azine nucleus phthallc which will und-ergo condensation reactions with alde\yd-es or an\y¿ri¿e.42 These reactions are generally believed' to proceed' via the methyl"n" union.49 Oxid-isingagentsmaybeconsidered.aselectronacceptorsand" the d-eactivated- diazine nuclei are consequently extremely resistant to oxidation. This is d.emonstrated- by the oxid.ation of phthalazinet (l), a fused benzodiazine, in which the benzo ring is preferentially pyrid.azine-4¡5-d-icarboxyl"ic oxid.ised- and opened ivith the formation of acid., (g).50 Red.uction, however, is favoured- by systems which can readily' act as electron acceptors so diazines are consequently reduced' lnthecaseofpyrid-azinetheringisopenedwiththeformatíonof the hetero ring l r4idiaminobutane.5l Theory would suggest that ofphthalazínewould'beattackedinpreferencetothebenzoring an. this is borne out by experinent'2-'6 (sctreme 1)' 6

ozH

c 02H

(6)

,T Na-Hq H N H rl (5)

cH zNH 2HCt

cl{ Ct 2NH2.H

Scheme 1 I

The nitrogen atoms of the d.iazines are basíc and are able to form N-oxid-ee v¡ith peracids.5T'58 These N-oxid.es¡ as in the case of the pyrid.ine analogue¡ und.ergo electrophilic substitution more read.ily than the parent heterocycles and afford. a oonvenient route to rnany PyrazLne a d.i-N-oxid."58 b,rt substitutod- diazines, will also form "" yet no d.ioxid.es of pyrimid-ine or pyfid.azine have been prepatred. The effect of the second nitrogen atom in d.iazines is to lower the basicity of these compounds compared. to that of pyridi n.,59 This consequence may be likened. to the eleotron withd¡alving effect of the nitro group of, nitropyrid.ines which have a much lovrer basicity than pyridíne itsolf.60 61 TABLE 1. --apK VAITUES 0F SOME HETffiOCYCLIC SASES

Comnound- oK Compound. '-ã"nK

Pyridazine 2,3 Quinazoline 3.5

Pyrimid,ine 1.3 Isoquinoline 5,1

Pyrazíne 0.6 Quinoline 4,85

Cinnoline 2,3 Pyrid.ine 5,1 Phthalazine 3.5 3-Nitropyrid ine6o,62 0.8

Q,uinoxaline o,7

o ( in v¡ater at 20-25 )

As would. be expected¡ because of the similarity in electronic configuration, the ultraviolet spectra of the d-iazines resemble those of pyrid.ine and b.nu"n ,63-65 The fused- benzo- derivatives, phthalazine¡ (f)r cinnoliner (f), quinoxaline, (B), and. quinazoline¡ (g), possess similar spectra to naphthalene and. the quÍnolines. fhe general effect of the nftrogen atoms Ís to cause a loss of flne structure and. to introd.uce a bathochromlc shift compared to the carbocyclic analogue.

(7t (8) (9)

I I I

The d.eficiency of oharge on the carbon atoms of the d.Íazines enables certäin ad.d.itíon reactions to tàke plaoe across the carbon-nitrogen bond-. This effect is most pronounced. in quinoxaline which will add- Ì¡ydrogen cyanide¡ Grignard, reagents and. sodium bisulphlte.66 The ínitial steps of the reactÍons of d.iazines with sod.amide and organolithir¡n compound-s also involve add-itions to the

-C=N- bontl although these reactions are generally consid.ered. to be essenti.ally nucleophilic. Pyrid.azlne also und"ergoes the Feely-Beavers reaction6? whictr is similar to a Reissert reaction and" involves the add-ition of hyd.rogen cyanid.e to the nucleus. The recently reported preparation of the adduct¡ (tO)r by reactÍon of pyrid-azine with two moles of maleic anhydrld-ef8 t" another example of ad.d.itíon across the

C=N bonci of a diazfne compound,

o

(10)

(u) FUSÐ DIAZTN$

(i) Phthalazines

0f the four fused. benzocliazines, the most reLevant to the present work is phthalazine¡ (l). The chemlstry of the phthalazones¡ -9- phthalhydrazid.es and- chlorophthalazines has received consid.erable attention but) the parent heterocyclic system has been neglected..6ga

Nitration has been shown to proceed.¡ with some d-ifficulty, in the !-positio nr69d but no nucleophilic substitutions of phthalazine have yet been reported. Free rad.ical substitutÍon of phthalazinel hast however, been achieved using N-nitrosoacetanilid-e as the rad.ical producing Thls method produoes in "g"nt.70 )-phenylphthalazine poor yield.. - [he oxid.ation and. red.uctlon of phthalazine have alread.y been d.iscussed. in connectÍon with the monocyclic d.iazines.

(ii ) Pvridoovridazi nes

Although twelve series of pyritlod.iazine compounds àre possÍble¡ to d,ate only eight are known as the for:r pyrid-ocinnoline systems have not yet been synthesísed. AII the pyridopyrimidines, (tt -lùr71 and p¡æÍd.opyrazines, ('t5rl6)r72'73 hu.r", however¡ been prepared and their d-erivatives have received a certain amount of etudy d.ue to the similarity which they show to the purlne ring system. At the outset of this investÍgation, however¡ the pyrid.opyridazines (1?) an¿ (fB) had. not been synthesised. and the few knov¡n derivatives of these compounds had., in almost all cases¡ been obtaíned. incid-entally to other research" The nomenclature suggested. by LU.P.AnC. requires compound (1?) to be classified as pyrido[Zr3-ÈJprridazine but the names 116r7- triazanaphthalene and 1 ,6r]-pytitLop¡midazine have also been used in the literatu¡e" The original namel 1 r6r?-benzotrtazínel has now been discarded.. Compound (tB) is termed pyrid.o[¡r¿-¿]p¡nrid.azine by use of - 10 - the I.U.?.4.c. system but references !'o 223r6-p¡r¡id'op¡riid'azine and' ì 2¡3t6-6i'zanaphthalene may also be found., Henceforth, the preferable nomencl-ature suggesteil by f .U.P.A'C. wÍl] be ad-opted so as to avoid- Possible conf,usion.

N fir) ( r2) (13 ) (1¿ )

N6 2

( n[t 6 I 5¿ (15) (16) (17) (18) A scrutiny of the syntheses of pyrid-opyridazines reveal-s that they are aII extensions of the general preparative method's for phthalaz- j-nes, These syntheses all incorporate the formation and. cyclisation of the d-iazine moiety on to an aryl ring. The most general synthesis of phthalazines involVeq- the reaction between aryl g-d-icarbonyl compound-s,

(rg), and. hyd.razine þdrate (Scheme 2) .54'74'75 This reaction has not been applíed. to the preparation of pyrid-opyrid-azines because of the d.ifficulty in obtaining the py¡id.ine analogues of compound (ìg)' The method. may be extended to enable preparation of the phthalÌryd'razíd-es¡ (ZO), by the action of hydrazine hyd-rate on substituted. phthalic acid- esters, imides and- anklydrid.es (Scheme 3),76 This reaction has been mod'i- fied. by use of pyrid.ine g-d-iacid. derivatives to prod.ucè compound-s of the. pyrid.opyrid.azíne seríes and most of the knov¡n members of these Sroups have been obtained- in this DêÍIrIêre Typical prod.ucts of suoh reactíons -11 are the hyd.razid.es, (21) ancl (22), wtri.ch may be prepared- from the action of hydrazine hyd.rate on quinolini"?? tod. cfnchomeroni"?B -t acid- esters or an\ydrides respectively. These hyd.razid.es are tautomeric with the dihydroxyp¡rrid.op¡æid.azines and in alkaline solution they probably exist almost exclusively in the d.ilactim form,

coR \ N 2H4.H20 c0R (19) R Scheme 2

c02R N ¿'Hzo H R T c0 R N l{ 2 (20) Scheme 3

The reaction between lSrd.razine and' the d'iesters of ma4y aromatic and. heterocyclio g-d.iacíd.s has been shown to be general?Bo'79 and. has become the standard. method- for the preparation of substituted. dihyd-roxypyridopyridazines ,TTbs7g-82 A refinement of the method. uses ethylene glycol ae a solvent and. enables the o-d.iacid.s themselves to be .r""d..83 Substituted l¡ydrazines rnay also be employed. in these reactlons to prod.uoe N-substituted þd.razid-es. Various N-pher¡yl and.

I

{ NrNt-d-íphenyl d-erlvatives have been þrepared. tn this fiâIlherrBl'BZ'84 : ¡ !

. I

:

i i ) -12-

0

NH N H

rl,t t H

(2r) Qzt Related. cyclisatÍons involving the formation of a d-iazine ring from condensations with Ìr.yd.razine have been achieved using 3r4-d-isubstituted. pyridine d,erivativ""B4-89 (schemes {, 5), No condensations of the type shown in Scheme { to prod.uoe pyrid.o[Zr¡-4Jp¡æidazines have been reported, presumably due to the difficuJ-ty involved. in synthesising ' the required 2r3-disubstituted. pyridines. A similar synthesis to that shown in Scheme ) was, however, accomplished- by use of the ester-ketone, (24)t and, Ïgrdrazine which condensed. to give !-phenyl- B-\yd.roxypyrid.o[2,¡-qJp¡midazine, (2il,90 ¡to"/1'105 h." extended this work to the preparation of &chloro-5-phertylpyrid.o[Zr¡-Èlp¡rrid-azine¡

(26), by reacting the hyd.roxy compound-, (25) v¡ith phosphoryl chl-orid.e.

The chloro group of, compouna (Ze) is activated- by the ad.jacent nitrogen and undergoes nucleophilic attack by lSrd.razine to yield. the correspond ing byd.r azíno d.erivativ ., (27) . Compound.s ( z6 ) an¿ ( zZ ) were the first pyrid.opyrid.azines to be prepared. ',vhich rvere not substituted- by Ì:yd.roxyl groups in either the 5- or B-positions.

c0 R 2 N l"lz0 Nl{ R t* N H Scheme /. ( 23) - 13 - . Ì I

co R 2 N2H4.H20 H R, T t- N 0cH 3 CH 5 3 I Scheme i

sHs I I cocoHS N 2H¿,,'t2o . I

I

I ozcf s i OH (25) Q1' I c eHs sHs I

,| I P0ct3 N2H4.H20 - N I N ì

t HNHz I ( Q7) 26) Scheme 6 I I

I I cH0 N zH¿.HCt I

N C0 2Na H Scheme 7 ( 28)

A cond.ensation reactÍon related. to that shown in Scheme 6 was employed by Bottari and. carboni to produce the first monosubstituted- pyrid-opyridazine d-erivative, $-Ìrydroxypyrid.o [er ¡-d] pyrid-opyrid-azine¡

( zB ), ( scrreme ? ) . The ad-d.ition reaction between aromatio o-d-initriles and'

Lgrd"razine l¡yd.rate has been developed- by kunze to prod'uce heterocyclic dihydrazino compound".93 Phthalonltrlle¡ (Zg), when reacted' in this way, yiel¿s 1r4-d.ihydrazinophthalazíne' (¡O). The use of heterocyclic o-d.initriles and. azainflolenine d.erÍvatives has enabled' this synthesis B)' to be extended. to produce pyrid.opyridazine d.erivativ""9J"'94 lscneme -14-

HNH2

N NHilH 0 't CN t{NH2 (30) (2 9)

Nll 2

,T CN NH t{ .H 0 N CN NH ( 3t) (32) 2

I.{NH NH 2 ,l Nt{ H l-l r{ N

r{ I{ NH 2 ? (33) ( 34) Scheme B

d-ue to the only investigation of p¡æùdo[lr+-OJ pyrid-azines is of these compounds Rid.i95 who in 1!!! stud.ied a general- synthesis prod-ucts¡ however¡ (scrreme g). The highly substituted- nature of tbe involves severel¡rilimits the utÍ1ity of this procedure' The methòd' with an cr"Y-d'iketone the cond.ensation of an aminouracil derivative turn condensed to give a pyridopyrimid'ine d-erivative which is in (35)' This prod'uct may wíth hyd-razine hydrate to prod'uce compoun¿ potassium hydroxide to give be hydrolysed with either acetic acid- or interest that pyrid.o[¡r+-gJ gyrid-azlne d'erivatives (36' ]?)' It is of thisreactíonsequencea}soinvolvesthecyclisationofad-iazinering methods' on to a pyrid.ine ring as in all the preced-Íng I _1r_

NHz 0 coHs 5 P205

0 0 Rut c0 2

csH NR,- CeH s$ t* lgHaHz0 . NR,, Þ\C J' R, (36) 0 R,, c^H 0 b N R-, (3 5) .'[ H

N HR, N HR,, Scheme I ( 37)

In all, just over twenty pyrid.o[ir+-{Jpyrid.azines have been

reportecl ancl. prior to 1963 only fifteen d.erivatives of the

pyrid.o[2,:-èlpyrid-azine series were known. Subsequently¡ howevor, three papers have appeared ôeal-ing exclusively rvith the Latter

s eries. The first of these¡96 the possibÍlity of covalent "on"""ns hyd.ration in pyrid-o [2,:-Èlpyrid,azine and. its d.erivatives. Several d-i- and. tríaza-heterocycles have been stud.leù in this regard- by

Albert and. his colleagues at the AustralÍan National University" The process of covalent Ìrydration invol-ves the add-ition of lvater to

a C=N bond- of a heteroaromatÍc molÇcule, This type of hydration

has been observed- wlth the quinazoline catÍon and, the presenÈe of I

I -16-

: ¡ such structuïee as (38u,rb) was, d-etected- by ultraviol-et spectra and- i I ! I ionisation bonstant determination".gT'98

H H H H + i H t{ ,l H Nt{ I il I N N N HTIH H (39d (39b) ( 3 8a) (3I b) The study of covalent Lryd.ration was extend-ed- to the rrazaquinazolinesil and. in this series p\ysical measurements ind.icated. tlrat the cations of compounds (t 1-14) underv¡ent covalent Lryd.ration to a high d.ug""".71 ïn the rtazaquinoxalinerr'Broup, cornpound- (t6) *u" found to hydrat"99 *h"t"as compound (t5) remained an\yd-ro.r".72" These results l-ed Armarego to search for hy

ct L

I I cozH N2Ha.H2o. N t T' I N N 0cH 3 CH¡

HNH -p -Ts N p-Ts-NHNH2 0H-

^l H H3 3 (¿0)

Scheme 10

The remaining papers concern the nucleophilic d-isplacement

(4t Tvuo groups, reactÍons of 5r B-d.iohloropyrÍdo [2, ¡-ÊJ pyrid.azine, ), Nitta and coworkers Ín Jrpu,n101 an¿ Domagalina an¿ her associates in pol-and102 ind.up"ndantly developed the same synthesis of the d'ichloro compoundo This method- involved. the reaotion of phosphoryl chlorid-e and- climothylaniline rvith the d.ihydroxy compound, (Zl). The procedure was clàimed to be less time-consuming and to give higher yield,s. than Armaregor" r"thod-.101 !r 8-Dichloropyrid'o[2, ¡-È] pyrid'azine is a particularly suitable compound to use as a basis for investigating derÍvatives substituted. in the diazfne ring as both chlorinê atorns are activated tovuard.s nucleophilic attack' Prior to an examination of the chemical reactivity of this

compound, Nitta investigated. the relative reactivitfes of the chloro groups by theoretical procedure".101 The n-electronic characters of the varioue atoms ín the moLecule vrere d.etermined. using the linear combination of atomic orbítals-molecul-ar orbital proced,ure rvith the I I - 18 - : result as shovrn in diagrat (4t )' ¡ i QIr'sro 0.9¿3 I I 1.18 5 I I

{ 0.901 1.173 iI 0.955 l L Ctrglz I (11) I C0UL01'[B RESON r'0R TABL,E 2. PAÎAMET 0F l. I ¡ SUBSTITUIilN GROUPS I I

I

Substituent X a a I x I

¡ -c1 1.8 O.1B 0.8

ú =N- 0.6 0.1 1 ! i o* o where coulomb integral of X = +t*9 Ì I

I coulomb integral- of the carbon atom ad'jacent to X o*di. * o-F4"9

resonance integral- between that carbon atom and" X p c-x = 19

Ttisobviousthatthe!-positior¡whichhasthefovuest nuoleophilic zç-electron d.ensity, should be more reactive tov¡ards the reagents than the B-positíon" ['hís view is supported. by superderocarisabirity values for nucleophiric substitutÍonr tlt). the These values have been pred.icted. to have a closer relation to densities' replacement reaction than d.o other criteria such as charge _19_

value .A.l-though the thoory related. to this function is complex¡ its the r th may be summarised as rrthe greater s"r the more reactive is position of the compoundr,.l03 For position !, tf*) = 1.319 and for position u, tåt) -- 1,283. This theory therefore predicts, as do then-e.ectrond'ensities¡thatthe!-positionshouldund.ergo nucleophilÍc reaotion Ín preference to position B' Ðxperimental results generally are in agreement vrith these theoretical implications as the products resulting from reaction at position ! are mostly produced in higher yield than those resulting from dispfaoement at tho &posÍtion" fn mar¡y Ça6es both ohlorine reaction atoms may be substituted. by increasing the vigour of the conditions. A summary of the Various nucleophilic d-isplacement reactions is given below. rl.¡clrolvsis (4t)r Nitta and cowork"""101 found. the ¿ichloro compoundo to ({2) be unstable to alkali and. two t¡ydrolysis prod-ucts, compound's an¿ (43) *ere obtained, Domagalina was only able to isolate

B-chloropyrid.o [2, ¡-q] p¡æid.azinone¡ (41) .102 This d.erivative was also acetyl-ated to give compound' (q+)' lhe chloro group was able hydrazine to be replaced- by a hyd-razino substituent¡ by reaction rvith hyd.rate under forcing cond-itiong to give B-Ì¡yd.razinopyrid'o [2, ¡-qJ - pyrid-azinone¡ (q5). I

-20- t

c0cH 0 3 |lH N I 'l* 'l N N H N N

: NHNH ct 2 0 l (1,2) (¿3) Ulrl (¿5 )

: AlkoxyLation ¡

l sodium alkoxid-es react with the d.ichloro compound at room Ì isomeriC mixture of a'Ikoxy-chloro clerÍvatives' temperature to give an i I rjihen the d-ichloro d.erivative was heated. to IOOoC v¡ith excess

t' alkoxide¡ hovrever, a ¿ialkoxy compound , (46), *u" obtained' in yield.s of approximatery 8o76 (scireme '11).101

I'lercant at ion pyrid-o[Zr¡-¿J pyrid.azine-5,8-d.ithio1¡ (ql), was prepared by reaction of thiourea with the d,iohloro compound-, followed' by hydrolysis of the res¿lting bisthiuronium d-erivative with sod'ium hydroxide (Scheme 12),101

Aminatlon

A variety of amlnes, vlhen reacted in equimolar quantities ({Ba,b)' with the ¿ichloro compound, (41), prod-uce isomers of the typo

These derivatives undergo further reaction in the presence of alkoxides wÍth replacement of the second- chlorine atom (Scheme 14)' As in the case of alkoxylation, both chloro groups may be replaced' by use of vigorous conditions (scheme 15)'1o1 -21

R

Na0R T 1000 N N

R Scheme 1 1 (46)

NH il CNH 2 N (NHz)zCS. 'l Na0H J t N s c NH H il 2 N H G7l i3cheme 'l 2 t ct HR

RNHr.> r +

HR t (Lïbt ) 2

ct R R

Na0R RNHr

N HR HR (49 )

Scheme 1 / ct NHA r

ArNH2 N A l

Scheme 1 5 HAr -22-

The chlorohyd-razino d.erivatives, (4Bar¡; R=lÍi-I2) ¡ r,vhen h.eated- v¡ith acetic anhydride undergo cyclisation to forni the s-triazolo compouncls (5tarU; n=Ct).101 This cyclisation reaction appears to be general for compound-s containing a bydrazíno group o- to a hetero- nitrogen of an aromatic heterocycle. lìhe first systernatic stud-ies of this cyclisation method '¡/ere carried- out on þd-razino derivatives of phthalazLne and. pyrid-nrin".91'1O4 Recently2 Kunze has extended- the reaction to the cyclÍsation of hyclrazino compound-s prepared" in situ. lhthal-onitril-e and \ydrazine hydrate, together v¡ith d.inethylformamide as the cyclising reagent, produce the triazolo derivative, (50), in 90É Ola yie]cl.TJ" This method has also been applied. to pyrid.ine-211-dinitril"e, (¡l ), to prod-uce a fused. triazolo derivative of a hyclrazinoiryrido- l,¡/asr unlcnown [2, ¡-d] pyriC.azine. The direction of cyclisation howevere and- the procluct was assumed- to be either (51c or 51d; Iì=I{lnrTä, )'93"''105'106

R R

,t

NHNH 2 a,U,R'=CH (51b,d ( 50) (5la.c ) 3 ) c,d' R'= H

Both l{unz.93c11051106 ond- D",ruy91 have made stucl-ies of the verious reagents which bring about the oyelisation. l-ypical of these reagents are aliphatic carboxylic acid-s and. their anÌurd.rid.esr ethyl scetoacetate, d-imethylformamide and. {imethylacetamide" It is believed that reaction proceed,s by initial acylation or formylation of the hyd-razino group followed- by oyclisation to give the s-trÍazolo ring. _23_

The paucity of information concelning the pyrid.opyrid-azines has l-ecl to the present d.etailed- stud.y of these compound's' As they ale aza-analogues of phthalaz.ines¡ this r,vorlc becomes a natural extension of the phthalazine stud.ies which haVe previously been carríed out in this dePartment. The synthesis of the ur¡Icnov/n parent heterocycles, (1?)r an¿ (tB),:_" a necessary prerequisite to a systematic stud.y of the general ploperties and substitution reactions of these compounds' It ís al-so of interest to observe the grad.ation in properties of the series quinoline; phthalazinel pyrid"optrf,Ídazine and the series pyrid-ine, pyrÍd.azine, and" pyrid-optrridazine'

This v¡ork is mainl-y of a fund.amental nature but the possibiJ-ity of producing compounds possessing significant pl¡rsiological- activity is ever present. l! measure of the increasing

ar¡/arenoss of such potential in the pyrid.opyrÍd-azines may be found in the publications which have appeared subsequent to the commencement of the present investigation. In this regard-, Nitta has real-ised tha,t although several- phthalazine compound-s possess physiological-

action¡ fevu pyrid.opyrid.azines have been tested for such activity' :il-though only a smaLl number of pyrid.opyrid-azines are knorvn, three

clerivatives, compoun¿s (Z¡), (32) an¿ (34), trave alrea¿y found

therapeutic uses and- compound.s d.erived. from the pyrid.opyrid-azines such as the triazolo compounds, (5ta,t)' have also been utilised' as

medicinal- s. BEË.9!g.E 4I!

DTSCUSSTO N -24-

RESULTS .I\]\ID DISCUSSTON

CHAPTIR. 1. syNTHESTS AND pHysrcAr, pRopm.lrffi 0F prRrDofz.¡-¿j-

pyRrDAz¡rE AND praRTDo l¡. ¿-a'l ptnrDlznvE.

A review of the method.s of preparation of pyridop¡rrid-azines has ind.icated. that in all cases these are mod.ifications of known phthalazine syntheses and involve ad.d.ition of a d.iazine ring to a pyrÍd.o ring. The alternative process which requires cyclisation ofthe pyrido ring on to a diazine ring, is not particularly attractive as suitable pyridazine d.orivatives are not avaÍlab1e. lhe synthesis of the parent pyrid.op¡rrid.azines vúas therefore attempted. in two r,vays' These invoLved (a) removal of substituent groups from pyridopyrid.azine d-erivatives, ana (b) preparation of the requisite pyrid.ine-g- d.icarboxald.ehyd.es followed by cond.ensation. wÍth hyd.razíne Ìgrdrate.

Both methods have been successfully applied. to the synthesis of pyrid-o [2, ¡-¿] pyridazine and pyrid.o[¡,¿-¿l pyridazine.

1 a RIü,ÍOVAL 0F SUBSTITU]ü\I'I GROUPS

As no pynid.opyrid-azine d.erivatives unsubstituted. in the d-iazine ring vrere knor,vn príor to the present investigationr this proceduro required. removal of groups from the p¡æidazino ring. tr'ew systematic methods are knorvn for the removal of substituents from heterocyclÍc nuclei. Procedures have been devised. for the removal of chloro; mercapto and- ÌSrdrazino groups from heterocyclic compound.s which alth.ough suitable for specific compound.s have proved less -25- reliable in general cases, These method-s vrere accord.ingly applied. to chloro¡ þd.razino and. mercaptopyrid.opyrid-azines in an effort to replace such substituents by hydrogen atoms.

(") Rmilovrll, otr' Hr¡ÌìAZTNO GROUPS

A prerequisite for such an investigation is a suitable synthesis of the d.ihydrazino compound.s, (32)¡ and. (¡+). The key intermediates in the method. of Kunz e93'94 are the heterocyclic o-dinitriles, (31 ), and (>Z). The original patents, holvever, contaj-n no d"etails conoerning the preparation of theee dinitriles. Linstead. 14 ancl- cov¡orker"1 the gynthesis of pyrid.ine-2, 3-d.initrile ""potted. from quinolinamide in 1937, Although usual dehyd.rating agents failed., py:rolysi-s of the diamide at 32O-350o over a. silica ge1 cataLyst was claimed to produce the d-initrile in !y', yield.. Analytical figures for tiris compound. were quoted for nitrogen aÌone and, were only in approximate agreement r,vith the required, value. I,foreover a melting point of 13Oo r¡/as reported whereas this d-initrile is now known to melt at

BOo. It is probable that the d.initrile was obtained. but was contaminated. with another product such as quinolinimide¡ (56).

The only other l-iterature method. for the synthesis of pyrid.ine-2r3-dinitrile¡ (¡f )j07 in.rol.res the Feely-Seavers cyanation of amine salts proced-ure. Thùs method. requires the ad.d.ition of cyanid.e ion to N-alkoxy-quaternary salts of aza-aromatic heterocycles and enables cyano d.erivatives to be obtaine

CN

CN (52) rvork and no improvement in the yield. of Zrl-dicyanopyrid-ine could be achieved. As this procedure required the use of toxic reagents and extensive chromatography to separate the isomers¡ & Iltoro satisfactory method vras sought.

The preperatign o,f thc dinj.tri-tee (¡t ) and (54), ln adequate yiel¿s r,vas aohieved. by dehyd.ration of the requisite g-dÍamides by use of phosphoryl- ohloride and- pyrid-ine (Scheme 17). The d-iamid", (57),

CN N CN KCN N *t'l ,rqrq + N I CH CH 0cHg 3 3 (cH (s3) 3s04)- se N 1,. CN + N

Scheme 1 6

0

co Ac NH2C0NHZ zH ro - t{

c0 2H (s4) (5 5) (56)

CONH N NH: z pOCtg c6 oNH2 d''¡ CN (57)

Scheme 1 7 _27_

is a known compound-r and. has previously been prepared. by the action

of ammonia. on either tlie imid.e, 15e)109 ot the diethyl ester of quinolini" ucid.110 .4.s the anhydrid-e , (5il, and. imid.e rvere required. for subsequent reactions, the route via quinolinimid.e was preferred-.

Quinolinimid,e has previously been prepared. by the pyrolysis of the

diammonium salt of quinolinic acidl09'110 ot by reaction of acetamide with quÍnol-inic acid anhyd,r:.d.e.111 rt rvas found. more convenient,

hor,vever¡ to extend- the synthesis of phthalimid.e, from phthalic

anhyd-rid.e and- urear112 to the pyrid.ine series. The reaction between t ¡

and prod.uced. quinolinimid.e in BO-BJIL yield.. A somer,vhat similar

reaction has been stud-ied. by l{onclratreva and. Huang v¡ho heated- three

! rnol-es of urea x¡ith va,rious o-d-ioarboxylic acid-s in ethylene glycoI

et 19O-2O0o.113 ft was surprising that although this method- gave

1 good yield.s of cyclic imicles from phthalic acid. anrl several substÍtuted" cinchomeronic acid-s, no quinolinimid.e could- be obtained from quinolinic

acid, (5q). ¡

The d-ia,mide v¡as formed. from the imid-e by treatment ,,zith aqueous arroniu,.109 lhis reaction proceed.ed in good. yield- only rvhen

: ciilute ammonia rn/as used. ff ammonia of specific gravity O.BB was I

j employed- the yield, docreased bV 3O'/" and concentration of the filtrate prod.uced, a green gum from which no fr"irther amicLe could. be obtained.

Linstead has also noted. a similar relationship betv¡een yie1d. and- the concentration of the aqueous ammonia in a related. reacti on.114 28

A variety of method,s r{ere er,rployed- in an effort to dehyd.rate the d-iamid.e. The conventional proced-ure rvhich employs a,cetic anhyclride has been reported. to be ineff ective114 rnd- dehyd.ration coul-d- not be achieved. by use of phosphorus pentoxid.e in either xyf ene or d.imethylformamid.e. Other y/orkers have found, similar d.Ífficulty in d.ehydrating poJ.yamid-e functions. fn partÍcu1ar, l5 Lavrton ancl itcRitchiel r.luud. a large number of 'reagents in an atternpt to convert the tetra-amiae, (58) to the tetranitrife, (59). This dehyd.ration was finally achieved. by use of a mixture of thionyl clrl-orid,e ancl dimethylformamid-e.115¡116 rni" method- Ìves accord-ingly attempted on the diamÍae, (57) and a l}"il, yie]d. of pyrid-ine-Zt3- dinitrile r,vas obtained together with some quinolinimid_e. Tmid.e forrnati-on vas al-so noted- by Lavrbon and. I{cRitchiell5 rrr¿ presumably these products arise from the d.iamide by loss of ammonia.

The selectivity of reagents in amid-e d.ehyciration has also been observed. by i'/ei".117 Of the mar\y ï'eagents used- in an effort to convert the tetra-amid-e, (60), to furan-Zr3r4r5-tetranitrile¡ (eZ), only phosphoryl chlorid.e r,/as successful (Sctreme tB). This reagent was ineffective when applied. to tire d-iamid-e, (61), hovrever, and. a mixture of phosphoryl chlorÍcle and- pyrid.ine lvas required. to convert this compound to the tetranitrile¡ (eZ) (Scheme 19). The dehyd-ration of quinolinamid.e was successfully achieved. by use of the phosphoryl chloride-pyrid.ine method.. This reaction proceeded best on scales up to 20 g but ths use of larger quantities of d-iamide rvas accompanied. by a comespond-ing d-ecrease in yield.. -29-

CON H N N 2 s0ct OM.E

H c0NH2 CN

(58) (s9) Scheme 1 B

H/'lo c0NH2 N P0cl.3 - CN POCt g C6H5N CONH CN CONH H 2 2 (60) (61) (62)

Scheme 1 9

lhe phosphoryl chlorid.e-pyridine reagent was first employed. t,ol' by Freund.ler in 1911t b,rt the possibilities of this reagent

were umecognised- until 1958 when Delaby and- his colleagues investigated. its action on a smal.l but varied group of amid."s.119

The reagent may be used at room temperature and- in the presence of groups read-ily hyd-rolysecl by other proced¡res. Because of the exothermic nature of the reaction and. the apparent forrnation of a complex, neither of which occur. vríth phosphoryl chlorid-e alone,

Delaby suggested. that the pyrid-ine acted not only as a solvent but

actually was involved- in the reaction. Complex formation is highly probable' for ritreis has observerl red solutions Ín these r"*"tion"11?

and. in the present stud-y d-eep purpl-e solutions were produced.. A

possible rnechanism to account for these facts is shor,vn in Scheme 20.

Such a mechanism is also very simiLar to that suggested for a related reaction which invol-ves d-ehyd.ration of amides by arylsulphor¡y] chLorid.es -30-

2O\121 and pyridine.l The phosphoryl chlorid.e-pyrid.ine reagent could

r,vell find- v¡id.er application in organic synthesis as it enables

deþd.ration of a wid.e range of amid-es Ín good yield-s and- und.er mild.

cond-it ions, 0 q-ä-c cÂll qN RC0NHz PoCt' R. -¡ ccril NH ol H \-l¿0 H2o 3P0a -r-., 1 RC RcN + Po2cti + ìrll crl ' HCt LN

Scheme 20

Pyrirllire-1,{-d,initril-e was obtained, from cinchomeronic acid.r (e:), using the reaction sequence shown in Scheme 1?. fncreased-

yield-s of the ord.er of 5-1O"fo were obtained. Ín comparison v¡ith the equivalent procì.ucts of the other series.

ozH

oeH (63) the cyclisatÍon of g-dinitriles with hyd,razine lqyclrate has beerd achieved. by Kunze in yields of 9oiÅ93'94 Kunze found. the reaction to be acid. cataì-ysed. ancl that tbree mol-es of hyd.razine hyd.rate rvere necessary for complete reaction. It'loreover, ammonia v¡as deteiteif rluring the course of these cyclisations. These observations may be rationalised- by postulating the mechanism depicted- in Scheme 21. -31

I + H A t-l H I {ñ t H f ,ì, f-{ I T I I +H+ N H I H + 2 Nl{ + t NH H I ( 64a) I H HNH I 2 2 2N T -F N zruH, -.-\ H ? NHNH (64b) 2

Scheme 21

tr4uch evid.ence may be ad.vanced. in support of this mechanism. riddition of hydrazine to nitril-e groups has been observed. before. ?he rea.ction betv¡een hyd.razine and- ethyJ- 3-cyanoisonicotinate to f orm J-hyclroxy-B-aminopyrido [¡, ¿-è] p¡rrid.azine, (zÐ , must invorve such an add.ition.BB A similar ad-d.ition occurs betlveen thiocyanic

acid and. þdrazine (Scheme 22).122 riïhether the first step occurs

J¡ia a stepwise or a concerted. process is unkno.r,vnralthough. the former ad.dÍtion which rvould not require adjacent positive charges on the nitrogen atoms (as shov,rn in scheme 21 ) v¡ouId. probably be more likery. ldo ad-d-uct could. be isolated from the reaction of phenylhyd.razine an¿ pyridine-2¡3-dinitrile so it is probable that the initial addition is a reversible reaction.

N ttNH HS-C¡sN zH¿ H S-C:\NHNH2 Scheme 22 -32-

EVid.enc e f or the f ormat ion or 5 ¡B-d.iaminopyrid.o [2, ¡-q] - p;,.r:iclazine, (68¡),as an intermediate in this re¿ction v¡as obtained' by' isol-ation of this compound from a partia]ly reacted mixture.

JlquimoJ-ar quantities of 2r3-d-icyanopyrid-ine and- hyclrazine hJ'd¡ate afford a yellorv compouncl af'ber a reaction time of 5-10 minutes. ,gatisfactory analyticaL figures for this compouncl could' not be ob-rained as a suitable sol-vent for recrystall-isation couJ-d not be however, and found. .4, picrate of this compound ivas reacl-iIy formecì., for this clerivative a correct analysÍs lvas achieveù. convincing proof of the id-entity of this intermediate was afford-ed- by an unambÍguous accomplisheò synthesis o;1 5¡B-diaminopyrido [2,:-ql pyridazine' This v¡as by cleavage of the N-N boncls of the hyd.razino Sroups of 5t8-¿ihyarazíno- pyrrColZ,¡-È]pyridazine with Raney niokeL (Sctreme 23). The picrate cf i;he product froni this reaction was identical v¡ith that from the hydrate cij.amino compouni. isolated from the reaction between l¡rdrazine

and. the d-initrile There are very fev¡ analogies to the N-N cleavage reaction

r.eported in the literature. The conversion of azobenzenes to anilines by Raney nickel and hyri,rogen proceed-s wia the hyd'razobenzene d'erivative (Scheme vrhich, presumably, is then cleaved by the catalyst 24)'123 Ainsvrorth has shown that acid- \yd.razid-es may be converted- to amid'es rvith Ilaney nickel ,124t125 vut the only hyd.razine d'erivatives v¡hich

have been cleaved in such a manneï are L¡yd-razinofuranose compouncls and in these cases hyd-rogen was also pt"""nt'126 -33-

Pallad'iumoncarbgnhasalsobeenreported-toconvert\yd.razino employed' in the groups to amino Broups but again hyd'rogen ivas also reaction mixtu¡e.20 groups The scission of the N-N bond of aromatic \ydrazino for by Raney nickeJ appears to be a general reaction' l'8- d-ihyd-razinopyrÍd.o[¡,+-d]p¡rrid-azine, !-hydrazinopyrid'oIZ'¡-èJpyrid'azine have all been converted' to the and- 8-hyd.razinopyrido[2,3-d]pfridazine correspond.Íngarrinocompouncì.sbythisprocedureinthepresentinvesti- gation.Inthisdepartmentll4-ôiaminophthalazinehasalsobeen prepared from the d-ihyd-razino compound- by this meth oð''127

H NHNH 2 2 Raney Ni 'f T N N

H HNH 2 2 Scheme 23

H 2 N:N NHN

Scheme 24

Nointermecliated.iaminocompound.l.vasabletobeisolated. fromthereactionof3l{-d-icyanop¡'rid-inewitlranequimolecular spectra in dioxan' quantity of \yd.razine hydrate' Illtraviolet however,indicated.thepresenceofanintermediate:forafterthe progressed- for one hourt reaction with excess L¡yd.razine \ydrate had- apeak.appearedat32Jmp.Àfterthreehoursthespectrurnshovled mtr identical to the a should.er at 330 m¡.r and- a broad peak at 195 -34-

spectrun of the h4rdrazino d.erivative. 2r3-Dicyanopyrid.ine and.

excess \rd.razine gave a spectrum r,rith a broad- pealc at 351 m¡-t after

5-10 minutes simil-ar to the spectrum of 5, B-cliaminopyrid.o [2, ¡-q] - pyrid,azine. Àfter 1.5 hor.rrs the spectrum Ìvas id-entical to that of authentic 5, B-d.ihyd,razinopyrido[2,3-Èl pyrid.azíne with a shou]-der at

330 mu and a broad peak at {20 n¡t. Concurrent stud.ies in this department on the reaction of phthalonitrile with hydrazine hyd"rats have yielcì.ed. simil-ar results ani. after 5-10 minutes emaÌI quantities of 1¡4-d.iamino¡rhthalazine hr,lye Þeeq Isal=eted- from the reaeticn miäi.:ute1127

The final step in the proposed- mechanism requires nuicleophilÍc d.isplacement of ami-no groups by hyclrazine. Several ür'lalogies to such a process have been report"d..129 The cred-ibiIÍty oi i;Ìris step¡ hovrever, is demonstrated. by the fact that lrB- d iu.minopyriaof Z,3-4] pf¡id. azine will produce the d.ihyd.razino derivative vrhen treated. vrith hyd-razine hyclrate under the cond-itions of the original- reaction. An aqueous soLution of 1 r{-d-iaminopJ¡rido[¡r¿-È]- pyridazine, prepared. by the Raney nickel method- d.escribed. above, a.Iso f urnishecL l r 4-d.ihyd.razÍnopyrid.o [3 r 4-4] pyrid azine rvhen treat ed. wit h þd,razine hydrate. /llthough oxid,ation of hydrazino groups has been e,'

Char-baway invoked. a hyclroxyhyd.razine intermediate to account for these products" This rvas believed. to be unstable and- to clecompose in a rilanner unspecified¡ to the aromatic hyd.rocarbon, v¡ater and nitrogen:

Ar NII\TH2 + [ o] a¡ :rrNINHOHl -+ rirH + HZO * Nz

The recent proof of the existence of d-iimid-e as an intermecliate in many oxid.ations of hydrazine ancl in the reactions of þd-razine derivu.ti.r""131 deems it more logical to propose a similar intermediate¡ (6:?), in the oxid.ations of aryl\yd.razines. Such an intermecliate rvould. form by abstraction of trvo hyd.rogen atoms by the oxirlant. The d-iimide intermed.iate could then break dorvn in three rvays (Sctreme 25), ?ath (c) explains the formation of d.iaryls and as these are only formed in itt"" amounts¡ paths (a) .r.ncl/or (c) are obviously more favoured. Phenyl d.iimid.e has recently been prepared and in base it rapÍd.J-y forms benzeno, azobe1zene and. Wd.razoþenrun .132 'Ihese products vrere postulated- to arise from the anion, ('66; 15 = CrHr). -36-

Arl{r[rTHr* [O] * fLrtr=uu] + HzO (ei)

(u) *ârÂ,, ê0, --> Ar- + Nz + Hzo (¡) or-r$-, Êot Àr-N:w-.+Ari{ + ArN:IrIAr *ArNIil{I{Ar (66)

(") aÐllr=-ff)lì Ar'* N, -F H' Àr. -¡ fl. ArH Ar. *Ar. ->

Scheme 25

The traces of phenols observed- by chattavray v¡ere formed only

on very vigorous oxidation. It is probable that in such casest four electrons are abstracted by the oxidant to give a diazonium ion rrrNl rvhich would yie1d. a phenol in aqueous solution' oxida'bions of arylhyd-razines in acid- solution¡133-134 ¡y ferric chloriderl35 r¡¿ by potassium fegicyanid.ol35 tt"t also be considered to proceed 11þ-a d.iazonium ion intermediate as nucleophilic substitution of the aromatic ring occurs (Sctreme Z6). This may be explained by the

mechanism shown in Scheme 2?r which has been proposed for the specific 33 case of oxidation by hypohalot= u"id-'1

N s(cN) NHNH2 K HIO

Scheme 26 -37-

+ R - Irlil{H3 + 2IIOX +z{ + zl.t++ 2H20 + R-N-N+X --.-+-n-tf:l[ RX + N2

Scheme 27

some cred.ence is lent to this mechanism by tho isolation of an i:.zo d.ye from partially oxidised- ri*t*"".136 very few of these oxid.ative method.s have been applied. to generaì- organic synthesis and- a l-iterature sulvey reveaLed, less tlran a ð,ozen exampres of the replacement of arylhyd.razino groups by hyc1rog"n.137 il.ost of these procedures utilised- copper sulphate 37e ¿s the oxidant and only one methoul employed. mercuric oxid.e

(sctreme zB). The copper surphate method., hor,¡ever: is unreriabre as in some cases oxid-ation d-oes not occur and. in oihers, such as the 37" oxidation of hyd.razinocinnolinesrl t.rr" are ¡rrod.uced-.

I ( fn the present worìr, hoivever¡ the mercuric oxid.e method. has i been used extensively and ,¡¡ith consid-erable success. Ir,ionohyd.razino

€l:noups have been removed. in yielcls of BO7[ or better anc]- tyro groups

may be replaced by hydrogen atoms in 60-70')á yietd-. These yield.s are

superior to the copper sulphate procedure and. furthermore reaction cond-itions are mild. ancl- clo not affect other non-oxid.isabl_e groups.

rt is of interest that even in boiring water no hyd.roxy d.erivatives are observed- and this is in agreement rvith the ¿iimid.e intermediate theory. The yield is practically unaffected by heat but the rate of oxid.ation d.oes increase to some d.egree. Both varieties of -38- mel:curic oïid.e are capable oxidants but the ¡rsllevl oxide'afford.s slightly better yields than does the red-. HNH2

Cu S0¿

R Hgo

NHNH2

HNI{2 Hgo

IJNH 2 Scheme 28

3y application of this method- to the d-ihyd'razinopyrido- pyridazines, both the parent heterocycles were obtainecl ín JJ-6J'¡| yie3-d' (Scheme 28). lhe optimwn cond.itions required up to 5 g of dihyclrazino

cor-npound. and. if larger quantities lvere oxiclised- the yield' decreased. 'Ihe above procedure has also been employed. in this departrnentlz? to

produce phthalazine in lJclb yjel-ð, from 1,4-dihydrazinophthalazíne. j¡s the reactiorr of Lr.yd.razine with both arornatic and heterocyclic o-¿initriles also appears to be general, the overall reaction sequence should prove a useful synthetic route to mar¡y heterocyclic ring

syst erns. Subst itut ed. aro¡nat ic o-d.initriles shouJ-d also react- in a simil-ar manner so this procedure may also enabfe the preparation of pyrid.opyridazines substituted- in the pyrid'o rÍng,' -39-

(¡) RtrX\,IOVA-L OF C HLORO GROUPS

Removal of chloro substituents has received. more attention 'bhe than removar of either hydrazino or thior groups. As the dichl0ro compounds, (ql) an¿ (67), were more accessible than the monosubstituted- compounds, all initial attempts at d.echlorination rr¡ere carried- out on these d-erivatives" Three general proceclures have been employed- in the past for this purpose, [hese are¡ (i) conversion to the p-toluenesulphonhyd-razid.e follorved by reaction with alkali; (il) treatment rvith red phosphorus and- hyd.riod.ic acid,; (iii) red.uction with hydrogen and par-ladium Ín the presence of a baso.

The first method, u¡hich'was cliscovered- and studied. by AlbertJ38 ," recognised- as an excellent rneans of removing activated, monochloro substituents from a heterocyclic nucreus. only one successful 39 dechlorin¿rtion of a dichloro compound.1 t o" been achieved by this method, hourever, ancl with 1r4-dichlorophthal azinel v¡hich has a sirnilar a?Tangement of atoms in the d.iazine ring to !r&-pyri,io- (u¡, [¿, ¡-4]¡yridazine, and 1 ,{-p¡rrido¡r,+-ÈJpyridazin u, (67), no dechlorination has been accomplish"d.70, 127 t140 Similar difficulties occr.r-T rvith the recl phosphorus:þd.rioilic acid. red.uction ,orocess for ..-¿ although monochlo¡ophthalazines may be readily recLuced. by this rnethod,52t53'142 onty poor yields are obtained- from the dichroro similar d.erivativ "orpornd.?O "nd "r.141 -40-

Red.uctive catalytic dehalogenation has proved- the most general- method for removing chlorine atoms from heterocyclic compound.s. This procedure invol-ves hydrogenation over Jii pallad,ium on carbon in the presence of a ba,se v¡hich removes the hyclrogen chlorid-e which is formed as d.ehal-ogenation commences. The realisation that a base

\,yas essential for such reactions d.id not come until 1942 when

F.oblin and. cov/orkers d.ehalogenated compound-s in the pyrimid.ine *u"i"".143 The procedure has not¡ been used- with success on both r¡ono- and d.ichloro- pyrimidines pyrid-azin ,23t139'144 ""1145 2?'146 3Ba plrihalaøin6s'1 and ecrid.ines.l

i¡fhen the red-uction rvas applied. to the dichloropyridopyridazines¡ tlre parent heterocycles were obtained- in 6O-6>/" yield (Scfreme 29). It has been found, by \,[i-zzoni and. Spoerri that 3r6-d.ichloropyrldazine will- hydrogenate slol'rIy to pyridazine hydrochlorid-e in the absence of bu.=".145t No uptake of hyclro¡1en occurred, horvever, lvhen the clichloropyrid-opyridazines were reacted. without base present. Gaseous ammonia, ammonÍum hydroxÍcì.e and sod.ium hyclroxid.e v\Iere equally proficient

as beses ancl simil-ar yields were obtained- from each.

The 5, B-d.ichloropyrid.o [2, ¡-4] pyridazine lvas obtained LA 15-20îó higher yield-s by a modification of armaregors methoa-96 114-

Ðichloropyrido[f ,a-Ol pyricLazine'¡,, (61), a new compound¡ vras prepared. in simil-ar yield, by the same procedure. -41

Pd -H 2-Ol'l- r

t (67)

NHNH 2

,.J'l ,l N ¿t

N HNI{2 t

Ð e29

to (+t an¿ (6?), ,r""" also converted [he d.ichloro compouncrs, ) therespectÍved'ihydrazinoderivativesbyheatingovernightina rní:

(68) ancL (69), however, renders it far more convenient to use the d.ihydrazino or d.ichloro compounds as precursors to the parent pyrid"opyridazi nes.

( ( 68) 6g)

(") Ril.IOV^{I, OF TTIIOL GROUPS

The d_esul-phurisation reaction has in the past been successfully appliecl- to the cleavage of carbon-sulphr.rr bond-s in heterocyclic mercapto A typical example of this reaction is due to "otpo,rnd-".147 Bend-ich and covrorkers v¡ho obtained. purine, (Zf), from its 6-mercapto derivative, (lO), by treatment vrith Raney nickel in viater (Scheme 30).148 pyrimid'ine139 .td' 'I'he yield. from this reaction is only A,O'|L anù vrith phthalazi o"127 thiol compounds it falls to below 2Of'a. In tho latter case, cleavage of the Itr-N bond-¡ with the formation of ammoniå¡ v/âs found. i;o occur in some sol-vents. -43-

H

Raney Ni

N N H H (7 0't (71)

cHg

cH"l Raney r Ni t CH¡ SH (72) ->

Scheme 30

PyridoIe, pyridazÍne-5, ¡-41 8-díthlolI Ql ), rvas ìore])ared- frorn the dihyd-roxy ,phosphorus derivative and. pentasulphid.en. this corn,oound.

r'¡as unabl-e to be satisf,rctorily recrystallised_ and- ivas therefore convert ed t o the (met 5, &bis hytthio )pyrid.o fZ, 3_aJ pyrid azine, (l Z¡, which was shown to be id-entical to a sample prepared. by the meilrod. of Nitta and coworlcu=".101 v/hen the d.esul-phurisation reaction rvas applied- to the dithiot , (q,l), pyrid,o [2,:-dJ pyrid.azine v/as obtalne¿ in

1 6.51t" yield-.

2" PR.UPAIL{TTON OT' PYRIDTNE-o-DI C/lRll0,L4,LD tT{ïDl6

Pe¡haps the most wid.ely employed. synthesis of phthalazine is from the cond-ensation of phthaLaldehyde ,wittr llydrazine hycLrate (scheme 2; R=Rr=H). This proced-ure is rimited. only by the crifficurties -44- involved in obtaining the d-iald-ehyd.e,for the cond-ensation may be carried out Ín greater than )J"/" yíelù'54'74'149 Theextensionofthisprocesstotlrepreparationof pyrld-opyridazines required. the synthesis of pyrid-ine-2¡3-dicarbox- Both of a1dehyde, (l¡), an¿ pyridine-3r4-dicarboxaldehyder Oq). investigation these compound.s were unknown at the commencement of this although the presence of the d.ialdehyd.ee (z¡), had" been ind"icated- in the primary ozonolysis products of quinoline (Scheme 31)'15o The âiald-eþde v/as not isolatecl from this roaction but tv¡o derivatives yÍeId's r,yore prepared" The complex naturo of the prod'uots and' the Low of the d.erivatives of (t¡), rendered this me1hod impractical- as a route to pyrid'o [er¡-q] pyridazine'

cH0 cH0

0 cH0

(73) (71..1

The initial attempt to prepare pyridine-2¡3-d-icarboxaldehyde

was by the oxid.ation of 2¡3-lutidinq (?6)rv¡ith ch¡omium trioxide

and acetic anhydrid.e. ['his has previously proved a reliable method' for the synthesis of ald.ehydeg as oxid-ation through to the acid- is qem-d'iacetate I'rhich in many cases ¡trevented by the formation of a may be isolated. I,/lild. hydrolysis of the d.iacetate then liberates

the ard ehyd.e (schem . 3z).151 -45-

H c HO O3 + -250 I CH cHo

Scherme 11

CH(OAc), cHo CH 3 cro¡ 0H- AcrO H(0Ac) HO 3 2 Scheme 32

- HQ H3 Br'¡ Btz oH hu CHBr, HO 3 (75)

Scheme 13

Oxid,ation of Zr3-lutidinee Q6), by this method' appeared to ta.ke place as the reactÍon mixtu¡e gradually d,eveloped- a deep green colour, but the tetra-acetate¡ which presumably formedr was soluble in the acid.ic med-ium ancl could not be extracted. Sasification of the solution gave onl.y 213-lutid-ine. It is probable that the tetra-acetate vras l¡yd.ro]ysed. to the d.ialdehyd.e on basification and subsequent experience has sho¡,vn that pyrid-ine-2, l-d.icarboxald.ehyde cannot be extr¡:.cterl from d-ilute aqueous solution" By variation of the time ancl temperature of the oxid.ation and. by basification at O-5o a successful conversion into the diald.ehyde may have been achieved. but as a more convenient route to this compound. rvas,cliscovered, this approach was not fr.lrther investigated-. -46-

The sid.e-chaÍn bromination of o-xyrene und-er ul-traviolet J-ight, followecL by þd.rolysis of the resulting tetrabromo derivative¡

0¡), hars proved. to be the most efficient route to irhthal-al-d-ehyde

(scheme T),152 Di¡ect bromination of lutid-ine by this methocL

prod-uced- a bl-ack crystalline sorid., v¡hich d.id. not rnelt berovr 3500,

lnci co;oious quantities of hydrogen bromid.e r,vere evolved-. rt has ceen found, that the presence of hydrogen bromid.e prevents side chain bromin¿rtion of nitrogen heterocycles because Ít causes quaternisation

oi the nitrogen utor.153 1,1'oreover¡ if bromomethyr d-erivatives d.o Í'orm, the hyd-rogen bromide catal-yses the polymerisation of these 4 tr) cornpounds.'/'

:rchieved. by use of buffers to trap any \yd.rogen halicle on forrn^tion.154

Îhe clirect bromination of 2-¡ 3- and- 4-methyrp;rrictines and" the cìrlorination of 3-met\yrpyrid-ine have not¡ however, been achi"t"d-. 1 53

The 3-methyì- group is particularly inert d-ue to its position relative 'i,:r the nitrogen atom of the ring. The 2- ancl {-met[y] groups are .Lc-tivateclr hov,rever, and. in some cases react read,ily as the halogenation involves an ionic re"h,rni"r.154

A bromination proced-ure rryhich d-id. not involve þclrogen bromid-e forrnation ancl, lvhich was not ionÍc Ín mechanism r,¡as therefore required. ,Îhe use of lir-bromosuccinimide satisfied. both these stipulations as

::ecent mechanÍstic studies have ind.icated- that a free raclical process

is involvecl in such brominations and. that hyd-rogen bromid-e is present only in trace amounts,¡¡hich serve to promote a bromine atom chain.155'160 -47-

N-Bromosuccinimid.e v¡as first used' in sid-e-chain brominations of alkyl substituted. aromatics by schmid-t and- I(arrer rvho employed' from tolu .161 If tv¡o moLes this method. to obtain benzyl bromid-e "n of t{-bromosuccinimide are reacted with a xylene¡ the bis-bromomethyl derivative is the major pro¿oct.162 The reaction betv¡een four mores of irl-bromosuccinimid-e and- 9-xy1ene produces cJ'c:.'tò"ci.l-tetrabromo-o- been xylene¡ (1il.163 This sid.e-chain bromination proceclure has ìilinkeltunn163 successfully ad-apted- to heterocyclic compounds by

64 S bromomet hyl het erocycl es have anc ÍÌas eg (Scheme 34 ) . everal ^,rut and no nov,r been prepared by this method' but very few dibromo- 65 tetrabromomethyl d-erivatives have been repott"d''1

N,B.S. CH Br,picrate Hr9r 2 N 3

CH ,2 0 3 t, -_+¡Hr0 N zH4 o N N (76) (77) Scheme 34

The reaction of 213-lutid-iner(76)r r,vith foqr mol-es of N-bromo- highly succinimide ancl a littIe benzoylperoxide as catalyst gave a lachrymatory, orange oil which solidified.. on trituration in n-hexane' (ll), This product, which v¡as assumed to be the tetrabromo d-erivative, -48-

bui probably r,,ras contaminated. with small amounts of l-ower

brominated compounds, rvas obtained- in 3Zib yield.. The yield. ¡,yas not

only d.epenclant on the ease of quadruple bromination, but aLso on the solubility of the tetrabromo compound, (??), in carbon tetrachLoride¡

the solvent for the reaction. An efficient method- for removing the

remaining tètrabromo d-erivative from the resid-ue of succinimid.e lvas unable to be d.evised.

Ilyd.rolysis of the tetrabromo compound- in boil-ing rvater gave

a colourless sol-ution from which no ald-ehyd.e coul-d- be extractecì"" itn

ul-traviolet spectrum of a sample of thÍs solution showed, an absorption

pealc at Àrr* = 263 nvt id,entical to that from an authentic specimen of pyridíne-2e3-d.ial-d,eþde prepared- by another method.. Concentration of the aqueous solution and subsequent treatment lrith þrir azine hydrat e gave pyrid,o ['2, ¡-d] pyrÍd.azine (Scheme 34 ). The most inefficient step of this sequenco of reactions is the bromination v¿hich limits the overalr yield. of ,oyridc[2,¡-C]- pyrid-azine to less than ZO'ir, The same proced.ure, r,rhen applied to 3,4-lutidine¡ afforded pyrÍdo[¡r¿-qlpyridazine in a similar yield.

It is believed. these are the first examples of tetrabromination of the sid.e-chains of an aza-aromatic heterocyclè,,and- the only record.ed, cases of bromination of the 3-methyl group of a pyrid.ine compound.. 62a lo/ennerl noticed- in al-l brominations r,vith l{-bromosuccinimid-e that variable induction period.s occurred- before commetlcement of a vigorous reaction. It is of interest that sÍmilar time variations 'r,vere observed, u¡ith the bromination of the lutid.ines. An explanation -49- for this behaviour may be found- in the results of tho recent mechanistic stud,ie s.155-160 It has been suggested- that traces of bromine and, hyd-rogen bromid.e are necessary to initiate rad-ical chain formation so the commencement of bromination may therefore be d.ependant on the time of formation of small amounts of these compounds " Two method-s have recently been publish.ed- which describe the synthesis of pyrid-ine-d.icarboxald.ehyd.es by red-uction of tertiary amides ot of est"t"r167 lithíun aluminium h.yd-rid.e (scheme ,t66 "it¡, 35)" The reduction of the tertiary amide has been repeated- in the present stud.y and. the resulting dialdehyd.e has been shown to produce pyrido[Zr¡-4]pyrid.azine in 85-90$ yÍeId when treated rvith hyd"razine

Ìqrd-rat e.

ÇHg oÑ-c t{o R0f eHs LiAtHr L¡AtHl 00 - 900 0 RO T oHs 2 c H3

Scheme 35

).I PHYSICAI, PROPMI]ES

( a ) Gn[ERAI

Both the parent pyríd-opyrid.azines are colourless solid.s v¡hich are insoluble ín light petroleum (b.p" 4o-6o0)¡ moderately soluble in benzone and carbon tetrachlorid.e and. extremely soluble -50- in polar sol"vents such as chloroform and water. They are best obtainecl from aqueous solutions by repeated extraction with chloroform.

Soth of the parent heterocycles and ma4y of their derivatives may be purified- by sublimation which generally proceeds read.ily and. rvithout d-ecomposition. These heterocycfes are in fact extremely resistant to heat a.nd- v¡il1 withstand. temperatures of above 33Oo rvithout appreciabl e breakdown. n-electron deficient heterocyclés vrith high N:C ratios have been shorvn to be susceptible to hyd-rol-ysis. Pyrimicline, which has a lii¡C ratlo of 1:2t is hydrolysed to a small extent in hot, concentrated, alka1i21 and- pteridine (ratio 111.5) is readily hyd::o1ysed. und,er similar cond-itíons.'--168 The pyrid-opyrid.azines, which have a N:C ratio of 1:2.3s &Tês however, unaffected even by prolonged. heating vrith oler¡m containinB. 65it,¿ -^j d-issolved. sulphur trioxid.e and v¡arm caustic al-kali causes no d.etectabLe decomposition.

(¡) BÄSICITY

The determination and- interpretation of nKrs of nitrogen heterocycles has beèn extensively investigated. by :iLbert and- his colleaguet,59'169 Diazines are much weaker bases than pyrid-ine and. in some cases the reduction in basic strength may be 4 eq units. rll-bert bel-ieves three factors are involved.: (r) The electron attracting properties of the second. nitrogen atom which acts as a -I, -M substituent similar to a nitro group. I -5t

(¡) The formation of exactly equivalent d-ipolar structures in the non-ionised molecule which strengthen the resonance of this species at the expense of the ion. This has been postulated to explain the low basicity of pyrazine Ín comparison to the other d.iazines.59 Such a possibility¡ however, cannot exist in the case of the pyrid-opYridazÍnes.

(") Compounds such as pyridazine, cinnoline and phthalazine which pcssess ad.jacent annul-ar nitrogen atoms are stronger bases than pred.icted and. this anomaly is explained. by invoking hyclrogen bond'ing between two protonated species, as in structu¡e (?B), v¡frich thereby 59 attainr ad.d-itional resonance compared- to the non-ionised molecule' This phenomenon may possibly occur in the pyrid.opyrid-azine series.

(

/Innellation has been found- to hav.e very little effect on predict"d..l69b The introd-uction of oK'-, s and its cl"irection cannot be a nitrogen atom into a fused- benzo ring, however¡ causes a relayed ind.uotive effect v¡hich reduces baslcity. This is seen in the naphthyridine series (?9-82)r whích are rveaker bases than either quinoline or isoquinolinu.l3Tf The variation in basíc strength is, howeverr less for d.íaza compounds with nitrogen atoms in adjacent rings than for series with both nitrogen atoms in the samo ring. -q2-

. The --apK- of pyrid-o[2,¡-g]pyrid-azine lvas found to be 2.01 t O.06 and ithat of pyrido[¡r+-¿] r¡rridopyrid.azine was cal-culated- as

1.76 ! 0.03. Äs v¡ould be pred-icted- from the foregoing summary, they are weaker bases than the d-iazines, benzod.iazines or naphthyrid.ines.

Comparisons with the pK s of other triazanaphthalenes cannot be dravrn, however¡ as these compound.s und.ergo covalent þd.ration r,vhich produces rrfalse'r ionisatlon constants.lT'l Such hyd.ration effects d.o not ocour in tho pyrid.opyrldazlnee(soe p. 5? ). fhe small variation in basic strength which Ís found in series of bicyclfc compound-s with nitrogen atoms in both ringe is also apparent in the pfricl-qpy¡id.azines"

These compouncls appear to be rnonobasic as they only form rnonohydrochlorid-es and methiod-id.es and- only one pK" val-ue coul-d- be obtained- for each compound- within the limits of the instrument used.. ',¡lhich of the three nitrogen atoms is the most basic, horvever, has not yet been proved. conclusj-vely. As the d.iazine rings contain adjacent nitrogens these atoms vrould. be expected- to be less basic than the oyrid.o ring nitrogen because the ind-uctive effect of nitrogen atoms in the same ring is more base weakening than the relayed. ind.uctive effect between rings. The protonation of one of the d.iazíne nitrogen atoms, however¡ v¡or.ûd enable the forrnation of hyd.rogen bond-ed- d-imers oÍ'the type shov,rn in structure (20¡, and. these lvould- be resonance stabilised.. The prod.ucts of reactíons of pyrid.opyrid.azines are often expl-icabler however, if protonatÍon of the pyrid.o nitrogen atom is postulated (see chapt er 2). Än attempt to resolve the most basic nitrogen problem was mad.e by determination of the n.m.r. spectra of -53-

(79) (80) (81) (82)

the py¡id-opyrid-azines in d,ilute trifluoroacetic acid.. The resulting spectra, hovrever, were not sufficiently resolved- to enable interpretation. If, as Ís suggested, the most basic nitrogen is the pyrid-o

ring hetero atom, the nKu of pyrid-o[¡r+-g]pyrid-azine might be expebted to be slightly greater than that of pyrid-oIZrf-èlpyrid-azine because withdrawal of electrons occrìrs more readily from the o-position than from the 9-position in siùi1ar bicyclic compor.nd-u.169b The most brisic nitrogen atoms of some naphthyridines have been pred'icted- in th:-s manner.1 37f À1bert¡ however, has ind'icated- that there are so

rnany electronic effects responsible for variations in p{" that only

changes larger than 0.5 p{a unit can be ascribed vrith certainty to particular This apparent anomal.y in the case of the any "rt"u.169b pyrid-op¡'rid-azines may therefore be disregard-ed. The only other p¡æidopyrid-azine for v¡hich the basic strength

has been recorded is B-methylp¡rrÍd.o[Zr¡-èJp¡.tid-azine v¡hich has a p[ of 1.96 !0,04.96 This fr.¡¡ther serves to illustrate the base strengthening effect of methyl groups whioh has been observed. several times in the pt"t.1?0 -54-

(") IIITR,4.VTOLET SPECTRA

The ultraviolet absorption spectra of the mono- and- bicyclic

nitrogen heterocycles can be d.ivid.ed. into two sections. The major

portion of the spectrum is d.ue to n-n* transitions and- resembles that of the correspond-ing carbocyclic nrr"I"r".1?1 There are three main

absorption groups in the n-nx region of the spectrum and. these have been termed. either 9¡ p and. o band,s173 o" I, Tï and. rÏf band.s.174 The l-atter terminology v¿ÍIl be used. in the following d.iscussíon. 0f these band-s¡ flroup ï absorption is usually the most intense and occurs at shortest wavelengths. The lesser part of the spectrum is d.ue to the transition of an el-ectron located. in a non-bond-ing a -orbital of an annular nitrogen atom to an excited- *-orbital of the ring. This is termed. atr h-7t* transition and has no counterpart in the speotrum of the correspond.ing carbocyclic aromatic nucleus.1 7l 'l7z The introd.uction of a nitrogen atom does not greatly affect the shape of the spectrum compared- to the carbocyclic analogue.

There is, however¡ a loss of fine structure and- the group IfI band.

is intensified" as the resultant red.uction in s¡rmmetry caused. by the

nitrogen atom makes these z¡-zc* transitions more allov¿abf e. The group IIï band.s often shíft to slightly longer lvavelengths on the Íntrod.uction of a nitrogen atom,171'175 the n-rcx transition bands are pÌesent but barely observable in monoaza heterocyclics. Those band-sr which are d-ue to forbidd.en transÍtions, are of very 1ow íntensity and- consequently are often masked. by the stronger, ¡-z¡* transitíons. f'he æ-electron levels are -55-

l-o¡,vered by replacement o1'=CH- by -N= and thÍs effect increases with the number of nitrogen atorns. n-¡* Transitions therefore occu¡ at

progressively longer vravelengths for d.i- and. triazaheterocycl-es.

the lol'¡est energy n-¡c* band-s of azabenzenes or azanaphthalenes d.o

not vary greatly with increasing azasubstitution.lTla As a consequence,

the nwcx band"s may be more readily observed. v¡ith d-iazaheterocycles

as they und.ergo a pronounced. red- shift in comparison rvith the monoaza

compound-s. Consequently the n-7çx bands are often well separated- from i;he group fïï bandsn In the case of the o-diazines the l-one pairs of the ad.jacent nftrogen atoms interact 1n such a nanner as to further

l-ower n* leve1s and an increased. bathochromÍc shift of the n-rr* Ì.¡and.s resul-ts for these compound-s .171d'176

Ânnellation causes a larger shift in the nvcx band.s of a.zines th¿:.n l.¡ith the n-zrx bands and. this often results in the n-xx band.s of these cornpound.s being submerged beloiy the group III band-s.171a'e zi-zr* band-s show: no marked- solvent effects but the nwrx bands und-ergo a pronouncecl \ypoochromic shift in poì-ar solvents d.uo to hydrogen bond-ing effects betrveen the nitrogen lone-pair and. the solvent molecu1es"l 71d"

'I-o observe nvr* transitions 1n such compounds it is therefore necessary to use a non-polar solvent.176 The azanaphthalenes quinoline, isoquino)-ino¡ quinazoline, ohthalazine, quinoxa).ine and the naphthyrid-ines possess ultraviolet spectra very similar to that of naphthalene but in each case the group III absorption is more Íntense"171'137f Tho general ranges of the n-zr* band.s are group I: 200-220 n¡t, group II: 240-265 np, -56- and group III: 280-31 5 mP. n-lÛ transitions of the benzodiazines have al-so been observed when non-polar solvents are ompLoyed, Some anomalies do occu¡ hovrevel¡ In the case of the quinolines¡ group II and, group III absorptions merge and render interpretation of the spectrum most d.ífficult. The absorption band"s of cinnoliner rvhilst they retain the same shape of the naphthalene spectrumr show a marked. bathochromic shift and. this has been ascribed to the hÍgher energy of the ground- state of this heterocycl".176b The spectra of the pyridopyrimid.in""Tl and. pyrid-opyrazinet9B'99 have also been rsçorded and theeç ales folloy/ tho gencral Batterhc

Some group I absorptions presumably occur at wavelengths too short for detection, however, and. nwtx transitions \¡/ere only found in three of these compounds. The spectra of the parent ptr¡id.oplæid.azines were determined in vrater¡ )Jjt ethanol2 cyclohexane and. 1N' hyd-rochl-oric acid. [he group fI anfl group Ïff absorptÍons are plainly apparent in the regions

240-?-60 m¡.r and. 285-30, mP respectively. The limitations of inst¡ument and. solvent d.id, not a1lorv the group I absorption to be observed- in etha,nol or cyclohexane although strong band.s were observed at the ìu = 206-214 ml¿ in ',vater and- 1N \ydrochloric acid.. reliabilíty of these valuese however, is suspect as they were record-ed. at extreme limits of sensitivity. As expectedr the overall spectrum resembles that of other azanaphthalenes and- the group Ïff band- is of a higher intensity than for naphthalene. -57-

In an effort to observe n (* band-s, the 300_395 mp sections of the spectra were determined. using cyclohexane as sol-vent and. 5 cn. cells to increase the optical d.ensity and" thereby facilitate observation of these absorption bands. Each heterocycle showed- a number of iilL-d.efined.l low Íntensity b'ands which a¡e und-oubted"ly due to n-n* transi-tions. The bands rvhich occur at longest wavelength are probably those associated. with the o-d.iazine ring for reasons already outlined.. As has been observed. with phthalazi ner176c the apparent intensities increase on pæogression tolvards shorter wavelength d.ue to overJ"ap with the foot of the n-n* band-s. to/ COVA-LMM HT'R\TÏON

Practically aì-1 investigation of this phenomenon is d.ue to

.rrlbert and his colleagues Armarego, Perrin and- BarlÍn. îhe fund.amental featr:¡es of covalent \ydration have alread-y been d-iscussed. in the introduction. The reason for the occurrence of such hyd.ration in azaheterocycles also requires explanation.

llany reagents have been shown to ad-d, across the C=ltI bond. of azaheterocycles but it is surprising that v¡ater should. also ad.d. sirnilarly becauso it is only a weak nucleophile and- such an ad-d-ition l¡Jould be accompanied. by a loss of aromaticity. This ad-d,ition has been demonst¡ated. for only a small number of heterocycles. It is probablel however, that many other heterocycles undergo hyd.ration to a smalÌ extent but present d.ay techniques are inoapable of observing the pto""=".17? 58

The occu¡rence of add.itions to the c=N bond. is due to the presence of severar nitrogen atoms in a ring rvhich d.eplete the

n-electron cloud to such a d-egree by electron attraction that normal

aromatic stability is destroyed.. An isolated¡ highly polarised C=N

bond. ís therefore A similar resurt may be achieved. "*po="d-.177 from a consid.eration of the valence bond. picture of such compound.s. Tn

this case the same bond-s are found. to have a very high bond, ord.er. strong nucleophiles therefore attack these bond.s, but as rvater is only weakly nucleophilic, for ad.d.ition to occur extra st¿lbilisation such as that d.ue to resonance is nocessary. "tlbert has classifÍed. the i¡åTlôus pôsgiìdlê rêijóhance siabilisation processes into (a) amidinium

(b) guanídinium (c) urer ana (a) 2- and 4-aminopyrid.inium type resonances. These various stabil"ising effects have been used to explain covalent hydration in a number of substan""".177 !¡/ith phthal.azi-ne such strong resonance effects are not possible, and onry the very v¡eak 3-aminopyridazine type resonance is possible

j.n the pyrido[Zr¡-È]pyrid.azines. ;Lrmarego was unabl_e to d.etect any covalent hydration in either phthalazine or B-meilryì-pyrid,o[2, 3-È]- pyridazÍne ancl furthermore preclicted that pyrid.o lz, ¡-qJp¡rrid.azine j.tself v¡ouId. be pred.ominantly .nhyd.rou".96

The synthesis of both pyriao[2,3-È]p¡rricfazine and. pyrÍd.o-

Ilr+-0Jpyridazine has enabled. this postulate to be verified. The potentiometric titration curves of these heterocyclic bases were reprod.uced- on back-titration rvith a1kali. The l-aclc of a hysteresis -59-

loop is strong eviclence th¿:,t covalent hyd.ration does not occur to

any marked. d-egree. ff lqrdrated. species r'¡ere formedr there would. be

a range of pl{_s present and this woul-d. result Ín such a loop being formetl on reverse titration. The pK s of these heterocycles are also of a normal order v¡hereas in most cases the presence of covalent

\yd-ration causes a marlcerL rise compared to the expected. vaLues of the ionisatíon constants.

Further evid.ence v¡as obtained. by examining the uJ-traviolet

spectra in various sol-vents. Covalently Ìgrd.rated. molecules often

shorv marked variations in spectra betv¡een aqueous ancl aprotic sol-vents as hydrated. species in the l-atter should- absorb in d.ifferent regions of the The spectra of the pyrid.opyrid"azines in rvater, "pu"t"*.1?1 cyclohexane and. 1N hydrochl-oric acid. shor,ved- practically no variation

rn absorption marirra ,,vhich ind.icatecl -bhat both tÌre neutral rnof ecules The and the cations vrere ^oredominantly an\ydrous. similarity of spectra Ín both r,vater anc', ¿¿cid. has also been noted- for p¡ridine, quinoline¡ 1¡B-na¡:hthyrid.ine and oiher rran}¡Idrousrr contpound.".17B This

is d.ue to the fact that the main absorption band.s in these compouuds

¿.irise from n-n* transitions, and. protonation of the ring cannot greaÌ;Iy affect such transitions.

( ti ) ¡TUCLEqTì L,LIGN]II'IC RESONi\NCE SPI,'CTRA

Iluclear magnetic resonance (n.t.r. ) spectra afford- convincing proof of the structure of these compound.s as ,,'¡eIl as provid-ing much other information of interest. 6o

(1/ PYRIDO rYRTDirZfi{1tr (see Figure 1)' form Protons Hur H,n and- I{* of the pyrid'o ring' an,,ÁJ,[Ksysteminv¡hicha]lthechemicalshiftd-ifferencesareverymuch I! and IJ, of the cliazine greater than the coupling consts'nts' Protons ringarespin-coup].ed-and.H,isalsoinvolved.ininter-ringcoupling Hu as quartetsr HU as a with Hr. Thus the spectrum shows H*: Iir and' cloublet and- H,o as an octet' Theassignmentsofthevariousprotonsisbaseùonringcurrent The ring current may be compared anc)- magnetic anisotropic effects' protons Hrr Hu and- II, should- ';o that of naphthalene and- by analogy¡ anisotropy of the therefore ooctlr at loivest field-. The magnetic niirogenatomslwhicharisesfrom]-one-pairæ-orbitalpromotioneffects' causesHrtooccu-ratlolerfield-thanHUranclH*atlotverfield'than Ho vrould also be expected i-la. By comparison v¡ith pyricline and quinoline' is supported to occur at lor,¡er fiel¿ than H*.179-l9o This assignment bytheobservedsplittingpatternsand'couplirrgconstantsand.hasbeen verifiedbyspincouplingand-analysísofthespectraofsubstituted' derivat ives.

ITANTS FOÏI TA3I,E T _VA],UlÉ 1.¡.NL) COUPLING CONS

Pyrid.o +-¿l PYrid.azine Pyrido Iz f-d] PYrid-azine [¡, ' ?roton T Proton T

H 0. Bg H 1.6; d m H 2.13 H 2,15 m a o,67 H o.45 Hx 61

H 0.33 H o.27 J v H o.17 H o.27 z

Coupling Constants c/s Coupling ûonstants c/s

J ( *) 8,4 J .'.,^r) am am J (*) J 1.4 ax 4.3 mx J (*) 1.8 J o.4 rnx ax J (*) O.B J 1,5 mz yz

J (-) l.) J 0.8 yz xy J tt mz

* unabl-e to be d.etermined-

Coupl-ing Constants

The possibility of protons spin couplinl r,vith nitrogen atoms

is el-iminated- by quad.rupole reLaxatiortlS0 but a complete range of possible spin-spin couplings betrveen protons has been observed. lrroton H, ma¡r take part in two non-equivalent ortho couplings I'rith H* a.nd- H*. The coupling constants of these interactions are 4.3 c/s and. m 8.4 cfs respectively and. are in good agreement v¡ith the constants for equivalent coupJ-íngs in similar compound-s' For quino1inerlBl 182 Bt 1,5-naphthyrid-ine¡ (lÐ, and. 1 ¡6-naphthyrid.ine,' (go), these coupling constants occur in the range +1-4,2 cfs and- B.o-E.3 cfs

respectively. 'Ihe gglg coupling constant, Jmx, of 1.8 cfs is also normal as in the above examples this coupJ-ing is of the order of

1 .7r-1 .g c/r. J am J am J J J ax A ax ax J rß yz A J J JJ mx mx mz mz J J JJ mz mz mz mz

I o\ P I

H H H a m x q 590 465 4 495 5to 553 5 7 H rn Y ./t He N 1 ltr"rn,r. spectrum of pyrid-o[2, ¡-è]pyrid-azine in deuterochf oroform. ¡ Figure . H N x z -63-

Coupling over more than three bond-s is terrned. long-range 183 coupling.'-- Until recent years such coupling vras not v¡eI1 authenticated- for long-range coupling is usually very i,reak and. the resol"ution of the n.m.r. instruments was not alvlays sufficient to enable its detection. 0f pertinent interest is the inter-ring coupling v¡hich occurs over five bond-s. This has been found in both aromatic and- heterocyclic compounds ancl ste¡eochemical considerations have red to the belief that attzig-zagrrpath is invol-ved as in (Bl).183'184 jìara coupling is also includ-ed. in the scope of long-range sirin-spin spl- itt ing

The coupling const¿r.nts of these long-range interactions are not lveIl- record.ed- for azaheterocycles. This is d-ue to diffículties in interpretation of cornplex speotra caused by the rr¡eakness of the coup.Ling, multiple splitting, and. overlap of absorption peaks. The

,ores-;ent spectra, hoivever, are rel-atively uncomplicated. by such factors and are therefore of interest as the long-rar¡ge couplings are read-ity cliscernible, t-he Þa,ra and. inter-ring cou,olings in pyrid-o[Zr¡-O-l- pyrid-azine occu.r over fÍve bond.s. 'Ihe constants for these coupling inieractions, J--_ and. J_--, have magnitud.es and. O.B ' yz mz' of 1.3 c/s respectively. These values are roughly in accord- ,¡¡ith the magnitud.es of similar couplings in other aza-helerocycles. The para coupling constant, Jur, may be compared ro ,rr, of pyridine, 0.9 c/s]79'180 JzrS of pyrimid.ine, 1.4 c/srt3' ,,rB of 1¡6-naphtt¡*id.ine, (go), 0.45 cfsrl3z J- o of pymolohrz-a)pyrazine, (B+), l.jj J. o of )tö ' "/=185 "na )tó pyrrazoLo[l rl-e] pyridine, (Bl), 1.o2 c/s.185 6q

m

T N ç

(93) (84) (8 s)

81 82 J,ong-range inter-ring couplings of quinolin"rl 1 ¡ b-naphtn*roln"j B? BJ phthalazinerl 87 quinazolin"' and cinnorin"l have constants in the range of 0.4 to O.g ./". It is also of interest that protons Hu and- H, d.o not couple to tl or H--. As a zig-zag pallt is not possible with these proton d4 appositions this afford.s further evidence that a specific stereo- chemical rel-ationship between protons is necessaÌ'y for long-range coupling to occur'

(ii) PYRIDO [ ¡. ¿-A] P]IITDAZINtr

The n.m.r. speotrum of this compound (nigy1.e Z) is a little more complex than that of pyrido[213-o]pyrid.azine¿ The spectrum consists of a weakfy coupled. AIfi system upon rvhich long-range coupling

pealc protons lL and- ha,s been superimposed, together ','rith a single for I1z. This last peak cannot be resolved even uncler high resol-ution' lho rneta coupling constant, Ju,x, is very.sm¿I1 and- a]though I{, appears as a quartet and. H, and- H* as octets¡ most of the splitting rnay only be seen at high reeolution. H, and- HU cannot be completeì-y resolved but theoretically should exist as cruartets. The assignrnent of protons was macle by the same procedure as for pyrid-o[e,l-èJpyrid-azine H z H¡¡ H v H a Ha N

Å

H H x z m

o\ \Jî Ex

535 555 5 5 0 c/s

Figtlre 2. N.m.r. spectrum of p¡æid.o[¡r¿+]pyrid.azine in d.euterochLoroform. 66

a,nc. v/as verified. by the observed. splittings, coupring constants,

;r,nd. spin d-ecoupling techniques. H" and- H, occur at lov¡est field. and_ lk "t highest fie1d,.

Couolins Constants

lìhe magnitud.e of the ortho coupling constant , J is 6. j ^", "/" which is slightly higher than norrnaL. The equival-ent constants in

1 7 9' I Bo 82 is oouinol ine, 1, 6-naphthyrid,inel rnd. 2, 6-naphthyrid.ine have values of 6,o cfs. The meta coupling constant, J.x, is d.iscernible but very small ancl has been ascribed. a value of : O,\ c/s. fhis is in agreement with simil-ar couplings r¡¡hich occur via an intervening nitrogen atom as in most ca.ses this splitting is too smal-r to be deiected. Èor pyrimidinel86 ona quinazolinulB? this constant is recorded- as :O and for pyrid.in., J2r, is 0.4 "/".179t18O Four long-range couplings are possible in pyriO.o[3,4-e]- pyridazine anrl al.though al-l- are observed., coupling cons'bant val-ues coul-d- only be assigned- unambiguously to th¡ee of these. Two inter-ring couplings, J-..- and J*-, both invorving the path, xy mz' zig-zag are abre io be recognised- but the coupling constant of t*u was unable to be d-eternined-. J* has e. ma,gnitucì.e of O.B cfs, the same value as the equivalent coupling constant in pyridoIer:-È]pyrid.azine. Soth ¡¿gre cou¡rlings are observed. anrl J mxand Jyz v¡ere found to ha,ve values of 1.4 c/s and. I "5 c/s respectively vrhich are also of the same orcler as the pata couplÍng constant of pyrido[2, l-dJ pyridazine. -67-

r3y use of doubre irrad.iation techniques, the rerative signs of the couplin.q constants oir the pyrid.opyridazines may be ctetermined_. ?he ortho coupling constants are postulated to rrave a positive sign, an assumption which is macle in orcler to have a basis for compa"i*on.189 The other couplings are assignecl rerative to the J-argest ortho coupling constant of the pyrid.op¡'rid_azines. The results are shov¡n in Table 3. The n'rn'r' spectra of the pyridopyridazines are so distinctive that they enable a simple and- unequivocar efuciclation of the structures of substituted cì-erivatives to l¿e 4aç1e, ?he long=ï¿inge cou¡riin6 effeete nay ì:e allied' to chemical shifts to enabLe positivej r;.eterrninatj_o¡l of position of substitution.

Ch¡:r',qe ) ens ities

comparison of the n.m.T. spectra of tre pyridopyrid_azines those of ouinoline 'rith and. isoouinorine reveals marked- chenicar_ shÍft differences. These differences cannot be exprained. by an increased. Ir-ng c*rent in the diazine ring for the ring cr_rrrents of benzene, p¡'ridine and. pyrimid,ine are found to be al_most equivalent.lg} ¡.or al-l practicar purposes, i;hereforeo rir¡1 cwrent d.ifferences arê neglected.. o' variations -Bond between the ,oyrid_opyricì.aziiles, quinoline and isoquinorine shoulcr be negrígible and. ilre rnagnetic anisotro_oy effect of the pyrid-o nÍtrogen atom shouLcl bo al-most icLentical in e_,.1 compound.s. The differences in chemical shift betleen quinoJ.ine ancL pyriclo lzrl-l)pytidazine and between isoquinoline and, pyrico[:,+_¿J_ pyrÍdazine ûÞy therefore be interpreted. as d_ue to changes in n_el_ectron -68-

clensities. By use of 'bhe relationship

ô ao. 1

v¡here ô. Ís the chemical shift d.ifference and- a is a constant equal to -8.33 p. p.m./aharg"r19o relative values for the clifference in chi:,rge densities: Qir may be obtained.. TrrÍs process enabres the

charge d.ensities of the pyrid-opyridazines, quinoline ancl isoquinoline to be comparecL ('¡a¡f e 4). g,g_g

PnifDO [:, ¡-q] PyRr!¡\Zrirril PlîrrDO [:, +-g] P flìrD.rZrNE

ô ôt .5. qi ò ôr (J.ç o. Irrot on l- Prot or I (Eui.nor /- \ c/s ine ) c/u ./s \ J-Soqu].nol1ne / c/s

2 560 533 27 -0.o54 5 573 552 21 -o.042 ) 473 440 33 -0.066 1 546 509 JI -o.07 4 4 503 485 1B -o'036 Õ 412 -450 22 -o,044 8 590 485 48.6x -o.o97 I

Spectra run with an oscillator frequency of 6O Lic"

x ,ifter allowanco fol effects of grou.Ð. 'dj'cent ciazine

n-Efectron densities of quinoline and. isoquinorin"rl90 (g6) ana (gB),

ca,lcul-ated. by molecular orbital method.s, may then bo usecl_ to obtein rrquantitative a resurtrr. The outcome is d.epenclant to a rarge d.egree

on the reliability of the calculated n-electron densities so not a 69 great cleal of cred.enoe can be placed- on the magnitud-es of cha,rge d.ensit ies so obtained-. The relative magnitudes, houever, are lnost inf orrnat ive (diagra.as ( B? ) and. (gg ) ) .

0.9r¿ 0.981 0.8 78 1.0s4 r.021 099

0.976 0.7e N 123I 1'016 0.919 (s6) (87)

1.0 6 5 1.018 ê¿1.0 2l 4,877 0,97 3 0'80

1236 1.0r 9 r

0'8 3 2 0'97t 0.79 0

(88 ) (89)

Àbsolute values of charge d.ensities may be obtained from cheiiric¿rf shift d-ifferences compar.ed- to naphthalene. i\s al-I the carbon atoms of naphthal-ene have an electron d-çnsity of 1.0r subira,ction of the d-ifference in charge d,ensiiy, obtained' frorn the che¡nÍcaL shifts after making al-fotvance forbhe effects of nitrogen atons, procluces absolute n-efectron density vaLues chemicar shifts are affected- by' various factors .190-191 lhese are enumer¿¿ted belorv. (u) Ring currents. The ring cunent differences betr,veen naphthalene ancl the pyricìopyridazines are negligible for reasons stated above. -?0-

(U) l.lasnetic anisotroPl¡' causes a shield-ing Replacement e¡ ¿1 =CII- group by =N- ci the nitrogen atom' has effect of -0.33 p.p.m' for protons to practica,llynoeffecton[]protonsanclshiftsYprotonsupfie}d aff ected" by the by +0.03 n.p.*.191u IIU of ouinoline is also Dai1ey190 hn't'u estimated this magnetic anisotropy of Il-1 ' Gawer and- effectas.O.52p.p.m,butastheequivalentcorrectÍonsuseclfor.l;he a-¡F-and.Y-protonsb)'theseauthorsaremuchlargerthanthoseof quoted above and used Ín this stucly' Gil anci- l,Íúrrelil91a v,hÍch are of p'p'm', based on this figure rvas reinvestigated. À vafue -o'J8 quinoline spectra' has been dÍfferences betvreen the naphthalene and escribecl to this eff ect ' '

( ) El- ectric f ielcl ef f ect " Chemica]-shiftsa,ree-ffected.bytheclrangein¡,rotonshie}d-ing cu.eicthesubstitutionofa=CI.I-d"ipolebya=l[-d.ipole.lhiseffect and. p.D.m' for protons csuses chemic¿.ul_ sb.ifts of -0.a,2, -o.1gt -0.14 utot'191u ctr g ancl T respective to a nitrog"n

(¿) Iìeactig.n eleciric field Ís negrected' ,rhis is a smarl effect caused by the sorvent and

in t he Pres ent calcul- ilt ions ' fhechemicalshiftdifferencesbetv.¡eenthepyrid.opyrid'azines for the eff ects (¡) an¿ (c)' The anrJ. na,phthalene were corrected to changes in charge densÍtyt resiciual chemical shift was then equated- theremainingfactorv¡hichcancausechemicalslriftvaria,tions.Tlre -71

results of these cal-culations are sumrnarised- in Table I and_ d.epÍcted- diagramatically in d-iagrams (90) ana (gf ).

(r) TI\1¡Ìù\RtrÐ SPITTIìA

Àrmarego, Barlin ancl Spj-nn"1192 have cond.ucted- a stud.y of thþ

infrared- spectra of a number of bicyclic aza-aromatic compound-s and-

have founcl. that all observed absorption band.s in the region ¡T00-650

courd. bo empirically tabulated. into tvrenty groups. Thero "rl1 three shoulcl theoretically be tvrenty th¡ee vibrational band_s for the

triaTar,te,phthalenep buJ only rarely are all d,etcated, in praetie e, These band-s are composed of ten C-H bend-ing anct thirteen in-plane skeleta]

vibrat i ons .

/t'ccurate infra-red. measurements have been carried out on the

pyrid.opyrid-azines and- the absorption band-s have been found- to accord-

r'¡ith the assignment of Spinner and. his v¡orlcers. The assignments are shoryn in Table 6.

0.931 0.877 r.003 0.871 0.963 0.884 T '| 0.8s6 N N 0.903 0'868 0.871

(90) ( 9t) TASLE 5

PIRIDO [2, ¡-a jffnlDAzrtr-E

Correction Correction Proton ô ör (naphthal-ene) ô HB ]- ô. con. o. for (t) for (c) correction L '1

2 560 443 117 -20 -25.2 71.8 -o.144 3 473 443 30 o -11.4 18.6 -0.037 4 503 462 4t 1"8 - 8.4 34.4 -0.069 5 5æ 462 118 -1 9.8 -36,6 61.6 -o.123 B g.B I 5go 462 128 -l -36.6 -23.O 48.6 -o.097 -¡tu PYRTDo [ 3. 4-d,I PYRIDAZINE I

Correction Correct Proton ô ôr (naphthalene ô ion t ô. corr. o. ror (u) for (c.)

5 573 462 111 -1g.g -25.2 66 -o.132 7 546 443 103 -19.8 -25.2 5B -o.1 1 6 B 472 462 10 0 -11 .4 -1.4 o.003 1 583 462 121 :19.8 -36.6 64.6 -o.129 4 583 462 121 -19.8 -36.6 64.6 -o.129

ô varues ín cfs from T.M.s.; oscillator frequency 60 i{c; sol-vent: CDCI 3 TABLE 6. il{FiÌAiìED SP}ÐTRAI, BANDS OF THE PTRTDOPYRTDAZ]NTS

ï ïr IIT IV v VT VII VTIT I]K x COMPOU]TD skel- st. skel . st . " skel. st . skel.. st skeÌ . st . skel. st. CH in p.b. skel. st. CH in p.b. CH in p.b.

1312 s 1314 s Pyrid o [2, ¡-O]pvridazine '¡610 s l5B4 s 1563 n S 1464 1436 s 1 3BT vw 1344 s 't298 w 1271 nr

1309 v¡ Pyrid.o [¡, +-è] pyrid.azine t6tB 1179 m 1549 É m w 1481 1462 1436 vr 1405 s 1333 m 1297 w 1 280 rn I --J (¡J

XI XIÏ XIIÏ xïv xv XVI XVII XVIII XIX XX I COI,,[POUND p.b" I 't tH in CH in p.b. sÌ

923 s 833 m Pyrid.o pyridazine [2, ¡-q] 1186 m 1133 s 1100 m 1033 s 1009 w 961 s 915 s 8tl $¡ 992 w 9ol s

!2Bs 839 rt Pyrido s '100! [¡, +-4] ,pyridazine 1259 1155 w 1097 v¡ 1037 m vr 966 n 916 s Ur4 s !08 s

fntensitios d-enoted- by s = strongr IIt = med.iurn, vr = yrêâkr wr = very vieak skel.st. * skel a1 stretching; CH in p.b. = CH in-pLane bend.ing; skel.b. = skeletal bend-ing; CH o.p.b. = CH out-of-plane bendíng Wave numberõ are i-n cni-1 . Solvent: chl_oroform -74-

CI{APÎ-¡]R 2

REACTIOIIS OF PYRTDOPTRTDAZT]IË

(u) THEÐRET TC/.\-L COI{S TDtr}ìAT ÏONS

Prior to an investigation of the reactions of the pyri-d.o- pyrid.azines¡ some ind.ication of the suscepiibility of the nuclear carbon atoms tov¡ards attack by various reagents v/as d.esirable. Such information was obtained. by val-ence bond-, molecuÌar o¡bital and. n.m.r. consid-erat ions.

If structures lvhich contain either illong bond.srr or more than one l-ike charge are not includ.ed, eighteen val-ence bond- canonicaL f orms may be d.ravin for pyrid,o [2r 3-d] ,oyrld.azine and seventeen for pyrid.c[¡r+-E]pyrid.azine. The resultant overall electronic charge C.istribution diagrams, (92) an¿ (g¡), ind.icate that each annular carbon atom of the pyriclopyridazines is eLectron deficient in comparison to those of naphthalene. This method- pred.icts that the l-e¿;st d-eactivatecl c;¡rbon atom of pyrid.c[2,¡-¿]:yrid.azine is at position 3 and. that of pyrj.d.o[¡,+-g]pyrid.azine at position B. These positions are therefore the preferred. sites for electrophilic atta.ck. Such substitutlons lvould. be expocted. to proceecÌ v¡ith more d-ifficulty than for quinol-ine or isoquinoline because of the electron withd-yarving effect of the extra nitrogen atoms. Conversely¡ nucleophilic attack should- proceed. more read.ily than for quinoline or isoquinoline. Positions 2, ) and- ? of pyriaolZr3-4]pyridazine -75-

shor-rld be most susceptible to such substitution and_ for pyrÍd_o-

[¡r+-¿J pyrid.azine positio ns 1 ¡ 4t ! and- 7 aye activatec]. tov¡arcls nucl eophil ic at'tack.

These postulates are supported. by ilre absorute charge

clensiiies calculatecl fi:om R¡Í1.r. d-ata. rfinal proof of the vaJ_id-ity

of these assumptions l¡ras ltrovid-ed- by n-electron d-ensity calculations '"vhich r,'¡ere d-etermined. using the linear combÍnation of atomic orbitals - mol-ecular orbital procedwe. The resultant d.istributions are d-epicted- in d-iagrams (9¿) ana (gs), These resul-bs are of the same ord.er asthose obtained, from the n.rJr.r. d.ata. The major clisorepanoies invol-ve positions adjacent to nitrogen atoms and. past experience has shown that this is usual-ly a general v¡eakness in such calcuJ.ations. DÍfferences are not great, houreverr artd the overall result confirms 'ch.e pred-ictions concerning d.irection of substitution.

f+ f+ tt+ J+ f5+ + t+ N 3+ N ñ + + 6+ á+ t+ (9 2) (9 3)

0.9 05 0.86 3 0.968 086 I 66 0'977 \reoo 093 1.183

0.8 91 ñ,,',' 1'18sN N t1200 1205 0.87t 0894 08 5I

(94 ) ( 95) n-EI ectron Dsns j.{ isg -76-

0.920 0'890 0'995 0.902

0.992 .981 1.152 0.9?9 5 1'r 35

35 3 1.r 0'88 r 1.134 1.t83 50 1.203 0.912 0.883 0.885 (96) ß7t q¡-Iìì'ì ect Tro n D ê nsít ies ( iltrait a nrl l?esl ov)

2tg 2t3 N. th rh 1b It ñ N 2ls N 2t3 t4 43

(98) (9 9) .ipnroximate n-Bond Orclers

75 0'790 0 67 0783 0.708 03 0.6 2 0.538 0.461 0.608 0.532 t,57 0 10 0.69 N 788 0,6 73 84 (100) (101) Huckel-irl.0. n-3ond Orclers

1'37/. 11' 375 1.38 t3 t. 17 7

1-/. l.t 20 l't 21 36 29 6 l39l N '415 t3 3 fi 02) (103) Sond- Lenqths

0'458 0¿38 l'Lt 9 0'43 g N 040 b r 0416 22 0.119 21. N 117 0438 0¿6 r 0'43I'{

(104) (105) ilree Valence Numbers -77 -

À recent publication by yiait ancr. ìTes1ey193t ,-r"*" the charge clensities of several azanaphthalenes and. includ.es d-istributions for the 1r;.rid.opyridazines (.liagr¿ms (96) a,nA (gZ)). The rel-ative orders are simil-ar to those caJ'cul¿rted' in the present r'vork but the rna¡iniiucles are somer'¡hat larger. This'is d,ue to the basic assumptions and pararneters chosen and these are summerised- in 'Iabl-e 7'

T,IBLE 7

!'LiIT AN.I) FrT'Âc, TIITS i¡/ORK P,"uLÂlJiillIlR I//EJI,EY et al

 1 93h Cou.l-omb CL Y o'5 hr' = 0.58 Integral 5 +}\{ c \rT = \=0'6

Coulomb Integrals -of atoms ad.jacent t93c ònh* 0, alL same ô=0.1 'o = C.125 to nitrogen atoms h"r, = c

ít IÌesonance egral-s 9."=Ê"N=9Ml 0 =lJ l" -Y-11 rr-l-1 int c c c-L\",=1 cc cN f? -" Plrll--Ê. -, .wr<.7 tCCR "l[N-'

The rnaÍn variations betrveen the parameters of ÌTait ancÌ lVesley and. those of i;he present calculations invoLve the allovrances for Êr* and- the coulomb integrals of atoms ad.jacent to the nitrogen heteroatoms. .¡!s

',i¿,it, and. liresl-ey made no correction for these effectsr the c¿rLcul¿¿tions of the preisent investigation are perhaps moro accurate although the value of 0* = 0.67 9"" tty be questionabLe. [he v¿r1ue chosen for

ß* may be compared- to the value of g¡1¡¡ obtained- using the reLationship

tr'rom the tables of lviullikan, Rielce, Orloff and. ß'xx - constant,.Sxx . Or1offr193d and- v¡ith the assumption rN-N = rc-c = 1.39 1, and- -78-

"lü[ Zeff. N Zeff. C Prw B x = 3.90r = 3.25) 'cc ù = 0.61 fl = 0.61 - cc

Paulingrs method for the d-eterrnination of approximate æ-bond.

orcLe¡s gives the result shov¡n in (gB) ana (99) v¿hereas the more sophisticated- Iluckel - li{.0. treatment afford-s the bond- ord.ers d-epicted j.n (f OO) ana (tOt ). ff the pyriclopyriclazines v¡ere to undergo

e.dclition reactions the bond.s of highest n-bond- ord-er vrould be the most fr'rvoured. sites for reaction. These are the 1:21 324, .l:6 anc J:B bonds ¿ncì. of this group the c¿l,rbon-nitrogen bond-s of the d.iazine rings

Ìrsr¡e ¡nost d.oubie-bond- character, rhe bond- lengths of the pyrid.o- pyriclazines shown in diagrams (lOZ) an¿ (tOl), r'rere calculated" from the n-bond orders usin.,q the relationship

Bond length S q I o.7 -lr 1+ r br 4 *r.' Q vu'here s - l.)+.4

ct = 1.340 I br = n-bond- ord.er of rth boncl-. The susceptibility of the nuclear catbon atoms of the pyri-dopyrÍclazines to free radical. attack may be estimated from the free valence numbers,

These numbers are also cal-cul-ated from the n-bond- ord-ers by use of the equat ion

Tiì-jT\D.r _ _ ìt) Zs yrs r-r'l¡ ar a Iì r Free Valehce numbe¡ at atom r "na\.ê Þrs sum of the n-bond. ord,ers of al-l bond.s betrveen atoms s attached- to atom r. -79-

The calculated values shown ir (tO4) an¿ (f o5¡ ,ind.ibatê that free rad.ical attack on the nuclear carbon atoms should- proceed preferentially at position { for pyrid.o[Zr¡-g],ryrid,azine and position ! for pyrid,o[:,¿-4] :¡æidazine.

Due to a v¡orld shortage of cinchomeronic acid., onJ-y smaIl quantities of pyriao[3,4-È]pyrid.azine were avai-Iab1e and. consequently the reactions of pyrid.o[2,¡-q] pyrið,azíne \,vere studied. in far greater C-etail than those of the [¡,+-¿]isorner.

(u) AT?UIPIED NITRATION OF i,Y?fDOfe. 3-¿l i,fnt¡lZttiip

1!he zç=eleetpon density ¡i,n tþe rlng,s sf pyrirlo[e,¡=qlpyrielazíne is d-epleted. in comparison to naphthalene because of ihe electron attracting properties of the three nitrogen atoms. ft ',vould. be expected that electrophilic attack wouLd. proceed¡ if at al-l, vrith inuch more d-ifficulty than for either pyrid.ine or quinoline. This rvas found in oractice as, although extrernely'vÍgorous conùitions were enployed,¡ no nitration of pyrid.o[Zr;*dJpyridaz,ine cou]-d. be achieved..

The heterocycle was dissolved. in concentrated. sui-phuric acid- and. heated r,¡ith sol-id. potassium nitrate at 2O0o for eight hours. 1,Io nitro d.erivatives and no unreacted- material coulcl be obtained f¡om i;he reaction mÍxture. Quinoliniic acid-, an oxidration prod-uct, was however, isolated. via its copper complex in 55/" yieJ.d-. lhis prod-uct has since been shown to be prod.uced in similar oxid.ative d.egradations of pyrid-o [2, ¡-g] pyridazines. Bo

That oxid.ation shoulcÌ occur preferentially to nitration rvas not in itself surprising, but the site of the oxid-ation v¡as unexpectecl. Quinolinic acid obviousl-y arises from attack in the d.iazine ring which, in the neutral mo)-ecule, -Dossesses a, fower electron d-ensity than the pyrid.o-ri-ng. r-ts oxid-ising agents theoretically seek areas of high charge d-ensityr the pyrid-o ring r,,¡ould- be expected. to be the logical oxldation site. Und-er the reaction conditions employed¡ however, the pyrid.o[Zr3-Ê] :yrid-azine cation is undoubted-Iy present. 'Ihe d.irection of the oxid.ation may be explained- by assuming that the most basic nitrogen atom is 1ì-1. Protonation of this atom vlould. procluce a strongly electropositive centre in the pyrid.o ring and. oxid.ation r,vould then favour the cliazine ring as under these circumstances, this lvould- then become the region of greatest charge clensity. rt is obvi'ous that the presence of an acidic medium r'virl- increase the resistance of pyrido[2, ¡-¿]pyrid-azine tolvard-s eì.ectrophilic attack. irritra.tion, hovrever, is hard-ly likely to be facílitated" by use of a non-acidic med-ium. Nitroniurn tetrafLuoroborate has been usecl to nitrate several- d-eactivated. aromatic compouncls in neutral solution.194arb Recently the first attempt to nitrate azaheterocycles v¡ith this reag,ent v¡a,s made, Yfhen reacted. rvith pyrid-iner horveverl ¡u 1 ;1 complex r¡¡as formed. in which the nitroniurn ion formed- a d-ative bond- r'¡ith the hetero nittogun.194" This species v¡as claimecl to be more deactÍvating. than the pyrid-ine cation and nitration shoul-d. therofot'e be equally or _81

more d-ifficult in aprotic solvents than in acid.ic med-ia. The most

feasibl-e scheme for prod.uction of the nitro derivatives appears to be via nitration of the lV-oxid-es"

(" ) BROL,trl.LrTroN

The initial attempts to brominate p¡rricto [e, ¡-q]¡:yrid.azine also suffered- from the d,isacLvantages v¡hich prevented nitration: yiz. deactivation of the hetero rings toiyard"s electrophilic att¿rck ancÌ strongly acid.ic med-ia. 1r mixture of molqguJar b¡g¡r¡ine, ?Zi¿ sulphuric acid- and sil-ver sulphate has been successful-Iy employed

195 1 to brominate quinol-iner ,""rð,in"r 96 phthalazi nu.127 ^nd Pyridine, however: \rû.s found to be unaffected. even after extend.ed. reaction times .197 '198 The nature of the brominating species

invoLved in these reactions has received. consid-erable atrention and. . 199 is norn¡ generally beLÍeveri. to be either ÂgBr+ oT n"on+ .197 This bromination proced.ure v¡as applied to pyrid-o [2, ¡-g] pyrid.azine at el-ev¿:,tod- temperatures but from alL reactions the heterocycre was recovered quantitatively. Thin layer chromatography ind"icated. that not even trace amounts of a bromo d-erivatj-ve rvere procluced_.

Van d-er Does and. d-en Hertog have d.eveloped- a convenient method. for bromina,ting highly deactivated azaheteroeycles such as pyricline trncl picoline in the liquid- pttrn".198 Sromination v/as found- to occu¡ almost quantitatively by heating these at i 3oo for seven "orpound.* hours ¡,vith bromine ancL fuming sulphuric acid- containÍng 6!/l ciissolve¿ suJ-phu:: trioxide. The rea.ction is believecl to proceed r¡j.a the primary formation of a neutral adclition procluct betv¡een the heterocycle ancl -82- sulphul trioxid.e v¡hich i.s subsequently attackeci by a highly active brominating electrophile the nature of v¡hich \'/as unspecif ied-. pyrid.o [Zr:-dJ ¿yrid.azine 1ra.s reacted rvith this brominatin,q mixturre for 11 hor-:¡s at lOOo and for a fqrther 10 hours at 15Oo but u.gain the hèterocycle lvas recovered unchangecl and no traces of brominated prod.ucts l,vere d-etected by thin layer chromatogla*olgr'

The bromination of 1:¡,rid-o [2, ¡-q]pyriclazine \¡tes finally achieved by rearrangemen-b of the rrperbror,rid-err. L,iost aza-arornatic heterocycles form ad-d.ucts lvith halogens ancl of these the brornine acld.ucts have received. most attention.196'20o 'rhese compound-s are :florrnecl when bromine is acldecL to a solution of the heterocycie or i-is \yd-robromid-e in sol-vents such as vrar,ter, carbon tetr¿¿chloride or el'll-oroform' The structures and even-bhe constitution of -Lhese compounCs are highly conteirtious. Very fev¡ of the so-c¿rIIecl I'perbromiclesrr ¡tre stabl-e and. bromine is generally evolvecl on standing" r^naì-yses of these compounds often d-o not agree'r¡ith assigned fornulae for thís Têg,soh. Re¿;ction of equimolar quantities of bromine :Lncr. heterocycle usually þroduces compouncls rvhich analyse approximately for 1:1 moìe act¿ucis. Excess brornine may some'bimes produce,rrtetr¿.brornidesrr and- lesser

¿rncl this is perhaps the best means by whÍch to anaLyse these compound.s.

Various structures have been proposed for the perbromicles and. those ,,vhich have received most consÍcleration are the follorving;200d'te (u) co-ord.inat j.on of the nitrogen lone-pair rvith a bromine nol-ecul-e to form the structure )-gJ- --'-¡tô- (u) charge-transfer bonùing through the t-efectroir cl-oud (") dicoord.inate complexation of the typ" ( )iv)rl"*ltr-.

iïhen heated. in sol-vents such as carbon te-brachLoride, r,¡aterr methanol- or a.cetic acid, perbromicles rearrange to nuclear substituted. bromo derivatives. Pyrolysis and photolysir; of the aclclucts also cause bromination of the ring. These realrangements have been stuclied, by

-,i="h2ood ind chand-1"1196 in the quinoline ancl acrid.ine series respectivel-y. llecause of the uncertainiy of the structures of tlte frperbromicLesrr an uncLerstancling of the mechanism of the rearrangement is renclered. difficult. Bromination of quinoline by this method- proceerls preclominantly at the 3-position v¡hich has the highest ef ectron d-ensity in the pyrid-o riryJ. Disch ha,s proposed- tv¡o mechanisms to account for the bromination of ouinol-ine.200¿tf Th" brornine of this perbromide was cl-aimed- to be attachecl- to the hete::o-atot200e in the manner described- :-n (a) above. 'Ihe first mechanism involved ad.d-ition of bromine to give the compound.s (106) .or (loZ) foÌ1o,,:,'ed. by d-elrydrobromina.tion to give 3-bromoquinoline. /ts it r,vas d-ifficult to Bq postulate a satisfactory mech¿nism for such an el-imina-bion, Disch also proposed a rnechanism Ínvolving electrophil"ic'attack by quinoline

¡ perbromid.e on quinoline. This should occur preferentially at C-3

H B H Br H H Br -Br H Br r r Br

fi06 ) u07')

Br

+ f

N fi08) as a particularly favoured brid.ged bromoniurn ion transÍtion state: (tOA¡, can be formed¡ the configuration of which rrould- d'erive add-ed' stabilj.sation by coordination of the unshared eLectron pair of 3r+ ,¡¡ith the electron d.eficiencies at C-2 and- C-4. [his add'Ítional stabilisation is not possible in the benzo ring. I¡urther evidence for these mechanisms has been obtained. by d-ebromination of l-bromoquinoline at high temperatur"".200f -E5-

Ihe perbrornide o:Ê pyrid'o[2,¡-st.]pyrÍd"azine wes prepared- by rercting equimolar quantities of the heterocycle anû bromine in yelloYr-orange ad-d'uct formed' carbon tetrachl-orid.e soLution. The "r'hich reò possessecl a strong bromine-lilce odour and clecomposed slo"'r]y to a 8ur¡onexposuletotheatmosphere.i\freshlyprepared.sampleofthe iod'ine perbromicle l¡/as treatect r,¡ith potassium iodid-e and- the liberated-

vas titrated- ¡vith sod.j-um tTriosulphate. îhis procedure gave a pyrid-o[2, ¡-q]pyrÍd-azine:bromine ratio of exactl'y 1:2' 'i\s expected'

hovrever, microanalysis ga,vo only fair aBreerflent lvith the d'ibrorlid'e formula as analyses could only be carried out three to four days after preparation. The product d,id. not melt sharply as many other

perbromiiLes have been re¡'lorted to do¡ but began to decompose at 1150 This is and. finally gave a red liquid. at much higher temperatures' consistent v¡ith the observations of Chand'ler rvho states tlrat many of the rrmelting pointsrì of perbromides are pbobably the temperatures g6 of initial decompo"ition.l The perbromid,e r,¡as decomposed- by severaf metìlods. .¿\ mixture (f of pyrid.o [Z,f-dJpyrid-azine and 3-bromopyridof2r3-È]pl'ri'Ìazine, O9), was obtained v¡hen the pæbromid-e was al-Iov,red- to slovùy decornpose in air over ?-to aaye. The rate of decomposj-tion rvas variable ancL in one ['his case the l-bromo d.erivative was obtained as the sole prod'uci;' resul-t, however, could not bo repeated, The mixture of the 3-bromo clerivative ancl the parent heterocycLe obtained- in these reactious '¡¡as

sepa,rated. by chromatography using afumina as adsorbent' oo

Decomposition also 'ras achievecl by heatin¡1 the perbromid.e in carbon tetrachroride ano- again a mixture of pyricr.o[zr¡-gr]pyrid.azine anc'[ the 3-bronlo derÍvative i,was,obtained_. The use of pyridine as a \ydrogen bromid-e scaven.-qer in this reaction h¿rs been used. with success in the quinoline ¡rt ""ti""200d in the present case pyririine had. littre effect on the yiercl of brominated productr ;is it vras ilrought that oxygen may be a factor influencing the aerial d_ecomposÍtion, a rearrangernent carried "'¡as out in carbon tetrachLoride through vrhich a continuous stream of oxygen v/as bubbrecr. The yield of 3_bromo procluct was, horrvever, unaffectecr_. other faciors such as wate¡ vapour and right r'vhich coulcl possibly influence the aerial d-ecoraposÍtion were ¿¿1so studÌed-. photolysis of the perbromÍcr.e in ca,rbon îetrachrorid.e rrrocÌuced onJ-y tra,ces of brominated. prod.uct and. ïearranújement in v¿arm i¿queous sor-ution yieJ-d.ed a simir_ar mixture to that obtaÍnecL from re¿.ction in carbon tetrachrorÍde. rt can onì_y be inferred that the reamangement of the perbromid_e in aÍr is an autod.ocomposi.i;ion which rnay perhaps be catalysecì. by oxygen, v,,ater or light. I'yrolysis of the perbromide at 1 TO_l BOo gar,,e good. yields of the l-bromo derivative, together with smar.r amounts of the parent pyriclo- pyridazine' This has proved- the most efficient brominating procedure as it is r-ess time-consuniing than d,ecomposition by exposì..*e to the atmosphere. Tho structure of 3-bromopyrido [2, 3_d]pyrid azine rvas determined_ from its h.rr.T. spectrum (ligure 3). The characteristÍc II^ oua¡tet 87

rn v N I r N I Hx i I Ë I z I ! (109) I I ; T I t HE t H H yz i. m x 'l¡, ( i, t I i

lt lí

I

I t 1. :

I 450 ,2o ./t

IlÆ.], N.n.r. speotrum of l-¡totop¡rrido[2r3-ÈJp¡rrfdazlne 1n

d.eut eroohloroform. 88- of the parent heterocycl-e r'¡as absentr \ appearecl as a quartet resulting from coupling to Iì* and. I{rr and- Hx vrhÍch undergoes meta-coupling H, with Hm shov¡ed as a doublet. As in pyrid-o[Zr¡-Èlpy"id'azine being prod.uced appeared as a doublet and. H, as a quartet¡ tlre splitting by long-range coupling. j-n The formation of the 3-bromo derivative the above reactions precludesafree-radicalmechanismassuohaprocessshould theoretically yield- the {-substituted. derivative as the major product' The ad_d_ition-elÍmination mecha.nism also appears unlikely as add'ition be across the c=N bond.s of both the d,iazine and pyrÍd.o rings woul-d and- 8-bromo d'erivatives' expected- r,vith the formation of a mixture of 3-r 5- ,I,he electrophilic substitution mechanism proposed by Eisch, ho"vever.t is the explains the formation of the 3-bromo product as the l-position by most highly activaterl tor,vard-s such attack and- is also ad'joinecl is atoms v¡hich are electron d-eficient' The'ease of substitution explainedbythefactthatthespeciesundergoingsubstitutionisa resul"ts neutral moleôule and- does not suffer the d-eactivation i'¡hich from cation formation in polar media'

(a) /rrTrlTATroN

tril-ectron d.ensity consid-erations ind.ica.te that nucì-eophilic strbstitutíon of pyrid"o[2, ¡-d]pyrid.azine should- proceecl more readi]y than for quinoline, The d-irection of amination with soclamide cannot' B horvever, be reatlÍIy predicted as positions 2' 4¡ ! and' are all is activated towards nucleophilic attack. If the pyrid-o ring only 89

considered, aminatÍon '¡¡ouLcl be expected_ to occuï preferentiarly at c-2 but small quantitles of the {-amino d.erivative ruouLd- be expected- if excess reagent ou"tu r"ud.201 Â)-though the cliazine ring is theoreti-ca1Iy activated- torvard.s amination, no such substitution of ã'pyrid-azine has yet - been reported_ and even und.er vigorous cond-itÍons no amÍno prod-ucts are obtained- from phtrrur"uinu.127 Other diazines such as pyrazine give onry poor yierd-s of amino rlerivati-ves uncler similar cond.itions. 32, 33 The arnination of .oyrid.o[2, ¡_Ê] pyrid-azine,\,vas carried_ out usin,q equimolar quantities of the heterocycle and. sod_amicre. The use of liouid' ammonia as sol-vent produced- an amino d.erivative, r^¡hich in¡as

isolated. aS the picrate, in JBI!" yield.. Ilost of the pyrido[?,3_è] pyrid-azine rvas, hovrever, recovered. unchanged_. /r greater conversi_on v¡as achieved v¡hen tofuene v¡as used- as the solvent at temperatures of 6O-700, By this procedure yielcls of J2ia were obtained-.

The work-up of the aminationwas rend.ered- aifficur.t by the fact that amino derivatives of pyrido[Zrj_O]pyridazine are extrene].y sol-ubl-e in v¡ater and. eth¿rnol but insoluble in other solvents" lùtraction of' the amino compound- was th-erefore precrud,ed_ and removal- of solvent from the reaction mix'bwe left a prod,uct contanli¡ated_ .''¡Íth inorganic impurities. recause of thÍs fact a saiisfactory n.m.r. spectrum was unable ,l.he to be obtained-. only means of obtaining pr-rre samples vras by preparation of a d.erivative such as ilre picrate. Árnination almost certainly occumed. in the 2-position. This conclusion rvas arrivecl at by a ¡rrocess of elimination. A,naì.ysis sÌrov¡ed that the -90- product v/as a mono-amino compound, and' as only equimolar quantities of the reactants v¡ere used, substitution at position 4- may be considered highly unlikel-y.201 Authentic samples of the picrates of the ! and. B-mono-amino derivatives, the only other likely products of the reaction, were prepared- by independant method-s (see Chapter 3)' The amination prod.uct d-epressed. the melting point of each of these cornpouncls ancl the infra-red spectnu'n d.id, not correspond to those of these d.erivatives.

(u) Rli.iCTION 0F PYRTDC lz. ¡-al ìYRrDAz II{E TTîII ]ÌYI,OCMOIìOUS ;I.CID

A nev¡ reaction betlveen hypochlorous acid. and- nitrogen heterocycles has recently been d-eveloped. in this depelrtment. Ïn an attempt to prepare phthaLazine.perchloride, chforine was bubbl-ed' through ¿ 1JL aqueous solution of phthalazine. a rapid- evolution

of nitrogen commenced. immediately and-, ins-bead. of the expected-

perchloride, an BO,IL yiel¿ of phthalaldehyd.e rvas obtai n.d-.|27 The basic feature of this reaction is the fission of the d,iazine ring of phthalazine. This may be rationalised- by postulating as the initial step an add-Ítion across the C=Ì{ bond.s. These bond-s

have a high n-bond. order and are therefore susceptible to such an attack. The nature of the attacking speoies has not been unambiguously proven, although it appears that hypochl-orous acid is the most logical- reagent. The reaction is envisaged. as proceeding by the scheme shown

in Scheme 36. -9t -

R -0 OH R)c R R I ( R-C.N ..cL 111) =[rJ \R,, R,)c I R 0 ct il R-C -ñ -R" ( 110) ut2) Scheme 36

H H

H0ct NC

'l, H H

HO cH0 + + Nz,*Ct-4H+ cH0

H Scheme 37 The intermediate carbinolamine¡ (lfO)r maÍ und.ergo hyd-rolysis to a ketonê or alcleÌ¡yder (llt )¡ or oxidation to an N-chLoro-amid.ee (llZ)r depending on the substitution pattern. Reaction with phthalazine or phthalazine derivatlves bearing electron d.onating groups in the heterocyclic ring prooeeds by ad.d.ition and. hydrolysis with the heterocyclic nitrogen appearing finally as nitrogen gas. The formation of nitrogen is presr:nab1y the d.riving force causing ring fission and ald.ehyd.es or lcetones have only been lsolated fron reactions of hypo- cb-Iorite with g-d.iazines. lhe only related reactions reported. in the literature appear to be the reaction of chlorine with an aqueous solution of pyrid.ine?O)a¡ZO? -Q)- and the ad.ditlon of t-amyl-Ìlypochlorite to Schiff rs bases.2O2

lïhen chlorine was passed- through an aqueous solution of p¡rr iclo[2, ¡-4] pyridazine; pyrid.ine-2r 3-diald-eþde v¡as obtainecl in

71fL yíeLð,. The id,entity of this compound- r,¡as confirmecl by oxidation to quinolinic acid. by Tollenrs reagent and. by reaction r¡/ith hyd.razine in ethanol to regenerate pvriao[Zr 3-4]l¡yrid.azíne. The ul-travÍo]et and. infrared. spectra al-so supplied. confirmatory evidence anð- a Zr!- d.initrophenylhyd-razone rvas obtained- lvhich analysecl comectly. 1'he reduction of pyrid.i ne-Z r3-di (N-methyJ-anilicte) v¡ith lithium aluminíum hydrid,e has recently been reported. to yield, p¡rricline-2:3-dial-d-unyd",166

Repetition of this reaction gave an aì-d-e\yd-e, tine Ze{-d-initrophenyl- hydrazone of v¡hich rvas id-entical with th¿rt obtained- from the procluct of the above reaction of pyrido[2,¡-q]p]ridazine. Ji possible mechanism for the ring fission reaction is sltolvn in Scheme 37.

Tt is evid-ent that both the reaction of hyitochlorous acid. and- of sod-amid.e with azaheterocycles requi-re, as 'bhe initial step, an ¿ddition to the o=N bond. rn the case of pyrid-o[2,:-e]rJ¡ridaziner holevet, hypochlorous acid. ad.d.s to the d.iazine ring C=l{ bond-s whereas sod.amÍcle attacks the pyrÍd.o- C-N bond.. Sever.al- factors must be consiri.ered. to account for this apparent anomaly"

1.1i D]]ìTÐTTON OF AI,TINATION

Tho mechanism of the Chichibabin amination reaction has been critically surveyed. in recent years. A,:pyrid.yne intermediate r¡ras -01'- sugrgested. by Levitt and. Levitt2o3 U,-,t this postulate has since been runtenable proved to be ,2o4'2o5 itbramoviich ancl co-woirkers recentry reproposed- the ad.d.itÍon of sod,amicle to the C=III bond. as the first stage of amination. this initial process \¡ras claimed. to be reversibLe and. the rate d.etermining step shown to involve the loss of hydrid-e lon?o5 (sctreme 38).

NaNH-, -H- H -.+ ñ NH N N*z N NHNa 2 N a+

Scheme 38

Ad-d.ition to aromatic rrdouble bond.srr must d-epend. on (i) tona order and- (ii) polarÍty. If the C=N bond.s of pyrid-o[e,¡-g]oyrid-azine are consid.ered these tv¡o factors are found. to be approxirnately equivalent. Calculated n-electron densities and. bond- orders suggest that the diazine ring C=N bond-s would. be slightì-y more susceptible to such attack but the d.ifferonces are hard-1y sufficient to explaÍn the selective amination which ocours. Therefore the problem basicall;. requires an explanation as to why pyrid.ine aminates more efficientl-y than the diazines. No rationdlisation of this anomaly has yet been publisherl.

A stud.y of the transition state structu¡es ',','hich resul"t from amid-e ion add.ition, (l I ¡)-(f f l)r ind.icates 'i;hat acLd-itions to the d.iazine ring vrould, acliieve greatest resonance stabilisation. The rate d-etermining step, hovreverl is not the ad.d.ition ¡irocoss but the l-oss 94

of hydrid.e ion. As add-ition to the pyrid-o-ring produces the Least stable transition s1;atq it is possible that this intermedia'te may be of high enough energy to eject a hyclrid.e ion. lis the other acld-itions provide greater resonance stabilisation, f oss of hycirid-e ion in this manner would- be less 1ikely.

H NH 2 N t HeN NH 2 fi13) (114) (11s) One other factor must be consid.erecl. The loss of hyd-rid-e ion requires the eLectronic shifts sholn in structures (r I ¡)-( 115)' rn the d,iazine series the negative charge of the ad-d"uct is d'ispersed

betv¡een the two nitrogens by ind.uctive and mesomeric effects' The loss of \rclrid.e ion from the d-iazines v¡oul-c1 therefore be expected to proceed with more d.ifficul-ty than in the pyrÍclines','drere the negative charge is more Localised. This is borne out by the fact tha'u pyrazine is more d.ifficr-rlt to aminate than pyrid.ine â,nd for pyridazine¡ in ivhich the closer proximity of the nitrogen atoms rvoul-d be expectecl to enhance the charge sharing effect, no arnination has yet been achieved' Any reagent which promotes the loss of a. hyrlrid-e ion rvouLd.

enhance the likelihood. of amination of the diazúnes. In this regard-t oxid.ising agents such as potassium nitrate have been employefl in the arnination of quino1in".206 The use of such a reagent in the case of pyrid_azine might well enabfe aminatíon to be achieved. -95-

\ 11/ DfRLùCTIOII Oir¡' A)DfTfOirr 0i¡ HyPO CIrT,OROUS ,IICID

'Ihe selectÍvity of the ad-dition of hypochlorous acid to C=N

bond.s also requires expranation. trgain it must be assumed that the

differences in bond. order ancL polarity are not sufficient to account for the selective ad-dition. This is substa.ntiated- by ttre fact that

when chÌorine is passed. through an aqueous sol_ution of pyricline¡ an aciduct cRl{ÂN.l{0c1)) is obtainecl. Treatment of such a sorution with excess chlorine afford.s a num'ber of prod-ucts such as carbon dioxÍd.e

and- nitroøenr2ooat207 ,rhi"h ¡rresumably form by o:rid.ation of the

initíal ad-duct. rt i-s apparentrtherefore, that the p.yrid,o c=N bond rrdoubl-e has suff icient bond. characterrr for þpochl-orou.s acicl ad.ciition to occur.

rn the case of pyriclo[zr¡-c]¡:yrid-azine there are two eff ec-bs; r,¡hich tend to :pl-ain the small- amounts of lil-ohlorophthalazone r,'¡hich have been noticed. in the reaction v¡ith phthalazine (Scheme J9). -96-

+ + ñu NH N H

I I t NCt N ct N H ctfr 0

Scheme 39

The second. effect rvhich d-irects the site of reaction to the d-iazine ring is the fact that such an ad-d'itj-on eveutually results in the evolution of nitrogen, a stable entity. there is therefore a d-riving force for ad-d-ition in the d.iazo ring vrirereas no similar effect is possible from pyrid-o ring acld'ition'

(r) OXTDI{TION OF 1'lBTDOPllÀTÐAZINPS

The attempted. nitration of pyrid-o[2, ¡-q] pyricl-azine resuLted j.n oxid,ation to prod.uce quinolinic acid. This obselvation r'¡as ratíonal-ised- by postulating protonation of the py::iclo ritrg nÍtrogen atom. To verify this theory, a stucly of the oxidatiorr of boih pyrid"o-

p¡rrid.azines 14las undertaken using potassium permanganat e as oXidant

in acÍd-ic and- alL'¡aline media. oxiclising agents are electron acceptors and- for this reason

benzene rín¡1s are more susceptible to oxid'ation than theiT aza- heterocyclic analogues. r\s expected. the pyrÍdopyridazines are therefore oxiclised. only slolv]y by concentrated potassium permanganate' -97-

t,'xidation of pyrid o[2, :-¿].ryridazine by arkarine permanganate li/as cemplete in níne hou¡s and. prod.uced. {-aminopyriclazine-J-carboxylic

acid, (lle), in good- yield, together v¡ith a very sma11 amoun,r; of

quinolinic acid. Oxid.ation therofore proceed-s in the manner ;oredicted, for the most favoured. site of oxid.ation is the pyrid.o rÍng

rvhich is the ring of highest charge clensity in the neutral molec'¿l_e. l'yrido[¡r¿-e]pyridazine also oxidised slo',vly und-er aIkaline conditions to yield. the expected pyrid.azine-3t {-dicarboxylic acid_, (6), together with traces of cinchomeronic acid., (û), (Sctreme 40).

N 2H N c02 H I N + N ozH NH 2 (1r6)

0 H 0 H 2 N 2 T + N t ozH c0 H 2 Scheme 40

Under acÍd"ic--> conclit ions , oxid at ion of pyrid_o [2, ;-qj cyrÍclazine by potassium permanganate gave a l_ov¡ J¡ield- of quinolinic acid.. á\tensive breakd.own of the ring structures obviously occurred- as both ¡;ropionic and. butyric acid, rvere id-entifiecl in the reaction mixtu::e.

This resul-t was not unexpected. as it hacl previously been observecl that the pyrid-ine ring lvas fess stable to oxid.ation uncLer ecid- than under alkaline condition".20B pyrid-o[¡,¿-ÈJpyrid,azine, yihen oxidisec in a similar manne4 Eave cinchomeronic acid-. rt is apparent Jhat protonation of the pyrÍclo ring must occur for, as pred-icted, the 98-

d.iazine ring is attacked in both cases. Thes.e results are therefore

in accord. with the d.irection of oxid.ation obsorved v¡ith nitric aoid-

and. pyrid o [2, 3-è] pyridazi.ne. By carrying out the alkaline oxidation of pyrid-of 2r3-+J- pyrid.azine for periods less than required for complete oxidation, three unstable interrnediate products, Ar B, and. C, wei:e obtained. (faUfe B). These v¡ere isolatecl either by fractional crystallisation or by the preparation and subsequent decomposition of their copper

compl exes.

îABLÐ B. OXT:DATIOI\T 0¡, ?YI{ÐO r2. 1-dI PYË.TDI\ZT[!] IiITIf I¡'?.1ü,TÌ'TE

iC,{nOO AT 95-1OOo

COMPOUND z.o e/t hr z.o gf z nr z,o sf 4 l\r 1.j e/6.5 hr z.o e/9 Yv

A o.43 g

B 1.0 g 1.25 B

c o.7 g o'85 e 0.1 g

{-}tH^-pyrid.azine- 25 mg BoQ mg 1.45 I ' 5-cooH quinol-ini-c acid. 10 mg 15 mg 100 mg 250 mg copper complex pyrid o [2, ¡-d]- g 25 ng pyrid-azine 0.96

The structu¡es of A, 3 and. C rvere unable to be elucicìated-.

These compound.s are extremely unstable and. attempted. recrystall-isations from water in the presence of ci.ecolou¡ising charcoal caused conversion

of each compound- into 4-aminopyríd-azine-J-carboxylic acid, (lle). -99-

rinaryses ca¡riecl out on these compounds proved- unsatisfactory as

inor¿1anic inpr.rrities r/iere. ¡rresent. The only soì-vent sui.r,-abre fo¡

extraction of these compounds v¡as ethanor which also acte;d- as a sol-vent for inorganic salts which lvere preseni in the crucle reactlon

rnj-xture, Lepeated- extrs.ctions fairec. to produce iluïe specinnens.

Attempts to isol-ate these cornpouncls as the barium salts u,,er,e Lrnsuccessful_

as these derivatives ï/ere lvater soluble. Compouncls 3 ;¿ncl C formed.

copper cor,iprexes but tire prod-ucts obtained_ on breakd_ov¡n of these contplcxes t'¡ith byClogen sulphid"e cou1d. not be crystallised. v¡ithout

,lecorii:o e it 1on.

N.m.l. spectra incìicate that each compouncl- contains tr,¡o

alontatic protons and. no al-rlel¡rdic protons. .is ii, B ancl c are rèad.ily converted. into 5-aminop¡'ricÌaz,ine-{-carboxylic acid- their basic ring skel-eton must be as shown in (ll?). fnfrared- spectra shols that ir contains a. seconcÌary ainino Lgïoup

enC, crrbonyl peaks r,.¡hich appear at, l7O5 cñ1 ancl- 1630 crn-1 ind_icr-r,.;e

the probabre presence of ketonic and- acid- groups respectÍveÌ;r. coiroound.

sholvs NH ! two peaks in its infrared- speotrum, inclicating'bìre irlresence of a pr.i.rnary amino group ancì- carbc,,nyls at 167O cnll ¿nd. 16l: which "ñi rl¿ty a.gain be due to ketonic and- acicL functioLrs. The inflrarecÌ specirunr

of compound. c shor,¡s carbonyl peal

¿roups cou-ì-d- not be esteri:fied rvith d-iazomethane, horj/ever, and- r,¡arm solutions of Brady's reagent gave no precipita.bes. on the basis of - 100 -

the n.m.r. and infrarecì. spectral data, the tentative structures (f t a),

(tl9) ana (lz0) have been proposed for A, B and- c respectiveJ-y.

Structures involving aId-ehycle groups rn¡ere not consid.ered- as n.rn.T,

evidence ind-icatecl that such functions wete not present ancL und.er the

rea.cti_on conclitions the alclehycle group l,roulcl o>riclise rapid.ly to the

more stable carboxJ¡]ic acid-. Such structr.rres enable ll ancL C to be

formed- from the common precursor A.

oc0 H 0c0 FI ozH 2 N 2 N

,,1 ñ NFICO H Nll NHCO H 't 2 2 2 (117) (118) (119) (120)

The acid-ic oxide"t ion of pyrid o I Z r :-Èl -oyrid azine was also st udied u.sing sllorter reaction times than required. for compÌete oxid.ation. llfter J hours smal-l quantities of !- and B-pyricì.o[Zr¡-4]pyrid-azinone¡ (f zf ) ancl (122)' rvere obtained together rvith smafl ariounts of quÍnolinic acicl. The structures of compouncis (lZl) ancl (122) r'¡ere

assi-gned- following unambiguous syntheses (Cnapter 3). Ä ma>:imum yie1d. of qui.noJ.inic acid, r'¡a.s obtainecL after 6 horus anà after 1B hou¡s no soiid. products v/ero able to be isol¿rted.. These results fuuther

illustrate the clirection of attack by acid.ic or:iclising rigents anå efso demonstrate the instability of the p¡rrj¿ine ring to prol-ongeci

oxid-ation in an acid.ic med,ium. - 101 -

nt* ,f

N NH N 0 (121) (122)

rj ( tf ) ]¡I-OXTDÀTTO}tr

lhe nitrogen atoms of the pyrid-opyridazines possess a high charge d-ensity and are therefore susceptible to electrophilic attack. This is exemplified. by the formation of quaternary salis such as hydrochlorides and methiodid-es. ll furiher illustration of this potential is shown in the formation of Ìt-eai¿es of pyridolzr¡-È]- p¡æid-azine.

\Then reactéd.' in equimolar quantities at room temperature, peracid.s have littl-e effect on pyrid-o[Zr¡-g]->yrid.azine. Perbenzoic acid. anfl ¡-nitroperbenzoic acid gave small yielcls of an N-oxid.e mixture rvhiÌst monoperphthalic acid- d-icl not react at all. ¡-l[itro- perbenzoic aoid has been claimed. to be one of the most reactive of all peracid.s2o9 ond its relative inactivity in this instance is believed. to be d.ue to its low solubility in the soLvent v¡hich was employed..

N-Oxid-ation r,¡as finally achieved. by use of peracetic acid. at temperatures of )O-)Jo. Equimolar quantities of the peracid- and- pyrid.o[Zr¡-è]- pyrid.azine gave a mixture of N-oxid"es simil-ar to that obtaÍnetl from -102-

the perbenzoic ancl ¡-nitroperbenzoic acid. reactions, recovered.

heterocycle and- small amounts of a yel1ow sorid. r,vhich v¡as not

further investigat ed..

Tho lf-oxicle mixture was repeated.ly chromatographed. on alumina to eventually give two fractions which lvere finally purified.

by fractional sublimatÍon. The two compound.s so obtained. were shown

to be mono-N-oxid.es by microanalysís and. n.tTt¡r. spectra. These

N-oxid.es¡ which melt at 206-70 and. 2100, have been assigned. the structures, (t Z3) ana, (lZq), respectively¡ on the basis of their

rr.rD¡r. spectra (ligures 4 anð, 5).

N

I 'ìu*o N-r0 N N

(123) (lTt )

Very 1ittIe comparative work has been carried- out between the n.m.T. spectra of lü-e¡¡ifles and the spectra of parent heterocycles. The feature rvhich has provoked. most d-iscussion is the anisotropic r¿ effect of the bond- peri-protons. )ll -o on This has been observed. in the spectra of o.uinoline-1-oxid-e, 210 21o r211 "i*oIine-1-oxid.e, quinoxaline-1-oxid. .1210 and- substituted. d.erivatives of these In each case the proton C-B the N-oxid-es "otpotnd-*.210 at of is shifted- to lov¡er field-s¡ sometimes by {o cf s, in cornparison to the equivalent proton of the parent heterocycle. In both of the N-oxid-es of pyrido[Zr;-q]cyridazine the proton in the peri-position to N-1 und.er- goes a large shift to higher field.s. It is therefore obvious that no f f I i I

i I

i'

I

I i

I

I

E H v Y Ha N=>O I N

z g x I o E t, E z I .L

E m

475 530 57o c/s ElgE4.. N.tD.r.. spectrr:m of pyriclo[zrf-qJp]rridazine{-oxitte in tteuterochloroforu. a :F'ÈæffitwÉ' H H m v Ha N H I % Hx N+0 z

E H a x E n I Ào I

2 467 487 5o7 52o 53o 538 555 c/s

Eigure 5. N.!0.r. spectrum of pyriclo[Zr¡-q]p¡midazine-?-æxiile in d-euterochloroform. -10r- oxid.ation has occu¡red. at N-1. Fr¡rther evidence may be obtained. fron coupling constant data. The coupling constant J2r3 of quinoline and- of related. compounds has alread.y been quoted ae being of the order of 4.1-4.3 c/s. N-oxid.ation, however, converts the hetero ring to the equivalent of the quinolinium cation and. the coupling constant The value J^¿¡) ., is increased to a value of 6.0 ./".21o of 5.L6.o cfs has been found. to be general for the equlval-ent coupling constants of N-oxid,es. In both N-oxid.es of pyrido[Zr¡-è]pyridazine, however, the magnitud.e of the coupling constant trr3 t" practically unaltered fron tbat of pyrid.oler¡-è]prid-azine. [hls resu]-t'verifies the preced.ing conclusion that N-1 has not und.ergone oxidation. A further consequence of the >Ñ-O .group is to affect the chemioal shifts of neighbouring protons compared. to those of the unsubstituteù heterocycle. X'or p¡æidine the o- and. T-protons are shifted. to higher field. and. the Þproton moves to lorver field..214 This has been rationalised. by postuJ-ating electfonic shifts v¡hich increase the charge density at the o- and. Y-posJ-tions, thereby causlng a d.eshield.ing effect (structur. (lZ5)). À sirnilar effect occurs in the quinoline and- isoquinoline series where the shifts of protons o- and. Y- to the N-oxid-e groups are of the ord.er of 15-25 c/s upfield.. The Fproton undergoes a small upfield. shift which is in contrast to the shift of the equÍvalent proton in p¡rridine-N-oxid.e. No similar correlations of chemical shift variations betïveen the d.iazines and. their N-oxid.ee have been reported. either. Tbe shifts of the o-protons of quinoxaline and. quinazoline N-oxidesr oompa"red. to the parent heterocycles¡ are similar to those of the equivalent protons -106-

as the environment in the quinoline serles. this '¡tould- be expected- of such protons is not rad.ically altered. A completely d'ifferent set of d-ata is obtained¡ however, on consideration of the N-oxid'es of the o-d-iazines. The shift of the o-proton ín these N-oxid-es is ertremely large and varies between !B and. 65 c/s upfie1d.. The T- proton shift couLd. only be obsel:ved in two compounds but appears to be of the order of 15-20 c/s upfield-' There are two different I shifts possible in o-d'iazines' The first involves protons Þ to tbe N-oxide gr.oup where the intervening g (:Lig fhis group is =CH- and. has been ter¡ned for convenience =CH-). shift was founct to be of about 18 c/s downfield for both the nonocyclic and. tbe bicyclic diazines. It is apparent from a stud'y of such shifts that annellation causes an upfield- shift of such p-protons Ín the mono but not in the díaza. sêlies' l,\¡ith the second. type of I shift the intervening group between the proton uncl.er consid.eration and. the N-oxid'e fu¡rctio[ is -N=' These shifts have been ter¡ned. I (via =N-). Such shifts are upfield' and' are extraordÍnarily large in magn'itud-e¡ being of tb'e general order of 30-40 c/s. tlith cinnolÍns-1-oxid.e the F (viq =N-) shift is even larger but this may be partially attributed' to the fact that tb'e chemical shifts for cinnoline were obtained from a spectrum rurr using carbon tetrachlorid-e as solvent' A stud.y of published- data for substituted pyrid-a2in""212 ttd' their N-oxidesr215 ,.u"^Is th¿t substitutÍon has relatively littIe effect on tbe magnitudes of tbe variougr'sbift d-ifferences' For six - 107 - d.erivatives tbe average chemical shift d.ifferences ne¡'e øt -J'l cfsi (flie The ^f : -21 c/s; B (via -cH=): +13 c/s anô' P =N-): -!2 cfs. val-ues for other N-oxj.d.es are collected. in Table 9. At present the magnitud,es of the high fie1d. shifts obse:r¡ed. with the o-diazine N-oxid.es are inexplicable. Chenical shift differences are usually explained. in terms of changes in (a) ring cupent (U) d,ipole moment (c) magnetic anisotropy (cL) reactÍon electric field- and. (e) charge d.ensities. The ring current is assuned- to be constant for reasons alread.y outlined., the reaction electric field. effect is negligible and. the dipole moment should. not vary greatly on replacing N: by N+0. the resulting shifts must tberefore be approximately equated- to changes in charge d.ensity and- magnetio anisotropy. It appears unlikely¡ however, that these factors couLd. vary to such an ertent to account for the size of the observed. chernical shlft differences. The assignment of protons to the absorption peaks of the N-oxid.es of pyrid.o[Zr¡-q]pyrldazine v/as made possible by analysis of the splitting pattern and by the size of the couplit:g constants. The assignment of structuros to these compounds was then rrade by application of the chemical shift d.ata which has been d.iscussed. above. The resulting shifts were in very good. agreement wÍth expected values. tr\¡rther proof of structule was obtaÍned fron the fact that in each compound the proton ad.jacent to the unsubstituted. diazine rÍng nitrogen is broad-ened. by nuclea¡ quadrupole relaxation effects whereas the protons adjacent to the N-oxid.e fr:nctlon do not und.ergo this eftect so markodly and. appear as sharp peaks. TAB]JE q

HB o-PR0T0N T-PROTON p (& =cH-) F (via =N-) R COIúPOUND S OPA OPA OPA OPA OPA

210 Quinoline-1 -oxide / 525 485 40 514 533 -19 464 485 -21 436 440 4 210 f soquinol ine--1 -oxid e I tt ,26 552 -26 tj 4BB 5og -21 210 Quinazoline-3-oxid e 213 H2 549 57t -zz uo 5+6 562 -t6 210 t¡i noxal- ine-1 - ox 1d-e I 513 486 27 502 ,29 -27 520 529 -9 I 210 ine-1 4-clioxid e 32 494 494 529 o Quinoxal r I 518 486 ,29 -3}' -3y @ 215 P¡æd-d.a zi ne-1 -oxi d.e 212 495 5r4 -59 434 4r2 -18 470 452 1B 5tz 554 -4? I 210 Pht halazine-2-oxid,e I 516 574 -58 545 574 -9Q 211 Cinnol ine-1 -oxid-e r87 52o 5o9 11 45o 466 -16 500 553 -53 211 Cirurolin+-2-oxid.e t87 493 5r3 -60 484 466 rB / Pyrid.o le, ¡-g] pJ-id-azinæ j5B 6-oxid-e / lt9 i9o -ez 59o -32 Pyrido ¡-4] pyrid-azine- I [2, I jzj 59o -65 547 580 -33 | ?-oxiae * Actuall-y the sum of both an oF and. Þ (v!a =CH-) shift. AII spectra determined in CDCI, at 60 Mc/s except for cinnolj-ne which v,,as tutt in CC1O at 1OO Mc/s. Chernical snift" are record-ed- in c/s R = ¡eference to spectrum of N-oxid-" (O); S - reference to spectrum of parent heterocycle (P); A = Chemical- shift d.ifference; / ¡ Spectrurn d-eternineC in this work. -109-

One further consequence of the N-oxid.e group was apparent

on analysis of the spectra. Electronic shifts as shoryn in structures (lze) and. (l 27) would increase the charge d.ensity at the ringed.

positions. The protons in these positions all appeared- at higher

field. than those of the parent heterocycle ind.icating tbat such a

shift Ín cb.arge d.ensity had- in all probabilit.y taken pIace. Similar electronic effects may be d.etectetl fron¡ a comparison of the.yr.tno!.

spectra of phthal azine and. phthalazine-2-oxid.e.

n N ï*o l,oo N N .frJ,q 0'J (125) u2ü u27) EVidence that N-oxid.ation occuned in the d.iazinelring only

was obtained. by reacting the mixed. N-oxid.es with hypochlorous acid..

No nitrogen was evolved and. no carbor¡yl compound.s we¡e formed which indÍcatetL that the d.iazÍne ring nitrogens nust be blocked. The oxid-ation of the d-iazine rÍng nitrogen atoms in preference

to the pyrido nitrogen is again believecl to be d.ue to the protonation

of N-1 in the acidic med.ium employed. As only small quantities of

peracid. were used, this woul.d. attack the unquaternised. nitrogen

ato¡os preferentially to forn the observed. produots, Several attempts to unanbtguouely syntbesise the 1-oxid.e¡ (1!B), were made. The key intermediate of the proposed. synthesis was 2r3-

dÍcyanopyrid.ine-1-oxide, (tZa¡r which was to be cond.ensed with - 110 - hyd.razine and" the resuÌting prod.uct convefted into tho required. 1-oxifle by treatment wlth mercuric oxide. N-oxid.e formation is d-epend.ant on the availability of the nitrogen lone pair electrons. l-Cyanopyridine has a på of 1.36 and. 2-cyanopyrid.ine Ís an extrenely weak base of pq -0.26.216 It Ís obvious that with 2r3-d.icyanopyrid'iner in which two nitrile groups nay exert -I and- -M effectst the basicity wiLl be reduced. fr.æther to a value of about -1 15. unit. The availability of the lone-pair for.N-oxid.e fornation would- also be expected to be reduced- and. N-oxid.ation of this, d.initrile should. theoretically be most d.ifficult. This was found- in practice for perbenzoic, monoperphthalic and. p-nitroperbenzoic acid.s had. no effect on the d,initrile when used. for extend-ed period.s at room temperature- Peracetic acid, was ineffective at 600 and. at 95-'tOOo, cond.itions wbich enable oxid.ation of monocyanopyrid.ilres¡ ê product of structure, (flO), or, (131 ), was obtained r¡Àrich melted at 278-2790. This prod.uct d.id not appear to be a mixture as repeated fractÍonal sublination gave only one prod.uct,

N N

I N CN

u28) (129) 0 CONH CN 2 H ONH CN 2 H (t30) (131) (132) -111-

Linstead. and cowork"r"114 obtaÍned a compound. of m.p. 255-2600, the structure of which was believed. to be, (l¡O)r oxr (l¡l), ¡y

deþdration of quinolinamide with an acetic acid.-acetic anhydrid.e

mixture. ïn the present work this reaction was repeated. and. the product was found. to be contaminated with quinolinimid.e¡ (56). After purification, the cyanoarnid.e prepared- by this method" was found. to be identical wíth that obtained. from the d.initrfle. It has been suggested. that tlre cyanoanid.e may exist ln a tautomeric forn such as (l3Z).114 This appears unlikely to be the case in the solid- as the inf¡ered. "tu,t" specir,um in nujol shovrs a nitrilo Þeak at 25lO cifl and. an amide carbonyl band..

It appears probable that the fornation of the cyanoamid.e is due to hydrolysis of a nitrile group. firhen heated. with aqueous acetic acid- for 12 hours at 95-1OOo, however, pyrid.ine-2r3-d.initrile was recovered unchanged.. ff hyd.rolysis d-oes occur, therefore, it must be d-ue to the hyclrogen peroxid.e which is present in the reaction mixtu¡e. îhere is one other possibÍIity to account for the formation of the cyanoamide. The nitrile-N-oxid.e¡ (l¡¡), has recentl-y been reported. to rearrange to the amid-e, (t34), (Scheme 41),217 tt j.s conceivabre that N-oxíd.ation of the d.initrile occurs followed. by subsequent rearrangement. As a four-membered transition state wor.rld. be necessary, hovrever¡ and. as 2-cyanop¡rrid.ine-N-oxid.e d.oes not rearrarrge wrd.er sinilar conditions, this possibility is rather remote. -112-

H H H N N '+ ------+ YO2\ R N c HR

T I 0 lgñ c ONH 'ù N 2

(133) (134)

Scheme 41 - 113 -

CHAPTTR 3

RE,ACTIONS O¡' PYRTDO 2.3-dl PTRIDAZINE DMTV.ATTVES

The systematic stud.y of the pyrido[er¡-¿]pf"id'azines has been properties of extend.ed. to an investigation of the synthesis and- ôe=ivatives monosubstituted- in the d'iazine ring' Most of the phthalazine derivatives which possess pharmaceuticaL aotivity are As these compound.s which are sinilarly monosubstituted. in this ring' the compounds are generally prepared from 1-cbl'orophthalazinet synthesis of the monochloropyrid.o[Zr¡-g]pytid.azÍnes wo'ld' be an essential precì.¡.rsor to an investigation Of possible pþysiologically active d.erivatives in the pyrid.opJrrid.azine series. The monochloro may compounds possess read.ily replaceable substituents and therefore be converted. to a number of other d'erivatives of interest'

1. AND

(") IrrpROLySrs oF 5. B-IICHI,OROPYRIDOI2. 3-a:I?YRIÐAZINE (lZZ), are The 5- and. B-pyrid.o[2,3-dlp¡æidazinones r(lZl) anti The tautomers of the !- and- 8-Wdroxypf¡i"d"o[213-0]p¡rridazines' B-substituted. d.erivativer was synthesised. some years ago as a means (schene of establishing the structrrre of picorinic acid 3-aldehyd.e ù'92 Inthepresentworkbothcompounôswereobtainedas aoiclic intermed.iates in the oxidation of pyrid'o[er¡-g]py¡idazine with potassium permanganate (Cnapter 2). It was consíd-ered' more convenient to prepare these compound.e by the nethod. outlined' in scheme 42' -114- ct 0

N N H N H 0 I + ,t N H l, N ct ct (135) (136) j

(t22) (121 )

Scheme 42

fhe wdrolysis of the d.icbloro d-erivative was achieved' by und'er reflux heating an aqueous or alkaline solution of this compound for 0.! boi:rs. The infrared. spectrum ind'icated. that the product was very a nixture of (t35) and. (f¡6) as the carbor¡y1 region showed. a cm-1 region' broaù band- and. two C-CI peaks were present in the IOOO two isomers Repeated. fractional sublimation enabled separation of the and' which were finally crysta]lised. to derivatives of ro'p' 3O?-Bo (l¡¡) and (f¡6)' 296-7o. These compound.s were assÍgned structures respectively. The purity of these compounds oor¡l-d' be gauged- from the (r¡i) an¿ (t36) exhibit rl.¡n.ï. and' infrared spectra' ?ure sampLes of ¡'or (1 this only one C-CI infrared. band. in the 10OO cm-1 region. 35) (l¡e) peak is present at 1OO! band appears at 9BO cm-1 an¿ for this "t-1' The struoturar assignnent of the chloropyrido [2, 3-È] -ol'ridazinones The infrared absorption was based on both ph¡rsical and. chemical evidence' may be invoked' to frequencies of the oarbonyì. peaks of these oonpounds bond of the enable an initial assignment to be made, The carbor¡yI !-chloro d.erivative would. be expected to oocun at lower frequencies - :115 - 1

ct Ha H. N 6

I r T' NH H NHH N ¿( N X N o o ct (137) (138) (139) than that of the B-chloro d.erivative as a result of the electronic shifts as shown in (t¡Z). Such shifts are not possible in the p-chloro compound" The isomer with carbonyl frequency of 16?0 cm-1 wap therefore assuned ts ue (t35) and that with frequeney of 168r eru-1 was designated- a" (t36). Such evidence alone is insuffÍcient proof of structure, however, as l¡yd.rogen bond.ing effects are not consid.ered. in this treatment.

Structural assignments may also be made from a oomparison of the chemical shifts of the tf.m.r. speotra of these compound's. It wou1d. be pred.i-cted that protons H. and. H* would. be unaffected. by variation of the d.lazine ring substitution. A marked. downfield. shift in H- of (t39), due to the d.eshield.ing effect of the m !-oxo group, wou1d, hovrever¡ be expected. in comparison to the equivalent proton of the l-chloro-B-oxo d.erivative. These pred.ictions are borne out by analysis of the spectra d.etermined. in d.imethylsulphoxide. The spectra.were of an AID( type and. Hr, H, and. H* appeared. as three quartets as expected. For'compound. (l38) ttrese protons have Tval-ues of 1.95, 1.56 and 0.'f! respectively and. for (l¡g) the equivalent -116-

l varues are 1.99¡ 1.31 and- o.?3. As pred.icted. the protons H" and.

H, undergo little change in chemícal shift but H, of (t39) was shifüed 16 c/s d.ownfield- coropared- to the equivarent proton of (13g). Not only d-o these resul-ts verify the assignment based. on infrared. d.ata but they also ind.icate that the isomers exist pred.oninantly Ín the lrketorr form even in d.iroethylsulphoxid.e solution.

The assignment of structì.¡res was further verified. by convertÍng

the chloropyrido¡Zr:-4Jp¡æid.azlnones to known compound.s which had. been unambiguously synthesised. by other routes.

(¡) NUCLMPHILTC RÐLACE¡'IHù'I 0X' C}tr.,ORO GROUPS OF CIil,OROPYRTDC T .3-d.l- PYRIDAZINONES

synthesis of the !- and &pyrid.oler¡-q]pyrid.azinones from (r¡g) (t and ¡f) requires the removal of the chloro substituents. This was achieved' by replacement of the chloro groups by hyd.razino substituents and eubsequent removar of the ratter by ne:rcuric oxide oxidation. À11 attempts to replace the chloro groups using ethanoric lSrd-razine hydrate lvere unsuccessful even when heating at the reflux

temperature of the mixture was continued. for 14 hor:rs. This was most

surprising as monochloro derivatives which are activated. toward.s nucleophilic attack are generally replaced. in 1 5 ninutes und.er such conditions. The chlorine atoms of the chloropyriaofZr3_d]pyrtdazinones are also stable to prolonged. reaction with hot, concentrated. sod.ium byd.roxid.e. The chlorÍne atoros in simirar compound.s have arso been recognised. to be inactive toward.s nucleophiric attack. chlorop¡æið.az- -117-

lnones. 218 and cnlorophthaLazinon."2l9t22O b^u" been reported. to be particularly resistant to such attack. A sÍmilar situatÍon must also

occur with compound.s such as (f¿O) for although the synthesis of these d.erivatives involves the use of excess hyd-razine hyd.rate, no nucleophilÍc

d-isplacement of the amino group occurs.87-89

0 R 0

N IJ ,l H N N R lt rÌ ,|¡ N N N ft

H R

(140) (141) (t 2) (143) (141,)

0 H ct .9 .964 904 7 906 .85 2 14 65 7 71 975 1'17/. '985 1l1338 1.17 /. Ì 889 r 1jl54 .896 Nr.152 .904 N 1.328 N N 28 30 7 6 tro 1207 121t, 1.19 9 H

( l4s) r/.6) n47)

The reluctance of substituents T- to the carboqyl group to

undergo nucleophilic replacement has not been explained. in the literature. Infrared. spectra suggest that such compound.s exist in the rrketoil form, such as (t¿t ), in the solid. state. In the alkaline solutiolFemployed [enolrr Ín the attempted. substitutions, however, the tautomeric form is almost certainly the predoninating species present. In this formt - 118 -

electronic shifts such as shown io (t 42) are possible' Suoh shifts would- increase the charge d.ensity of the carbon aton to which the substituent R 1s attached.¡ thereby rend,ering nucleophilic replacernent less favourable. n-electron d.enslty calcr¡lations for the chlorohyd.roxy- p¡rrid.olzr¡-g] p¡æid.azines support this theory (diagr".*s (l+l)-?4?) ). A similar effect would. also be expected. with compound.s containing alkoxy substituents such as in (f¿¡). Substítutlon of both -R and.

-0R groups is possible in these compounds und.er. forcing cond.itions. fn the case of the "hydroxyil compounds suoh as (l+Z)¡ however, the structure is more accurately represented by the anion¡ (lqq), (see

Chapter 4) which wor:Ld. enhance the elect¡on donating effects, as d.escribed for the neutral molecule¡ to a very large d.egree. Substitution is therefore far more d.ifficult with such compounds than for the alkoxy d.erivatives where anion fornation is prevented. Domagalina has successfully employed high boiling solvents to effect nucleophilic substitution in such "y"t"t".219 Dietlr.ylene g1ycol was therefore used. as solvent for the reaction of Wdrazine with the chlorop¡rrid.oler3-È]py:ridazinones. 3y this means substitution was achieved and, the resulting lo¡rd.razÍno d.erivatives lqere reacted with nercu¡ic oxid.e to yie1d. the corresponding pyrido[213-4]pyrid,azinones, (lzl)r ard (lzz), in good. yield. -119-

(") RTÐUCTIVE CATAT, YTTC DEHAI,OG ÐIATTON OF THE CIü..,oROpynræ I .3-a1-

PYR]DAZTNONES

The pyrid-o[zr¡-g]pyridazinones were arso prepared from the

chlorop¡rrid-o[213-4J,¡y¡id.azinones by reductive catalytio d.ehalogenatlon

uslng 5fi parrad,ium on carbon in the presence of smarl amounts of

ammonium hyd.roxÍd.e as an acid bind.ing reagent. fhese red.uctione rtrere

carried- out und-er a variety of cond.itions and. two prod.ucts were able to be obtained. from each chlorop¡rc:.do [zr3-ê]pyrid.azinone. Reduction of 8-chroro-!-pvriao[2, ¡-ÈJplæi¿azinone¡ (r ¡6), proceed-ed. slowly room at ternperature and. pressure and. uptake of $rd.rogen ceased after J hour.s. the product was 1r2r3r4-tetrahydro-!-pyæidolzr¡_È]_ p¡æidazinone, (r¿g)¡ which was contanÍnated. by traces of amrnonium

chlorid'e. Separation was aohieved. by fractional sublimation followed. by crystallisation. The d.iazine ring could- not be hyd¡ogenated. even und,er atmospheres 100 pressure. The tetráhyd.ro compound, (l¿a)¡ wES again the onry prod,uct und.er these cond.itions. By carrying out the red.uction such that uptake of only one more of Ì¡yd.rogen occurred, the desired- 5-p¡rrid-o[zr¡-4Jprid.azinone, (lzl)r was obtained. as the major prod.uct together with smarl anounts of (138). Again the mixtu¡e Ìvas separated by repeated. fractional sublination and. the prod.uots finally purified by crystal"Ilsat ion.

fJ .I

r NH N N H H (148 ) (149 ) -120-

Reduction of !-chloro-B-p¡.ri¿o[e, 3-41 pf¡id.azinone was found to follow a simÍIar pattern. At room tenperature and. pressure, uptake

of one mole of \ydrogen yield.ed the products (lzl) an¿ (149)r with B-p¡ncidoler¡-4]p¡æidazinone¡ (lZl), being the major component. Hyd.rogen- ation at higher teroperatures and pressures prod.uced. onfy (t49). llhe assignrnent of structures to compounds (lzl), hzZ), (148), and. (149) followed fron both physical and. chemical evidence. The n.m.r.

spectra of the p¡æid"o[e, ¡-d]p¡æid.azinonês, Ín d.Ímethylsulphoxide as solvent, appea" as th¡oe quarbets which arise from the Al0( systen of the pyrido ringr together with a single peak due to the proton of the d.iazine ring. The proton at C-{¡ Hr¡ und.ergoes a d.oshield.ing effect of 10 cf s ín the !-d.erivatíve oompared to the B-j-somer. This again afford.s strong evÍd.ence for the structures (la ) and. (lzZ) and. ind.icates that even in d.imethylsulphoxid.e the rrketorr form j-s stil-} the pred-ominatÍng species in tb.e tautomeric equilibrium. The d.iazine ring proton appears at 'l=1.5j in each compound which means an upfield- shift of =1 T unÍt has occurred compared to the parent heterocycle. This could. in part be due to an Íncrease in electron d.ensity at this position but may be better explained. on the basÍs that the protons in these compound.s are less rraronaticrr and. are more ahin to the proton of the -CH=N- group of phenylþyd.Tazones. These protons have been shown to absorb in the same reglon.. 221

The n.m.r. spectra of (l4B) and. (lqg) coupled. with elementary analyses enabled art assignation of structures to these compouncls. -121-

The spectra werê run in KZCO3/llDO and. d.irnethylsulphoxide respectively and. d-irect comparisons of the chenical shifts of these conpound's ï\tere not therefore possible. Compound. (t+B) gave three peaks in the aliphatic region and one aromatic peak which integration showed' to be in the ratio l;Qz2:'1. The alipbatic peaks occuged at T =6'97 (tripfet), ?.BZ (triplet) and 8.41 (multiplet) and. these corresponded- to the o, f an¿ g metþlene groups of the pyrid.o ring. The aromatio proton appeared at T=2.71. Conpound, (149), *r" only soluble in dimethylsulphoxid-e and- the met\ylene protons were therefore masked. Consequentty only the lone aromatic proton ( I = 2.43) was vlsible'

(¿) CATA].,YTTC EI\TATION O¡' (r48) AND (I¿g)

(l+B) (149) been Fr:¡ther evidence for the structure= "d has obtained. by tbe catalytic d.eþdrogenation of these compound's to the pyrido[2r3-È]pyrid.azinones. The literature contains few reports of the preparative d.el¡yd.rogenation of perhyd.roazaheterocycles. Pallad-ium on alumin palladir.¡n on carbon2z3 Yu'ru" however been eucceesfully ^222 ^nð, used as catalysts for such tlebyd.rogenations in solvents sucb as nitrobenzene and decalin. De[ydrogenatÍon of the tetrahydro d.erlvatives¡ (t¿g), and., hqС wâa effected by heating these compounds for two d.ays with 5É pallad.lum on carbon in d-ecalln. The correspond.ing pyríd-o[Zr¡-g]- pyridazinones were obtained. ín yie),d's of 7O/,. This procedure provid'es a useful arternative to l¡vdrogenation of (l¡i) and' (136) usine one more of hydrogen. -122-

Subsequent to this investigation an abstract to the work of Domagalina on the aqueous hydrolysls of 5rg-d.ichÌoropr¡id.o[2, 3-g]- p¡æidazine, (U), has appeat"d..102 Only compound. (l ¡g): rv&s isolated.¡

however¡ and no d.etails of the structr:¡aI assÍgnnent'were mentioned.. rn 1965, Nitta and coworkers published. a more thorough accou¡t of

this þd.roryuiu-101 Both isomers were obtai.ned. and v¡ere separated. by the difference in solubility of the sodium salts in d.ilute sod"ium

h¡rd-roride sorutlon. The melting points of (t35) an¿ (l¡e) obtained by this procedure were 2B9o anð. 2750 compared_ to the reelting points anð' of 3O?-8o 296-70 found in the present stud-y. The separation method. of Nitta and. coworkers t/ras repeated. and. the prod.ucts were found. to be mixtu¡es with one isomer pred.oninating. îhis was d.etermined. by tb,e previously described- method involving inspection of the region of C-CI absorption of the infrared spectra. rt has now been fou¡rd. that the most efficient means of separating these compound.s Ís to first apply Nittars proced.ure and. subsequently fraotionally subline the resuJ.tlng products. Nittars structurar assignroent for the cb.LoropyrÍd.o[zr¡-e - p¡rridazinones ü¡as in agreenent with that of the present stud¡r. Nitta also employed red-uctive catal¡rtic d.ehalogenation but used. 2ol palladiun on carbon as the catãIyst. Both (l¡¡) and. (t36) were hydrogenated. by proced,ure this but the onry prod.uct obtained. was (lqg) whioh was formed fro¡r reduction or (135). rn the present work, the mfrder catalyst employed' enabled the isolation of four prod.ucts f¡om these conpounds. -123-

a critical facto¡ as in The activity of the oatalyst is probably thisinvestigationtheweaklyactiverutheniumoncarboncatalyst proved h+g) to be id'entical has been shown to be ineffective. Nitta to the prod.uct forned from reduction of B-pyriaof2'3-4]pfridazinone Bottari and' carboni'92 In" wbich was obtained. by the method. of and' that of (l¡6) structu¡e of (t35) was therefore able to be d'ed'uced'

was assumed' bY elimination' Nitta obtaÍned' (l ¡5) ana From the alkaline lrydrolysis reaction ratio was found to (r¡6) in the ratio 6¡ 122' In the present work the enployed gave purê sanples this ratio is be 2¿3 ar¡d. as tbe separation held to be t accuratê.

(") THE

(r ¡o ) ¡,¡ro (l rr)

Althou8hthepyricl'o[2,3-e]p¡¡rÍdazinoneshadbeenobtained.by for¡rind.epend'antnethods,noneofthesewereentirel.yunarobiguousas separatlonandíd.entífícationofisomerswesrequireôineachproced.ute. by the unambiguous Proof of structure was finally rendered absolute of the l-actones (150) and' synthesis of these compounde by conversion by reaction witb (f fl ) to the correspond.ing alciehyde-aciòs follo''¡¡ed' hyùrazine tgrdrate' (r¡o), has recently The 2-lrydroxymethylnicotlnic acid. lactone¡ by two method's224'225 been synthesised from ethyl 2-nettrylnicotinate acid' lactone¡ (f 5l)t and the structure of the J-Wdroxyroethylpicolinic isa}sobeyond'questionasthiscompound.hasbeenr,rnambiguously t of the two lactones synthesised from 6-hyd,roxyquinoline?6 ^i"tL'¡re I -124- has also been obtained¡ albeit in poor yield.¡ frour the cataì-ytic paLladir¡n \ydrogenatlon of quinolinic acid anhydrid.e at lOOo usÍng 5Ø on carbon as cata}yrl.227 The procedure for separation of these isomers, bowever¡ was inefficient. The other existing syntheses of

(ffO) and. (t51) require lengthy reaction sêquences or starting materials which are not readily available. Other nethods of obtaining these lactones were therefore investigated''

Two new routes:to these compor:.nds were established.r of which the most satisfactory involved. the partial red'uction of quinolinic acid" anhydrÍtle wÍth lithiun alurninfr:n hydride. [rith excess of this red.uci.ng agent, cyclio aromatlc acid' an|¡ydrid'es forn d'ialcohols such (l but it bas been shown that partial red-uotion is possible "s 52)1228 if half a mole of lithium a1u¡nlnir¡¡n hydrid.e is used' for each mole of anþydrid.e. 3y use of this techniquer phthalic anhydride has been reduced to phthalÍde¡ (rf¡), ía 4r% yierd''229t23o The reduction of quinolinic acÍd an\rdrid.e by this method. was achieved by ad.d-ition of an ethereal solution containing one-ha]f mole of lithium aluminium Ïryd.ride to a solution of the anhyd'ride in ether. Such a proced.ure lessens the possibility of formation of the d.iol anù in practice nonê of this oompound. was obtained'. Both lactones were formed. |n an overall yieltl of 39|s end separation was achieved' by fractional sublination. This reaction proceeded. equally weI] whon (l¡O) tetra\ydrofuran was used. as the solvent. The ratio of (151) rto was found to be !:! whereas the catal¡rüíc red.uction nethod' gave a ratio of Z¿7.227 Conpoun¿ (f fO) was id.entlfied by oornparÍson wlth en -125-

H2 0H

H 0r{ 2 (150) (151) (1s2)

H c0 2 0 HO r (153) (15/.) (155)

H OI.I t{ 2

cH0 N Br fi56) (157t (15 8) o2 0

2H 0 2 0 2

N NO 2

(159) (160)

authentic sampre prepared- from ethyl-2-met\ylnicotinat e224 and, trre second lactone was assuned. to b" (151 ) by elimination. Metting points, infrared. and. ultraviolet spectrae and. d.erivatives confirmed. these assignments " A less satisfactory method. for the synthesis of these lactones

involved. reaction of qulnolinimíd,e with potassiulr hyd.roxid.e and- zinc powd.er" This reactÍon ie analogous to the preparation of phthalid.e from phth*1iti¿s.231 Both lactones wêre obtained. in a total yie1d. of -126-

26fi anð, the ratlo of (l5t ) to (tfo) was 'l :{. The key step in the synthesis of the p¡æid.o[Zr¡-q]p¡neid.azÍnones from these lactones is an extension of the preparation of phtbal- aldehyd.ic acid, (l>S), from phthalid.e. this reaction requires the bronination of the rnethylene group of the phthalid.e, either by bromine23z or N-bromosuccinimia"r233 followed. by aqueous Wd¡olysis of the resul-ting 3-bromophthalid.e¡ (lSq)¡ to phthalald.ehyd.ic acid.. Substituted phthalald.ehyd.ic acids have been synthesised by a similar p"o""d.*".234 Sromination of the lactones, (lfo), and., (lfl), is only possible

by employment of N-bromosucoininid.e for reasons alread.y d.iscussed, in

connection with the bromination of the lutid,ines (Ctrapter 1 ). By use of this reagentr bromination of the laotones proceed.ed snoothly. fhe productsr hlghly lachrymatory bromo-derivatives, were not investigated..

These compounds were Ì¡rdrolysed. by heating in water and the aqueous

solutions¡ orr rêêction with hyd.razine hyd.rate, yielded. the respective

p¡rrid.o[Zr¡-d]pyid.azinones. The latter condensation is simply an extension of the preparation of phthalazinone from phthalaldehyd.ic ,"ið..235 The overall yield.s of 5- and. 8-pyriaol2rl-{]pyridazinone from the lactones weTe qq# xd 4ú respectively, These compound.s were id-entical in every respect üo those obtained. by the method.s previously d.escribed,.

One of the intermediates in this sequence of reactions, picolinic acld..3-alclehyd.e, had previously been eynthesised by a d.ifferent tott"92 and. therefore no attenpt was mad.e to isolate this conpound.. Nicotinic acld 2-ald.elqrde¡ (lSl)¡ howeverr had. not been prevlously reported. and this compound. was therefore isolated. from the -127-

mixture which resuLted. from the hydrolysis of tho bromo-lactonq (156).

The Ìqrgroscopic nature of this ald.ehyd.e-acid. mad-e isolation

extremely d-ifficult and a d,ry solid. sarnple. was transformed. to a sticþ gu.rn within two minutes on êxposure to air, The ald.ehyd.e-acid. was characterised, by reactíon witb hyd.razíne hyd.rate which prod.uced.

B-p¡rrid-o[zr¡-d] py.rid.azinone, (tzz), tn Bj/' yÍeId.. Vfhen ref]uxed. wlth

Srad.yrs reagent for 30 mÍnutesr a yellow precipitate, presumably the 2r{-dínLtrophenylhyd,râzone¡ (l>g), formed. On fr:rther heating this product v/as converted. to a colourless solÍd, beLieved- to be (t6O). Analogous cyc}isations in acid, solution have been reported. by several *orkers. 9 2 t96, 1 50, 236

The infrared spectrun of the ald.ehyd.e-acid. ind.icated. that a mixture of the tautoneric forms (l>l) and. (158) was present in tb.e 1 eolid state" Band.s at 3450 Ø and 1 775 cn-1 ind.icated- the presence of the lactone (f fB), while weak bands at 2?00 and. 2550 cg-1 together with a strong band. at t?00 cm-1 pointed. to the presence of the ald.eþde-acid form (lll). This was not surprÍsing as for nost of the phthalald.ehyd.ic acid. d.erivatives, the 3-Wdroxylactone forn Ís by far the major component in the solid, A roore balanced, mixture "t"t".237 of the two forms has been ehown to exist with o-benzoylbenzoi" ."id..237d

2, 5- AND 8-CHLOROPTRTDOIZ,S-¿JprnrnAZrNE

The synthesis of the pyrid.o[2r3-e]pyrÍd.azinones enabled. the monochlo¡o d.erivatives to be prepared by ¡eaction with a nixtu¡e of phosphorus pentaohloride and- phosphoryl chlorid-e. lbig was achieved. - 128 -

1n good- yield. but as the overall ¡oute to these compor¡nd.s was te¿ious and. extreme care was required. in the final work-up to prevent acfd. llyd.rolysis, a more convenient route was sought. rn this work it has been found. that both chloro groups of 5r B-d-ichlorop¡rrido [2, ¡-È] pyridazine may be replaceil. by prolonged heating with ethanoric þd.razine þdrate to give the !r&-d,iÌlyd.razino derivative. Nitta and. his colreagues investigàted. this reaction und'er less extreme cond.itions and. fourrd that ¡nonosubstitution occr¡¡red. with the formation of (t6t ) an¿ (16Z).

c{ NHNH 0 2 Z-Z

N

'f I N N N HNH 2 ( 161) (162) (163)

ct 0 HNH 2 N IJ ,l T ,[ N N N N H H 3 3 (164) (t65 ) (166)

IJ 2

T N N N NH 2 Hz

n67) (168 ) (169) -129-

Nittars procedure was slightly mod.ified and extended. to enable a eimple and less ted.ious synthesls of the monochlorop¡æido[er¡-4]- p¡æidazine", (68) ana (69). This synthesis again ernploys mercu¡ic oxide to remove the \ydrazino group. As the chloro groups in these oompounds are more stable to aqueous hyd.rolysls than their counterparts in the d.ichloro d.erivative¡ (+l), the reaction nay even be carried. out at 4O-50o. The high yield.s obtained, fron these debyd.razination reactions again demonstrate the practicability of this procedure. Soth chloro derivatives are stable in solution but the solid.s dcoompose on eTpost¡.Te to air to orange-brown¡ higbmeltlng so]id.s.

These prod.ucts were not examined but probably bave structtlres of the type, (t6¡), by analogy with the deco¡nposition of 1-cb-Lorophthalauío..244 The infrared s¡iectl¡n of the 5-chloro derivative¡ (69)r contains a C-Cl band at 985 cr-1 and. the Lchloro compoundr (68), shows a simila¡ peak at 1O2O cf1. These bands und.orgo tittle variation on substitution of other atoms of the ring system as¡ they occur in similar positions in the corresponding chloropyrÍd.o [2, 3-a]pytidazinones. The n.m.r" spectra of the chloropyrido[Zr3-È]pyrid-azines

(nigures 6 and. ?) were analysed. in d.etail as they enable convincing proof to be obtained. of the protons involved. in the long-range coupling observed in pyrid.oler¡-4]pyridazine. The protons of the pyrid,o rings prod-uoed. the usual th¡ee quartets of the AtrD[ systen. t, of the

8-cÏ¡loro compound. cannot participate in long-range coupÌing with the protons of the pyrid.o ring and- therefore appeared. as a singlet at low field.. The proton H" of the 5-chloro derivative, however, appeared H m t E H N z I 'H¡ N N z

I wo I

E a E3 E

460 500 yo 57o 590 c/e Figure 6. N.m.1.. spectrum of !-chlorop¡rrid.o[Zr¡+]p¡rriitaaine in deuterochloroform. E v

H m v

T Hr N ct I

I E m

E a Hx

460 49o ,n 540 580 c/s Figu¡e I[.rtr.1.. spectrum of Lchloropyrid.o[Zr¡dJpftid,azine in cleuterochloroform. ?. T -132-

as a d.oublet d.ue to long-range coupling with H, over a l-bond. "zLg- zagrr path. H_ therefore shored. as an octet. The coupling constant

J*- was found. to be which is good. agreenent the mz 1.O c/a in with magnitud.e of such coupling in other members of tbe pyrid.o[Zr¡-È] pyrid.azine sertes. [he signs of the coupling constants wers also

d.etermined. by use of the d.ouble irrad.iation technique.

The chloro groups of the chlorop¡rrid-o[2r3-4]py¡id-azines are

activated. towards nucleophiLic attaclc. Hyd.rolysfs at lOOo fr¡¡nished. the pyrÍdo[2,3-4]pyrld.azinones, (121) and (lZZ). îbis ls in contrast to 1-ohlorophthalaztne whloh yleLd.s an analogous prod.uet to (l$).244 The chlorohyd.razinopyrid.c[Zr3-d]pvrid.azines, (l6t ) and. (leZ¡, und.ergo

a similar þyd.rolysis to yield. l¡ydrazinopyrid.o[2, 3-È]o¡mi<ì.azinonee which were shown to be id.entical to the prod.ucts obtained. frorn

reactj-on of the chloropyriao [2r 3-d] pyrid.azinones with ].¡ydrazine

Ìryd.rate in dietþy1ene glycol. !-Ch).oro-B-methylpyrid"otZr ¡-,1]p¡rrid.azine¡ U6q), obtainetl by the method. of Armare go196 also hyd.rolysed- in the same manner to yield. 8-methyL-!-p¡rrld.o [e, ¡-q] p¡mid.azinone, h e5¡ . fn each case tho B-chloro d.erivative was far more resistant to hyd.rolysis than was the l-c}ùoro compound.. Nucleophilic reagents such as byd.razine and ammonla read.ily replace the chloro groups of the chloropyrid.o [2r3-ÈJpyrid.azines. The monohyd.razino derivatives, (1 66) and. (16?) were obtained. by heating an ethanolic solution of either

(68) or (6g),JÍith hydrazine Srdrate u¡nd.er reflux for O.! hours. The mildness of this procedure was ln sbarp contrast to the cond.itions required. to effect replacement of the chloro groups ín the chloro- p¡rrid.o [2, ¡-g] p¡rridazlnorrês c - 133 -

Thehyclrazinogroup.softhesecompoundsread.ilyund'ergothe give the ancl N-N cleavage reaction with Raneyi'nlckel to f- (t69). These compounds B-aminopyriclo[2,¡-èJpfridazlnes, (168) an¿ solvents for recrystallieatlon were analysd @ the picrates as suitable were also experienced with could, not be found. Similar d'ifficulties the 2-amino and. !r8-d'iamino derivatives' Themonoaminod.erivativeswerealsoprepared-d-irectlyfromthe arnmonium hydroxid'e and' chloro compouncls by reaction witb conoentrated was found' to be ethanol in a steeÌ tube' The prod'uct surprisingly thehyd'rochlorid-ealthoughexoessbasewasused.Ínthereaction.A is reacted und'er similar result is obtained' when 1-chlorophthalazine are read-ily similar cond,ition".140 [he ch].orop¡æido[2r3-ÈIpf¡id'azines over palladit¡m on charcoal dehalogenatecl. by catalytlc hydrogenation 5f" to glve pyrid-o[zr¡-g]pyrid'azine in good yÍelùs'

).ì

fhegeneralbackgroundconcernlngthepreparationoftriazo}o compound'sfrom}qrd'razLnod-erivativesofpyriòazineand.phthalazinehas alread.ybeencovered.Inthisòepartment4-Wd.razino-1-phthalazinone to tbe correspond'ing triazolo has been cyclised. with a number of reagents has involved' d.erivativ"""238 A1I recent work on such cyclisations proposed' for derivatives of g-òíazines. Inspection of tbe mechanism al1 aromatic beterocy'clic'' the cyclisatfone, (Scheme 43)r indicates that compoundswhichpossessabyclrazinogroupa'djacenttoaheteronitrogen -134-

should. und-ergo thls reaction. The only.report to substantlate this hypothesis howeverl is the reaction of 2-þdrazinoquinoline, (tZO)t with formic acid. to produce the triazolo d.erivative (171).239

RCOzH ñ r H H \r --s NHNH2 N-NH 2 N-NHCOR

N -Hzo

I H CROH R

H tl

Seheme 43 Dibyd.razino derivatives d.o not und.ergo a d.ouble cyclisation.

One l¡ydrazino group has been found" to cyclise to form a triazolo

ring but the second. Sroup is only acylatecL by the exceõs reagent. 1,4-Dlhydrazinophthalazine forns conpound (llZ) with excess formic

compound (t?3) with excesa acetoacetio acid.93" and ""t"".240b Kunze was unable to prepare derivatives such as (50) from

d.i\ydrazino derivatÍves and. usual formylating agents but obviatecl' this problem by use of a mÍrture of an aromatic o-d.initrile¡ hyd.razine

hydrate and, ttimethylfor¡namide. By such a process the d.i$d.razino clerivative is generated. Ín situ and undergoes fornylation and. cyclieation to yielct compound.s analogous to (50).24Oa When this

reaction was applietl to p¡rrid.ine-2r3-clinltrile¡ two prod.ucts¡ (r1.,

and. !1d; R.NHNH2), weTe possible and. Kunze was unable to d.etermine which isoner was foímed. - 135 -

NHNH N 2 I N cH0 u70') n7t) u72)

H^ N 6 Hz

I N Hx N N N=cÆHg 'cH2c02c2H5 v

(173) q74) ( 175) ct

N H 3 I ¡ CH J 3 i

i¡ i i w6) u77') u7e) I i ct

H r 3 CH 3 N

N

n79) (r8 0) -136-

The resolution of this problem has been'achieved. by use of

compounds and. techniques d.eveloped in the present stud.y. The

rrcompoundrr obtained. by Kunze has now been shown to be a mlxture of

both the possible isomers (51c and. 51d; R-NHNË'). In the present work, the reaction with p¡rrid.ine-2r3-dinitrile was repeated. to give

a prod.uct of m.p. 24O-243o . 518-Dlhydrazinop¡rrid.o[2, 3-è]py¡ídazine was also reactecl with an equimolar quantity of fornic acid.r and. the reacticn, contrary to the suggestion of Kunzer proceed.ecl smootb.ly to yield. a prod.uct of n.p. 311o, Both prod.ucts were separately treatecl with merouric oxfd.e to remove the l¡yd.razino groups and- the col.ot¡¡less solitls obtained. from these reactions were fractionally sublined..

Each product yieì.d.ed the new heterocyclic compounds p¡rnido[Zr¡-g]-

s-t riazol o [4 , 3-4] p¡æid.azi ne , (17 4) , and. p¡rrid.o [¡ r e-g] -s-triazol o-

[¿' ¡-g] p¡rrf.d.azine, (t75) - The assignment of structures to tb.ese compound.s was made by

unambiguous synthesÍs from 5- and- 8-hyd.razlnop¡rrid.ol2r3-g]p¡rrid.azine. lVhen the J-hydrazino derívative was heated. with formic acid. for 0.J hours, the heterooyole' hl>), was produced. Cyclisation of the &-hydrazino derivative to (llq) requfred. a much longer reaction time. These cyctised prod.ucts were shown to be id.entical with tbe prod.ucts

obtained. from the d.ehydrazlnation reactíons. Further proof was obtained by synthesis of compound¡ (t?e¡r101 followed. by replacement of the chloro subetituent by a hyd.razino groì¡p subsequant .and. dehydrazlnation. This procedure afford.ed. (lZ¿) which was shown to be

the same as the compound. aésÍgned. thls structt¡¡e by the previous method.. -137-

The n.m.T. spectra of the triazolo compound.s were record.ed.

in d.imethylsulphoxid.e at 10Oo and. supply additionaL st¡uctura1

evidence. H- of compound. (lll) d.eshield.ed. by m is the ring current of the triazolo ring and- occurs at 18 c/s lower fie1d. than the

equivalent proton¡ Hrr of compouna (tZ+). Inter-ring coupling between H-my ancl H- of compound. hl>) arso occuxs whereas in (l J{) sucb coupling is not possible.

Conpound (ll+) vvas the najor component of the mirtr¡re obtainecl via the procedure of Kunze whereas in the rnixtu¡e afford.ed. by tbe dihyd.razino compound., (llS) predoroinated.. The d.ifference nay welr be d,ue to the fact that the nethod of Kunze uses a basic mediun whereas tbe atternatlve proced.ure require's an acid.ic ned.iun.

Kunze was able to cyclise 5rB-d.ihyd.razinop¡neid.o[2r3-è]- p¡neid.azlne, (lZ¡, with excess ethyl acetoacetate, but again was not able to deternlne in which d,irection the cycltsati-on had proce"d."d..240b This reaction was repeated. using only one nole of acetoacetic ester and. by the sane proced.ure employed- above¡ the resurting prod,uct was again ehown to be a nirtr:ro. trbactional sublimation of the dehydrazinated. prod.uct yíe1d.ed 3-methylpyrido ler ¡-è]- and. l-netþyI- py¡icl-o[¡, e-gl-s-triazoro14, 3-è]p¡midazine¡ (r ZZ), and. (t Ze¡, respective)-y.

Assignment of struotr¡re was again based. on chemical nethod.s.

Soth 5- and 8-þd.razinop¡rriao [2, 3-4]pyridazine nere smoothly converted to tbe l-methyl-g-triazolo d.erivatives by refluxing with acetic anþd.rid.e for 0.J hours. tr'inal proof was achieved. by conversion of the chloro derivatives¡ (fZg) and. (l80)r13O to tbe byd.razino derivatives - 138 - by heating wtth ethanoric hyd.razine hydrate. subeequent removar of the hydrazlno groupe by nercurio oxicLe fu¡nishecl (tll) an¿ (t?B) which were Ld.entical ûo the prod.uots fron the cyolisation of > ana B-Uyd.ra zi nop¡rrid,o [2, 3-è J p¡r¡ida zi ne. Kunze h¿s claimed. therapeutio uses for the hyd.razino trconpoulxd.srl. As these are in faat mtxtr¡¡es it wo¡r1d. be of interest to d.eternine whether the¡ meclioinar properties are d.ue to one component or both.

t t I r ;

I i

I ¡ t ;

;

:

ì

.D

I I t

ì I

I I

t

:

ç -139-

CHÂPTT'iR d

N.M.R. AND U.V. SPECTRA OF PYBTDOPYRIDAZINE Ðffi VATTVES

The spectra of the parent heterocycles h¿ve been describecL in some d.etail but those of the d-erivatives have been d.iscussed. only in connection with structural assigirme[ts, Conpilation of spectral data b¿s enabled. cogelations to be made within the p¡æid.opyrid-azine series themselves. llhe only conpound to be discussed in this section for whioh the preparation has not previously received' nention is Lnethyl- pyrid.o[Zr¡-4]p¡mid-azine, (¿o). The synthesis of this compound was essentially the same as that of Am"rego96 (sc¡,ene 1o). The 5- chloro-8-met\y1p¡rriaolzr3-ê]py¡idazíne2 h6q)¡ lr€ùs however¡ converted' to the Ì¡yd.razino d.erivative¡ (lBt )r erd dehyclrazinated. with n¡ercuric oxid.e. This method. enabled. irnproved. yield.s to be achieved in conparison with the original prooedure. IINH 2 f+

CH¡

( 181) (182)

1. N.M.R. SPECTRA

(") couPlrNe coNSTAxrs

Throughout the series the magnitud.es of the coupling constants fl.uctuate onLy slightly (Table 1O), For the pyrid.o[2r3-dlp¡æid.azines -140- the slzes of the coupling constants were found. to be:- t rr3. 4.2-4.6 8.1-8. 6 c/s, , 1.J-2.o c/s, tSrBt 1.2-1'J cf s c/s, J 3r4, rr4, ancl J4rB: O.7-1.O c/s. The long-range inter-ring coupling over five bond-s which is present in the parent is also ôisplayed' by those

(see Chapter 1 clerivatives in which a 'tzíg-zagrr pathway is possible )' In the case of the B-metryI derivative¡ (¿O), coupling was also observed between tbe protons of the metlayl group anfl a ring proton which appearecl to be Hr. Spin cLeoouplfng conclusively proved that H5 was the proton involved. fn this coupling. The coupling oonstãnt for this lntcraetiôn wå,s 0.! e/s. eoupiings of nothyL SrÕupc is to g- and 4-ring protons has,:been observeô previousIy183 u,rt thÍs believetl to be the first exanple of p-coupling in such a ln¿tr'ulêrr

(¡) srGNS o¡' THE couPlrNc coNSîAN'rs

spin d,ecoupling techniques were employed to d.eternine the signs cases t J of the coupling constants of sir compounds. In all rrr, 3r4, trro were founð to be of the sane slgn. This was assumed to be "^ positive for reasons outlined' in Chapter 1. In nost cases the signs of the long-range coupling oonstants cor¡Id not be detern¡ined' but it that JOrg of pyri¿o[Zr3-d]p¡r¡idazine were probably appeared "tdJr;U negative and' positive reepectively.

(")\-, ffi'Fncr oF suBSTrI'uu{TS

The nethyl group of 8-nethylpyrid'o[Zt¡-è]pJæidazine has no effect on the p¡æitlo rÍngr compared to the parent heterocyclet but cêuaes an upfielct shift of 11 c/e of the !-proton' As the only effect -141- likely to change suffioiently to cause sucb. an effect is charge density, this shift may be interpreted" as due to an increase of zc-electronic charge of 0.02 e in the l-position due to the + I effect of the methyl group. Similar effects are also observed. in tb.e chloro compound.s. The 5- and. B-chloro derivatives cause an upfield. shift of 7 c,/s in the p-position which can be interpreted as due to a + M effect of the chloro gxoup. fhis is in oontrast to the electron withd.rawing effect of halogens in the carbooyclio analogues. This anomaly probably a¡ises from the strong ind.uctive effects as ind,icated. in etructìre (l8Z). lhe chloro groups also have a marked effect on the !er!- positions of pyrid.op¡midazines. Comparlson of l-chloro¡ &-chloro ancl. !, 8-d.ichlorppyrfd.oþr3-È]p¡rid.azlnes reveals a l.ow fle1d. shift of 13-15 cfs ín the peri-positions to the chloro Sroups. This is also found in the pyrido[¡r¿-4]p¡rrid.azine series. It is also apparent that if such effects as reaction electrlo field. are neglected.¡ the ohenical shift changes of protons H, and H, comPared. to the parent pyrid.o- [2,¡-d]pyrÍdazine, must be regard.ed as d.ue to electron withd.rawal from the pyrido ring by the cìrÌoro groups. Thls effect is epparently ad.ditive as the largest eLectron withd¡awal fron this rlng 1s found. w:ith the dichloro compound, (4t ).

2. UIJIRAVIOLIfI. SPIPÎRA

llhe ultraviolet spectra of the p¡rrido [Zr¡-g] pyrid'azines reveal the expected. group I, II antl. III absorptÍons previously -142-

, discussed in regard. to the parent heterocycte (rarte t.t ). Bands in the 2oo'220 n¡t region have been crassed es d.ue to group r type transitions but the rerlabirity of the intensities nay be suspect as such absorptlonË occur at the linits of sensitivÍty of apparatus and. solvent.

substituents such as chroro, bromo¡ arninoe \yd.razino and" net\yr groups all cause bathochromic shifts. The group III absorption peak undergoes tbe greatest shift, This is particularly welr d,emonstrated. by e comparison of the absorption ruaxir¡a of the p¡æid.oler¡-q]- pyridazlnones ar¡d the chloropyrid.o[Zr¡-e]p¡rridazinones. The pyrid.o_ s-triazolof4,3-a]py"idazines aLso give simirar r¡Ltraviolet spectra to the pyrid.op¡æid-azines and. all three r.* absorption regions are read'ily d'iscernibre. No attempts v/ere mad.e to d.etect p, * transitions in these compound.s or any of the other pyrid.opyrid.azine d.erivatives. The epectrum of quinolinic aoid. \¡rdrazid.e (5r&pyid,olZr3_gl_ pyrÍdazinedione, (zl)) varfes markedry in different sorvents (F:.gure B)' This possibty is due to the exlstence of the d.ifferent tautomerÍc for¡ns (zl), (ree (rB?) ¡, and (rgg) ¡vtrich wor.¡rd. be erpected. to possess dissimÍIar absorption phtharhyd.razide¡ spectra. r r4-pr¡idazined.Íone and 1r{-pyrid.azined-ithione have been shov¡n to exist in the forms (re3¡, (lea¡ (185) and' respectivery, 1n both the solfd. state and in ethanoric

solution¡ on the baeic of thei¡ inf¡ared ancl. rùtravioret "p".t"".243 5- and" B-pyrid-olzr¡-d]p¡rrid.azinone und.oubteclry exist in the 'rketorr form in the solid' etate¡ in aqueous sorution and. in dimetþrsurphoxide from the infrared and' n.n.!. spectra of these compound.s. rf rrg- -143- pJrrÍdo[Zr¡-g]p¡rridazined.ione rrçere to exist in a form such as (,|86) or (l8Z)r its ultraviolet spectrr¡m would. be expected, to be very sÍnÍ}ar to those of 5- ancl 8-pyriao[2r3-È]pf¡idazÍnone but wÍth a slight bathochro¡nic shfft introduced. by the -0H ar.¡¡ochrome. This is the case when the spectrun¡ is run in agueous solution and. it is suggested. that in this rnediun the structr¡res (t86) and. (lB7) are the principal tautomeric forns present. Gheorghiu??t hr" also record.ed. the spectrum of 5¡8-pyrido[2, 3-4]pyrid.azined.lone but neglected to inc]ud.e the natr¡¡e of the solvent in his report. Fron the results of the present stud.ies it is almost certain that the spectrum was d.eternined in water.

It has previously been shown that pyrÍd.ones exist in the enol form in atkaline eolution24l ar¡d the Raman spectrum of an alkaline solution of phthalÌ¡yd-razid.e ind.icates that in this med.iu¡n the dilactin forrn pred.orin"t"".242 It wor.rltl therefore be expectecl that )r&- p¡rrid.o[Zr¡-4]o¡mid.azined.ione wou]d. exist in the d.ilactin form (l88) in basic solution. This is indicated by the fact that this cornpound is soluble in cold. potassium Ìryd.roxid.e but almost insoluble in cold. water. In 1N potassium Ìryd.roxid.e this compor.¡nd" shows three peaks at 22J ntt¡ Z6Z ntrt and- 338 rn¡l which couespond. to tbe tb¡ee rr.-r* absorption groups. The batúochromic shift of the group III band. compared to other pyrid.o[Zr¡-ÈJpyidazfne derivatives is probably due to the at¡xoch¡omic effect of -0- groups of structr:¡e (lB8). 4,5

water ----- 95í ethanol- --"'-" llI potassiun þclroxid.e 4.O

\\ \ I \ \ s (¡) \ 5 I a0 f \ o I \ r{ t a \ \ 3.5 \

\ \ \ \ \ \ \ t \ t t 3.O 1 200 220 24O 260 ?' ('¡.) 280 300 320 34o Fisure 8, Ultraviolet spectra of quinolinic acid. \nirazid.e in various solvents. -145-

The spectrum is therefore renarkably simirar to that of 5t8-d.iamino-

pyridc[zr¡-q]prid.azine in which a simirar effect operates. The 338 m¡t absorption band. is also responsibre for the pare yellow colour of the alkaline solution. The chlorop¡rrid.olzr¡-g]py¡idazinones give

similar spectra in alkatine solution to that of (t ee¡ but the group fÏI bandr which again und.ergoes a bathochroroic shift, d.oes not shift to the same degree as 1n the d.iractin câso¡ These resurts are conslstent with the formation of the species (te9¡ ed (t9o) tn the alkaline ned.iu¡n.

It is of interLst that no absorption occr¡¡s in the 3OO m¡,r region of 5t8-p¡'rido [2, ¡-d] p¡æid.azined,ione, (zl), or 5r B-pyrido [e, ¡-g]- p¡æid.azined.ithione, (47), in ethanolic sorution. rt Ís possibre that transitions d.o occur in these regions but are nasked. by the tair of other stronger transitions. Such masked" transitions, however wouLd. be of very weak intensity. À more likery expranation is that these compound.s exist in the rrketo[ forms, (zl ) ana (4r/), in such solutions. fn this case only the p¡rrid.o rings wouLd. shovr appreciabLe aromatic character and. the absorption band. which occurs ar 25o-z7o m¡.r, in these compound.s may then be ascribecl to group rrr transitÍons of pyrid.ine derivatives. Structures (tgg)-(tgg) either contain fu1ly aromatic bicycric systems or extensive conjugation between the d.iazine and. pyrid.o rings and. therefore the zr-lt* transitions of these tautoners wourd. be expected. to undergo a rrred shifttr in comparison to those of structure (zl), -146-

Thereasonforthedifferenceinspectruminwaterand. ethanol is probably d.ue to the presence'of different tautomeric To forms but why this should occt¡¡ cannot be read-iIy expLained' woul'd be oomplete the above tautomeric structìrraI assignrnents it of interest to stud.y the -ocË, and. -NCH, derivatives and' a knowledge of the psts of the compound,s stud.ied. woulô also be d'esirable'

H ,l t{ H l-

'l' N N r N

H H r-l H (18 (183) (184) (185 ) 6)

t{ 0- ct

fr/ N N T I N N ,[ H N N N '|l o- 0- (189) (19 (187 ) (188 ) 0)

r0 76 ) 3 I 5 9 L T T L 9 N 8 N 5 3 t0 ì 7 6

1 2

(192) ( 191) TABLE 10. N.M.R. SPECTRÀL DÀTA OF PYRTDOPTRIDAZÏNES

pvarDAZL'ù (") PTRTDC [2, ¡-d ] rjs

Ï V.AIUES cOUPLrNc ColiSTAl{IS (c/s) CO¡iIPOUIID o u Hz HB NH J J J J "j "4 ', (oH) 213 '3r4 2r4 5rB 4rB

Parent * 0.67 2,15 1,62 0.33 0,17 + 4.3 +8,4 +1 .B (-e) l.¡ (+t) o.B l-Chloro- :tÊ o.65 2.44 1,37 o.2B + 4.3 + 8.5 +1.7 1'o 8-Chl-oro- * o.61 2.02 t.55 o.45 + 4,5 +8,1 +1 .8 ¡ &Methyl-a * o,72 2.15 o.52 + +8.2 +1.9 1.66 4"4 .Þ .-¡ 5, &Ðichloro- * 0.58 1.97 1,34 + 4.2 + 8.6 +1 .5 I l-Bromo- * o.7z 1.51 o.42 o.1g 2.O 1.3 0.8 J-Oxíd e :x O. BB 2.42 1.72 O. BB 1.25 + 4.3 + 8.3 +1 .7 1.4 0.8 6-0xid-e * 0.gB 2.27 1.BB 1.37 o.7t 4.2 8,5 1.7 1.2 o.7 &Chl-oro-!-pyrid o- o.73 1.99 1 .31 -3.1 0 4.5 B.j 2.O [2, ¡-O] pyridazinone I !-Chloro-8-pyrid.o- o.7g 1.95 1.56 -3.14 4"5 8.4 1.6 [2, ¡-È] c¡nrid.azinone I J-Pyrido [2, ¡-Ol - .B p¡rrid.azinone / o. Bo 2.11 t.3) 1.53 -2.99 4,6 8.1 1 B-Pyriac Ie, ¡-¿] - .53 p¡mid-azinone I o. 86 2.O2 t.52 1 4.4 8,2 1.8

!, &Diamino- J o.86 z.o6 1 .33 3. Bc 4.3 B.¡ t.7 (u) PYRTDo[3, 4-d]rrnrrxzrttæ

Ï VALUES OOUPLING OONSTAIüIS (c/s) COIPOUND S tr Hg J?rB tirl trro J4rB J J '4 "5 '7 115 5rB Parent * o.27 O,27 O.45 0. Bg 2.13 6.5 <0.4 1.5 rÊ* 0.8 1.4 1 * r{-Dichloro- o.24 o.75 1.92 5.6 *JÊ 1.1

(") ÙfISCfr.,LA}IMUS

T V.TLUIS 0oUPLING CoNSîÀNIS ("/t) COMPOUND S I Hz s3'4 H6 HB tlrB'7rg Jgrg JBrlo Jgrto J5r1o s % t "9 "ro @ I 1 ,2t3t4-Tetrahydro- Lpyrido [2, ¡;d1- 2.52 pJE]-ctaz].none" I

1 ,2r3r4-TetraþCro- l-pyrido [2, 3-e] - / .97 8.41 7.82 2.74 p¡rridazinone P¡mido[2, ¡-d] -s- t¡iazolo [¿, ¡-dl - / 1.79 o.90 1.33 2.O3 0.73 pJmL(l.az]-nev 8.3 1.8 4.6 0.8 P¡rrid.o [¡, z-d] -"- tr,iazo1-o [4,3-dl- o,96 o.47 0.Bo 1 .g3 p¡rridazinec I 1. 4.5 1.7 8.3 S=Solvonti x=CHCIT; Dimetþlsulphoxide; /= / = HDO; T HDO assurned- to be !.{ *rç: present but unable to be resolved.; -r a. TCB3 = 6.g7t t5,rr- = o'5 c/si b: NH = 3.28 c3 See numbering in diagrams (tgf ), (f 92) r TABLE 1 1 . ULI'Råi.IIOLET SPIpTRÂ1-, DATA OF PTRIDOPIR.IDAZI}IES

(") PARTNT HETUìocycLES

col,æOrND S ^-ßx lI-7r* GROUP I GROIJP II CROUP TII Pyrido 'w (4.57 [2, ¡-¿]- 2o6 2ß( 3 .63 r253s 275 s 3"23 284 pyrid.azine (j.r7 (¡.+o) , ) , 2,63 ß.zz)t 295 = (¡.oe) * " 224 (3.67) 244 ( 3 .58), 253 s z8l (¡.oB), 294 s (3.50 ) (2.98) a 214 (4.48) 245 ( 3 s 48), 255 285 (3.t6)t 296 s I (¡.+¡ ) ( r.oa ¡ Þ c 218 241 ( 3 .55), 256 s \o ß.66) 274 s (¡.zo), 286 324 S (2,34), 3 33s ß.>t ) , 265 (¡.¡¿) (3.t7)r (j.15) (z.t I " 46 e) 1 .%), 352 (r .B?),'344s( 359 s (l.e3) :36!s( 1 ,77), 373 (r ,73 t 382 h .s4¡, 387 S (t . ,7 ) P¡rrid.o [¡, ¿-g] - v/ 206 (4.60) 241 ( 3. 79 ) 254 S 296 pyrid-azine ß.qz), io6 s ß.e 3 ) (¡.¿r ) * 2 226 s (3.51) zqq ( 67)' 258 s 295 (3.34), jo5 s (t.sq ) (¡.¡o) a (+.9) ) 211 2ß( ). ?B), 25 5 S 294 ß"60), 305 s ( ¡.2¡ ) ß.59) c 248 ( 3. ?3), 254 s 2B3s (¡':t), 288 s l 26s (e.lt) , 332 S 266 È ( (¡. ß.>g ), 3.41) ¡r ) , 294 (.¡"¿o ) , ( 2.26 ), 341 s (2. 17), 100 S (¡.¡?),306 (r (¡. 3 54s .e7) , 36 1s 36 ) ( 1 .91 ), 36,7 S (r .B?), 3?3s (r .84 ) , 383s ( 1 .75 ) (u) prnroo[2, l-q] rrtrnzrNu DmrvArrvns

T}?E OF ABSORHTION cOÌPotiND S n-rx GROUP I GROUP ÏI GROUP TTI !-Chl oro-B-net hyL- * 225 4.N 267 3.69 3OO s 3.39 ,3OBs ß.24) (3 l, B-Dichloro- * 213 (4 o6), 22J s 247 ( 3 .75), 263 s 304 .58), 312 s (3. Bo ) ß.>t ) ß.+q) ( B-MetÌ¡yI- * 21 i s (3.84), 224 242 s (3.57), z5o z86 s 3.18), 297 s (4 .12) (¡.lg), 262 (¡.52), (¡.or ) t 306 S (2.86 ) 269 s (l.qz)" I .* 225 ß.72) 254 (3.62), Z6Z s 306 (¡.6?),316 s \n ¡Bromo- (¡.e r) o ß.st) I B-CbLoro- * 214 s (3.9r ), zz7 243 s (l.eZ¡, 258 z9l s (¡ .3t ), eB? s (¿.r ¡) (1.62) (¡.r?) t 292 s (1.04¡, 3O0 s (z .86 ) l-Chloro- :r 24 Q.12) 256 ß.$) eB3 s (¡ .33), zBB s (3. zo) , 293 s (r.oa¡, 302 s (z.92) .r (3.69), (3.45) 5, &Uitryarazíno- 21 1 (¡ .81 ), zz7 269 282 s 3?0 (4 .03)," 242 s (¡.?B) (1.59), zB? s (1,+g)' 299 s (¡.¡o) l, B-Diamino- * 228 ( 3 .90), 236 s 264 ß.7o) l4g ß.+z) (:. ?¡ ) 7-Oxid-e * z1B s (¡.t8)r 233 s 248 s (l.gz)t 253 294 ß.96)' 3oo s (r.ae¡ ß.92) (¡.gc), 3o4 = (¡.t6) [¡55 " (3.00¡i n-nx?] 6-0xid-e * zt3 s (¡.æ), 232 249 s (q.n)¡ 255 z96 (4.ü), 3o? s (4,o2) ( (3.8e 4.22) ) (l.to)i [:55 " n - ¡x?]

-"-*ÈtGt'r#4+?qf'ÉI 5, &Dione * 211 s (¡.r¡), 226 350 s ( s (¡.gs) 3.42 ) ,257 ß.qz ), 264 ( 3.45 ) t 272 s ( 3 3B ) b 22j ß.86) z6z (t.B>) 338 ß.+g) YI (q.4t)o nl 226 ù 255 ß.?¡), 268 s 305 ß.5q) (¡. ez ) (¡.re) 5, &Dithione lÉ zo8 s (f.e5¡, 212 246 s( 3. 63) t 25'l s (:.45¡ t 217 s (1. a4 ¡ (3,6 2), 258 (¡.eo), 265 (3. 60), z7B" s (¡.rT) * !-Pyrirto [2, ¡-dJ- 212 s (¡.tr), zz3 236 (¡. 73), 243 s 27' s ( 3.52), zjz s p¡æiilazinone (¡. ze) ( o) 3.7 ß.>t) , Ð2( l" 58) , 303 s ( 3.56), 307 s (¡.5¡) \tr B-Pyrido * [2, ¡-¿]- 213 s (¡.r¡), 226 243 275 s (¡.ls), 293 pyrid.azinone (t.az¡ ß.ez), 304 s (3.58), 308 s (¡.55) &Chloro-J-pyrido- .tÊ (1.86¡,224 zl9 s zqz (t.84), 2Jo s 294 s'(r.05¡, 306 [zr ]-d]prridazinone (r.e7¡ (¡. ar ) (3.67), 31 6 s (t.ez) 224 (3.88) 252 (3 .76), z68 s (¡.5r I (¡.e¡) ¡¡¡ ) !-Chloro-8-pyrid o- * z1B s (¡.zr), 226 239 s (¡.e¡), 25o zB5 s (¡.eo) , 290 s ( ez) L2r3-dJpyridazinone ¡. (i. ea ¡ ß.e4¡, 301 ( 3.66), 31 2 s (:.00¡ b zz6 (r. es ¡ 254 (4.0¡ ) ¡25 (¡.?o) B-Hethl-I-!-pyrid.o- * 211 (r.oe¡,zzJ 241 (3.76), 246 272 s (¡.5t z9l s ¡-dJ pyridazinone (¡.æ) ) , tZ, (3. 16) (3.6r ), 296 ( 3.68) (") MfSCEI,L.âNÐUS

1 r4-Dichlorop¡æiåo- * (q.t6), 231 s (¡"e¿) u> 244 s ,263s 306 ( 3. 67 ) , 31 6 S [¡, ¿-È] pyridazine (3.??),274 ( ß.72) ¡, za) ( 3 .6 1 ) 1 t2,3)4-Tetraþdro-J- * 214 (¡.8?), g3 s zB¡ (¡.5r ) 30 2 ( 3. e¡), 3n pyrido[2,3-4] - Q.z6) (¡ p¡midazinone 40 ) 1 t213r4-Tetraþdro-& * ?r3 !.(¡.+g), ?zB z7o (¡"¡6), 2Bc s 295 s (¡ 64 ) r 306 p¡nrido[e, ¡-O]- (¡.lB), 2l.4 (3.5?) (¡.lr" (1.s5 p¡æid.azinone " ) ), 31 B " ( ¡.¿8) Pyrido[r,z-¿] q. * 212 s (l.ee¡, 234 z6J s ß.Ss), 271 s 3oB ( .o?), 320 s triazolo [+, f-01- (4,o6), 246 s (l.aa¡ 276 (3"43), (3.o2 pJæid-azine ß.qg), ) zjl s (¡"¡¡) " I Pyrid.o [2, ¡-d] -s. :x 230 s (q.zl), (¡ 87 267 .69), z8o s 3i 1 (1.29) \n triazolo[4,3-d] - (4.24), 248 s (¿"0¡) (¡.r¡) zB5 (¡.¿o) N) pJælcrazt-ne , " ! * 3-Merhylpyrido [¡, z-dl - zl8 248 s zlz ( ), 284 s 3rB (¡.04) s-triazot. [+, f+J - ( 3 9 Í1'ou'' (¡. ¡e p¡midazine 1.lr

3-i[ethytpyrid o * ( [e, ¡-¿l- 214 s 3. Bz¡, zl8 s 275 s ß.qi) t2B1s 308 c (3.24¡, 32o s s-triazotc [+, ¡-{] - ( ¡.4¡ ) ¡227s (t.96), 292 (¡.¡g) ( pyrid,azine ß.qÐ , 3 1 3 ) 234 s (4.o4¡ , z4 1 " (+.o5¡ 6-chloropyrid c [2, f-AJ - * 22o s (4.t z), 228 s-t¡iazolc [a, 3-d] - (q.zt), z4 ¡( 4.25), plmldaz]-ne 254 s (4.oe)

Log g values are given in brackets x=95% s=sslvsnf,; ethanol-; w=water; a=1NHcl; b=1NKoH; c=cycrohexane; s=should.er

Yrlavelengths in m¡.r Ël

}D(PEIR.TMTNTAI,

GÐIERÁI

Melting points were determined in caplllaries in a Gal"lenkamp melting point apparatus and are uncorrected. Inf¡ared. spectra were determined with Perkin-Ð.mer Infracord. l¡iod.el 13? anù 23? spectrophotometers. The spectra of p¡rrid.o[Zr¡-¿]- pyrid.azine and" pyrido[¡,+-¿]pyrid.azine were obtained. by use of a

Grubb-Parsons DB1 Irrfrareù Spectrometer.

Ultraviolet spectra vrere determined. with a Perkin-Elroer 1 37 U.V, record.ing spectrophotometer. The letter rrsil quoted. together with an absorption wavelength maximum ind-icates a should'er. Nuclear magnetic resonance spectra were record-ed. by Dr. T.M.

Spotsnood and Mr. !. Pal-tridge on 107å solutions with a Varian D'P' 60 spectrometerl operated. at 60 Mc/s and. using tetramethylsilane as an internal standard. Spectra were calibrated- by the sid'e-band' technique using a Illuirhead--lVigan D 890 A aud.io-oscillator. Ðouble resonancê

e:rperinents were mad.e by operatÍng in tb.e lower sid-e-band. mod-e of the

V3521 integrator. Spectra recorded at 10Oo were determined using a Varian variable temperature probe accessory unit I'fod-el V-4340 with a

Dewar Probe Insert Mod.e] V4331-fm. Coupling constants and chemical shifts were obtained" by first-ord-er analysÍs. Ðr. R.A. Jones by use of a ¡K'-a curves were deternined by Rad.iometeT record.ing pH meter' Þ!' values were calculated by the

method. of Albert and. Serj . nt.245 -1r4-

High pressure h¡rd.rogenations were cond.ucted. using a Parr

IlP þd.rogenation apparatus. ThÍn layer chromatography was carried- out using either al.uminir:m oxid.e or silica geI ad.sorbents of approximately 0.3 ron thickness. Ðevelopment was effected, by placing the plates in an iod.ine tank. The a1u¡nina used for all chromatography was Spence U-G.1 and' the silica ge1 was Merck Kieselgel G Small scale sublimations were carried- out by use of an electric sublimator block. The conventional procedure using a paraffin bath was employed. for large scale sublimations. Microanalyses u'ere carried. out by the Australian Mj-croanalytical

Service¡ Melbourne. All organic extracts were d.ried over an\yd.rous magnesiurn sulphate.

I,VORK DESCRIBFÐ TN CHAPTffi, 1

3-Cyanop.rr¡id.ine

This compound. was prepared as a colourless solid', ra-p. !1o

(rit.246 uy the method- of league and. short.246 ^.p. 5o-51o),

3-Cyanop.vridi ne-1 -oxid"e

This compound. was prepared. fro¡o 3-cyanop¡rrid-ine by the proced.ure of Katritzþ, Beard and- Cortu247 as a colourless solid¡ I!.p. 175o (tit.247 m.p.174-1750). -155-

Cvanation of ì-cvanonvridine-1-oxide

îreatment of l-cyanop¡rrÍdine-1-oxid.e with ¡nsthyl sulphate and. potassium cyanid.e according to the method of TanilOT g^u" 2¡3-dicyano-

p¡æidine as a colourless solid-, m.p. Bo-Bto (rit.107 ù,.p. Bo-Bzo) an¿ o 2rJ-dícyanop¡rridino as a coIor.,¡¡Less so1id., m.p. 1l t (rit.107 m.p. 111- 1120). rt was necessary to chromatograph the mixed. crude prod.uct three

times on arumina using 10"Á chroroform-benzene as eluant in ord.er to achieve conplete separation.

Quinolinic Acid

Vfhen commercial (pfr¡ra) supplies were unavailabLe, this conpound. vras prepared. either by the method. of Stix and, Bu1gat""h248 or that of Srrch.rd-.r111 The latter proced.ure which involved. oxid-ation of

&-hyd-roxyquinoline with nitric acid (d - 1.51 ) was the most prefarable for large scale preparations. Suchard.a cl-aims that concentratÍon of the mixture, after oxid.ation was complete, caused- quinolinic acid. to soparate. ïn the present work a water soluble salt¡ pyrid.inium-2rl- d.icarboxylic acid, nitratê¡ r(ês obtained. at this stage whfch when shaken with the requisite quantity of d.ilute base afford.ed quinolÍnic acid, rD.p. 1 89-l9jo (tit.249 190-1 g5o). ^.p.

Quirrolinic Acid Anhyd.rid e

The proced.r¡ro of Do*250 gave this compound. as a colourless solid. of m,p. (rit.25o [he (nujol) showed. t34o ^.p.134o). infrared. spectrum carbonyl peaks at 1840 ancL l ?70 cn-1. _156_

Cinchomeronic Acid. Anhydrid.e

This cornpound. was obtained. by the procedure of Fers251 "" . col.ou¡Iess soIid., m.p. 76-770 in 93:/" yield (tit. yield25l ^.p.252 73o; 78-86íÅ).

Quinolinimide (a) Thls compound. was obtained. fron quinorinic acid. and.

acetamide by the method. of suchardalll as corou¡less need,l-es f¡om alcohol l m.po 233-n4o (ltt.1 1 1 ,.p. 23lo). (ir) Quínolinic aciri anfyd.rid.e (zo u, 0.134 roole) and urea (5 g, O.OBB nole) were powd.ered in a mortar. The resulting intimate mixture was placed- in a large fLask and. heated. slow1y over a paraffin bath. The mixture grad.ually melted. and. d.arkened. untir at 125o carbon d'ioxid-e evolution commenoed.. The mixture frothed. violently an¿ the temperature rose rapid.ly to 1600. External heating was ceased. at this stage and, the mixture was stimed. for a further !,J nin. until evolutÍon of gas had. stopped.. The contents of the flask were allowed. to cool, 20 mI of water q¡ere ad.d.ed. and. the precipitate filtered, washed. and- recrystarlised. from ethanol to give corourl_ess needf.es (14.7 g, 75l) of n.p. 233-50t undepreesed. by admixtr¡re with sa^mple fron' (a). Alternatively the molten contents of the flask were poured. on to a large sheet of rnetal, allorved. to solid.ify and. purified. as above to yield corourless needle* (,l7.9 * 9o/,). The infrared. spectrun (nujol) g.ve maxima at 31BOr 3075¡ 1770¡ 1730, 1710 cm-1. -157-

C i nchorneronimide

(") This compouncl was prepared from cinchomoronic acid.

an\yd.rid.e and. acetamid-e by the nethod. of Blanchard, Dearborn, Lasagna and Buhle as colourless needles from etLranol, m.p. zli-Zo (tit. m.p. 231-20).

(¡) Cincho¡oeronic acid- anliyd.ride (t 3.0 g, O.OB'i mole) was

mixed intimately u/ith powdered u¡ea (4.0 Br 0.067 mole) and. heated. in

an open flask to 1ooo. The mirbure sì.owry mel-ted. and. then frothed-

vigorously. After about 10 min the mixtu¡e solid-ified.. The prod.uct

was filtered.r washed with water and ethanol. and. recrystaLlised. from

ethanol to coLourless needlos (12.4 B¡ 96#), n.p. ZJ1-Zo¡ undepressed- by ad.mixture with sample from (a). An infrared- spectral comparison of the prod.ucts from (a) and. (U) showed- them to be icrentical.

ô.uinolinamide

flhe procedure of Philips109 in which quinolinimid.e was treated. v¡ith concentrated amrnonia (a = O.BBO) gave only a J6![ yíeird. of quinolinamid-e. concentration of the filtrate from this reaction prociuced. a Breen gunt from v¡hich no nore amid-e coul,cl be obtained.. The use of lOlá aqueous ammonia, however, enabled. an 81Ø ¡nief¿ of quinolinamid-e to be achieved.. lhis compound. was obtained. as colo¡r1ess need-les from ethanol which on heating melted. at 190o, resoLid.ified. after loss of ammonia to form the imid.e and. remelted. at 2330. [his behaviour was iderrtical to that rscorded. by Phirips.l09 The infrared. spectrum

(nujo1) showed. band-s at 34OO, 3125, 1690 and. 1645 cf1. It was often found convenient to prepare the amid.e d.irectly from tho mol.ten imid.e prepared as above. _ 158 _

Cinchomeronamid.e

This compound- was prepard- by the proced.ure of Gabriel and. coh^un254 as colourless needLes from ethanol, m.p. l?60 (rit.254 ^.p. 175-60). The anide lost amnonia at its meLtÍng point ancl, resolidified.

as the imid.e which melted at 2310. Th:is nethod- employed. alcohol,ic

am¡nonia but in contrast to the experience of Gabriel and- Colnran¡ no prod.uct was folmed. on cooling the roixtt¡¡e. The a¡¡id.e was obtained- in

?O yield. after removal of the ethanol- und.er red.uced. pressure. It

was found more convenient to use lOy' aqueous ammonia es this gave an

Ijf y:.efti of cinchomeronamiåe on coo).ing. fhe infrared spectrum

(nujol) gave peaks at 33201 3200, 1685 and. 16ZO cr-1 .

2, 3-Dicyanop:,ryid.Íne

(a) Quinolinamid.e (5 g) and pbosphorus pentoxide (30 g) were susperrd.ed, in xylene (lOO rt) and. heated. for 2 hr at 1400. The mirtr¡re

was cooled¡ filtered. and. the resid.ue extracted. with boiling xylene

(¡ m1). The combined- extracts were d¡ied. and. removed " l5 the solvent und.er reduced pressu.Te. No prod.uct was obtained.. the resid.ue rras

treated. with water (50 rf)r concentrated. to 20 ml- und.er vacuum, cooled.

and. filtered to give unreacted- quinolinanid.e (4.7 ù, m.p. 1!Oo, undepressed by admixture with an authentic samplo.

(U) Quinolinamid.e (5 g) and. phosphorus pentoxidu (¡O g) were

suspend.ed in dimet\ylformamid." (tOO mI) and- heated- for 2 hr at 150o.

The mixture rr\ras cooled, filtered. and. the filtrate was d.iIuted. with

water (3OO rf). The filtrate was extracted. with chloroform (¡ * ?5 rf), the combined. ertracts d.ried and. the soLvent removed. under vacuum to -1r9- togivequinolinamid.e(0.¡e).Thed.imethylfornamide-waternixture wastakentodrynessundervacuumanc].thoresiduefronthereaction (r) yield, fr.rrther quantíties of unreacted mixture was wo¡ked" up as ir, to g and tbe prod'uct quinolinamid'e. fhe total recovery was 4'6 '¡sas ídentified'bymixed'D.p.êfldinfraredspectrr:rnconparisonwithan authentic sPecimen' procedr:re of (") the following methoò was based' on the 116 suspended in d'imetþylformanid-e 3ailey et g!. euinolinamide (6 g) was (to mI) was added to tbe stirred' suspension at 600 ancl thionyl chl0ri¿e for a fr:rther 10 hT at 60-?00' over t hr. The mixture wa's then stirred hydrochl-oric acid- and' extracted' t'he d.ark solution was poured into d'ilute wj-tbchloroform(¡*toOml).Theconbinedortractsweredried,and- thesolventtemoved-underreducedpressuretogived'imethy}formamide potassir:n hyd'roxide anô (f.6 g). [he solution was basified with 10É (¡ m])' [he extraots rvere ùried again extracteù with chloroform x IOO andthechloroformtemovedunderreducedpressuletogiveadarkliquid whichsolid'ified.onstanding.Theinfrared-spectrr:mofthisproouct indicatedthepresenceofanitri}etogetherwithtracesofquinolinimide. ligbt petroleun (u'p' 60-800) crystallisatíon of the crude nixture fron (0.48 10. 1fo), n'Þ'BO-B.o (Iit'10? gave pure Zr3-dicyaHopyrid.ine Br of this compound was Ídentioal ro.p. Bo-Bzo). [ho infrared..spectrum tothatofthespecimenobtained'bythemethodTaniandamixtureof The infrared specttun (CHC13) shorved' the two samples roelted. at BO-81o. band's at 1565¡ 15500 1415 and- a nitrile poak at 2225 c¡n1 and strong (g>:þ ethanol) showeù absorption 1t0o cn-1. lhe ultraviolet spectr' - 160 - maxina at 213 s (tog ê = 3.62), Ð3 (3.84), 241 s (3.?l), 2rB (3-21), 265 (3.23) , 272 (l.zz) anct 281 mp (3.09)- (a) euinotinaniae (15 g) was suspended. in d¡.y, red.istilled. p¡rrid.ine (40 mf) and. phosphoryl chlorid.e (¿l tf) was ad-d-ed- in portions over 1! mins. Heat was evolved. and. a d'eep purple solution formed'' The mixtu¡e was maintainea at 650 for ! hr, cooled. and cautÍously poured. into a mirbure of ice anð water (8OO nf). The resul'ting dark solution was cooled¡ filtered. and. the filtrate shaken with chloroforrn (¿OO mf). An emulsion almost invariably formed. at thls stage which was broken up by centrifugation. the use of ether as solvent produced. similar emulsíons. &traction with chLoroform was repeated. three times, the combined extracts were d.ried- and the solvent removed under reduced pressure to yiel-d- a d.ark liquid- which solid-ified. on stand-ing to an almost colourless solid. (1.¡ S). An infrared spectrum of this prod-uct showed it to be nainly 213-dicyanopyrid'ino together with traces of quinoJ-inimid.e. RecrystalÌisation from light petroleum (b'p'

6O-8O0) gave colouyl-ess need.les (?.O U, 60'/'), n.p. BO-81o. [he prod.uct was id.entified, by Ínfrared spectral compari-son and' mixed. m.p. with an authentic specimen. De\ydrations of quinolinarìúde on larger scales gave decreased yield.s of 2¡3dioyanop¡rrid'ine.

ì . 4-Dí cvanoo:r¡idíne

1.his compoqnd was prepared from cÍnchomeronamid.e by procedure

(¿) empfoyed. above to synthesise 2¡3-d.icyanop¡rrid.ine. It was crystallised from light petroleum to colourless need.les, (6f/")r m.p. 79-7g.5o. - 161

(Found.: C, 65.12; Ii, 2.61; N, 32.6Uf,. t?t3*3 requires C, 6¡,.'t1i

Hr 2.34i N, 32.55"Á). The infrared spectrum (cucrr) ind.icated. a

nitrile peak at 2225 cnî1 and. strong bancts occu¡red. at 1565, 1540, 1470¡ 1390¡ 1180, 845 and. BeO c^-1 . The ultraviolet spectrvrn (g5r/" ethanol) shovred absorption maxima at 7,. - 231 (fog c = 3.?O)r 234 s (1.69¡, 238 s (¡.¿5)¡ z4o (3.18), 277 s (1.+¡), z}:- (3.51) (3.41). " and 293 "

5, B-Di hvd-ra z i no prr¡i d-o [2, 3 -d J p.rrri da zi ne

This compound. rvas prepared. by the procedure of Zerweck and- K,r,rr"93ô as an orange-red. solid. (gl/") of rn.p. lB3o ¿ (Iit.93d ^.p. lBTo å). Ultraviolot spectral d-ata for this compound. is record.ed. in [able 11.

1 . 4-Di hvd.ra zinop.y¡idg [3 . 4-cÙcyridazine

Hydrazine h¡rdrate (f ¿ rf , 997", 0.286 mole) was ad_d.ed. dropwise

over 10-15 minutes to lr{-dicyanopyridine (to g, o.o'/g n:ole) d"issolved. in a mixture of d-ioxan (l5O mf) and. glacial acetic acid- (3 mt). lrfter ad.d.ition was complete, the mixture rvas stimed. over a lvater-bath at 9o-g5o for 3 h¡, cooled and. firtered.. 1r4-Dihyd.razinop¡æ:-ao[¡r¿-È]- pyrÍd.azine ¡rvas obtained. as a buff coloured. solid. (gl/"), n.p. 193-40 d.

React ion of Eouimol-ar 0uantities of 2. l-Dicvanobenzene and Hvrl¡ez 1n ê

Hyd.rat e

2rl-Dicyanopyrid.ino (2.5 g, o.o19 nole) v¡as d.issorved- in d.ioxan (¡o rf ) and. glacial acetic acid (0.5 mI). Hydrazine \yd.rat" (l.o mt, O.O21 mole) was ad.d.ed- to the solution anci. the mixture was stirreci at

4oo for 10 minutes' The mixture was cooled- and. fil-tered. to give -162-

5eB-diaminopJæid.olZr¡-eJpyridazinu (2.4 e, 77'þ) as a yetlow solid. rû.p. 251-20. This compound was solubl-e in water and. ethanol but the

only solvent suitable for recrystallisation v¡as nitrornethane. :Ifter

six recrystallisations from this solvent anal¡rüical sarnples were found. to contain small amounts of oxygen which ind.icated. that a roaction

had. taken place between the d.iamino cornpound- and. the nitronethane.

A solution of !¡B-d.ianinopyrid.o[Zr¡-Èlpyrld.azine in water v/as treated.

with an aqueous solution of picric acid. to give 5t8-d.iaminopyrid.o- [er¡-O]oyridazine picrater v¡hicb was recrystallised. from water to yellow naed]@s¡ Ecpc 196-8o, (Found.s Cr 39.92q Ìlp 2.82; l{, 28,88.,fr, tr requires C, QO.O¡' H: 2.58; N, 28.71ú/á). N.m.r. and. 3HtONBOT i ultraviolet spoctral data for !¡ B-d.iaminop¡rrid-o[Zr¡-d]pyid.azine are listed. in lables 10 and 11. Reaction of 3r4-d-icyanop¡æid.ine vrith an equimolar quantity of hydrazine lqrdrate, as above, for three hours gave no precipitate. Removal of the solvent uncl.er red.uced. pressure gave an intractable gum.

These reactions were also foLlowed- by observing the changes i-n the ultraviolet spectra of aliquots removed. at regular interval-s from the reaction mixtures. The results of this stud-y have alread.y been prosented- in Chapter 1 of the d.iscussion.

Attempted- Ad-dition of Phenylhydrazine to 2. 3-DÍcyanop.wrid-ine

2r3-Dicyanopyridine (1.0 * 0.0076 mole) in d.ioxan (Zf rr) and. acetic acid (1.0 mI) *a" treated. with phenyllqrd,razÍne (2.6 g, O.O24 mole), dropwise over 15 minutes. The solution was then stimed. and. heated. over a water bath at 9O-95o for 4 hr. [he mixture vÍas concentrated. - 163 -

to 25 ml ancl cooled but no precipitate fo:.med.. trIater (T5 rr) ru"

ad.d.ed. and the mixture v¡as basified_ witA rc11, sod.iu.u \rdroxide. yellow mercu¡ic oxid.e (f O g¡ rvas ad.d.ed. anrl the mixture was stirred. until

evol-ution of nitrogen ceased. (e n"). The precipitatecl mercu¡y v'¡as

filtered. and- the fll-trate extracted. repeateùly with chloroforn (6 x

1OO mì-). The combinerl extracts rvere d.ried- and taken to d.ryness und,er red-uced pressì.rre to give 2¡ 3-dicyanopyrid-ine (o.Bo g), n.p. go-B1 o.

The prod"uct was id.entified. by infrared. spoctral- comparisoir and-

mixed. m.p. with an authentic specimen.

¿ no l_

To a stirred- suspension of yellovr nercuric or:id-e (21.7 s, o'loo mole) in water (z5o rnl") *r" ad.d.ed. finely grounct- Jr&- d.ihyclrazinop¡æid.o[er¡-È]cyrid.azin" (I. O g, O.026 mol_e) in poriions

over 1.5 hr, After ad.d.ition rvas compì.ete, the mixtu¡e ryas stirred_ a fu¡ther 2 bT. At this stage nitrogen evolution had. ceased. and. ilre rnixture lvas a black colour d.ue to the formation of fine particles of mercì.rjry. 'Ihe mixture was cenirifuged. and. the brown ì-iquid. d.ecanted. from the resid.ue of rnercu¡y and. mercurÍc oxid.e. This solution was extracted with ch-loroform (4 x 1oo mI)n tho combined. extracts were d.rÍed. and- the solvent removed. under red.uced. pressure to give crud.e pyrid.otzrl-ù]oyridazine (e.28 e) as a ye1low so1id.. Recrystallisation from a benzene-right petroleum (¡.p. 40-600) mirture or f¡om ì_igroÍn failed to remove the colour. SublimatÍon (fi0-1 15o/ O.2 ,r) gave colou_ rless needles (Z.l g; 6'tu,{), m.p. 154-1j5o. (Found: C, 64.tlt Ht 3.91; *: 31.74'/". a?t5*¡ requires Cr 64.1't; H, 3.84; N, 31.o;51q. Spectral - 164 - d.ata for this compouncl are to be found. in Table I (n.n.r.), Table

6 (inrrare,l) and- îable 11 (ultraviolet)" p\ ar 2J?: 2,o1 t o. UO (concentration: 0.093? M). Pyrid-oler¡-4]py¡id.azine is very soluble i-n water¡ ethanol , methanol , chloroform, acetone and acid.sr moclerately sol-ub1e in benzene and- carbon tetrachl-oride and insoluble in cold. hexane, cyclohexane, and. Iight petro)-eum.

I'.ylido[2" 3-dJ pyrirl-azine picrate was-'formed. by ad,roixture of elther aqueous or ethanoLic solutions of picric acid. pyriao[Zr3-d]pfridazine. rlhis compound crystallised. as yellorv needles from either water or ethanoÌ, ü.pr 1960 d. (irouna' Ç¡ 4),61i \ 2*>5i Qr ),1.1"þ.

Ct3tg,O6O? requires C, 43.34: H' 2.24, and. O, 31.O9"f").

Pvrid-o[2" ]-d-l p:rrid azine hydrochl-ori,le was prepared by passing dry hydrogen chloride through a solution of pyriao[2r3-gipf¡idazine in ¿ry chloroform. The white preci.pitate was filtered" ancl recrystallised. frono ethanol to give a colourless so]id., n.p. 2O2-203o d., (Found.: c, 50.21i Hr 3.66; N, 24,7871. C?H6N30I requires C, 5o.16i Hr 3.61; Ne 25.o7/").

Pvrid c l-2. ¡-aJ pvrid-azine methiodid e was formed" by ad.dition of nethyl iod.id-e to a warr¡ solution of pyrid.oler¡-È]pf.id.azine in toluene. [he mirtu¡e was cooled, the precipitate filtered and recrystallised. from ethanol- to give yellorv crystals, m.p. 2300. (Forur¿: Cr 34.g6i Hr 3.11t Nr 15.27"Å. C8HBN3I requires C, 35.18; H' 2.95; N' 15-39i¿) - Repetition of the above preparation of p¡æido[Zrf-eJpyrid.azine using 14 e of 5rB-dihytuazinopyriaolzr¡-dlprridazíne gavo a d.eep brown centrifugate from vù,ich only 3.O e (¡t.ltÁ) ot heterocycle coul-d' be -165-

isolated.. Best percentage yield.s were obtained. with 5 B or l-ess of the d.ihyd.razino conpound. The use of red. rnercuric oxid.e instead. of

the yellow variety gave pyrið.oL2r3-g]pfrid.azine in 5ld/" yLeIð,.

P,'¡ri d,oi 3. 4-d l p.rr¡id azíne

1r4-Dihydrazinopyr:-d.ol 3r4-g]pyridazine (5.O e, O.026 mole) when oxid,ised. with ye1low mercuric oxid.e (Zl.l Br O.1OO mole) in the manner d.escribed above for pyrid.ol 213-ê]pyrid.azinel gave crucì.e pfrido[314-gJ- pyrid.azin. (2.25 ù as a yelIow solid- of m.p. 1550. Repeated. subLimation (l 35o/o.5 oun) gave colou¡less needles (2.o g, tB.¡"É) or

m. p. 1lo-1720 . (Found : cr 64.11i I{, 3.93; N, 3t .8o7. t?t5*l requires C, 64.11i Hr 3.84; Nr 32.05"Á). Spectral d-ata for this

compound are to be found j-n Tab1e 3 (n.m.r.), Table 6 (infrared.) and. Table 11 (ultraviolet). p\at 25o: 1.76 t O.O3 (concentration: o.0691 M). Pyrid.o[3r4-g]py¡id.azÍne is soluble in water, methanol,

ethanol, chloroform, acetone and. acids, mod.erately soLubLe in carbon

tetrach-l-orid.e and. benzene and insoLuble Ín light petroleum, cycl-ohexane

and. n-hexane.

Prrrid.of 3,4-d-'lpyrid.azÍne picrate¡ yeli-ow needLes from methanole m.p. 184-50 (sinters at 1640). (Found.: Cr 43.42; H, 2.45; lf, 23.16þ. Cr3HBN6O7 requires At 43.34; Ii, 2.24; N, 23.Tf"). Pvrid.oi l. 4-dl pyridazine hydrochlorid.e , buff colot¡¡ed. solid. from ¡rethanol- ether¡ m.p. 2170 d (rapid-heat). (Found.: Ct 49.79; H, 3.75; N, 24.76'1". C?H6N3CI requires C, 50.16i i{r 3.61; N, 25.O77;). -166-

Oxid.ation of 15 g of 1 r{-d'ihyd-razLnopyrLao[¡r+-ÈJ pyridazine as above gave onty 30.41b yield. of pyrid.o[¡r+-ê]pyridazine. Scales involving 5 g or l"ess of diiryc1razino compound- gave best yiel¿s (>S- 581,"). Red mercurj-c o:>-eOú) were practically unchanged.

Raney t'tickel (Wf ) 25' This reagent was prepaned. by the mothod" of Vogol,

J R aon*ìn of tr R-T'!i 1¡ r¡¡l ¡a zJ- nnnrrz.i ¿nl z -ì-rì I "¡¡¡rid azine rxtì L h Ranev ltiiclcel

To a suspension of 5rB-a:-nyarazÍnopyrido[er¡{Jpyrid.azine (l '6 e) in water (50 ml) was ao.d.ed. Raney nicke] (v¡?, 14 d-ays oldr 1 g)" The mixture was heated. at its ¡efIr:x tenperature until evolution of ammonia ceased (about 3 hr). The nickel rvas removed. by repeated gravity filtration until a clear, amber filtrate was obtaine'i. The filtrate was concentrated. to 20 mI, treated. rvith a saturated aqueous solution of picric acid., and cooled. The resulting precipitate v¡as filtereùl washed. with ethanol and- crystallised. from v¡ater to gÍve yellovr need.les of 5t8-d.iaroinopyrid.o [2, ¡-4]p¡oid.azine picrato¡ (1.+l 8¡ 45.1þ), n.P. 2960. A mixed. m.p. with a specimen obtained. from reaction of \rd,razine hyd.rate u/1th 2r3-dicyanopyrid.ine d.id. not depress and- the infrared spectrum was id.entical with that of an.authentÍc sample. -167-

Reaction of 1 o4-Dihydrazinoprrrldol J, 4-d.] p¡rrid azine with Raney Nickel

1 r4-Dihydrazinopyrid.ofl¡ 4-4lprrid.azine (e.o s) in water (50 rnf ) was heated- with Raney nickel (lV?, 18 d-ays o1d., 1.5 B) until evolution of ammonia had- ceased (about 2 Ìrr). The prod.uct was isolated. as in the preceding reaction as a yelÌow pÍcrato (l.ZB g, 31'/) v/ních was recrystallised from d.ilute acetic acid. to yeIlow neeôIes of m.p. 312-

3130 d.. (Found . C, O.JO; H, 2.9O; 0, 28.89. Ct requires 3ttONBO? C, !O.01; Hr 2.58; O, 28.7O).

Reaction of 5. B-Diaminop:r-¡id.of2, 3-d I r:v-¡id.azine th Hydrazine Hyd.rate

To 5¡8-d.iaminop¡rrid"o[2,¡-è]pfiùazine (0.5 g, O.OO31 molo), suspended, in d.ioxan (75 rof ), w." ad.ded- l4lrdrazine hyd.rate (gg-p, 1.0 mI, o.o2o4 roole). The mixture was stirred. and. heated on a water bath at

9}-9ro for 3 hr. Evolutj-on of ¿ummonia occu¡red. over this period..

The mixtr¡re l¡ras cooled, the precipÍtate tvas filtered., washed. with ethanol, ancl d.ried. at 750 . 5r8-Dihyd.razinopyrid.olZ, 3-d]pyrid.azíne

(O.57 g, 95o/") was obtained. as an orangFred solid. of m.p. lBJo d-. A mixed. m.p. with an authentic sample d.id, not depress and- the infrared. spectra of the sample and. the above procluct were id.entical.

Reaction of I .4-Diaminoovrid-o[¡.¿-¿l o¡mida-zine with Hvrìr azina Hvd ? t ßl

An aqueous sol.ution of 1 r{-d.iaminopyrido[lr+-4Jpyrid.azine was prepared. by the action of ììaney nicker on. 1r{-d.i}¡ydrazinop¡rrid.o[f r+-e]- pyrid.azine as described above. The amount of d.iamino compound_ in - 168 - solution was determined. approximaiely by preparation of a picrate from an aliquot of ths filtrate from the Raney nicke] reaction.

1 r4-Diaminopyrid.of¡r+-gjprrid-azin. (0.4 g, O.OO2! mole) in rvater (ZO mL) *t= treaterL v¡ith hyd'razine hyd'rate (l.O ott, 9ft', O.O2O4 mole) and. heated. at lOOo for 3 hr. The mixture v/as cooled.¡ flltered and. the product was v¡ashecL r,vith eÌ;hano1 and- d.ried.. 1r4-Dlhyd-razino- p¡nrid.o[¡r+-gjpyrid.azin" (o.38 g, B51L) v,u, obtained. as a buff co]-oured' solid. of m.p. and. mixed. m.p" 193od.,An infrared. spectrum of the prod.uct was id.entical with that of an authentic specimen.

t

This compound was prepared. by tho method- of Armar ego96 with the foilowing mod.ification. After rer¡oval of phosphoryl chlorid-e und.er vacuullr beazene (25 mI) v¡as add.ed. to the mÍxture which was again talcen to dryness und.er reduceà pressure on a rotary evaporator. This procedure was repeated {-! times in ord-er to remove the last traces of phosphoryl chloride from the mixture. The remainder of the work up \Ías id-entical to that of Armarego. 3y use of the above technique and- by carrying out the work up rapid.ly to prevent hyd.rolysis, the yie1d. v¡as increased, by about 20-257;. Jr8-Dichloropyrid.o[e, ¡-g.lpyridazine (S>-gOi[) *as obtained. as colourless needfes from light petroleum (¡-p. 6o-8o0), m.p. 1670 (t:.t. m.p. 1 63-1640¡96 169or1o1) spectrar d.ata for this conpound may bo found in Table 1O (n.m.r.) and. Tab1e 11 (ultraviolet). Infrared. peaks (Cf$fr) at 13OO¡ 1280 and.1015 cm-1 are presunably due to C-CI absorptions. -169-

Quj.nol inic Acid- Hyd-razid e ( 5, B-pv-i¿o[2, 3-dJ c;'¡ridazined.ionu ( el ) ) .

This compound was -orepared. by the nethod. of Gheorghiu7?a a=

a col-ourLess soLid, m.p. 31 20 (Iii 20). "77 ^.p. r 311-1

lhe proced.ure of cheorghiu?Bb gave this compound. as a colourless (rit.78 solid. m.p. 364-60 ".p. ¡650).

1 .4-Dichloron:æido [¡. ¿-¿l cvridazine

The following proced-u¡e was based. on that of Armare go"96 i ¡4- lyrid.of3r4-{Jcrridazinedion" (5.0 g, O.O3Ol nole) and. phosphorus pentachlorid.e (14.0 g, 0.06? mole) j.n freshly distj-lIed. phosphoryl chl-orid.e (toO tf) were heated. at tho roflw tenperature of the rnirbure

u¡rtil a clear, bro'wn solution formed (about 6 hr). 'Ihe solvent was

then removed. unrì.er v&cuLut. Senzene (¿ mI) v¡as ad.d-ed. to ihe " ¡O resid-ue¡ and. áIso removed und.er vacuun. The resid.ue vuas treated vrÍth a mixture of ice, chloroforrn and sodium bicarbonate until- a clear

bro.¡¡n sol-ution rn¡as obtained.. Tho temperature was máinbaineC at O-!o d-uring these operations" The solution was entracted- ,,vith chloroform

(4 * IOO m])r the combined. extracts wore d.ried ancl the solvent was rernoved und,er reduced pressure. The resid.ue ''¡/as passed. through an alumÍna column using benzene as eLuant and. the prod-uct so obtained was

either recrystallised. from )-ight petroleum (¡.p. 60-800) or sublimed. to give col-ourless needles (5.0 g, BztÁ), of m.p. 115-60 . (!'ound.: -170- c¡ 42.47i Hr 1.76; N, 21.o9%. a7t3*3ate roquires ct 42.o3i H:

1.51; N, 21.O1".Å)" The infrared. spectru¡o (CUCI3) shovred. peaks at

1280, 125ot 1045 and IOOO cm-1 v¡hich are presumably d,ue to C-Cl absorptions. N.m.r. and, ultraviol-ei spectral cLata for this compound. a¡e listed- in TabLes 10 and 11 respectlvely.

Reaction of 5,8-Dichloropy¡ido[2.¡-¿"ìlr]¡ridazine vrith Hydrazine ]Iyti.rate.

5rB-DichLoropyridc lzrl-!]pyrid.azine (0.6 g, O.OO3 mole) in methanoL (50 mf) wa" treated. v¡ith hyd.razine hyd.rate (gg",r, 10 ml, O.2O4 mole) and- heated at the reflr:x temperatuz'e of the mixtu¡e for

16 h:e. The mixture was then cooled-, and- filtered-. lhe prod.uct rvas washed with ethanol and. d.ried. at 75o. 5rB-Ðihyd.razinop¡æiao[2r3-Ê] - pyrid,azine was obtained. as an oranBe-reC solid. (O.5 er 8'/iii) of m.p. I B3o ¿ both alone and when'mixed. with an authentic sample.

Rea.ct lô nof 1 -¿-Ði chl oro nrn'i d o l1 - A-ò1n¡rni rì s za n a rri {h Hrrrl TAZLne Ê"rr,l À

fhe above proced.ure vrhen applied to 1r4-d.Íchioropyrid-o[:r¿-q]- pyridazi-ne (O.4 b O,OO2 mole) and. þd.razlno hydrate (99ír, 10 mL t O.ZO4 mole) in ethanol (50 m1) ror 10 hr, gave 1r4-dihyd.razirropyri,lol]r4-è]- p¡nridazine, (0.33 g, 91íL), m.p. 193o a both alone and v¡hen mixed. r,vith an authentic samp)-e.

Reductive Cata1l'tic Dehalosenation of 5. &Dichloron¡r¡idof Z. ,,-dl - plrriðrazine

SrLDichloropyrid-oIZr¡-q]pyriclazÍne (0.6 g, 0.003 ¡nole) in d,loxan (loo rr) ancL ammonia (d = 0.88, 1.0 mI , o.o25 mole) was hydrogenated. - 171 aveT 5lþ pal]ad,iu¡r on oarbon until the theoretical upiake of \yd-rogen (l¿O rr) fraa been achievec (about 4"5 h¡). the mixture v¡as filrerod. to remove the catal-yst ancÌ *uhe filtrate rvas concentrated- to 5 ml und.er red.uced presisrlre. I'iater (25 rf ) oru." ad.d.ed. to the concentrate v¡hich was then extracted with. chlolofo¡rn (¡ x tOO r0l-). 'Ihe cornbined extracts were dried" and. the sol-vent removed. u.nd"er reduced pressÈre to give crud.e pyrid-o[Zr¡-4]pyrid-azine. Ad-clition of aqueous picric acid. and. recrystall- isation of the precipitate from ethanol gave yellovt¡ needles of pyrid-o- lzrl-llpyrrið.azir,e picrate (0.71 Et 691ò, m.p. 196o a afone and. ,,r'hen mj-xed with an arrthentic sarnplo. The infrared spectrum of the prod.uct lvas id.entical vrith that of an authentÍc specimen..

trYhen no ammoniun hydroxid.e was used., no uptake of hycì-rogen cou1d. be achieved.. Yield-s of 6ô-7A/" were obtained. by use of d.ioxan containing d-i.ssolved. am¡nonia gas or by use of smal-L quantities of 5f' sod.ium hyd.roxid-e as the base.

ReC-uctive Catal:rtÍc DehaloÊen¿rtion of 1,4-Dicblorop.y¡iao [3 r4-d-l - rrrríd-azine

1 r4-Dichl-oropyrid.o[¡r¿-q]pyridazlne (0,4 gr O.OO2 nnole) in dioxan (loo rr) ana ammonia (d = o.BB, 1.0 m1, o,o25 mole) vras hydrogen- ated- over 5'i" paì-J,aùium on carbon until the theoreticaL uptake of hyrLrogen (90 mf ) fraa been ¿¡,chieved.. The reaction v¡as worked up as in the preced-ing experiment to give pyrid.c [¡r4-g]py"id-azine pÍcrate (o.46 s, 6t/') as yellow needles from methanol¡ n.p. 184-5o. The product was id.entified. by infrared spectral comparison with an autbentic specimon and by mixed m.p. -172-

Py¡ i-d.o f2. l-dl ¡rr¡ida.zi ne- 5" Õ-d]-tnr- ôn ê

(") This proced"u::e was based. on the r:ethocr. of parsonsrl2? 5,B-Pjæido[2,3-4]p¡rrid.azined-ione (5.O e, O.O3O? mole),,vas intimaiety

mixed. vrith phosphorus pentasuJ-phid.e (22.2 g2 o.1oo nole) and. d.ry

pyrid'ine (zOO mf ) aaaea, whereupon an exothermic reactlon occr:rred-.

After 6 hr reflux the pyrid.ine v,¡as removed und,er red.uced. pressure

and the remaÍning black resid.ue was digested. in v¡ater (s x l5o mr) on a steam bath (Z tt"¡" The combined filtrates v/ere conoentraied. to 200 rnlr cooled.e aoid.iÍ'iod- with d.ilute sulphulic acid-, and. fil-tered.

Pyr.Ído[2,:-g]pv"id,azine-!r&dithio:.u (3.9 g, 65"þ) urn, obtained, es an orange-brolrn solid- which on heating sintered. above 23Oo anct at about 2?oo slowly began to decornpose before finalry liquefying at higher ternperatures. (ri.t.101 fi.pn > 2600). ültravioret spectrar d.a-ca of this coropou.nd. is listed. in ,Iab1e 11"

(¡) îhis compounci v¿as also prepared. by the proced,ume of Nitta ancl his l'he melting point of a mixture prod.ucts "oono"k""".1o1 of the from (a) ana (b) shorved. the same properties as the m.p. of the cornpound- obtaÍned by method- (a), The infrared. spectra of both prod.ucts were identical.

(rnet 5. B-Bis hvlthio ) ov-riclo I a " ]-d I orrni rì n z.i ¡ p

samples of pyrid.o [2, ¡-g]pyridazine-5rLd,ithione prepa]ed by methods (a) and. (u) above \¡rere converted. into !¡B-bis(methylthj.o)- pyrido[2,¡-!Jpytid.azine by tho proced.ur.e of Nittal Matsuura and. Yonedr.101

Soth saniples yield.ed. id.entical proctucts which crystatlised. from ethanol- as yelJ.ow plates, m.p. 246-8o (t:.t.1ot ,.n. 24go). -173-

pro Õ-cllô r.,t ï rtaone. C,la.'caJ ic DesuLphuri satiorr of Prrrido [2,3-¿l i-d.azLne-5 . rvi'th Ranev Nickel-

Pyrid.olzr¡-g]pyrid-azine-5rB-aithÍone (3.0 U, O'01 55 mole) and'

Raney nÍcke1 (V/?r 1 g) were reflu:

1rhe mixture was cooled, the catalyst filtered arrcl the filtrate concen- trated to 15 ml- under vacuua. lTater (¡ x tOO nl) tt"" ad-ded' and the soLution was taken to d.ryness. The resid-ue was then red'issolved in

sooir:m hyd.roxid-e (tOO *f , 5"/") and extracted with chloroforn (3 x IOO ¡¿). pyrid.oler¡.q]py-"idazine (0.33 S, 16"51i,) was obtained fron: the conbined, d.ried extracts after removaf of the solvent' Sublimation

and crystallisation from benzene-Iight petroleum (¡.p. 40-600) gave colonrless needles, m.p. '154-50 both alone and on ad-mixture wÍth an authentic specimen.

Att e¡nnted Svnt i.s of Pvríd- ne-2.l-d-ial bv Oxidation of

2. J-Lutidine

Acotic anhyd.ride (lO rf )r glacial acei;ic acid- (5 roi), sulphuric acia (92p¡ 1.5 nr)t 2r3-rutidine (5 g) and. chromium trioxide (to *¡,

were mixed. and. aLlowed. to stand. 6.5 h1. at 1O?. the resulting green solution lvas pouTed. into v¡ater (ZOO rf) Uut no soliù separateo" ktraction r,vith both etber and chloroform failed. to yield- any prod.uot frorn the aquoous solution. 'Iho sol,ution was then basitieù (25þ

sodium hyd-roxid-e) and- re-extracied wii;tr chloroform (3 x 150 ¡:l). The

combined extracts were d.ried and. the ohl-oroforn removed in vacuo to -174-

give 253-tutid.in" (0. 39 ù as a cLearl pungent smelling liquid-. Infrared spectral compaiison (1Íquid. film ancl CHC13 solution) showed. the prod.uct to be identical- '¡'ith authentic 223-lutid.ine.

.'l L tennted Bromination of 2" ]-Lutid.ine rvith Líauid" Bromine

2, 3-Lut id. j-ne ( 20 Bo O. 1 88 mo)- e ) vras st irred. and- heat ed' und.er refl-ux to 12Oo. Liquid bror:rne (38.5 tf , 119 B¡ 0.757 mole) was then

ad-d.ed, d.ropvrise over I hr" After ad.d-ition¡ the tenperature was ¡aised.

to 14Oo for 3 hr and. the rni>:iu¡e v/as illuminated. by an uIt¡aviolet lamp

at 135-1400 for a fulther 1.25 by. Vast cuantities of hydrogen broroid.e

r','ere evolved at this stage, [he mixture nas cooleC and. the black

crystalline soLid (Zr.l g) coÌlected-. This prod-uct d.id. not meit bel-ow

350o.

ll¡ominati.on of 2. 1-Lutidine v¡ith lti-Brornosuccinimi.d-e

2,3-Luiidj-ne (tO g, o.O!{ mole) in aiy carbon tetrachloride

(ZOO mf treated nrith freshly crystaliised. N-bromosuccinimid.e ) "ra" (6?,0 s, 0.3?6 mole) ancl dibenzoyLperoxide'(l .5 g, 0.0068 mole)" The nix'ùr.rt'e was stirred. under refl-ux and. after varÍable inòuction period.s

(0,5-3 h=) . vigorous reaction occu¡red. /$ter 19 hr the mixture ì,sas filtered. hot to remove the bul-k of the dark succlnimid.e which forned. and. the filtrate rvas alfov¡ed. to cool-. tr'urther succininricle which

separated v¡as filtored ancl the filtrate vras taken to d.ryness to gÍve a highly lacLrrymatory orange oiL which solidified. on tritu:ration with hexane an

3?Á basea on conplete conversion to the tetrabromo compound.)r m.p.

150-1BOo. As this cornpounci was unstable no attempts to analyse it were made and- it was reacted. immed-Íately after preparatlon. An attempt rvas made to obtain ftorê of ine ötötütrtJt-tetrabro¡ao-?r3- Lutid-ine by extraction of the resiclue of the reaction (mainly succinÍmid.e) with ethanol, This process gave only euccininid.e and. no further tetrabromo prod-uct.

Hyd.rol ysi s of r^¡, e, @1 r :cabro mo- 2, 3-l ttt Íd-ine "o.r -Tet

Cru¿.e c.trt trt st rd'-tetrabromo-2r 3-lutid.ine (11 g) was ad.d.ed. to water (l5O mf ) and. the mirüure was..heated. at the reflr¡ç temperature for 60 hr. The pale ye1low solution ',vhich formed v¡as frli;eredr cooled anri extracted- with chLoroform (3 x 1OO m1). The combined, d-ried, extracts yield-ed. only benzoic acid- (frot the d.ibenzoylperoxid-e) when taken to dryness. The solution was concentrated. to 75 ml on a rotary evaporator and- the ultraviolet speci;rum of an aliquot vras d-etermined.. The spectrum shov¡ed a strong peak af' 263 m¡.r and t'ras id-entical with a spectrrr.n of aqueous pyrid.ine-2r3-d-Ía1d-ehyd.e obtairred" from another route.

Reaction of an Aoueous Solution of Pyricline-2,1-dÍaldehYd.e with Hyarazine

H.ydrate

The above solution of pyrid.lne-223-diald"ei:yde rvas treated with þdrazine htydrate (99'Ár 8.0 ml-) ancl heated. under reflux for 10 hr.

The solution was cooled, extracted- with chloroform (3 x tOO m]) and. the combined¡ dried- extracts were taken to dryness (in ,tacuo) to -176-

give pyliaofzr3-!]nvrÍaazine (r.S rl,he *¡. procì.uct was identified by ro'pe mixed' m.p- (lsq-5o), ¡ infrared. an¿ ur-traviorot spectra an. by the properties of its picrate d,erivative. The overall yierd. of pyridof2,3d]pyridazíne îront 2¡3-lutidin e was 16"þ.

Br 10n 1 ¡IOSUCC d

3r{-Luti.in. (r5 g, o-141 mole) in d.ry carbon tetrachlorid.e (e5O mf ) *"s treated. rvith i\t-brornosuccinimÍd.e (lOO.5 g, 0.564 nole) and d.ibenzoyrperoxi¿e (r ,5 g, 0.006g more). The mixture r,vas refr_uxed. 1B hrr cooled-, fÍIterec ancr the.firtra¡e tar

Pvrid"i ne- 2. 3-d i a1 d,ehvC.e

T¡is cor:upound vas ob'¡ained as a colourless solid by the method. of lìied. anà Neid.hardt.166 'ihe bis (zr4-dtn trophenylhydrazone) *a" obtained as an o"u.rgu-"nd. solid. of m.p. Z6Z-2630 (c¡ud-e), which was recrystallised. from d.imethylformarei-de to crystals of m.p. 279-EOo, (t:-t. 166'167 t.n. 2650, no solverrt na¡red)'

Ro=nti a n Prmi di na-2- 1-rl iald ahr¡rla "rith I{vdr.a.c,f ne i{vdrate p¡rrÍd.ine-2r3-dialoeÌryd.e (O.>> e) in ethanol,þO ml) *"" treated vuith l:ydrazine hydrat u (g9l¡, 1 mL). lhe mixture v¡as heatecl unaer reflux for 2 br. The ethanol was renoved und-er reCuced. pressure, the resid.ue taken up in water and. the aqueous sol-u'cion Yras exiracted rvith

chioroform (3 x 30 m1). lbe combíned. extracts lrere d-ried- and- tht-r soLveni removed to give crud.e pyrid,o[2r3-Aioyridazíne. The prod-uct

vras purified. to coLourl-ess needles (4.7 g, 8873), m.p. 1fl-{o and-

id-entified- bY the usual mea,ns.

iTO}ìK D}]SCRI3ED IN C}LA.I''IER. 2

1'! tr L ernot ed- Nitratio n of Pyrid-o f2. 3-dl o:rrid a.zíne

pyri¿c[e,¡-g]pyridazin" (0.7 g) was d.issolved. in su]phuric acid

ßA71, 15 ml) and, heared to 130o. Potassium nltrate (25 g) v¡as ad.d.ed-

over 2 hr and- the temperature was grad.ually raised to 1BO-2OOo. The mixture was maintained at this temperature for a further 6 hr, cooled¡ basified, with sod.ium hydroxid.e and extracted. with chforoform (3 x 50 r0l)' ¿tlo- 4c)

The combined-, d.ried- extz'ac'cs gave no prod-uct vrhen taken to d.ryness. The solution r'¡as acid,ified. lvith hyd.rochioric acid- an¿ concent¡ated. to

15 ml. rnorganic saLts c.r:ystalÌj-sed- d.uling this pÌocess and v,rere

repeated-Iy fiJ-tered.. Th.e combined inorganic salts l/yere extracted.

vrith ethanorr the extract r,¡as talcen to dryrress and. the resid.ue d-issolved- in water and. ad.d-ed. to the original filtrate" This solution

vras adjusted to pH 6 and- heateci v¡ith a satu¡ated. solution of copper

sulphate at 9oo for 0.5 hr. 'rhe blue-green soLution vras al-l-ovred. to

stand. overnight to precipitate a bl-ue solid.. QuinoJ-inic acid. copper

complex (0.? g, 55i5) was filtered. and v¡ashed with etÌranot" The

þÎod-uct was identified. by infrared. spec'r;ral- comparison v,,ith an

authentic sampre of the copper cornplex of quinorinic acid. prepared.

from quinolinic acid. ancl copper sutphate in the marrner d.escribeci above.

oniinat ion of ?../r'id.o [e, 3-a-J p.vri dazíne with a Silver Sul phat e/ Sulphu¡ic acið,/ Brorni ne Írlix-¡ulre.

The foLlolving proceciule is based. on the method. of Chand.l "r.196 silver suì"phate (o.q Ð was ad.d,ed. to a sor.ution of pyrÍd.olzr:-êl- pyridazine (0.5 g, O.OO3B mole) in warm sulphuric acia (92,¡61 6 rf ).

Bromine (o-25 nt, O.OO4B mote) was ad.d.ed. rvhen the mixtr¡re had reached- room temperature. The mixture was shaken in the d.ark in a closed. vessel for 1 5.5 br at 95-1OOo. The reaction mixture wes then d.iLuted, vrith water (lo m]) and- the excess of bro¡rine d.estroyed. v¡ith sod.Íum suJ-phite (o-z ù. The mÍxture was filtered and the residue rvashed -179-

virh 9Zþ suJ-phuric acid- (3 x 10 ml) and- hot vrater (+ x lo m1). The

combined. filtrate and. washirrgs vras basified v¡ith aqueous sod.ium hyd-roxid-e, cooled. and fili;eled. fro¡n inorganic sal-bs. 'Ihe filtrate

r,vas extracted. vrith chloroforrn (3 x 1OO m1), the combined. extracts

were d.ried. and. the sol-vent removed. to give unchanged- pyrúd.oiZr¡-ê]-

pyridazine (O.44 g)r m.p. 1540 botir al-one ancl on admixture v¡ith authentic pyrido[2r3-Cpf'rid.azíne. The Ínfrared- spectra of the

product, both in nujol and. chi,oroforrn, were identical with rhose of the starting material-. Thin layer chromatograplly (siÌica gel, ethanol

eluant ) gave only one spot of \' = 0.32, id.entical to that of pyrid.o [2, ¡-q]prid-azine.

Attempted. Bromination of Pyrid-o[2"3-a]pvrid-azj-ne vrith Fumins Sulnhlu.ic

Acid and. Bromine

The folIowÍng procedure is based. on the method. of van d-er )oes .t9ga ancL d.en Hertog.'

Pyrido[2r3-g]pyridazine (0"5 e, O.Oo3B no]e) was dÍssolvecr in fuming sulphuric acid containing 657'á aissolved. sulphur trioxiae (6 rnf ) and, the solution was pl-acecL in a thick-rvallecL tube (1,, * 30"). ïlhen the coirtents of the tube were homogeneous, bromine (O.S¡ g, O.OO{1 mole) was introd.uced. and- the tube rvas seaÌed.. The tube and- its contents rvere then shaken in a paraffin b¿rth at lOo for 11 hr and. fo¡ a furthe¡ 10 hr at 1500. The tube was then coolecl and- unsealedl and. the d.ark solution was poured. on to icel basified v¡ith 2J7L aqueous sod.iu¡n - 180 -

hydroxid.e anC extracted. wj-th chl-orofoln (3 x 'îOO rú). The cornbinecl

extracts rr¡ere dried- and the sol-vent removed. to give unchangetl

p¡rrid.ot2rl-è]p¡nri¿azine (O.++ ù, m.p. 1 54-15jo undepressed. by ad.mixture v¡iih an authentic sample. îhin layer chromatography (silica gel: ethanol eluant) gave only one spot, RI. = 0.33, identical to that of authentic pyrid.o[2, 3-g]pyrid.azine.

do ið,az P

Pyrid.oiZ, ¡-g]pyri,lazine (1 .O g, 0.00?6 moi-e) ra" dissotved. in a 1 :'l rnixture sf earbolre egraehloriiìe (D,D.il, "Ánaf årr s ?5 nL) anct cìrÌoroform ("A.R.", 25 nI) and. a sofution of brom:-ne (0.4 mt, 1.24 gt

O,OO?? mole) in carbon tetrachloriae (B.D.it. rrAnalarrr¡ 15 nù) was acl.i-ed slo'¡¡Iy: wi-bh shaking, over 10 m1n. The flaslc v¡as covereC- with tin foil, chilled- foy 2 hr. ancl- the coatents filtered. to give an orange soLid.. This rvas v¡ashed with carbon tetrachlorid.e and. stood- in.the d-ark in a d.esiccatoi: containing potassi.,rm hyd.roxid.e peÌlets and. chips of paraffin wax. Pyrid.olZr¡-g]pyri,Jazine was obtainerj- as an orange solid. (1.95 A, B?iá) vritich had. a strong bromine-]ike od.ou¡ and. on heating began to d-ecompose at 1150 berore rnelting to a cl-eer liquid. at ternperatures in excess of 2OOo. (Found.: C, 26.90ì Ht 1"99q Br,

54.45'i". a?rr'rjBt, requires C, 2B.B9i H, 1 .73 anct Br, 54.94i¿) . Analysis for available bromine: Fres[Ly prepared. sanples were tareC anri treated with qOib potassÍum iod.ide solution (15 ml) and liii acetic acid (15 mI). The liberated. iod.ine rvas t iiratecl- r,vith stanclard-ised. sodiwn thiosul-phate solution. Founcl-: Br, 54.58rÍ. t?t5*j0", requires

Br, 54.94/". A satisfactory infrared. spectrum of ilrÍs conpound. was - 181

and' v¡ith unable to be achieved. Nujo] v/as appa"ently brorninated rrfluorubeil no mulI could be obtained'

tion o ne

gr ( ) to the at pyrid.o[2,3-d]pyridazlne perbromide (0.5 e) in an open beaker wasexposed.totheatmosphereforlOdays.Attheend.ofthisperiod' thecontentsoftheflaskhadchangeòtoad.eepred.browngum gum transferred (presrmably the ÏSrd.robromid,es of the proc'ucts). 'Ihe was (l'l'lt' rrAnal-arrrr to a ffask and- reflixed v'ith carbon tetrachlorid-e vrere cooled, 'treated -25 m;-) for B hr. The contents of the fl-ask (tOO ml) and- shaken' t'he carbon vrith acid'ified 1O7á potassiun iodi¿e run off tetrachlòrid,e ]ayer¡ which contained the liberated' iod'ine) üras with chloroform (3 x and- the aqueous layeilras basifiod and. extracted ihe sol-vent rernoved an¿ i;he 1oo mI). The combined- extracts were d-riede using 1Oiá ether-benzene resid.ue (O.lf g) v¡as chromatographed- on a1¡mina 2']-g]- as el-uant. The first prod-uct to be efuted' was 3-bromop¡*lctof pyridazine, folLowed by a mixture and finalry pyrid'of2'3-g]pyrid'azine

gave z r ¡-g] p¡rriciazine was er ut ed . Rechromat ography 3-bromopyrid"ol (0.16 Thin (O.tZ g, ì,þ) and.pyri.do[2,3-g]pyridazine ù¡ 'n.p. 154--5o. gave iþ values of layer chromatography (silica geL: othanol eluant) 0.49 an¿ 0.3! respectively, for the products. l-Sronopyrid'ol2,3-g]- petroLeum (¡'p' 40-600)' p¡rrid.azine was recrystallised- from benzene-light (Found': C' 39'91; or cyclohexane to a colo'rless solid' m'p' fl1o d' N'm'r' anc ultraviolet H, 2.1g-þ. crHONrBr requires c, {o'03; H' l 'gt/")' -182-

spectrel d.ata are listed- in IabIes,iO and. 11. Pyrid.of 213-È]pyrid.azine

v,'as identlfied. by thin layer chromatograPl\Yr infrared. spectral

comparison, m.p. and. mixed. m"p. Yie1d.s from this reaction varied. wid-ely as d.id. times of d.ecornposition. The above 1s a representative exanple. fn one case

l-bromopyrid.ol 2r3-4]pyrid.azin" (8¿¡) v¡as obtained. exclusively, It is noÌ; strictly necessary to heet tho guirr in carbon tetrachl-oride before

vrork up, but if incomplete rearrangement has occurred- this proced.ure

errebl-es higher yield.s to be obtained..

(¡ ) Decomposition in carbon tetrachlorid-e Pyrid.of 2,3-g] pyridazine perbromide (0.7 g)lva" refl"uxed. with

carbon tetrachlorid.e (8.Ð.H. ilAnalarrr, zOC ml) for 16.5 'nr. ât r¡o

stage d.id. the perbromid.e completely dissoJve and after heating

insoluble b¡rd.robromid.es of the products were present. 'Ihe mixture was treated with acj.d.ified lOZi potassium iod.id" (t!O ni) and- worked. up as in (a) above. fbom the chloroform extract was obtained. a solid. which when chromatographed on a thin layer plato (silica gel; ethanol

eluant ) gave 1þ values of 0.27 anð, 0.47 id.entical to those of authentic pyrido[ 2, ]-4] pyrid-azine and J-bromopyrid.ol 21 3-ê]p¡æicì.azine" The crwÌe procluct (0.+g g) gave l-broniopyrid.ol2,3-4]pyrid-azine (0"23 b 461.L), m,p. 1'l5o d, and. pyrid-ol 213-g]pyrÍdazine (0. 19 ù¡ llìrpe 154-50. Both produots were id,entified. by mÍxed" m.p., infrared. and. ultraviolet spectral comparisons and thin layer clrromatograpLgr. - 183 -

(") T),¡eomn osition in carbon tetrachlorid-e in the presence of

2 cont inual- str ea.m of oxvsen Reaction (b) *r* repeated on the same scale while a continuous stream of oxygen was bubbl-ed through the mixture for 18-5 h?.

3-Bromopyrid o [e, 3-ê]pl.rid. azine (o.zo5 B¡ 41fr) ana pyrido [2, ¡-qJ- pyrid.azine (0.20 g) were obtained. as above and. id.entified. by ihe usual lIlOêflS ¡

(a) Decomnosit ion in carbon t etrachloride/p:r¡Í,line Reaction (¡) ,v"s repeated on half the scale in the presence of da'y py¡id:.ne (5 mt). Afrer reaction as in (U), tfre carbon tetrachlorid.e was d.ecanted. from the pyrid.ine Ì¡rrlrobrornid.e layer and r'¡orked. up as above to give 3-bromopyriao[2r3-gipyri,i.azine (o.ol g) and. pyrid.o[z'¡-g]- pfrid.azine (0.05 g), vrhich were id.entified. by the usual means" lhe low yield.s obtained were probably d-ue to the forøation of hyd,robronid.es of the product r'/hich being insoluble v¡ere discard.ed. al-ong with the pyrid.ine hydrobromid.e:, laYer.

( e ) DecomnosÍtion uncler uLtraviolet light A stirred. suspension of pyriao [er3-g]pr¡id.azinø perbromide (O.l g) in carbon tetrachloride was irradiated. unier ultraviolet light for 13.5 hr. A yellow solid. was formed' in this process whicl:' on work up as in (l) gave a product (0.38 g) which infrared. (CUCf, solution) ancl thin layer chromatography shorved to be mainly pyrido[er¡-gi- p¡'rid-azine with only trace a¡nounts of the 3-bromo d-erivative present. Sublimation and recrystall"isation of the prod-uct gave pyriao[er3-gJ- pyrid.azine (0.38 g)r m.p. 154-ro. -184-

(r) D nosition in water pyrid,o[213-g]pyridazine perbromid.e (0.5 g) was reacted as in

(U) for 14 u1. with the exception that watet (50 ml) was employed- instead of carbon tetrachloride. lVork up as in the preced.ing exampleo pv¡Íd-o[ gave 3-bromop¡rrid.ol Z,¡-g]pyrid.azlne (O,OB g, 2&) anð' 2'3-q]- py¡idazin" (0.22 g) which were identified by the usual methoùs.

(e) Decomoosit i on bv ovrolvsÍs Pyrido[ 2r3-g]pyricrazine perbromide (0.5 g) wae heated. at residue 175-1BOo for 3 hr to give a dark semi-solÍd. üéùss¿ The cooled was worked up as in (¡) and the orude prod'uot (0,40 g) ohromatographed as above to give 3-bromopyrid.ol213-ê]pyrid.azLne (O.23 * 64ió) ana pyridol213-¿]pyzid.azine (0.14 ù. The products were identified by all the previously d-esoribed' methods'

Aminat i on of Pv¡id. ol z. l-al nv¡idazine with Sod-amid-e

(.) sod_ium (o.25 g, 0.0109 mole) anù ferric nitrate (o.ot g) were added- to red.istil.led ammonia (ZOO mf) urtd the mixture etirred

25 mins to give a greyish suspension of sodamid'e (theoretically O.425 8¡

O.O1O9 mole). P¡mi¿ol er¡-g]pyrid.azine (1.0 g, 0.00?6 roole) was ad.ded' to the suspension and the resuLting d.ark mixtr¡re was stirred at room temperature for 12 ry. The ammonia was then a]lowed' to evaporate and' )/ aqueous so¿ir:m hydroxide solution (t5 tf) *u" added- to the resídue' fhe resulting solution was taken to d'ryness on a rotary evaporator and the dark soLi¿ so obtained was extracted. with boiling chloroform (3 x dryness to give 50 m1). lhe combinecl, d.ried. ertracts were taken to -185-

unreacted. pyrid.of213-Ê]p¡æid-azine (0.7O5 e¡ 71%), r.p. 154-50,

undepressed. by admixture with an authentíc sample. The resi¿ue was

taken up in water¡ neutraLised. to pH 7 ¡ taken to d.ryness, d.issolved, in ethanor (5 mr) and treated. with an ethanoric sorution of picric

acid.. The resulting solutíon was concentrated., cooled, filtered. and. the solid. so obtaÍned was d-igested with benzene to remove unreacted

picric acid.. The resid.ue (0.165 ùr m.p. 257-610¡ wBS recrystaLlisecl from a small volume of ethanol to give yellow crystals of 2-aninopyrid.o-

IZr¡-g]pyrid.azine picrate (O.147 e, 38Ø based. on reacted. starting material ), m.p. 284-50. (Found: C, {Z.o'l; H, 2.73i N, Zr.6ù,fi. t., requires C, H, ¡tg"TO? 41 .60; 2.42; N, 26.13,ft) . (¡) The above procedure was repeated. on the same scale with

the exceptlon that toluene was ad.d.ed to the suspension of sod.amid.e in amnonia and. the ammonia alrowed. to evaporate. To the resulting

suspension of sod.amid.e in toluene was add.ed. p¡rrid-o[2r3-g]p¡rrid.azine

(1.0 g, 0.0076 moLe) and. the mixture was stirred at 60-T00 for 1 2 hr" Work up as in (a) above gave unreacted. ppidof2r3-g]p¡æid.azine

(0"¡gf g) and. 2-a^minopyrid.ol2,3-è]p¡æidazine picrate (O"476 e, 5Zþ bas&. on reacted. pyrid.ol zr¡:È]pyrid.azine)r m.p. z}3-5o, id.entical in every respect to the prod.uct obtained. rron (a). The infrared. spectrum (nujor) showed a strong primary amino d.oublet at 3?OO and. 3600 . Adnixtu¡e "f1 of the picrate obtaÍned. rrom (a) ana (b) *itu authentic samples of l-aminopyrid.ol 2, ]1{] p¡."id azine picrat e and. B-aninopyrl¿o[ 2, 3-g] - p¡mid.azine pÍcrate caused a marked. depressíofr in m.p. - 186 -

Reaction of chlorine with an aoueous solutÍon of Ie, ¡-¿] p.lr¡idazine

Chlorine gas ïyas bubbled. through a 1/o aqueous solution of pyrid.o[Zr¡-gJpyrid.azine (0.38 g). Nitrogen was evolveô stead.ily and the solution first turned. orange before eventually assurning a yeÌlow colour.

After O.75 ttt¡ the flow of chlorine was stopped.¡ the solution was basified. with satr:rated. sod.ium bicarbonate solution and ertracted. with chloroform (3 x 75 nI). The conbined. extracts v¡e¡e dried and. the solvent removed. on a rotaly evaporator to glve a brov¡n semi-solid." Thls resÍd.ue was recrystallised. from benzene-light petroleum to give pyrid.ine-2¡3-diald.ehyd.e (O.29 e, 71ft), sinters at 600, m.p. 83-B5o d (a clear melt was not obtained.). The infrared. spectrum (CUCf, solution) showed an ald.elryde CH peak at ZB75 cttr1 and. ald.ehyd.e carbor¡yt absorptions at 1?BO (weak) and- 1?OO cn-1 (intense), fhe ultraviolet spectrvn (9r% ethanol) showed naxima at I = Z6Z (toe e = 3.60) 26J a (i.eO¡ t 294 s (f.00) (3.00), and. 310 " The intensities quoted. here roay be slightì.y inaccurate as the sample used was not analysed. to d.etermine its prrrity. Pyridine-2r3-diald.ehyd.e tts(er4-ainitrophenyl}ryd.razone) was prepared. by ad.d.lng Brad.yrs reagent to an ethanolic solution of the d.ialdehyd.e. rt was obtained. as yellow crystars from d.irethyrsurphoxid,el m,p. 2?!-8oo und.epressed. by ad.mixture with an authentic sample prepared. by the method. Nied.hardt.166 (rit (Founds of Ried and .166"67 ^.n. z(5o). c, 46.21i H, 2.41fi. argtr¡N9Og requires C, 46.06; and. H, 2.65þ). - 187 -

Chemical Proof of Structure of ne-2. 1-dial rlehvr1 e

( a ) 0xidation

A solution of p¡mid.inæ2¡3-dialdehy¿e (0.03 e) in water (l ,f ) was ad.d,ed. to a sorution of Tollents reagent prepared. by the method. of vog.r.2'6 An immed.iate precipitate of sirver was obtained. rhe 'nixture was heated. on a water bath for 1 b, filtered. and. the filtrate acidified, with dilute þdrochloric acid. to precÍpitate remaining silver as'silver chl-oride" The mixtu-Te ïras refiltered., the filtrate ad.justed. to pH 6 and. treated. with a saturated. solution of copper

sulphate (4 rl). The blue solution so obtained was heated to B5o for 0.5 fu, cooled. and. stood. for { brs. The precipitate was filtered., washed. with water and. ethanol and. d-ried, at 75o to give quinolinic acid. copper complex (O.Olt g¡ 60%). The prod,uct was id,entified. by infrared. spectral comparison wíth an authentÍc sample.

(¡) Reaction with hvd.razine hvdrate

P¡reidine-2r3-dialdeþôe (O.175 g, O.OO13 nole) in ethanol (¡O ml) was heated w:ith hyd.razíne Srd.rate (gg/', o.oz1 ¡nore) at the refrux temperature of the mixture for 2 hr. The reaction nirtr:re was worked. as described. previously to give pyrid.o[2r3-ê]pfridazine (O.l6O g,

Bg'ft), n,po êrrd. mixed m.p. 'l 54-50"

Oxida. t l on of Pvr i anfz- ì-dlov¡idazine with AIkaIine Potassíum P nat e

(r) P¡rrid.o[zr¡-g]pyridazine (e.o g¡ .was d.issol.ved. in 10"/ aqueous potassiurn \rdroxid.e (5 rr) ana a solution of potassium permanganate

(lo g¡ in (eoo mr) add,ed. water "." srowly over 2J nins. The nixture - 188 -

was stirxed and heated- at )O-)Jo fo¡ a further O.?5 hr. E"thanol

(t5 rf ) *"" ad.ded. to d-estroy excess oxidant and. tbe mixtu¡e was

stirred, a fr¡¡ther O,25 br, cooled. and. the precipitate of manganese d-ioxid.e filtered. The filtrate was extracted. wÍth chloroform (3 x

150 nl), tUe combined. extracts dried and. the solvent removed. to give

unreacted. p¡rrid.o[Zr¡-g]p¡æid.azine (0.96 ù¡ rnopr 154-50, und.epressed. by adnixture with an authentic sample. [he aqueoua layer from the

extraction was acidified. with d,ilute hydrochloric acid. (gas evolved.

at this gtage) and. concentrated. on a rotary evaporator to a volune

of 15-20 ml. The mixture of organic and. inorganic solid,s which

preclpitated was filteretl ahd. extracted. with cold. ethanol (3 x 5O rf). Removal of the solvent gave a resid-ue which was in turn repeated.ly extracted with cold. ethanol. A colourless soIid., A, (0.43 g)r m.p.

21O-212o d was obtained. The infrared. spectrurn (nujo1) showed. an

NH peak at 32OO carbonyl band.s at 1705 and cm-1 and. a "r-1, 1630 carboxylic acid- d,oublet at 2600 and. 2!OO fhe h.m.r. spectrum "r-1, (f¡OO) gave two equal intensity peaks at Í =1.57 and. 1.32 (assuning HDO to have a T of 5.4). Analysis of this cornpound, whish has been tentativoly assigned structrr" (llB), indicated. the-presence of

inorganlc impurities. No precipitate could. be obtaÍned fron ad.d.itibn of Brad.yrs reagent to an ethanolic solution of this oompound.. pyriaolzr3-Èlpf¡idazine (u) . (e.O e) was stirred. and. heatod. at 9O-100o with a mÍxture of 10% aqueous potassium hydroxide (¡ rf) and. a solutÍon of potassium permanganate (lO U¡ Ín water (ZOO rf). -189-

.After 2 hr heatlng vas stopped and, ethanol (t5 tf) *u," ad.ded. dropwise with stirring over O.25 bT. The manganese dioxid.e precipitate was filtered. to Ieave a coiourless soJution which on extraction with chloroform (3 x 1oO ml) gave pyrid.olzr¡-g]pyrid.azine (o.oz5 8)¡ m.P.

154-50 which was identified. by nixed. fi.p. âlld. spectral comparisons. fhe aquoouo layer from the extraction was acid,ifíed. vrith d.Ílute hyd.rochloric aciò (gas evolvod), concentrated. to 25 nI on a rotary evaporator and. cooled. The precipitate was filtered¡ extracted' wÍth cold- ethanol and the solvent removed to give a buff coloured residue. ThÍs solid was twice more extracted. with ethanol and. then recrystalllsed from n-butanol-ether to givo B, (t.O U¡¡ lll.po 29L3OOo. Analysis of this compouncl also indicated the presence of inorganic i-mpurities.

Various preparations Save d.ifferent melting points d.ue to thÍs fact. lhe melting point quoted. above was for the best samplo obtained. The infrared spectrum (nujol) showed a primary amlno grciup d.oublet at

3j50 and 3zz5 cú-1 another peak at 3OB5 crn-1 (-cooue), carboxyJ-ic acid.

crn-1 and carbonyl band-s at 1670 and. 1 61, . peako at 2720 and 2400 "f1 B has been assigned the tentative structure (llg). No precipitate could' be obtained by use of Srad.yts reagent. Vúhen an aqueous solution of 3 was heatea at B5o with a satu¡ated solutÍon of copper sulphate¡ a copper complex was obtained. An attempt was nade to esterify B by use of d.iazomethane" ¡ (0. 5 g), suspended in anhyd.rous ether r'57 *"" treated. with an ethoreal solution of d.iazomethane at O-5o. No evolution of gas occurred- and. filtration of the mirture after 24 M gave rêcovered ¡ (0.48 e)" An attempt to prep¿rre the barium salt of B was also unsuccessfÈL. A solutíon of 3 (0.3 g) in freshly boiled. water (tO mf) _ 190 _

been was treated w'ith a solution of barium chloride in water which had- filtered.throughasinteredglassfunnel:NoprecÍpitateformed.. ' The original filtrate from the reaction mixturo was ad'justed- sulphate to to pH 6 and. heated. v¡ith a saturated solution of copper allowing B5o for 0.5 br. A copper complex (O.26 g) was obtained. after (lO the solution to stand. t hr. This was Ëuspend'ed in hot water mf) passed through and. stirred. vigorously whi)-e hydrogen sulphide r¡as precipltate copper sulphid'e was the mfxture for 1 "5 hÌ. The of flLtered and the aqueous solution taken to dryness on a rotary evaporator to glve C (0.20 g), m.p. Z9Z-4o d, (clear melt at 3O3o). The infrared'

sþéetibni shoç¿d, oa¡bonyl poakg at i6?5 ain=1 (shourtar) and 1625 öm-1

and a secondary amino peak at 3380 cm-1 . The Il.û1.r. spectrum çXrCOr,¡ (assuming HDg) gave two peaks of equal intensity at T=1.48 and 1.?3 sum to 1Od and THD. = ,.4). Microanalyses of thÍs compound' d'id' not (fZO)' Srad'yrs were in very approximate agreement with structure c' reagent gave no precípitate with an ethanolic solution of 12-24 hrs after fiLtration of the copper complex of Cr the filtrate precipitated (0.5 g) a buff colou¡ed soli'd'' m'p' a fr¡¡ther quantity of C itself "" 2g2-294o d., The filtrate from the formation of the copper sulphate complex precipitate whioh of c was allowed. to stand another 2 days' rhe blue give quinolinic formed was firtered, washed with ethanol and. èried. to epectra1 acid. copper complex (0.01 g) which was identified' by infrared comparison with an authenti'c sarnple' -191-

(") P¡rrido[zr¡-elpyrid.azina (2.O g) *"" oxidised. as in (b) for 4 hrs, Work up as above gave no unreacted conpound. 3 ('¡.25 g) was obtained. with another solid., The mixtr:¡e was washed. with a small

volume of water which d.issolved, 3 and. left a residue which was filtered and recrystallised from water to give {-aminopyrid.azine-l- carboxylic acid. (o.oz5 g)r m.p. 31g-2oo. (Found.: a; 43.13; H, 3.62¡ N, 29.97fi. altr"3O, requires C; 43.17- Hr 3.62i N, 30.21/"). The

infrared. spectrum (nujoI) of this compouncl showed. primary amino peaks

at 3290 an¿L 3140 cm-1 and a carbonyl peak at 16zo cnf1. The ultra-

violet spectrum in alcohol- showed. maxina at )r - 272 (Log ê= 3.55) and.

301 s (3.28), The n.n.r. spectrum (xrcor/rmo) gave two peaks of T (assr:ming equal intensity at values T HÐO = 5.4) 1.71, 2.o4. Compound- C was obiained as before (0.85 g as Cu compÌ,ex and

0.1 g precipÍtate; total weight of C, 0.85 g), !'inally quinolinic acid. was Ísolated as the blue copper compLex (o.ot5 ù. (a) P¡rrido[2,¡-g]pyrld.azine (t.5 e) was oxidised. for 6.5 br with a mixtt¡¡e of 1O/" potassiu.ur hydroxid.e (f rf) and. potassj-um permanganate (?.5 g) in water (zoo mf). Tb.e reaction was worked up as described in (b). Concentration of tha acidified. filtrate gave a precipitate of 4-aminopy:eidazine-!-carboxylic acid. (O.B g)r m.p.

31 9-3200 before inorganic salte precipitated.. C (o.t e) and. quinoiinic acld copper complex (0.1 g) were obtalned- as in (b).

(") P¡rrid.o[zr¡-g]pyrid.azine (2.0 B) was oxidised. for ! h¡s as in (t) to give d-aminopyridazine-!-carboxylic acid. (1.+> g) an¿ quinolinic acia copper complex (0. Z5 g) which were isolated. and. id.entified. as d.escribed. previously. _192_

All attempted recrystalllsations of compounds A, B and. c from v¡ater in the presence of decolourising charcoal gave

4-aminopr¡ idazin*J-carboxyl i c acid'

rl o*i nn of P'r¡ridnfl- -À'i nvni rì az. 1ne with I kel ì he Potassium PermanBang.te

Pyrid.o[],+-g]prtid-azine (r.> ù was hêateð' ar 95-1000 with 1OÉ potassium hyd.roxid.e (5 tf) and' a solution of potassium permanganate (fo u¡ in water (j5o m1) for t hï. The excess ôxid.ant lras d'estroyed. with ethanol (fl rf), the precipitated manganese d.ioxid.e filtered and- the filtrate acld.ified. with d.ilute hydrochloric acid. The resulting solutÍon was taken to dryness on a rotary evaporator and. washed' with water (lO rf) to remove inorganic salts. The resiùuo was d'igested- with hot water (?.5 tt), littered. and. the filtrate allowed' to crystallise to give pyrid.azinæ4r5-d.icarboxytic acid. (0.75 g) t.p. et30(rit.50 m.p. 212-213.5o). This compound was identified. by mixed- m.p. (ZIZ-

Z13o) with a sample prepared from the oxldation of phthalazíne by the metho¿ of Gabriel5o una by infrared spectral conparison. The residue from the filtration after aqueous extraction of pyrid.azine-4,!-d'icarboxylic acid was recrystallised. from water to give cinchomeronic acid' (O'04 ù', m.p" 219-2600 (fit.258 m.p. zi1-259o), undepressed. by admixture with an authentic samPle.

vì¡l¡iinn af Pvrldaf2 ^ 1-À'1 nrrr"i r1 e zi ne wit Ani d l_ c Potassium Permanaanate

(.) Pyrid.o[2,¡-g]p¡neid.azine (t.5 g) was d,issolved. in sulphuric

acið, (94,, 5 ml) and. potassium permanganate (7.5 e) in water (Z5O mf) was add.ed. over 20 mins. The rnixture \{as then heated' at 95-1000 for -193-

3 hr. Dbhanol (t5 *f) was ad.d.ed. to d.estroy excess oxidant, the manganese d.íoxid.e.'fi1tered,, and. the filtrate ad-justed- to pH 6 and. concentrated. to 10 ml on a rotary evaporator. The precipitate was filtered. and the resid.ue washed with water (lO.m1). The solid which remained und.issolved. after this prooess was washed. with ethanol and. sublimed- (zooofo.5 mm) to give 5-pyrido[2,3:¿lpyrid.azinone (0.095 e), m"p. 2770. (tr.ouna: Cr 57.12; Hr 3.590þ. t7t5t3O requires C, 57 .14¡ H, 3.43/"). fhe rr.m.T. and. ultraviolet spectral d.ata of this compound. are listed. in Tablesl0 and. 11. lhe infrared spectrum (nujoÌ) showed a carbonyl at 166Z crl-l and weak absorptionsat l1 20 and 3040 cm-1 presumably d,ue to an NH group.

The washings of the original resid.ue were ad.d.ed. to the filtratet a saturated solution of copper sulphate was ad.d.ed. and. the resulting soLution heated. at B5o for 0.5 br. fhe mixtr¡re was cooled, filtered., the resid-ue washed with water and decomposed with hyd.rogen sulphid.e as d.escribed. above to give a colourless solid- (O.Z5O g). This was fractionally sublimed. (zOoo anð, 23oo/0.5 mm) several times to give

!-pyrido[2, ¡-g]l¡oidazinone (o.ot B)r m.p. 2770 anð, B-pyrido[2,3-g]- py¡id-azinone (0.1 g), m.p. (tit.92 (Found.: % 326-80 ^.p. 3ooo). C, 57.19; H, 3.63i N, Z8.ZO%. t't5*30 requires C, 57.14i Hr 3.43;

N, 28.56t/"). The !l.m.x. and- r¡ltravíolet spectral d.ata for thÍs compound- are listed in lab1es,10and 11, The infrared spectrurn (nujo1) shows a carbo4yl band. at t67O cr-1 and. peaks at 3110 and. 3060 cm-1 presuroably due to an NH group. Soth 5- and. 8-pyrid.o[2r3-e]pfei¿azj.none were ld.entÍfied. by oomparison with authentic samples prepared. by method.s d.escribed. in the section related. to the work of Chapter 3. -194-

[he filtrate from the filtration of the copper complex was allowed. to stand.2 d.ays and d.eposÍted. quinolinic acid- copper complex as a blue so]id. (0.035 g)r which was identÍfied. by infrared spectral comparison with an authentic sample. (u) p¡rrid.o[e,¡-g]py"id.azine (r.> ù was heated. with sulphurio (25 aaí¿ (94"r 5 mI) an¿ a solution of potassium permanganate ù in water (¡lO rf) at 95-lOOo for 6 hr. Work up as d.escribed. above gave only quinolinic acid. copper complex (0.?5 g), id-entified- by infrared spectral oomparisonwlth an authentic spepimen.

(s) Pyrido[ao¡-g] ptrridazine (1,0 g) 11as heated $'ith sulphurie

acið. (gú, 5 mI) an¿ a sofutÍon of potassiu¡n per¡nanganate (tO g) in r,'[ork water (l5O mf ) at 95-lOOo for 18 hr. up as described above gave no copper complex and- a strong odor¡r of lower fatty acid's was noticeable. An aliquot of the filtrate after work-up was investigated by paper chromatograpÏ\y. The solution was applied to Vhatman No. I paper and (ltl The d.eveloped with n-butanol: l-!N ammonium bydroxid'e "/u)' paper was sprayed. with bromocresol greon and. d.isplayed- spots at to values of authentíc h 0.12, o,2o and. 0.28 which correspond-ed. h acetic¡ propionic and- butyríc acid-.

I z1-d'l nvr. zi ne wit Aa l_ rì Lc Pol a.ssium Permanganat e i Ä¡ tion ^f Pvridof ^ icla Pyritlo[lr+-e)pyri¿azine (1 .O g) was heated' with sulphu¡ic acid' (gtþr 5 p1) and a solution of potassium permanganate (tO g) ln water (ZOO rf) for 6 hr at 95-1OOo. The excess oxidant was destroyed' with

(t5 and- the precipitateô manganese d"ioxid'e was filtered" ethanol ^f) -195-

The filtrate was ad.justed to pH 6 and- taken to drynes5 o'n a rotary evaporator. 1rhe resid.ue was shaken with water (eO p1) an¿ filtered.. The solid so obtained was recrystallised' twice from water to give (tit.258 cinchomeronic acid. (o.27 B)r m. p. 258-z6o0 ^.p. ZrUzSgo) undepressed. by ad'mixture with an authentic specimen'

d. t

(r) pyrid.o[er¡,È]'yridazino (1.0 g, 0.00?6 mole) was dissolved in acetic acíd. (tOO mI) and.3Cr'/ nyarogen peroxide (1.O n1r O.OO88 mole) was ad.d.ed,. The solution wae etirred and heated. to 9Oo on a water bath for 10 hT, cooled and concentrated. to 15 m} in@' Ðthanol was ad.d.ed_ and. the solutíon again concentrated. to 1 5 nù on a rotary evaporator" 'Ihe mixture was filtered. and a yellow soliò (O.f B g) was obtained which was recrystallised. from ethanol to need-}es, m.p. 2O9o' The infrared spectrum of this cornpound- (nujoL) was not well define{ sod'iun but showed- a ca¡bonyl band-. The filtrate was neutral-ised with bicarbonate and, extracted. with chloroforrn (5 x IOO 61). The combined' extraots wero dried- and- the solvent removed. to give an al-most coLourless redid.ue (O.67 ù" This resid"ue was repeateùLy chromatographed on al-umina unreacted- (flO g) using !O7! cp.oroform-benzene as eluant to first give Z9 ¡n.P. 154-5o undepressed- by ad.mixture pyrid.o[Zr¡-gJpyrid.azin" Í0. e)r with an authentic sample. The second. compound obtainefl vras pyrid'o- (O.21 recrystallised- as [Zr¡-g]py:eidazine-?-oxide B¡ 24d.), which needles¡ rnrp. 206-70 from carbon tetrachloride. I . (Found.: C, 56.7i H, 3.6i Nr zï"ti-.Æ?t5*¡O requires C, 57'1; H' 3'4; N' ZB.r/"). The tì.'.ro and ultraviolet spectral data for this compound _196_ are listed. in TabIes lO and. 11 . The infrared.. spectrut (CttCt, soJ.ution) gavo peaks at 1165¡ 1150 and. 1120 ci--1 which were not present in pyrid.ol2rl-4lpfriaazine and are probably d'ue to the N-oxÍde group.

The third. fraction from tbe colwnn was a mixtu¡e of the 6- and.

?-oxid.es (0.04 g). This was shown by infrared. ancl p.¡.T. spectra. The final fraction from the column, pyrid-o[er¡-g]pytid.azine-6-oxide was sublimed. at 1209/O.15 nm and, recrystallised. from carbon tetrachlorid.e to glve color¡¡less needles (o,12 g r l47i based' on reacted. pyrido[zr¡-g]- pyridazine), m.p. 2Og-1oo . (Founa: Cr 57 .1; Hr 3.6i Nr 28,oib.

Ç?O5N3n rcquirsê 0e 57-1; Hr 3,4"; Nr 28,5'Á). The rl¡Ilì¡r'¡ and. ultra- violet spectral data for this compound are listed. in Tables 10 ancl 11. The infrared spectrum (chloroform solution) gave peaks at 1575¡ 1185t

11?0 and, 't115 crl-l v¡hich were not present in the ?-oxide. The column was finalLy stripped. with ethanol but no further product was obtained.. The total yie1d. of oxide based on reacted. p¡rrid.o[213-glpyrid.azine was

44/,, I (¡) ?yrid-o[2,¡-¿Jpyridazine (0.! g, O.OO38 mole) uras d.isso]ved.

(75 and. treated with an ethereal solution of in anl¡ydrous ether ^t) monoperphtharÍc (¡o tor, o.75 g of perphthalic acid, 0'0041 ""ia259^ mole). îhe solution was allowed. to stand. at Oo for ? d.ays and. at room temperature for a fr:rther B d.ays' The other wae lemoved on a rotary ev¿porator, the residue d.issolved. in sodium bicarbonate sol-ution and extractgd with chloroform (¡ * t!O mI). lhe combined extracts we¡e d.ried,, the solvent removed. and. the resid.ue ohromatographed. on alumina -197-

05/" cbloroform:benzene) to give unreacted pyrid.o[e, ¡-g] pyrid.azine

(O.+eS B)r m. p. 154-50 id.entified. by all tb.e usuat method.s previously described.

(") P¡rrid.o[2, ¡-q]py"id.azine (1 .o g, 0.00?6 mole) was d.issolved in chl-oroform (JO ml) and. treated. vrith a solution of chlorofom (30 ml) containing perbenzoic acid (l.z g, o.oo88 mole) prepared by the method of Vogel.259b lhe solution was stood. { d.ays at Oo and" ? d.ays at room tenperatu¡e and. then rvorkecl up as fn (U) to give pyriao[Zr3-lJp¡rridazíne (O.gZ g) and. a mixtt¡¡e of the 6- and. ?- oxides (O.Ot g), id.entified. by lnfrared and. uLtraviolet spectral comparison. (a) Pyrido[2,¡-g]prrid.azino (o'5 e, o.oo38 mole), dissolved. in chl-orororm (t50 ml) and. ¿-nitroperbenzoic acid (0.?3 g, O.OO41 mole) prepared by the method of Lynch and. Pausacker¡'59t *u, added' to the solution. The suspension was stoocl for ? days at Oo and. ? days at room temperatule ând. was shaken at intervals. The insoluble acid. was filtered., the chloroform solution concentrated. in vacuo and- refiltered. to remove further quantities of B-nitrobenzoic acid. The fil-trate rvas then taken to dryness and. chromatographed. on al-umina using l5ll chloroform-benzene as eluant to give unreacted. pyrid.of213-4]pr¡idazi\e (0.445,8)r m.p. 154-50 and. a mixture of the

6- and- 7-oxides (O.OZ5 g), Ídentifiecl. by rÍnfrared. and. ultraviolet spectral conparison. -198-

Ätt ênrÐtecl Oxid-ation of 2.3-Dic.vanopy¡id.ine rvíth Peracid-s.

(") Zr3-Dicyanopyridine (0.5 gr O.Oo39 mole) was dissolved. in ether (lO rf) containing monoperphthalic acid- (O.75 g, O.OO41 mole) and stood at 0o for ? d.ays and. ali room temperature for 6 d.ays.

'Ihe ether was then rqnoved. on a rotary evaporator, the resid'ue taken up in aqueous sod.ium bicarbonate ancl. the resulting solution extracted. (¡ m1). The combined-, d.ried. extracts were w|th chloroform " tOO taken to dryness and chromatographed. on alumina with !Ord, benzene- chloroform to give unreact ed. 213-d.icyanopy-rid-ine (O.ql 8)r m.P" Bo-81o, und.êpl.ðsgeå by ad.mixirte wiih an auihentic sample. (¡) 213-Dicyanopyri,iine (0.5 g¡ 0.0039 mole) in chl-oroform (þ rf) **= treated. with a solution of perbenzoic acid (O.eS e, O.OO47 mole) in chLorofotm (30 mL). lhe solution was stood. ? days at Oo, 7 aays at room temperature and. then worked. up as in (a) to give unreaced 2¡3-dÍcyanopyrid.ine (o.46 B)r m.P. Bo-Blo undepressed- by ad-mixture

',vith an authentíc sample. (") 213-Dicyanopyridine (1.0 g, O.oO?8 mol-e) in chloroform (tOO rf) *r" treated- with ¡-nitroperbenzoic acid (1.45 g, O.OO82 mole)" fhe suspension was stood 1 day at Oo and. J d"ays at room temperature t and was shaken at intervals. Work up as for the pyrid-ole,¡-g]- pyridazine oxid.ation above gave ugeacted. 2¡3-ùicyanopyridine (0.89 g)t m.p. 8O-B1o¡ undepressed. by ad.mixture with an authentic sampLe. (a) Zr3-Dícyanopyridine (2.o g, 0.0156 mole) was dissorved in gracial acetic acid (1oo ml), 30Ø hyùrogen peroxi-de (5 mrr o.o44o mole) was added and- the colourless solution v/as stirred. and. heated. ar )o-)Jo for 3 hr. More 3Ofo lqrd.rogen peroxid.e (5 tf , o.o44} mole) -199-

was then ad.d.ed., the solution was heated. a fwther t hr and. cooled.. Colourless need.les (t.5 g) separated and. were filtered.. The filtrate v/as concentrated. to 1O-15 mI ü EEr cooled. and. filtered. to give fu¡ther solid- (0.7 g). The combined. products were sublimed. (21|of

0.3 mm) to give a, soLid. which vúas recrystallised. from ethanol to give 2-cyanonicotinamld.e (or 3-cyanopicolinamid-e) as colourless needles, (1.85 u, 8l%) n.p. 278-go. (Found.: c, 57.12; Hr 3.47; N, 28,3O/o" t?t5"¡O requires C, ,7.14i H, 3.43; N, 28.56i"). The n.rnoro

spectrum (d.imethylsulphoxid.e) shov¡ed. the three quartets which arise

from Hrr H, and. HO of a pyrid.ine ring. The ultraviolot spectrurn (95$

ethanol) showed rnaxima at l, = 233 (1og e = 3.82);258 s (3.27)1 263 s ß.zz), 266 s (3,20), z7o (3.1?) and. 279 mþ (3.03). The infrared.

spectrum (nujol) shorved. NH peaks at 34OO and. 31BO cs¡1, a nitrile peak

at 2220 cnî1 and an amÍd.e carborlyl at t 685 . When this reactÍon "of1 was carried. out at 600 and. worked- up as for the oxid.ation of p¡æid.o-

[Zr¡-gJp¡æidazine with peracetic acid., only unreacted. dinitrÍle was recovered.

Attemnted Hvd.rolvsis of 2.3-Dicvanoo¡r¡idine with Aoueous Acetic Acid

2rl-Dicyanopyridine (0.5 g) w"s stlrred- and. heated with an \Ofi aqueous solution of acetic aoid (tOO m]) at 9O-95o for 12 br, The solution was cooled, taken to d.ryness of1 a rotary evaporator and. the resid.ue recrystallised. from light petroleun¡ b.p. 6O-800, to give unreacted. 2r3-dícyanopyrld.ine (0.47, B)r In.p. BO-81o, und-epressed. by admixture with an authentic sample. -200-

Mixture

the d.ehydration of quinolinamid.e by an acetic acid.-acetic anhyd.rid.e mixture to give 3-cyanopicolinamid.e (or 2-cyanonicotinamid.e) was carried out by the method. of Linstead., Noble and.'[Vright.114 [he

product was found to be contaminated with quinolinimid,e (by the

infrared. spectru.m) and on recrystallÍsation from water and. subsequent

sublimation a pure sample¡ üopr 278-go was obtained. which gave

id-entical infrared. and. ultraviolet spectra to the specimen obtained.

by the action of peracetic acid. on 2r3-dicyanop¡rrid.ine. The m.p.

of an intimate mixtu¡e of the two samples E¡as not d,epressed..

V/ORK D¡SCRTSED ÏN CIÍ]\PTM.

l_

(.) 5,8-DichloroplæÍdo lzr¡-g]o¡mld.azine (3.0 g) was d.issolved. in water (eO m1), reflr¡red.30 mins and. cooled.. The solution was taken to d,ryness on a rotary evaporator and. the resid.ue fractionally sublined. repeatedly. 8-Chl-oro-!-pyrid.oler¡-gJpyrid.azinono (Z.o g, 73f"), n.p. 102) 2960.(ILr,. rnopr 275or1O1 284-5o ,o"" obtained. by sublimation at

lBOo/O.J mm followed. by recryetallisation from ethanol. (Found.: C,

46.17 i Hr 2.3oi N, 22.69'ft. c?H4N3c1o requires a, 46.30; H, 2.22i

Nr 23.141"). lhe rl.n.r. and r¡ltraviolet epectral d.ata for this compound. are listed, in Tab1es 10 and.11. The infrared. spectrurn (nu¡ol) showed. a carbonyl at 1 685 om-1 , NH peaks at 31 30 and. 3O5O cril and. a C-Cl band. at 1OOJ c¡¡-1 . !-Chloro-8-pyriao[er3-4]prriaazinone (o.65 g, 1ú), -201- m.p..306-?0 (t:.t.1o1 m.p. zggo ¿) was obtained by sublimation at

21Oo/O.! mm followed. by recrystallísation from ethanol (Found.: C, 46.27i Hr z.rot N, z3.oZfo. c?H4N3c1o requires c, 4Ç-3o; H' 2.22i N, 23.14t/"). N.m.t. and. ultraviolet spectral d-ata for this compound. are summarised. in Tables 10 and 11. Îhe infrared spectrun (nuio1) shows a carbonyl peak at 1670 cr-l NH peaks at 3160 and. 3o5o cm-1 and. a C-Cl band at 9Bo cm-1.

(u) !, B-Dich1-oropyrid.o Izr ¡-g] pyridazine (4.5 g) was refluxed. wít]h Jþ sod.ium hyd-roxid'e (too tr) ror 60 minutesl cooled and- the crud,e solid. filtered.. The precÍpitate ïvas d.issolved. in water acidifled. lvith acetic acid.¡ cooled and. filtered to give crud.e 5-chloro-B-pyrid.o-

[er¡-qlpyrid.azinone. Fractiona]. sublimation first at lBOofO.! mm gave small amounts of B-chloro-!-pyri¿o[er3-dlpyrid.azinone (o.o¡l g)

At zioo/o.! mm pure 8-chloro-!-pyrid.o[zr¡-glp¡æid.azinone (1 .25 g,

311")¡ n.p. 306-70, was obtained. [he fi]trate f¡¡om the reaction mixture vras acid.ified. with acetic acld., filtered. and- the product so obtained was sublimed' h\oofO.5 mr) and recrystallised. from ethanol to give !-chLoro-&- pyrid,o[2r 3-g] p]Tidazinone (t .85 B)r m.p. 2960. Total yie1d. was

1 .89 g¡ 47/"). (") It was often found. convenient to prepare these compound.s without the isolation of the d.ichloro compound.. )r8-Pyrid.o[Zr¡-gl- pyrid-azinedione (5.0 g) was heated. with phosphorus pentachloride (lf e) and phosphorus oxychlorid" (tOO mI) ror 6 n¡s at 1OOo, the solution was cooled and, the solvent removed. in vacuo. The resid.ue was then hydrolysed. elther by nethod. (a) or (b) above. -202- th t 10

(")Bothch}oropyrid.o[2,3:È]pyrid.azinonesbehaved.inid.entical fashion in the following experiment' [he chloropynid'ol2'3-È]prrid'azinone (tOO m1) and' hydrazine (O,Z g) was refluned. in a mixtu¡e of ethanof Ì:yd.rat"(gfÁr4d)for15hrs'Thesolutionwascooledandtakento drynessonarotaIyevaporator¡thelasttracesofhydrazinehyd"rate wereremovedbyrepeated-addÍtionofsmallvo]umesofwaterfollov¡ed' from ethanol by removal under vacuum. The resid-uo was recrystallísed' (o't? g) ancÌ sublined- to give the initlal chlorop¡æidol213-4]pr¡id'azinone identffieè by m.pcç r4ixeè IIlcpc ê$è infsared sPeçtr4l sCIÛ¡parisQn" (o'5 g) was refluxed (¡) 8-chloro-5-nvr:'ao[ 2,3-g]pyrid'azino"" hydrat" (gg'ft, in a nixture of diethyJ.ene glycol (lo rr) and. hyd'razine solution was cooled, concentrated !.0 mI) tor 1o h¡s" The resulting reù mf)' [he suspension was to 15 m1 g vacuo ancl diluteò with water ç35 stoodovernighttoallowittosettleand'thenfilteredtogive (0.3 61"Å), m.P. 284o B-hydrazino-)-pyrid.ol 2, 3-4] pyrid.azinone B, (tit"1ot *.n. 28oo). (O'5 g) was heated' (") !-Chloro-B-pr¡Íd'o[ 2' 3-g]pyrld'azinone (5 *f) at the reflux with diethylene glyool (lO *f) and hydrazine hydrate up as in (U) to give temperature of the mixture for 15 hr and' worked' m'p" > 3OOo' j-Wdrazino-8-pyriaol 213-d.]pyrid.azinone (0"e8 e, 57fi),

+ ra sl- s t

pyridol 2, 3-dl Pwidazinoneq (, o'o22 mole) (") To a stirred suspension of mercuric oxid-e e, in boiling water (50 mI) was ad.ded.8-hyd.razino-5-pyri¿ol2,3-glplæidazinone -20J_

(0.3 g, O.OO1B mole). The mixture was heated. I hr, filtered. hot,

and the filtrate taken to dryness on a rotary evaporator. The residue was sublimed. (2ooo/o.5 mro) to give !-pyritio[213-q]pyridazinone, (0.18 g, 71Á), n.p.2770, und,epressed by admixtr¡re with an authentic

sample obtained. fron the acid.ic oxidation of p¡rrid-o[ Zr j-¿]pyrid.azine.

(¡) !-Hyd,razino-8-pyriaol 2,3-4]prrid.azinone (0. zB g) "rs treated. with mercuric oxide (¡ g) in the samê mannêr as in (a) to give

&-pyrid-o[ 21 3-g]pyridazinone (0. 17 g¡ 73/"), m.p. 3z5-Bo, und.epressed. by ad.mixture with an authentic sample obtained. frorn the acid.io oxid.àtion

of pyrido[ Z, ¡-g] pyrÍd.azine.

Reductive Catal.ytic DehalosenatÍon of &C oro-5-p¡r¡idol 2. l-dl - p.v-ridazinone (see Tabì. e l2)

A typical experiment is d-escribed. below:

B-chloro-!-pyrid.of 213-g]pyridazinone ( r.5 * o.oo82 more) was suspend-ed. in ethanor (l¡o mÌ) and arnmonium hyd.roxid-e (d = o.BBo, 2 ù, o.o5o more) and' J/' palladium on carbon (O.ZO g), prepared. by the method, of trtiozingo1260 was ad.d.ed-. The mixture was hyd.rogenated. at 10O atroospheres and_ 2!o for 5 b¡, transferred from the \yd.rogenation apparatus to another vessel and. refluxed. for ) min. The suspension was filtered. hot to re¡nove the catalyst and. the filtrate was taken to ùryness on a rotary evaporator.

[he residue was first sublimed. at 150-1 600/o.!mm to give main]y ammonir.rm chlorid-e together with traces of organic material. sublimation at zzoofl mm followed by crystarrisation from methanol gave 1rz¡3t4- tetrahydro-5-pyrido[ 2,3-d] p¡rridazinone ( 1.12 g, 9o%), n.p. 262-30 . TABI,E 12. RÐUCTIVE C¡JAIYT IC DU{AIOGNIÀîTON OF STTLOROPYRIDO| 2, 3-dJ PYRIDAZII{ONTs

& cHroRO- 5-PYRTDOI 2, 3-g] PY-RIIÌÀZrNOIIE

CONDITTONS PRODUCT 1.5 gl1oo at,.f 1 8/þ'5 at./ t.> e/7 r'r/ .60:) g/tt1 mol-err 25'/5 t)r 25"/3 nr R.T.P. uptake/R'"T.P'

2, 3 Z r ¡-a] 1, t 4-Ietrah¡rdro-!-pyrid-o[ - o.7 1.oJ g, 84d/" pyridazinone 1.12 e, 90# &n U% !-Pyrid.o[ 2, 3-È] pyr ida zinone 0.38 e, 18í g &-Ch1 oro-5-pyridol 2 r l-g] pyridazi rrone o.o9 I t\) èo 2, 3:È] Pri rDAzrNONE 5-CELOR0-B-PYRrI0[ I

CONDITIONS PRODUCl 2 00 at .z e/'ro at./ ''r8fi7 al "/ .55 g/"1 molerl å(t/qtu 50"/3,5 ¡r hr uptake

1 t2 t 3 ¡{-Tetrahydro-Lpyrid.o[ 2, 3-q] - 0.135 e!fr 0.142 8r!þ 0.66 p¡æid-azinone * es e, 4t B-Ppnido[ 2, 3-gl pyridaz.i- none 0.60 g, 37'þ 0.315 B, 1ú

!-Chl oro-B-pyrid-o[ 2, 3-È] pyrid,az inone 0.13 g

1rZr3t4-Tetrahyrtro-&-pyrid,o[ Zr¡-glp¡:ridazinone v/as obtaine^d- by sublimation at lgoo/O.! mnr and. crystal-).ised- as needl-es from methanol, m.p. 237-|JJ90 (rit.101 m.p. 227-.Bo) (Fou¡d: C, 55.20; H, 6.43; N, 2I.37fi. t?t9tlo requires C, 55.61i Hr 6.oo; N, 27.8Úþ). The infrared spectn:m (nujol) sbows NH peaks at 3315 and- 31OO cm-1 and. carbonyl peaks at 1625 and 1595 cr-1. N.m.r. and ultraviolet spectral data are listed- in Tables 10 and 11. -205-

(Found.: Cr 55.9ot Hr 6.01 ; Nr 27.39f". t?t9t3o roquires C, 55'61; H, 6.00; N, 27.BO/.). N.m.l. an¿ ultraviolet spectral data are listed. in Tables 10 and 11" lhe infrared spectrurn (nujol) showed' NH peaks at 3285,3225 anð, io75 cm-1, a carbonyl peak at 1630 cm-1

and. a rnore Íntense peak at 1590 cn-1 perhaps also due to a carbor¡y1 group.

An attempted reduction of B-chloro-5-pyrid.of 21 3-E]pyridazinone pressure using !,6 ruthenium on carbon as catalyst at room temperature and' in the presence of ammoníum h¡rd.roxid'e gave no uptake of hydrogen after 1? hr, A quanüitative recovery of starting material 1/as achieved.

D.hydrogenatíon of the 1, 2. 3.4-Tetrah-vdropvËidol 2..ì-dl Þrridazinones

The procedure used in the following reactions is based. on the

method of Burnett and- Ain"worth.223

(") A mixture of 1 r Z¡3¡4-tetrahydro-!-p¡rrid.ol zr¡-g]pyridazinone

(O.tO g) and- !/á palladium on carbon (0.05 B) were heated' at the reflux temperature of dry decal:-n (25 mf), for 2 days. The solid which collected on the upper sid.es of the flask was removed and' recrystallised' from methanol to give 5-pl.rie.o[ 213-g]pf¡id'aàinone (0.68 g)" 'l'he reaction mixtu:ro was filtered. hot and the filtrate taken to dryness g }lry to give fr¡¡ther prod.uct (O.Ot 5 e)' !-Pyridof 213-g]pyrid-azinone (O' 695 es

I39þ), rr.p. ZIla, was identified by mixed m.p. and. infrared spectral comparison with an authentic specimen'

(U) /r. mixture of 1 I 2r3r4-tetralSrdro-Lpyrid-ol e, ¡-4]pyridazinone (O.tO6 g) an¿ Ji, pa¡IadiUm on carbon (O.tO g) *"re heated at the reflux temperature of d.ry d.ecalin (25 nt) for 2 days. [he mixture was filtered' 206 hot and. the filtrate taken to dryness E W- No product vtas obtained.. The recovercd, J$ pallad.iu.ut on charcoal was extracted- for 24 hrs using a Soxhlet extractor. The ethanol was taken to dryness to give a residue (O.gg g) which on fractional subLimation as in the previous set of experiments gave unreacted. 1t2r3t {-tetrahyd.ro-

B-pyrid.of 2, 3-g] pyridazinono (0.23 g) m.p. 236-80 , and- &pyrid'of 2, 3-g]- pyrid-azinone (0.57 g, 71'f" Vased' on reacted. starting rnaterial).

Rthanol and. xylene were found- to be unsuitable as med.ia for the d,ehyd.rogenations described. in (a) ana (U).

Lthvl 2-met h-v1 nicot inat e

This compou¡d was prepared as a col-ourless liquid-, b.P. 1O5o/ g-amino- 12 mm, by the procedure of sato and. lúishi^u.'6' The ethyl 262 crotonate used- in this experiment was prepared. by the method. of Fanta.

2-H.vd.r nicotinic Acicl Ï¡actone

'oy This compound was prepared. from ethyl 2-methylnicotinate the procedure of Sator ïwashige anù Mlyad. as colourless needles ""ur224 zz7¡. from ethanor¡ m.p. 143-40 (rit. m.p' 141-142o224t225 142-1ßa The infrared. spectru¡o (CnCf, solution) shoived a factotre carbonyl at

1??B cm-1 and the ultraviolet spectrrn (95"/" ethanol) nua maxirna at ^^" = 221 (roe r = 3.76), 264 s (3.63), 27o (3.?o) anù 276 s (1.53). (lit."I The picrate of this cornpound melted. at 13?-Bo ^.r" t36-8o).

R erìrrn*ì n¡ nf l-llr'i n oli nia Anid A n hr¡rl rid-e bv Lithium Aluminíum Iìvdritle

Quinolinic acid anhydrid'e (1, g, 0.101 mole) was stirred' with sod.ium.dried, ether (5OO mf ) until almost complete solution had been -207- obtained.. A solution of lithiurn aluninium hyd'ride (1 .9O 8, O.O5O1 mol-e) in dry ether was add-ed. droprvise with stirring over t hr. The mixture was stirred- further (1 hr), filtered.¡ and' the filtrate taken to d.ryness to give unreacted. quinolinic acid. an!¡yd'rid.e (3.2 g¡r m.p.

1360, undepressed. by ad.mixture with an authentio sampì-e. The insol-ub1e complex obtained. by filtration of the reaction mixture was carofully decomposed with water (lO tf ) and' then d'iluted. with lvater to !O m1. The incrganic precipitate was filtered and the filtrate acidified. to pH 2 with hyd-rochloric acid.. This solution was continuousLy extracted. '¡¡ith chloroform fot 2 days, the extract d.ried. and the solvent removed" on a ¡otary evaporator to give a mixtwe of 2-hydroxpnethylnicotinic acÍd- lactone and. 3-hydroxymethylpicolinic acíd Lactone. The mixture was sublimed- on a water bath at lOo then crystallised. from ethanol to give 2-hydroxymethylnicotinic acid lactone (2.5 g, 2r%)r rnrpr 143-40¡ und.epressed by admixture with a sample prepared by tho method. of Sato et aI. The resid.ue from the sublimation was recrystallised- from ethanol to give 3-l¡yd.roxymethylpicolinic acid Lactone (1 .4 * 14'Ð, m.p. 163-40 (cllcrj (lit. m.p. 16101226 162-3o "7). The infrared spectrum solution) of this compound shorved- a lactone carbonyl at I ?84 cm-1 with a should,er at l72o crr-l and. the ul-traviolet spectrw (95# ethanol) ft"a maxlma at I = zn (IoB e = 3.8?), 264 s (¡.ee) ¡ 271 (3.8?) and 2?8 mF s (3.68). [etrahyd.rofuran was also found. to be a suitable so]-vent for thÍs reaction and gave símilar yield.s. 208

Reaction of Ouinolinimid.e with Zinc Dust and. Potassium llvd.roxid.e

Powdered. zínc ().5 e), copper sulphate (0.05 g) and. water

(Z rf ) were stirred to thick paste and, ZO']L sod.ium hydroxide (f t rf ) v¡as ad.ded. the mixture was stirred, cooled. to 0o and. quinoLinirnde

(f g) was ad.d.ed. in portions such that the temperature d.id. not exceed.

5o. The mixture was stirred. for a further 0.5 hr after ad.d.ition was complete and then heated- for 3 h¡ on a water bath. lhe mixtu¡e v/ac then acid,ified. with hyd.rochloric acid. and boiled. for t hr. The cooLed solution was ad.justed. to pH 2,and. continuously erbracted. wíth chloroform for 2 d,ays. lhe exttact was d.rfed.r the solvent removed. on a rotary evaporator and the resid.ue sublimed as in the preced-ing experiment to give 2-\ydroxymethylnicotinic acid. lactone (0.96 g, 21"i), m.p. '143-40, picrate m.p. 13?-Bo, both m.p.s und.epressed. by admixture with authentic specimensi and. 3-hyd.roxymetlgrlpicolinic acid lactone (o.24 er 5'ft)¡ n.þ. 163-40, ì undepressed when mixed with a samþle prepared by the alternative procedure above,

Conversion of the Lactones Ínto Pyrid.of 2.3-d.lpyrÍd.azinones

The following experiments are based. on the procedure of Brown and. Newbo Id,,234

(r) 2-Hyd.roxymethylnicotinic acid, lactone ( 1.O g¡ O.OO?4 mole) in anhyd.rous carbon tetrachloride (lOO *f) *r" treated. with N-bromo- succinimid" (l .4 g¡ O.OO?9 mole) and. dibenzoylperox:.¿e (O.t g). The mixture was refluxed 3.5 hrr cooled.¡ filtered. from succinimide and. the filtrate tkaen to d.ryness on a rotary evaporator to give a lachryn,atory -209- yeIIow-orange oil (presr;rnably the 3-bromolactone). The oi1 was refluxed. with water (2, m1) tor O.?5 hr. The resulting clear solution u/as concentrated. to I mI but no ald.ehyd.e acid. separated on cooling. This solution was treated with ÌgrtLrazine hydrate (gg/',0.5 m]) and. heated at the reflt¡x temperatrrre for 0.5 hÌ. [he solution was cooled- and. the solvent removed on a rotary evaporator to give an oily resid-ue (aue to excess hyd.razine hyd.rate). Water (5 nl) was add'ed' to the resid.ue and again sol-vent was removed under red.uced. pressune. This process was repeated. until a, solid. resid.ue was obtained.. The residue was sublimed. at 2OOofO.) mm and- finally recrystallised. from ethanol to give !-pyrid.o[213-g]pyrid.azinone (0.48 g, 44"/,)r m.P- 2770, identified, by infrared and. ultraviolet spectra and by mixed- m.p. with an authentic sample. (U) l-Hyd.roxymethylnicotinic acid- lactone (1.0 g, O.OO?4 mole) in anhyd-rous carbon tetrachloride (loo tr) *"" treated. with N-bromo- succinimi¿e (t .4 gt O.OO?9 nole) and' d.íbenzoylperoxid.e (0.1 g). The reaction was refluxed. for 4.5 bt and worked. up as in (a) above to give B-pyridol 213-g]p¡rridazinone (0.46 S, 4t/")' m.p. and mixed' m.p. 326-80. The yield.s quoted in (a) ana (U) *" for the overall conversion of the lactones tnto the p¡æid.o[213-g]p¡mid.azinones and not for the final step.

t-Hvd"ox.y- fsoLation and. Cha¡acterisation of 2-Formvlnicotinic Acid- (3

2-hvclrox.vmet hylnicot inic acid. I actone )

(') fsolat ion 2-Hydrox¡anethylnicotinic acid. lactone (1.5 g) was converted' -210-

to the 3t-bromoderivative as in (u) UV heatùng a mixture of N-bromo- succinimid" (t .9 e) and. dÍbenzoyl peroxiae (0.1 e) in anhydrous carbon tetrachl,oride (lOO ml) at the refl,ux ternperature of the mixture for

3 hr. The orud-e bromoderivative was lgrd,rolysed. by boiling with water for t ht and. the water was removed on a rotary evaporator. The resid.ue was heated with chloroform at the refh.¡x temperature for 1 bt the chloroform d.ecanied fron an orange-brown gumr dried.r and- the solvent renove,l to glve unreacted. 2-hyd.roxymethylnicotinic acid. Iactone (0.5 ù,

m.p. and. mixed m.p. 143-40. The resid.ual guro from the reaction rnixture

was sucked. d.ry at the pump for 24 br¡ washed. wùth acetone (3 x 25 ml) and redried.. Crud.e 2-formylpicolinic acid. (0.9 g, BOÉ) was obtained. as an extrernely \rgroscopic off-white solid which changed. to a brorvnish gum on exposure to the atmosphere for 2 mins. Vlhen d¡ied. as above the

originaJ- solid TÍas regenerated from the gr:m. An accurate m.p. was

rend.ered. d,ifficuLt because of the hygroscopic nature of this compound.t but by use of a sealed tubee 2-formylnicotinic acid. was found. to

soften at lOOo,and melt al 1550" The infrared. spectrum (nujo1) showed.

peaks àt 3450 cm-1 (ou or lactone form), 1775 crnl (lactone carbonyl),

z7oo, z55o cm-l (coou) and. 1?00 cm-1 (coott carbo¡¡yI). îhe ultraviolet spectrum (95fi atcohol) gave maxima at }u = 224, 267 s and, 2'l2 m¡-r. fhe

log E vaLues were found. to be 3.921 3.79 and. 3.78 respectively, but because of the impure natu¡e of the compound., tbeSe values are d,oubtful.

(u) Cbaracterisation (i) Crude 2-fornylpicolinic acid. (0.5 e) in water (to tr) t"as

heated. at 1000 with hydrazine Ìgrd.rate (0.5 mt) for 3 br. îhe work up -211- was id,entical to that of (a) of the preced.ing experiment. !-P¡rrid'o- Ier¡-A]p]r¡idazinone (0.41 Bt 85¡s) was obtaÍned. as a colourÌess soLid- m.p. 2770. (ii) Cru¿e 2-formylpicolinic acid- (0.01 g) in ethanol (ZO mf) was heated under reflux with Brad.y's reagent (? tf) tor 0.5 hr' A yellow precipitate formed whlch on fu¡ther heating gave a colourless so]id. lhe solution was cooled.r, filtered. and' the crud.e residue washed with ethanol. Sublination (ZOOof 0.5 mm) Bave a colourless solid'¡ (4.5 presumably 6-(2r4-d.initrophenyl)-5-pfrido[ er¡-g]p¡mid-azinone, ^e), tl.p. 2550.

å P.Yrid.o- Srrnth asr í S of 5- 8-c hl oroov¡id-ol 2. I n'¡ridazine from the

I z. r-al nlrridazinones

(") !-Pyrid.o[ 213-g]p¡rrid-azinone (o'5 g) and phosphorus pentachlorid,e ( 2.O g) were heated under reflt¡x with phosphoryl chlorid'e (50 mf) until a solution was obtained (B ¡"). The phosphorus oxycblorid'e was d.Ísti11e0 und,er reduced. pressure and' the residue shaken with e mixture of ice, chloroforr¡ and. saturated sod-iun bicarbonate until complete solution was achieved¡ wÍthout the temperature of tbe nixtr:re exceed-ing 5o. The solution was extracted with chlorofo:m (¡ * tgO ml-) tUe cornbined. extracts were diied and. the solvent removed' und-er red'uced' pressure. 1rhe resid.ue (O.48 g) was chromatographed. on alr¡mina using

1o% chroroform-benzene as eluant to give !-chloropyridol 213-g]p¡æidazine (0.+¡l B, 7o/") as a colourfess so1Íd. lhls compound had no d,efinite melting point and on heating eppeared- to s1owIy decompose above lOOo -212-

(Founa: to another color¡rless solid whioh d.id. not nelt below 3OOo. C, 5l.O9i Ht 2.98; Nr 24.94'í. C?H4CIN3 requires C, 50'77i Hr 2'44i N, Zj.3B!/"). 5-Chloropyridol zr3-üpyrid.azine decomposed slowly on standing in light and. air to an oran8e high-melting solid. The above analysis cor¡}d. òrùy be obtainetl tbree d.ays after prêparation and' as a not consequence very close agreement with the required' values could' be achieved. The n.m.r- spectrum of a fresh sa"mple¡ bowever' ind'icated' that no impurity was present. N.ÛI.r. and. ultraviolet spectral d-ata are listed. in Tab1es 10 and 11. Bhe infrared' spectru¡o (CHCf, solution) shows C-CI peaks al 129ot 1300 and' at )BJ ct-1 ' (t) B-Py¡ido[ 213-g]pyridazinot" (2.0 g) and" phosphorus penta- chloride (8.0 g) were heated under reflux with phosphoryl chloride for I hr. The reaction mixture waÊ worked up as in (a) above and. the crud.e prod,uct chromatographed' on alumina with 1Oþ chloroform-benzene to give LchJ.oropy¡id-ol 2r]-g]pyrid.azÍne (1 '81 &t 7?fÐ w]nich was recrystallised. from benzene-light petro)-eum as a colourless solid'' and' on This compound also d.ecomposed. slowly in air to an orange solid' heating d.id. not nelt but appeared. to slowly change into another oompound' ct i (tr'ound.: c, 51 .o2; Hr 2.85; Nr 24.784 t?t4ttt3 requires 50'77 H, 2.44i N, 25.38/"), N.m;'r. an¿ ul,fraviolet spectral òata are (cuc:', summarised. in Tables 1O and 11. Tha infrared spectrum solution) shows C-C} peaks at 1305 and' 1020 cm-1'

HYd.rate Reaction s. B-Dichloronvrid,ol 2. i-d.I oræid.azi ne with Hvdrazine at Room Temperatu¡e

lhe following is a motlification of the method. of Nitta, Matsuu¡a

and. Toned.a.101 _213-

5rB-DichloropJmidol zr¡-q]pyrid.azinu (4-o g, o.o2 mole) was d.lssolved. in a 1:1 mixture of chloroform and' methanol (f5O tf) and' (99'þ, 0.061 mole) in methariol (toO tr) hydrazine \ydrat e 3 ml, "as ad.ded. dropwise with stirrÍng at room temperatr.¡rè over 0.75 lnT. The mixture was stirred for a further 3 hr and- then concentrated. in vacuo to 30-40 mI. The solid which separated. at this stage was fj-ltered. and. the filtrate taken to d.ryness. The resid.ue was washed- with chloroforrn to remove unreacted d.ichloro compound. (0.¡ g) and. the remainder combined with the original precipitate. This mirture was separated' by the method. of Nitta .t C01 to give )-hyd.razino-8-chloropyrid.o- Ie,¡-e]py¡id.azine (1.3 g, ¡3Ø), m.p. 196-70 a (tit.101 t.p. 196-?0 d) C-C1 band- in infrared (nujo}) at 1O2O cm-1 and !-chJ.oro-&-hydrazino- pyrid.of 213-g]p¡rridazine (2,1 g, 54í) n.p. 173-175o (tit.101 IDrp. 174-175o).

ct io

0xid-e

(") )-Hyùrazj¡o-B-chloropvrid.ol 2, 3-g] pyrid-azine (0.5 g) was finely powdered. in a mortar and. added. in portions to a stirred suspension of ye1low mercuric oxid.e (2., ù in water (50 mf). After ad'dition was complete (O.1j ¡r) tire mixtr.¡re was stirred. a fr:rther 3.5 hr, filtered and. filtrate centrifuged. to ræove the last particles of mercury. The filtrate v¿as extracted. with chloroform (3 x 75 4]), tUe combined extracts were dried repeated.lyr and. the solvent rernoved on a rotary evaporator. fhe resid.ue was recrystallised. from benzene-]ight petroleum (b.p. 40-600), to give colourless crystals of B-clùoropyrid-of213-d]- py¡idazin" (0.375 * 89É) which was id-entÍfied. by infrared. and. uÌtra- _214_ violet spectral comparison with the product prepared from 8-p¡æid.o- Ier¡-g]p¡nridazinone, rlhis reaction is a]so able to be carried, out at 6o-?O0 as the B-chloro compouncl is stable to aqueous \yd.rolysis at these temperatures" The infrared spectn¡m of the prod.uct showed- no traces of the t-chloro derivative which inclicated. that the separation procedure of Nitta et al in the previous experiment was efficient. Thin layer chromatograpl¡y (silica gel: ethanol as eluant) gave orùy one spot "t b - 0.43. (u) !-Chloro-8-hyd-razinol2r3-Ê]plæid.azine (t .o g¡ was add.ed. to a suspensíon of mercurÍc oxid.e (¿ g) in v¡ater and the ¡nixture stirred. for 3.5 hT. ûlorit up as abovo gave !-chloropyrido[zr¡-g]p¡æidazirre (O.74 g, Al/") as a colourless solid. from benzene-light petroleum (¡.p. 4O-6O0). This compound was id.entified- by infrared and ultra- viol-et spectral comparison with an authentÍc specimen. Thin lpyer chromatography (silica gel: ethanol as eluant) gave only one spot .t \, = O.r1 and. the infrared- spectrun shovred. no traces of the 8-chloro derivative.

Hydrolysis of Chl-orop.yrido[ 2. 3-d.l p.y¡idazine Derivatives

(r) !-ChJ,orop¡.rid.o[ 2r3-g]py¡id.azine (0. z5 ù was heated. in water (25 und.er reflux for hr. A clear solution was formed. which ^t) t was taken to dryness on a rotary evaporator and the resid-uo so obtained. was sublimed at ?fl}ofO.! mm to give 5-p¡rrido[213-3]pyrid.azinone (0.æ B¡ gO'/"), m.p. êrd mixed. rn.p. 2770. _215_

(U) B-chloropyrid.ol 2r3-q]pyrid.azin" (0.2 g) was boiled. with water (25 for hr and- the sol-ution taken to d-ryness on a rotary ^t) 3 evaporator. Extraction of the residue with chloroform gave unreacted 8-chloro derivative (0. 165 ù, identified.' by the infrared spectrum and an insoluble product (0.016 g) which on sublÍmation at z3}ofo.) mm gave B-pyrid.ol 213:È]pyrid-azinone (o.ol1 8)r m.p. and mixed n.p. 326-B0. (") 8-Chlorop¡rrido[ 2r3-4]p¡rrid.azino (o.zi g) was heatecì. with locfo aqueous sod.ium Lryd,roxid-e (2, nt) for 2 hr. The solution rvas cooled-, neutralisedr taken to dryness on a rotary evaporator and. sublimed at z3oofo.! mm to givo &-prriôo[213-g]pyrid.azinone (0.19 B¡

BB/'), m.p. and, mixed m.p. 326-80. (a) B-Methyl-!-chloroprrid.o[ 2r3-g]pyrid-ad-ne (0. J g) prepared. by the method of ArmareUog6 *u" boiled. with r,vater (2, ¡ù) for 3 hr.

The solution rvas concentrã,ted. to 3 mI and. cooled. to gÍve colourless crystals of B-methyl-!-pyrido[2,¡-g]pyridazÍne (O.21 B¡ IB'i") n.p. 2490 (tit.96 An sample of the prod.uct was prepared ^.r, z4g-zroo). authentic by the procedure of Armaregog6 ?na the ü.p. of a mixture of the two prod-ucts d.id- not depress.

(") !-Chloro-B-hydrazinop¡.rid.of 2, 3-g]pyrid.azine (0. 2 B) was \ydrolysed as in (a) to give B-hyd.razino-!-pyrido[ 2r3-È]p¡mid.azinone, (O.15 g, B5'/"), ^.p" 283-40. This compound. was id.entified. by mixed. m.p. with an authentic sample prêpared. as d.escribed- previously.

(r) !-Hyd.razino-B-chloropl.ri,iol 2r ]-g]pyridazine (o'2 g) vras heated with 1Ooy' aquoous sod.ium \ydroxid,e (t5 tf) for 3 h¡, cool-ed and acid.ified. with acetic acíd to give !-hyd.razino-B-pyriaofZr3-g]pf¡iaazine -216-

(o.o96 g, 53fò, ^.p. )3ooo. This product was id.entified. by infrared. spectra)- compaiison with a specimen prepared previousLy in this investigation.

Reductive Catal:rbic Dehalogenation of the Chlorop.y¡idol2,3-dlp.yridazines

(.) !-Chloropy¡id.o[.2,3-g]pyrid.azine (0.5 e) in ethanoL (too mr) and. anrnonium hydroxid.e (d = 0.881 1 d) was hydrogenated over !iá pallad.ium on carbon until the theoretical uptake of hydrogen (68 mI) haa been achieved. The mixtr¡¡e was filtered. to remove tho catalyst and- the filtrate was concentrated to ! mI under reduced ptessuroo Water (+O tf) was ad.ded and. the solution was extracted. with chloroforn (3 x ?5 rn]). fhe combÍned extracts were d.ried, and. the sol,vent removed. to give a residue of orude pyridof 213-g]p¡rrid.azine. fhis vras d,isso]ved in vrater and. converted. to the picrate (0.9 g, $!Á), m.p. and mixed. m.p, 1960 d.

(u) 8-Chlorop¡rrid.of 213-q]pyrid.azine (0.5 g) was reduced as in (a) to give pyridof 213-g]pyrid.azine picrat" (o.BB g, Bl7"), m.p. and nixed. m.p. 1960 ù.

Reaction of the Chl-oronvridol 2.l-d-l p¡r¡idazines wÍth Ammonia.

(") !-Chroropyrido[ 213-d]pyrid-azin" (0. z5 ù was d.issolved. in ethanof (Zo ml) and. arunonium hydroxidä (d = o.BB, 15 mI) and. heated at lOOo in sealed steel tube for 5 hr. The cooled, solution rsas taken to d.ryness on a rotary evaporator and the resid.ue co]lected. as a tan soIid.. A sample of this product when dissolved. in water gave a precipitate with silver nitrate and. typÍcal Wclrochlorid.e peaks in the 2!OO cn-1 regÍon of the infrared. spectru.ur (nujot). This reaction -217- prod.uct, !-aminopyrid.o[ 2,3-4]py¡id.azine hydrochloride, d.id. not raelt below 3ooo but sintered an¿ d.arkened above 2350. The hydrochlorid'e was d.issolved in water and treated. with aqueous picric acid- to give

!-aminopyrid.o[ 213-e]prrid.azine picrate (o.49 e, 86/")t which recrystallised from either water or ethanol as yeIIow crystals, m.p. 285-60 ù. (Foun¿: C¡ 41.9Oi Hr 2.60; Or 29.5/". t.,jtg"?O? requires Cr 41'60; Hr 2'42i O, 29.B5fò. the infrared.r,spectrrm of this compound (nujol) showed. NH peaks at 34oO and. 3t 50 cril . (u) &-Chloropyrid'o[2,3-È]pl-¡id"azine (o.zo e) in ethanol (loo ml) anfl ammonium hydroxÍde (d = O.BB, 10 ml) ur.= heated at lOOo Ín a seafed steel tube for 10 h:.. The reaction mixtu¡e was worked up as in (a) to give the \ydrochloride. 0n treatnent with aqueous picric acid. the hydrochloride gave !-aminopyrùd.ol 2, 3-g] pyrid.azíne picrate (O.4 g, 88/"), which recrystallised. from water or ethanol as: yellow crystals, m.p. 292o . (Found: Qt 41.49; H, 2.62; N, 25'7/"' t.,3t9t?o? requires ct 41 .6oi H, 2.42, N' 26.1%). The infrared

(nujoI) shows NH peaks at 3350 and" 31BO spectrum "m-1 '

Reaction of the oronvrid.ol z. l-¿l pvrid.azines rvith Hvd.razine HYdrate

(r) !-cbloropyrido[213-A]pvrid'azine (o.e e) Ín ethanot (50 rn1) was treated. with hyd"razine hyd.rate (gg',1, 0.5 m1) and- hoated. at the refLux temperature for O.2, lnT. The solution was taken to dryness on a rotary evaporator and. excess hyd.razine hyd.rate removed by repeated- ad.d.ition of ethanoÌ and- evaporatíon ! .ry. !-Hyd'razinopyrid'ol2r3-d]- p¡rridazine (0.175 g¡ B9/") recrystallised. fron ethanol as orange-red crystals¡ n.p. 263-50 d. -218-

heated witb (¡) B-chloropvr:ido[ 2]-d)pvridazin" (o'z5 ù was as above to give B-hyd'razino- an ethanolic solution of lSrdrazine hyd'rate as orange-reò p¡æidof 2r3-g]pyrid-azins (o'21 8t B?Ø) wirich crystallised needfes from ethanol, n'p' 232-2330 d'

dol I pr¡ri d-azi nes with Raney Nickel R tion the Hvd.razi vr1 2.3-d (r)J-Hydrazinop¡æid-o[2,3-g]pvrid'azin"(o'3g)andfreshiy

(vrf 0"3 g) *u'" heated' in water prepared- Raney nickel ?r '225 ceased (e'5 f'¡)' The catalyst at 10Oo until' evolution of ammonia wasremoved.bygravityfiltration,thefiltrateconcentrated.to !mland.anaqueoussjolutfonofpicricacid.added',Ihemixtu¡ewas picrate cooled and firtered to give !-aminopyridol e'¡-g]pyrid'azine from (0"47 e, el/") as a yellow solid which \{as recrystaLlised' an authentic sample d'id' ethanol to m.p. 2860 d-. A mixed. n.p. with not dePress. (o'2 was reacted (t) B-Hydrazinop¡æid-ol 2,3-g]pyrid'azin" g)

picrat" (0"34 &¡ as in (") tu give B-aminopyridolZ,¡-g]pyrid'azine by Itl) as yellow crystals from ethanol¡ m'p' 2920' und'epressed' admixture with an authentic sample'

tio t th e (0'10 was treated witb' (") f-Hyd'razinopvrid'ol 2r3'üpyrid'azin" e) pyridol2t3-g]py¡id'azine mercuric oxide in the usuaL manner to give (0.06? er 84ò, m.p- 154-ro' (o g was i reat ed as (¡ ) B-Hydrazinopy¡idol 2, 3-4] p¡æid-azi ne ' oB ) in (a) to give pyrid'ol2,3-4]pyrid'azin" (o'055 g' 841') as co]ourress needlesr m.P. 1r3-5o. _219_

P¡rridof 2, 3-dl -s-triazol of 4 . 3-dl p.widazine

B-Hydrazinopyrid.o[ 213-d]pyridazine (0.02 g) was heated. at the refl-ux temperature of formic aci¿ (98-1Oúr 5 mI) for 17 hr. The

solution was taken to d-ryness on a rotary evaporator, the resid.ue

chromatographed. on alumina using chloroform as eluant and. final]y

sublimed. at 1750/O.1 mm to give pyri¿olZr3-ê]-g-triazolo[4r3-g]pyridazine

(o.ot 65 e, 78"Á), m.þ. 283-50. (Found.: c, 5r.85i Hr 3.29'þ cgH5N5 requires C, 56.13) H¡ 2.94!i.). Th'e I\oIn.?. and ultraviolet spectral d.ata for this compound are listed. in Tab1es 10 and- 11.

When the above reaction was carried. out using shorter reaction times (Z-i tt")¡ chromatograpl¡y gave a prod.uct containing a carbonyl function (Uy infrared) and. no cyclised naterial- was obtained.

Pvr.i ¡l r'[ 1^ 2-d I -s-tria c,o1 ol ¿. l-dl pr¡¡id.azÍne

J-Hydrazínopyrid.o[ 2, ]-4]py¡id.azine (0.20 ù was heated under reflux with formic acid. (TUIOOþ, 15 mI) for 1.5 yE and worked- up as in the preced.ing experiment. Sublimation at 14OofO.1 mm gave pyridol 3,2-g]-s-triazolo[4r3-e]pyridazíne (o.l14 e, 73/à) as a corou¡less solid, m.p. 223-5o. (Found: C, 56.28; Hr 3.23/o. t't5t5 requires C, ,6.13i Ht 2.94"/). lhe Þ.r.r. ahd- ultraviolet spectral data for this compound are ]isted. in Tab1es 't0 and' 11.

React i n af 5.8-Dihvdrazinonv¡id.ol 2. l-d.lp:rrid azíne with Forrnic ¿cid-

5rB-Dihyd.razinopyrido[ 2,3:È]p¡æidazine (2,o 8, O.01O5 mo]e) was suspended in d.imethylfornramid," (¿O ml) and. formic acid. (98-1OOio, O.! mI, 0.013 mole). The mixture was stirred. and. heated on a boiling water -220-

bath for 3 hr, cooled- and. filtered to give a mixture of compound.s (5lc and 5ld; R=NII'IH2), h.l5 e, 641ù as a'pink solid., m.p. 310-311o d'.

React ion 2.3-Dicvanoo¡rridine vrith Hvdrazine Hyd.rate in the Presence of Dimetb-vlformamide

This reaction was carried. out by the method. of Kunz"93" to

give a mixture of (5la) and. (ff¡) as an orange-red. so1id., m.p. 240-2450 (rit.93" *.p. z4o-243o).

0xicLation of the Prod-ucts of the Preced.ing two Reactions v¡ith i\'fercuric

0xid-e

(") The prod.uct of the reactÍon between for¡oic acid. and. !r8-

d-ihydrazinopyrido[ 213-9]pyridazine (1.35 g) rryas add"ed in portions over t hr to a stirred suspension of rnercuric oxide (tO g) in water (?5

mI) at 9O-1OOo. After ad-d.ition was complete, the mixture rvas filtered

hot and. the filtrate, when cool¡ was extracted. with chlorofornr (6 x

1OO ml). The combined. extracts were d.ried. and- the solvent removed in vacuo to give a colourless resid,ue (0.62 ùr rn.p. 255-2650. [his

solid, was fractionally sublimed. first at 13OofO.1 mm and after no more

subLimate was obtained. at this temperature, the remainder was subLimed.

at 180-1gOo/o.1 mm. The fÍrst sublimate was pyrid.ofZr3-g]-e-triazolo- ,' [+,¡-q]pyrid,azin" (0.2o5 ú 19|/), m.p. 224-50, undepressed. by ad.mixture v¡ith an authentic sample. lhe second prod-uct was pyridoiZ,¡-g]-S-

triazolo[4r3-g]pyridazin" (0.385 g, 34oÅ), n.þ. 284-50, aLso und.epressed. by ad.mixture with an authentic sample. Both prod,ucts v¡ere afso

identified. by ultraviolet and. infrared spectral comparison v¡ith known

specimens. - 221

(¡) The prod.uct of m.p. 240-245o¡ prepared by the method of Kunzer @.>¡ g) *a" oxidised. and wo::ked up as in (a) to give pyrido-

[ ¡re-e]-s-triazolol4r3-g]pyrid.azíne (0,19 g, 41"þ), m.p. 224-50 and,

p¡r¡id.ol 2,3-4]-S-triazolo[ 4,3-4] pyridazine (0.05 g, 11'þ), m.p. 284-jo .

Soth prod.ucts were id.entified. by mixeù m.p. ancl infrared and-

ultraviolet spectral comparison with authentic sampì-es.

Thin layer ch¡omatography of the prod.ucts of (a) and. (b) on

silica ge1 as ad.sorbent and. using ethanol as eluant shorved- that

efficient separations were achieved. by sublimation. The compound. m.p. 224-50 had an R' = 0.44 and that of m.p. 284-50 had an \, = 0.33. These \, values were identica] to those of authentic pyrido[:r 2-g]-S- tirazolol4r3-g]pyridazine and pyrÍdo[2r3-g]-s-triazolo[4r3-Ê]pyrid.azine

respectively which were run on the same pJ-ate for comparison.

6-ChI oro lr.'rrid.ol- Z. ¡-al -s-t ri a zol o[ 4, 3-d I'o¡r¡ id azj. ne

This compound was prepared by the method- of Nitta, Lfatsuu¡a

and. Yoned. ur1O1 ancl sublimed. to colourl ess need.lês o.p. z7z4o (t:-t .101 m.p. z7l-zo).

Dehaloaenation of 6-Chloron¡r¡idol 2.1-d'ì-s-tríazotol4.l-dlo.r¡i,l a.z,in¡¿

6-Chloropy¡id.ol 2, 3-gJ -s-triazol o[ 4, 3-g] pyrid.azíne ( o. o5 s ) was heatêcl tn'a mixture of ethanol (30 rf) and. \ydrazine hyd.rat" (99ii,0.5 ml) under reflux for 10 hr. The reaction mixtr:re v/as cool-e<Ì and. the solvent removed. under reduced pressure to give the 6-hyd,razíno d.erivative, together with unreacted. lgrd.razine Ìgrd.rate. This prod.uct was reacted without fu¡ther purification with a suspension of mercu¡ic oxi,le (1 g) -222- in boilÍng water (ZO mf). The mixture was stirred- 4 tlr¡ filtered' hot, the filtrate cooled and extracted' with chloroforn (4 x 75 ml)'

The combined extracts were d.ried., the solvent removed. and- the rasidue sublimed. to give py¡idol e, 3-4]-S-triazolol 4, 3-g] pyridazine

(O.Ott g, 26% overall yie1d.) as a colourless solid rn.p. 283-50. This compound. was identified. by mixed, m.P.r infrared- and. ultraviolet

spectra arid. by thin layer chromatograplqlr.

pvrid.azíne hvlo¡¡rld.oi 2 - ì-dl -s-triazotol 4. 3-d,l

8-Hydrazinopyrido[ 2r3-g]p¡rrid.azine (0.04 g) was heated under reflux with acetic anhyd.ríd.e (20 ml) fot 3 hr. The mixture was cooled-

and. the solvent removed. under reduced pt""=*.. Fractional sublimation of the residue gave acetylhydrazine, m.p. 6?0, d.iacetyÌ\ydrazine, p¡æid.azine rïr. pr 14oo , and crude 3-met.Wlpyridol Z, 3-q]-s-triazolo[ 4r 3-4] (0.035 g). The last compouncl. was reeublimed. to give a colourLess so1i¿ (O.OZ9 g, 63oi)t n.p. 275-6o. (Found.: C, 58.59i Hr 4.17#. t9t?t5 requires C, 58.3?i Hr 3.81/"). Ultraviolet spectral data for this compound is listed' Ín fable 11. The srnall quantitles of substituted. \yd.razines rvere formed' by reaction of acetic anhyd,rid-e with excess l¡rd.razine hyd.rate which v¿as not completely re¡noved on preparation of the B-\yd'razino derivative' Acetyl\ydrazine was id.entified. by mixeù m.p. and- infrared spectral

comparison with an authentic sample. Diacetylhyd'razine was prepared from acetic antlyd.rid-e and. hyd.razlne Lrydrate as a colourless solid- (rit ,263 l4Oo). Admixtr¡¡e with the suspected m.p. 14oo ^,n. d.iaoetylhydrazine from the sublimation caused no depression of m'p' -223-

1-Met h r¡l nrrni d.tl 1- 2-dl -s-tTi r^[.4-1-d I nrmi.rlazine

!-Hyd.razinopyrid.ol 2r3-4]pyridazíne (0.03 g) v¡as heated- under refÌu( with acetic an\rcì.ride (20 m}) for 3 hrr cooled and' pouled into water. The resulting solution was taken.to dryness on a rotary evaporator and. the resid.ue fractionally sublimed. to give acetylhyd.razinet m.p. 6'10, d,iacetylhyd.razínø, m.p. 140o ancl 3-methylpyrid'of 3t 2-È]-S- (Found-: triazolo[ 4r 3-g]pyrid.azine (0.021 B; 61"íl), n.p. 23O-Z3lo . o, 58.'l2i H, 4.26dfo. t9t?t5 requires C, ,8,37i H, 4'26/")' Ultraviolet spectral" d.ata for thls compound is summarised. in Table 11.

R 2 zl

Acetoacetat e

(Z.Oe, O.01 O5 5, LDihyd.razinop¡rrid.ol 2, 3-4]p¡rrid azine mole) in isopropanol (50 rf) *a" treatod with etiryl acetoacetate (1.5 * 0.0116 mole) dropwise over 0.5 br. The mixture was stirred' t hr at 600 and' a further 3 hr at 95or cooled ancl filtered' to give a nixture of j-met hyI- 6-hyùr azinopy¡ idol Z, ]-4] -S-t rl azol o[ 4, 3-4] pyrid.azi ne and (l 3-metWl-6-hydrazinop¡r¡idol 3, 2-g] -g-triazolo[ 4, 3-4] pf¡id.azi ne .9 e,

B+7ò as an orange solid m.p. 2580 d,. Kun .24Ob has also prepared a simÍIar mixture but did not record a m'p'

l_o Pmd. Pr

The above mixture (t.9 g) was powdered. Ín a mortarl dehydrazinated with mercuric oxid.e in the manner previously d-escribed' to give a coLou¡1ess solid. (1.44 8)¡ ir Subl.imation at 13Oo/O.1 mm gave 3-met$l- _224_

p¡rridof 31 2-g]-s-triazolol 4,3-g]p¡*idazine (0. 66 g, 4O,Á), m.p. 230_

2310t as a colou¡less solid,. Mixed. m.p., infrared. and" ul.traviolet spectra and' thin layer chromatography showed, this compound. to be id.enticaL to

that obtained from l-hyd-razinop¡rrid.oi 213-g]p¡rrid-azine and. acetic anÌgrd,rid.e. sublimatíon of the remaind,er of the reaction prod.uct at 1g5o/o.1 wn gave l-methylpyrÍd.o[ 213-,d]-s-triazolol 4r3-4]pfrid azíne (O.eg g, 4fp), m'p. 2710. This compound. was id.entified. by infrared. and. ultraviolet

spectrar comparison, and. by mixed. rnop. ¡ wlth an authentÍc s¡mprêo

-6-c T1 -d ZI

,rbhe This sompound. vvas pleparcd by rriethod. Nítta, Matsuura and Yon"d."101 as a colourless solid.¡ m.p. eg3o a 1tit.101 m.p. zg3o a).

D hal f d

p.ylidazi ne

3-Methvr-6-chroropvrid.ol 2, j-g] -s-triazotol 4, 3-d] py¡id.azi ne (0, j e ) was heated. under reflux for 3 h¡ with a mixture of ethanof (50 mf) and Ìgrd.razine hydrate (99%, o.r '1). The solutÍon was cool_ed, the ethanol removed- und.er reduced. pressure and. the resid.ue siirred. with suspension a of mercuiic oxid_e (S ù in water (50 nl) at 95_1000 for 5 hr. The mixtr.¡re rilas filtered. hot and. the cooled. filtrate extracted. (4 wÍth chloroform x 75 nt). The combined- extracts were dried. and- the chloroform removed. und.er reduced. pressurê to give 3-methylpy¡idol 213-g]- s-triazolol pyrid.azine (0. ¿, ¡-e] 13 g, |1oÁ) t n.p. 2I1o , und.epressed. by ad.mixture with an authentic samplà" -22r-

-6 zoI Matsuu¡a This compound was prepared. by the proced.ure of Nittar (rit.101 2JZ-3o ¿). u,nd yoned"101 as a color¡rress sorid, m.p. 25240 ¿ m.p.

-s-tr

Ducid-azine (0.o9 3-MetWl-6-chloropyr.i.d.o[ 3r2-g]-s-trj.azolo[4r3-g]p¡.¡id,azLne g) r"" reacted. with hyd.razine hydrate an¿ then d.el¡yd.razinated' with mercuric oxid-e as in the foregoing erperiment on the isomeiic J-metwl- 6-chtoro oompound. 3-ùtetW1-6-chloropyrid.ol ¡, 2-Ê]-g-triazo]o[ 4, 3-d]- p¡rridazine (0.048 g, 8!,[) was obtained as a color:r1ess solid, m'p' and mixed. m.p. 230-2310.

II/ORK DESCR]3Ð TN CII\PTM 4

Nicotinic Acid-1 -oxide

fhis compound was obtained as color¡rless needJês¡ lllrp. 2r4o

(ti"t.'64 2540) by the method of Ruo'265 ^.n.

2-Àcetylnicotinic Acid-1 -oxid e

proced'ure This compound was prepared. from nicotinic acid. by the saxton266 a colourless solid. of m.p. 2480 ð' (tit'266 of Bain an¿ ^t m.p. 247-Bo d).

q-Ch1 oro-8,met hy1 pyridof 2. 3-d.l pvri da zi ne

This compound was prepared, from 2-acetylnicotinic acÍd-1-oxid'e 226 by the method. of a¡marego.96 M.p. 1630 (tit.196 m.p, 16z40)'

The infrared spectrum (CttCl, solution) showed C-CI band's at 1 295 anð' ))O cm-1 '.

q plæ z ne -Hydra zi no-8-met hvl ptæid.of 2 . 3 -d.l ida i

This compound. was prepared. fron the above l-chloro d.erivative (l.z g¡ as a yerlovü-oxangê sorid' (1.0 g, 9o%), m.p, z75o d (rit'196 ¡topo >1800 d), by heattng in ethanolic lryd.razine hyd.rate for 0.5 hrr cooS-ing and. filteríng.

FÍ ne1 y p owd er ed. 5-hydra z ino-8-methyl p¡r¡idol 2 r 3-d] p¡rr Íd.azi ne (t.O 6) wa" treated with mercr:ric oxid-e (? g) in the usual mannor. Chromatography of the crude product on alumina¡ using benzene as eluant, followed. by sublimation (Bgo/O.l nm) gave colourless needles (Iit.196 '114-115o). The nixed m.p. (0.69 e, B3/,), n.p. 113-1140 ^.p. with an authentic was 113-115o. This 8-met$I d.erivative "urop1"26? slowly turned red on êxposure to the atmosphere.

N.m.r. Soectra

[he follovling n.m.r. spectra, d.etermined. in chloroform solutiont were used. as reference spectra. in Chapter 2.

1 Phthalazine H1 t 1 = 0.43 'H4 2. Naphthalene H1 t I = 2.30 Hz' T - 2.62 227 -

2 OuinoI ine H2t T= 1.12 Lt. T = 2.67 J T = 1.92 tt" T 1.92 Õ = U.lJ. T= o.Bo 4. IEpSginotine 1 H.: T = 1.52 5 ,4 Te 2.5

5. Quinoxaline HZ rH3t f = 1.18

TJ ¡f f 1.9O B = U)l Étl ()l àl f'l I Êl f'l I f'. I Hl úl -228-

Rff,ffi.B\TCES

1. Bad,ger¡ G.M.r ilThe chemistry of HeteTocyclic conpor'mdsrr, Acad'emio Press, New Tork and' Lond-on¡ 1)61t p' V' 2. P¡rridazine: Jacobs, T.L., in ilHeterocyclic cornpound.srr¡ Ðderfield¡ R.C. t ed.., !Yi1ey, New York¡ 1957t VoI' 6, p' 10]' 3. Pyrinid'ine: ||Heterocyclic 4o Kenner¡ G.I,/v.' and Tod'd', Sir 4.R., in Compoundsll , .Ðtd.erfield, R.C., ed.¡ Wiley, New York, 1957, VoI' 6, p' 234'

b, Lythgoer B. t .Rev. , 1949¡ ),181. c. Brown¡ D.J., Rev.Pure Appl.Chen.(Australia), 1953¡ i¡ 11r. d.Brown¡D.J.'in|lÎheChemistryofHeterocyclicCompound's||, ïveissbergêr¡ a.r ed., Interscience, New York, 1962t vol. 16. 4. Pyrazine: 4o Pratt¡ T.T., in l|Heterocyclic Compounds|1, Ðd'erfield'' R.c.' ed.¡ !Vi1ey, New Tork, 1957¡ Vol' 6¡ p' 377' b. Krems¡ I.J.r and' Spoerrir P'8.' Chem.Rev. , 1947, N., 279' ).tr Clews¡ C.J.B.r arid. Cochran¡ W"r &jg:ËLÏüt 1949¡ ?, 46' 6. Vüheatley, P.J.r Acta Crvst. ¡ 1955t 9¡ 224' A.M.rActa cryst' 1956¡ 7. Bertinotti, F.¡ Giacomello¡ G., and. Liquolir ¡ 2' 510' g. Herbstein, F.g.¡ and Schmid.tr G.M.J.r .@Itt 1955, 9, 3gg, 406. 9. Schomaker, V., and. Pauling, 1,., @, 1939, Ø, 1769. 10, Maccoll, 4., J.Chem'Soc' ¡ 1946, 670' -))o-

11. Hückel, W., and' Jahnenl'z¡ \\.r 9@!er,.;1942¡ f5t 1438'

12. Lowd-in, P. O. , J. Chem. PLvs . t , 1951 , 12, 1323'

13. schneider, llI.C., J.Amer.Chem.Soc. ¡ 1948, J.9t 627'

14. Orgel, L.E., Cottrellr T.L., Dick, !Y', and' Sutton, L'E',

Tranç.Ieredgf,-þa, 1951 , 4f, 11 3. 60. 15. E\irans, R.C., and. lViselogle, F.Y., J.Amer.Chem.Soc. ¡ 1945t fl¡

16. Tjebbes, J., Acta Chem.lcand. , 1)62r fi; 916.

17. Davies, D.y{.¡ Trans.Fargdav Soh¡ 1955t L, 449"

18. Cha1vet, 0., and- Sandorfy, C., 99@t 1949, Ø, 566' 83' 19. Brownl R.D., and. Heffernan, M.L.r Aust'J'Chem' ¡ 1956¡ 2, 20. Ðixon¡ S., and V/iggins, L.F., !@p95¡,¡ 195Ot 3236'

21. Lythgoe¡ 3., and Rayner; L.S.r J'Chem'Soc', 1951, 232)'

22, Sayward.¡ J.M., U.S.P. 21391r745f 194r.

23. winnek¡ P.S., U.S.P., 2r3961066/1946.

24. Reference 3 d., p. 139.

25. Reference 3 d. r p. 171.

2õ" Reference 3 d. r pr 295.

27. Po1onevski'M.¡and'Pesson¡M.,@¡194Bl15l68B.

28. Lythgoe,B.,Tod.d'¡A.R.,and.TophaIII¡A.'{@,1944,315.

29" Ð_lingson, R.C.¡ and. Henryr R.1,., in a paper presented. at the 109th meeting of the American chemical society; atlantic cityr New Jersey. 3o.I{armas,G.,and.Spoerri,P.E.,@,19,7,f2,6B0. 31. Brown, R.D. in rrcurrent trends in Heterocyclic chemistryrrr Àlbert¡ A., Badger¡ G.M., and. shoppee¡ c.lll.¡ eds., Sutterworthr Lond.on¡ 195\ p. 13. -230-

32. Crossley¡ M.L.¡ and. Engtishr J.P.r U.S.P. 213941963/1946'

33. Shreve, R.N.r and. Berg¡ L., @¡ 1947, Ø-, 2116'

34. Joiner¡R.R.'and'Spoerri¡,P.E.'@l1941,Ø.,1929.

35. Newbold¡ G.T.r and. Springr F.S.r LbgIlbLt 1947¡ 373'

36. a. Ochiai¡ 8., and. Yanai, M., J.Pharm,Soc.Japan¡ 1939, 52r 18; and- Supplement t P. 97. b. Oohiai, 8., and. Yanai, M., Chem.Zentr. t 1941¡ !, 1806.

37. Letsinger, R.L.r and, Lasco¡ R., J1Q¡g¡Q@t 1956t 21t 816'

38. Bredereck,H.,Gompper,R.,and.Her1inger'H.,.@.'

1958, 19., 571. 39. Sred.ereck, H., Gompper, R., and Herlinger, H',, Chem'3er' t 1958t %-, 2832' trHeterocyclic 40. pratt, T.T., in compound.slr, Et-derfield-¡ R.C.r ed.¡ Vliley¡ New Yorkr 1957¡ Vo}. 6, P, 4O4.

41. Reference 3 d.r p. 187.

42. Jacobs, T.L., in rrHeteroc¡rcf ic Compoundsrr¡ Ð'd'erfield't R'C" ed'r

rlÍi1ey¡ Nev¡ Yorkr 1957¡ Vol. 6r p. 111.

43. pratt, Y.T., in llHeterocyolic compoundsrr¡ Eld.erfield.r R.C.r ed.r Wileyr Nevr Torkr 1957¡ VoI. 6¡ p. 391.

44. Reference 3 d. r p. 162. rrHeterocycllc 45. Jacobs, T.L., in compoundsrt¡ l}d,erfield.r R.C., ed.r $liley¡ New Yorkr 1957¡ VoI. 6s P- 123. trHeterocycl.iC 46. 4. Albert, 4., chemistryl' Athlone Press, London, 1959, p. 80. 231

b, Illuminatir G., in rrAdvances in Heterocyclic Chemistryil, Katritzþ, A.R. r ed., Acad.emic Press, New York and. Londont 1963, vol. 3r po 285.

47. Referenco 3 d., p. 125.

48. Baker, ill., and Taylor, T.IV.J.r 'tSidgwickrs Organic Chemistry of Nitrogentr, Clarend.on Oxford. Press¡ Lond-on1 1937, p. 533.

49. fngold.¡ C.K.r fistructure and iüechanisn in Organic Chemistryrrt BelI¡ London, 1953¡ p. 174.

50. Gabriel, S., Chem.3er. ¡ 19O3t É., 3373.

51. Marquis¡ M.R. ¡ Compt.renå. 1903, 136, 369.

52. Gabrie],S.landEschenbach,G.,.@.'1B97'39.'3o22. 53. Paul, V., Chem,3er. , 1899, E, 2014. 54. Gabriel, S., and. Pinkus, G., Chen.Ber. 1893, 4-¡ 2210. 55. Gabriel, S., and Neumannr A.r -@., 1893, 26, J21t 7O5. 56. tr'ränckel , K., Chem.Ber. 19001 3.3,, 2808.

57. Reference 3 d., pp. 1 2Br 382.

58. ãoNewbo}d-¡e.|[.'and.Spr1ng,tr..S.,@.¡1947l1183. b. Gallagherr J.J., Newbold.r G.T., Spring, F.S.r and' Wood.s¡ J.C.¡

J. Chem.Soc. 1949¡ 910. c¡ Koe1sch, C.F.r and. Gumprechtr W.H.r J.Org.Chem. t 1958t 4.t 1603. ,9. ALbert, 4., Goldacrel R., and. Philips, J.N., J.Chem.Soc., 1948¡ 2240. 60. 3rown, D.J.¡ and Harper¡ J.S.r !@Qgq.¡ 1961t 1298. 61. Albert, [., rrHeterooyclic Chemistryrr¡ Ath]one Press¡ lrondon¡ 1959t ch. ïX. 62. Bryson, 4., @, 1960, 82, 4871. -232- bJ. Sadger¡ G.M., rrThe chemistry of Heterocyclic compound.srr, Acad.emic

Press, New Tork and. London¡ 1961 r p. 368'

64 AIbert, A., rrHeterocyclic Chemistryrr, Atblone Pressl London, 1959¡

p. 300. 65. Mason¡ S.F. r J.Chern.Soc. , 1959, 1240, 1247 ' 66. Bergstromr F.M.2 and. Ogg, R.À.r @t 1931, 5), 245' ô(. Ogata, M., Chem.and- Pharm.Bull. ¡ 1)63t lt 1122'

68. Cookson¡R.c.'andIsaacs,N.S.,@,1963lJ2¡1237.

69. ã. simpson, J.C.E., in rrThe chemistry of Heterooyclic compoundsrr, Weissberger, A.r ed., fnterscience, New Tork, 19!1, Vol' 5, p. 69. b. Vaughan, 1¡/.R., CJrern.Rev. t 1948t !)t 447' rrHet6rooyoLio oo Eld"erfieldl R.C. ¡ and. Yfythe¡ s.Lr. r in compound.srr¡ ES.derfiel-d.r R.C.r ed.¡ WiIey, New York, 1957; Vol' 6¡ p' 186' d. Kanahara, S., Yakugaku Zasshi, 1964¡ 94, 483'

70. Atkinson, C.M.r and. Sharpel C.J.r J.Chen'Soc', 1962, 4094' 71. Arrnarego¡ W.L.F.r J.Chem.Soc. , 1962, 4094'

72. ã. Petrow, V., and Saper, J., L'Chem'Soc', 1948, 1389' b. Leese¡ C.L., and- Rydonr H.l{', J'Chem'Sgc' t 1955¡ 303' c. Albert, A. , ancl Barlln, G"3. r J.Chem'Soc' t 1963¡ 5737 ' 73. &c Koenigs¡ 8., Bueren, H'¡ and Jung, G.' Chem.Ber. ¡ 1g36, Ø., 2690. b. Albert , L., and. Pederson, C., L.Chem'åoc'.t 1956t 4683' 74. Gabriel, S', and Mi.iller, F., Chem. Ber. 1895, &., 1830. 7r. sÍmpson, J.C.E., in rrThe chemistry of Heterocyclic compoundsrr, lVeissberger, A.r ed., Intersùíenoer New York, 1951t Vol' 5, pr to. -233-

76. idem, íbid-., P. 14o- 630' 77. ã. Cheorghiu¡ G. , bulI .soc. chim-France ¡ 1930 ¡ &t b. GÌeu, K., and' lTackernager, K', J'prakt'chem' ¡ 1937' ßþ' 72'

78, a. Meyer, H., and. I\fa11y, J., l!9gþþr 1912, Ðr 411' b. Gheorghtu, G., Bull.Soc.chim.France¡ 1933t 5), 1r1' Ml Perry¡ F'M' cr Yal e¡ H.IJ. r L,osee, K., Martins, J', Ho1singr ' t and Sernstein, J., J.Amer.Chem'Soc' t 1956, J9, 159'

79. Jones, R.G., J.Amer,Chen.Soc. ¡ 1956, f9, 159'

Bo. Papini, P.r Rid.ir M.r Checchi, S', Cazzetta' 196Ot Ð; 1399' 1957, 728' 81 Ridi, M., and checchi, s.r Ann.chùm.(Italv), AJ-,

82. Bavin,E.M.'Drain,D.J.'SeiIer,M.,and.Seymor:r,D.E.,@ Pharmacol. I 1)52t !.t 844t Br5. S'S'S'R.' 83. Kond"ratteva¡ G.Ya.¡ and. Chih-Hâng Huanelr Doklad'v Akaû'Nauk 1)601131t 94; chem.Abs.l 1)60' 5at 12131' u. Yee-ShengKaoland'Robinson,SirR.,[email protected]. 85. Micheel, F., and Dralle¡ H., @].4e 1963, Ø; ,7'

86. Gard,ner¡ T.S.r Smfth, F'4.' Wenis, E', and' Lee¡ J" L&'@t 1956t 4t 530' 286. 87. Reid,er¡ M.J.¡ and Elderfie]d,, R.C.r J.OrÂ.Chem,.¡ 1942t ft

BB. Novacek¡L.,Pa1at,K.,Be1adnik,M.,and.Irtatuskova,E.,9@, 1g62¡ lJt 76. 89. Musante, C.¡ and Fatutta¡ S., Ann.Chim.(Italy) t 1957, !J, JB5' 843' 90. Jeitel-es, 8., @þLr 1901¡ Et 1951t 19'' 91. Druey¡ J., and Ringier¡ B.H.¡ Helv'Chim'Actat ]A, _234-

S' Gazzetta.t 1956¡ 86, 99O' 92. Sottari, F., and. Carboni, ¡

93. ã. Kunze¡ !V.¡ B.P. 7O71337f19r4' b. c.I.3.4., B.P. 743r2j4f19r6. c. Kunze¡ lV.r G.P. 947¡971hgre ' d.- zerweck¡ w.¡ and Kunze, w', B'P' 732t521/1955' ê.ReynoIds¡G.A.'Vana11an¡J.A.¡and-Tinker,J.F.,l.9@l 1959¡ 4; 1205' 217861839/1957' 94. Zerweck, W.¡ and .Kunzer Ï1.¡ U'S'P' 95. Rid,i, M., Ann'.chim.(rtalv) t 1959t L2¡ 944. ì¡V.Ir"F,, 60?3' 96, Armarego¡ L-Ç!Ê.g¿Epg., 1963, 97. A1bert,L.,Armarego¡!T.IJ.F.¡andSpinner,E.,@,1961, 2689, 5267;

98, Armarego¡ II/.L.F., !@!9g¡ 1962¡ 561' J'Chem'Soc' 1963¡ 99. Albert, 4., and 3arIin, G'B', t 51'6'

1 00. A1bert,A.,Howe11'c.F.¡andSpinner,E.,@,1962,2,95.

101 . Nitta¡Y.rMatsuurarI'randloned'arF"Chem'andPharrn'Bull-" 1g65, Ê., 586. 102. Domaga1ina¡E.,Kurpie1,I.,and.MoJejko,J.,@,l964l É, ziJ¡ chem.Abs. , 1964, 61-, 10678. and Nagata¡ C', Sull'Chem'Soc'Ja,pan¡ 1954t 1 03. tr'ukui¡ K., ïonezawa, T.¡ 4-' 423' 029/1949' 104. Hartmann, M., and. Druey, J', U'S'P' 2¡484, liV., G'P' 1 05. Zerweck, and' Kunze, W', 951r992f1956'

106. Kunze¡ w. , G.P. 951 ,993f 1956. Chem.Àbs. 1961, 14449. 107. lani¡ H.¡ Yakusaku Zasshi¡ 1961r.91r 141t , 55, _235_

8.M., J.llmer.Chem.Soc. 1959t 4OO4' 1 08. Fee1y¡ I¡/.E., and- Beavers¡ t U,

109. Philips, 4., @}g, 1895, zffi., 253' 110. Ðrgler, C., ÊqBer¡-, 1894, 4, 1784' 111. Sucharda¡ 8., 9þem.þr., 1925t &t 1727'

112. Herzog, \l,t @@t 1919, 2, 301 ' t Huang¡ Zhu¡'priklad-'Khim" 113. Kondrat eva¡ G.Ya., and- Chih-H6ng t962; 35t 199.

114. Linstead,R.P.,NobIe¡E.G.,and.Wright,J.M.'@¡1937,911. 26. 11r. L,awton¡ 8.4., and- McRitchie¡D.D., J.Org.chem. ¡ 1959, 4,

116. Bai].eylA.S.'Henn¡B.R.¡and.I,angd'on,J.M.,@¡1963¡ D, 161.

117 . rr,Jeis, C.D., J.Org.Chem., 1)62t !l; 3514. 1911t 738' 11 B. Freundler, P., BuLL.Soc.chim'France, 2¡

119. DelabyrR.r[satsasrG.randLusinichirX',Bu]l-'Soc'chim'France¡ 1958, 409. J'Amer'Chem'Soc.' 120. Stephensr C.R., Bianco, E'J.¡ and' Pilgrim, F'J" 1955¡ lf-¡ 1701.

121. ÐiIingsfeId.,H.'Seefe1d'er,M.,and'lVeid.ingeT'H.r4@, 1g60, J2, 836.

122. îrievbkornr B.r G.P. 1 r1o7r214/1959' ilReactions Organic Compounds over 123. Ad.kins, H., of Hydrogen with Press¡ Copper-ihromium Oxiôe an¿ Nickel Catalystsrr, WisconsÍn

ì[adison¡ 1937 ¡ P. J6.

124. Ainsworth, C,, J.i\mer.Chem'Soc' , 1954, ß, 5774'

125. Ainsworth, Ç., J.Amer.Chem.Soc. t 1956, f9, 1636' 236

126. a. Coxon, 3., and. Hough, L., J.Chem.Soc. t 1961t 1643. b. Hard.egger, Ð., Zanettl, G., and. Steiner¡ K., Helv.Chim.Acta¡ 1963, Æ., 282. 127. Parsons, P.G., personal conrnunication.

128. Errans, R.F., Rev.Pu¡e Appl.Chem.(ltustralia) r, 1962, 12, 146.

129. Singh¡ 8., and. Sahoia¡ S.S., J.Ind-ian Chem.Soc. , 1961, .3,9,, ,69. 130. d. Chattaway, F.D., J.Chem.Soc.1 1907t %_t 1323. b. Chattaway, F,D., J.Chem.Soc. z 1908t g}t 27O.

131. Hunig¡ S., Mül1er, H.R., and, Thier, lV., Ansew. Chem, (Int. ed. ). 1965, 4., 271. 132. Kosower¡ 8.M., and. Huang, P.C., J.Ainer,Chem.Ëocar 1965, t_, 4645.

1 33. Linholter, S., Rosenorn, R.¡ and. Vincents, L., Acta.Chem.Scand-..

1963¡ LL¡ 960. 134, Zeið.ee 0.4., Sherlin¡ S.M., and. Bras, G.I., J.prakt.Chem. t j933, 1S' 225' 135. Zeíd.e, 0r.A.r Sherlin¡ S.M., ancl 3ras, G.f ., J. p¡akt . Chem. , 1933¡

1 38r 55. 136. Miller, C.0., and. Furman, N.H., J.l\.mer.Chem.Soc. t 1937, D, 161. 137 . ã. thielepapè, 8., and- spreckelson, 0., chern.Ser. ¡ 1g22t l5t 292g. b. Maaskant, L., Rec.Trav.chim. , 1937, fi., 211. Schofield., K., and. SwaÍn, T., J. Chem. Soc. t 1950t 392. d. Baumgartner¡ H.8., and. Su, H.C., J.Amer.Chem.Soc. t 1)J22 f!, 3828. ê. 3eyer, H., Lassigr Vìi., Bu1ka¡ 8., and. Beh¡ens¡ Ði, Chem.Ber.¡ 1954, fl, 1392. f. Albert , A., . Chem. Soc. 1960, 1790.

B. Armarego¡ l/\r.!.F., J. ÀonÌ . Chem. 1961, 11, 70. _237-

h. Rapoport, H., and. Batcho, 4.D., J.Ors,.Chem. ¡ 1963¡ 28, 1713. i. Drur/¡ K., Ansew.chem.(rnt.ed..), 1965¡ h 296. j. Ikekawa¡ N., @t 1958¡ 6t 269.

1 38. a. Albert, A. , and. iÏill-is, J,3. , J. Soc. Chem. ïnd. ¡ 1946, Ø., 26. b. Albert, 4., Brown¡ D.J., ancl Duewe11, H., {:9bg3þ, 1948, 12U. c. Albert, 4., and Royer, R., J.Chem.Soc.. 1949t 1148.

139. Soarland-, l,[.P.V., McOmie¡ J.F.Vd. ¡ artd. Timns, 4,.N. t J. Chem. Soc.

1952¡ 4691. 140. Rod.d.a, H.J. r unpublished. results.

141 . AtkÍnson, C.M., and Sharpe, C.J., J.Chem.Soc., 1959, 2858.

't42. Hatt¡ H.H., and- Stephenson, E.F.M., {.Chem.S,q.t 1943t 658.

143. Robì.in¡ R.0., Viinnek, ?.S.r and" E\rglishr J.P., J.lmer'. Chem. Soc. , 1942, Ø, 567.

144. ã¿ Whitaker, N. t J. Chem.Soc. 1951 t 1565. b. S/hitaker, If., J.Chem.Soc. ¡ 1953t 1646. J.Chem.Soc.. c. ldarshal.l r J. R. r arld lValkerr J. 1 1951 t 1004. d. Overberger, C.G"r and, Kegq¡, I.C.t J. Amer.Chem.Soc. 1954t 1Á, 1879, ê. Smith, V. H., and- Christensen, B.8., J. Orq . Chem. 1955, 2O., 829,

145. a, Mizzoní, R.H., and. Spoerri, P.E., J . Amer . C hem. S o c . 1951, 73,

1 871.

b Steck, 8.4., Brund.age, R.P. r and. Fletcherr L.T., J.Amer.Chem.Soc., 1954t lÉ-, 3225. c Horning, R.H., and Amstutz, E.D.r J.Ors.Chem. t 1955> ZOt 7O7.

146, €t. Stephenson, E.F.M., Chem.and. fnd.. t' 1957t 174. b Stephenson¡ E.f'.M., J.Chem.Soc. ¡ 1963¡ 1913. 238

147. â. Pettit, G.R,¡ and Van Tamelenr E.8., in rrOrganic Reactior¡srr,

Ad.ams, R., g| ed".¡ !Yi1ey, New York, Vol-. p. "1. 1962, 12, 356. b. Bad.ger¡ G.M. t Aust.J.Science 1958t Z_, 45.

148. Bend.ich, A. , Russell ¡ P.J. r and. Fox, J.J. , J . Amer. Chem. So c. ¡ 1954t 15, 6073. 149. Hirsch, 4.,, and- Orphanos, Ð., J,Het.Chem. t 1964t 2¡ 206. 150. V/ibaut, J.P.¡ ard Soer¡ H., 3gkgæbi&¡ 1955¡ JA¡ 241. 151. ã, Thiele, J., and. Y/ínterr 4., Annalen, 19OOt 311¡ 360. b. CoIeman, G.H. r and. He¡sywe11¡ G.E. r in r'Organic Synthesesrr,

V/iIeXr New Yorke 1944t 0oII,Vo}, 2e p" 443, 152" 8i11, J.C., and. larbelI, D.S., Ore.Synth.t 1954, ]A, 82. 153. Mathes, l\I., and. Schuly, H.r Angerv.Chem.(fnù;ed.) , 't963t Z¡ 144.

154. d. Hammiokr D.L. t J. Chem. Soc. 1923, 2882. b. Hammick, D.L., J.Chem.Soc. , 1926, 1302. c. Dyson, P., and Hammick, D.L., J.C-hem.Soc. , 1939, 781.

d.. Brown¡ B.R. r Hammick, Ð.L. r and. Thewlis, 8.H., J. Chem. Soc. .

1951 ¡ 1145. o. Brown¡ B.R., Hammick, D.L., Thewlis¡ B.H. r and- V/albrid.ge¡ J., J.Chem.Soc,, 1953, 1369.

Ad.ams Gosselain, P.A. atrd. Gold.f Nature¡ 155 " , J., r ingerr P., 1953, .l-llr 7O4, BulL.Soc.chim.3e1ses, 1956, Ø., 533.

156" Russellr G.4., DeSoer¡ C., and Desnond, K.M.t J . Amer . Chem. S oc . 1963ç þ.t 369, 3139. 157. fanner, D.D., @t 1964, &., 4674. 158. Pearson, R.8., and Martin, J.C., J.Amer.Chem.Soc. . 1963, þ., 354, 3142. -"lq-

159, tlYaì-1ing,C.,Rieger'A.L.¡andTanner¡D.D.'@, 1963, ü) 3129, 3134- 160. x[cGrath1B.P.'and-Ted.d'er,J.M.,@,1961,1511.

161 . Schmid, H., anù Karrer, P., Helv.Chim'Acta¡ 1946, ë-, 573'

162. ã. Vlenner¡ TÍ.r [email protected]:t 1952¡ 1J-¡ 523' b. Misra¡ G.S., and- Shukla, J.S., @, 1951, 4., 277 c. Qvist, Vl., Acta.Acad-.Aboensis l'4ath'Phvs' , 1952, 18, 14'

163. \Tinkelmann, E.H., Ph.D. thesis, University of u!øLnz> 1957'

164. Hasegawa¡ M., Chem.and' lharm.Bul-l-' ; 1953¡ L¡ 47, 293'

16r. Horner, L., and- ìilinkeLnann, E'H.t Ansew. Chem. , 1959, fJ' 349 "

and- Neid.hardt¡ G., Anna!g¡1, 1963, 6#, 148' 166 " Ried, ll,, 258, 167 . Queguiner, G., and PastoL¡rr P.t Compt.rend. t 1964, 5903. Publ' 124' 1 68. à. Albert, 4., Chem.Soc.Special t 1955, J, b. Albert, À., rrHeterocyclic Chemistrytr, Athlone Presst Londont 1959, P- 49. 169. &o Albert, 4., in I'Physical Method.s in Heterocyclic Chernistryrr, Katritzky, A.R.r ed., Academic Presp, New York and' Lond'ont

1963, VoI. 1¡ p. 1. b. albert, A. , in rrHeterocyclic chenistryil, Atlr-lone Press, Irondont 1959, po 3J6. c. Clarlc, J ., and Perrin, D.D.t Quart.Rev. , 1964, 295. 17O. ãc X'elsingt \ÃI.A.r and. Siggsr B. S., J.Amer.Chem.soc. ¡ 1933t 55t 3624. b. Albert, 4., and Qo1d'acre, R., !þqþ, 1946t 706' chemistryrr¡ 171. ê. Mason, S.F., in 'rPhysical- Methods in Heterocyclic Katritzlcy, Á..R.¡ od., Academic Press, New York and London, 1963, YoI. 2, p. 1. _240-

b. Jaff á, H.H. and- OrchÍnr ì[., ilTheory ancl AppJ"ications of

Ul-traviolet Spectroscopyrr, 1/i1ey¡ New Y6rk, 1962, p. 361. c. tilurrell-, J.N., rrThe Theory of the Ðectronic Spectra of Organic Molecu1esil, Methuenr Londont 1963t p. 176. d. Mason, S.F., Chem.Soc, Special Publ. ¡ 1955¡ 3¡ 139.

ê¡ MasoÍlr S.F. t J. Chem.Soc. , 1962, 493. 172. d. Ilalverson, F., and- Hirt, R.C., J. Chem. Phvs . . 1951, Ê-, ?tl. b. Reid r C., J. Chem.Phys. 1953, 4t 1906. c. Goodman, L., @, 1961, 6, 109-

d. Mason, S.F. t J. Chem. Soc 1959t 1240. ilAromatische 17 3. Clar¡ E., Kohlenwasserstofferr¡ Berlinr 1941.

174. à. Braud.e¡ E.A. r Ann.Reports ¡ 1945, Æ., 123. b. Bad.ger; G.M.r ancl Pearc€¡ R.S.r Jr!¡@éoc. t 1950t 3012, 175. Baùger¡ G.M., Pearce, R.S., and. Pettit, R.r LChut.S*., 1951, 3199.

176, ã. Bad.ger¡ G.M.r and. lValkerr I.S.t J.Chem.Soc., 1956t 122.

b. Amstutz¡ E.D. t J OrB.Chem.. 1952t LL¡ 1 5oB. c. Hirt, R.C., King¡ F.T., and. Cavagnol, J.C., !þgq.-þyL, 1956t ë., 574' d. Hearn, J.fuI. r Morton, R.A. r and, SimpsoÞ¡ J.C.E' r J.Cþg..Sog. t

1951, 331 8. e. Mül1er, R., and Dörr, F.r &Eec.;!gggþ4¡ 1959t 63, 1150. rrAdvances 177. Albert, Â., and Armaregor VJ.L.F., in in Heterocyclic

Chemistrytr, Katritzky, A.R.¡ êd., Acad-emic Pressr I'iew York and' London, 1965, VoI, 4r p. 1. - 24'l

178. Albert, A., rrHeterocyclic Chemistryrr, Àthlone Press, Lond.on,

1959t P. 303. 179. Pop1el J.4., Schneid.er, W.G.r and. Bernsteinr H.J.r rrHigh Resolution

NucLear Magnetic Resonancetr, McGraw-Hillr New Yorkr 1959. rrPhysical 1 Bo. White, R.F.M.¡ in ùlethod-s in Heterocyclic Chemistryrr¡

Katritzky, A.R.r ed., Academic Press, New York and. Lond.on,

1!61, VoI. 2, p. 141.

181 . 31ack, P.J., and- Heffernan, M.L., Aust .J. Chem. , 1964, 1l-, 558. 182. Paud.ler, W.W., and Kress, T,J., J.Het.Chem., 1965¡ 2, 393. (eustralia) 1 83. Sternhel-1, S. t Rev. Pure Appl. Chem. , 1964, U., 15. 184. BanwelL, C.Iü.¡ and Sheppard., N.t Ðis cuss.tr'arad.a¡¡ Soc. , 1962, !4., 115. 185. Paud.l-er¡ W.lV., and Dunhamr D.8., J-:Ëg!--@, 1965¡ 2¡ 41O"

186. ào Red.d.y¡ G.S., Hobgood.¡ R.T., and. GoLd.stein, J.H., J.rtmer:.Chenl.Soc. t

t962t 84, 336. b. Gronowltz, S., an

187. 3lack, P.J., and. Heffernan, M.L., Aust.J.Chem.. 1965, t8, 7O7.

1 88. GiacomelLor G., Gualtierir ìF., Riccieryr F.l{. , and- Stein, M.L.,

Tetrahed,ron.Letters, 1965, 16,, 1117,

Abraham¡ Bishop, Ð.0.r and. Richards, R.E., j{üb,Þ.t 1Bg " &. R.J., 1g6o¡ J, 485, b. Berry¡ R.S., Dehl¡ R., and Vaughan, lV.R., J.Chem.Phvs. t 1961,

3A, 1460- c. Hoffrnan, R.4., and. Gestblom, 8., J.I{ol.Spectroscopy, 1964, ß., 221. 190. Gawer¡ A.H.r and. ÐaiIey, 3.P., J.Chem.Phvs. t 1965¡ E¡ 2658. -242-

191. ão GiI, V.lvI.S., and lúurrell, J.N., @, 1964, 12, 248. b. Schaefer¡ [., and Schneider, iv.G., Can¿¿d..J.Chem., 1963, L, 966. 192. Armarego, W.L.F., Barlin, G.B.r and. Spinner, 8., Þpectrochin.Acta,

1966, 22, 117.

1 93. &. Wait, S.C., and.'fJesley, J.lT., @, 1966, 19, 2r. b. Vliberg, K.8., "PÌqrsical Organic Chemistryfle lVileyr New York,

1964, p. 78. c. Streitweiser, A. r ttMolecula¡ Orbital Theory for Organic ChemÍstsrr,

rrVileyr New York, 1)61t ch. 5, d.. Mulliken, R.S., Rieke¡ C.A.r Orloff¡ D.r and Orloff, H.t J.Chem.Phvs.. 1949¡ lJ, 1248. 194. à. 01ah1 G.4., antì. Kuhn, S.J., J.Amer.Chem.Soc., 1961, -9f, 4164.

b. 01ah, G.4., Kuhn¡ S.J.r and. Flood-r S.H.t J.Amer. Chem. Soc. , 1962, il., 3684. c. Jones, J., and. Jones, J., Tetrahed-ron Letters, 1964¡ 2117

195. De la Marer P.B.D., Kiamud-Dinr M.¡ and Rid.d., J.H., J.Chem.Soc., 1960, j61.

196. Chand.lerr G.S., Ph.D. Thesis, UniversÍty of Ad.e1aicle, 1964.

197. Derbyshire, D.H.r and. lÀ/atersr r/V.A.t J. Chem. Soc. t 1950¡ 564, 573.

1gB. a. Van d.er Does, L., d.en Hertog¡ H.J., and. I-,and.heere C.4., Rec.Trav.chim., 1962, 81, 864. b. Van d.er Does, L., and den Hertog¡ H.J.r Rec.Trav.chim.t 1965, 94, 95t ' 199. Arotsky, J., and, S¡rmond.s, M.C.R., Quart.R.gv., 1962, 2582. _243_

2oo.ê.Trowbrid'ge'P.F.'and'Ðieh1'o.c.,@,1B97, D: 5|,B' b. lVilliamsr D.lvl., I:Ch"t.So* ¡ 1931t 2783' c.Acheson,R.M.'Hou]-t,T.G.¡andBarnard¡K.A.'{@.'

1954¡ 4142.

d. Disch, J.J., J.org.chem. , 1)62t ?L 1 31 B. €. Eisch¡ J.J.t and Jaselskis, B', J'Org'Chem', 1963t 28, 2865' f. Ðisch, J.J., J.Ors.Chem. t 1962¡ ?L, 468Z' 2o1,Leffler¡M.T.,in||OrganicReactions,Ad-amslR.,etaj..reils.' rlJileyr New York¡ 1942¡ '.üoI. 1¡ p. 91. 2O2. Musante¡ C., and Fusco, R., Gazzettal 1936, 66, 639'

203. Levitt, L.S., and' Levittr 3.Ïtr't Chem. and- Ind-. , 1963, 1621 -

204. Ba¡rettr G.C.¡ and Schofield, K., Chem.and, Ind-. r 1963, 1980. 20r. Abrarnovitch'R.A.,HeIner,tr..,andSaha,J.G.,9b@' 1964, 659. rrstructtire chernistryrr, 206 Ingold.¡ c.K., and. Mechanisn in Organic Be1I¡ Lond-on, 1957¡ p. 809.

207. Kaiser¡ 8.H., A¡ncf.Chem..J.., 1BB7r Br 312. 208. a. Delápine¡ M., @¡ 1927t Lt 39o' b. Tronov¡ 3,V. r and' Itlikonova, L'S', J'Russ'Phys'Chem'Soc" t 1929¡ Ø, 54t' 209. VÍ1kas, M., Bul-I.Soc.chim.France¡ 1959t 1401'

210. Tori¡ K., Ogata, LI.¡ and. Xãno, H', Chem'and' Pharm'3u1l" 1963' !_, 681 . 211. ogata¡ lÍ.¡ Kano¡ H.¡ an¿ lori¡ K., Chem.and. Pharm.Bull., 196), 11, 1527. 244

21 2. Tori¡ K., and Ogata¡ M., @¡ 1964t E, 272.

21 3. Àrmarego¡!v.L.F.¡andVli11ette¡R.E.'{@¡1965l1258.

214. Harris, R.K,r Katritzkyr 4.R., fksne, S., Bailey, A.S-, and tff.G. Paterson¡ t J. Chem.Soc. , 1963, 197. 215. Tori¡ K., Ogata, M., and. I(¿¡¡e, H. r @ 1963t !-, 235. 216. lvlason¡ S.F., J.Chem.Soc. , 1959, 1247. 217. Tennant, G., Chem. and. Ind.. , 1964, 1622. 218. Coad, P., and. Coad, R.A.r J.Ore.Chem.¡ 1963, 28, 1919.

219. Domaga1inâ¡E.,and'BaIoniak¡S.,@,1)62tþt2,3. 220. Stephenson¡ E.tr'.M., !@þ1t 1944, 678. 221. Karabatsos, G.J., Shapiror 8.L., Vano¡ tr'.M., Flemingr J.S.¡ and

Ratka¡ J.s., J.Ame¡.Chom.Soo. r 1963r -95,r 27U, 222. Schmid-Ie, C.J., and. IúansfieJ.d., R.C.r J.Amer.Chem.Soc- , 1956, -Ét

1702.

223. Surnett, J.P.¡ and. Ainsworth, C., J.Org.Chem., 1958¡ С 1382. 224. Sato¡ Y. r fwashige¡ T., ancl Miyad'erê¡ T. r @, 1960, B, 427.

225. Hurst, J., and. TÍibberley¡ D.G., J.Chem.Soc. , 1962, 119-

226. Zínke¡ T., and. Viinzheimer¡ 8., 3!gg]94r 1896, g, 3r3. 227. Hemmerich, P., and. Fal-labl S.r þ!gft!4.¡!1¡þ,¡ 1958t !L, 498. 228. Gaylord¡ N.G.r rtRed.uction with Complex Meta1 Hyd-rid.esrr¡ Inter-

science, New York, 1956t p. 373.

229. Papineau-Couture¡ G., Richard.son, Ð.M.r and' Grant, G.A.r Canad' ., 1949t 248.¡ 9o2' _245_

230. Parrini, \tr., Gaz"ettø¡ 1957¡ BL¡ 1147. 231. Reissert, A., Chem.3er,, 1913, &, 1489. 232. Racine¡ C., @!g, 1887t l2, 79. 233, Hirshberg,Y.,Lavie,Ð.,and.Bergmann,E.D.'@¡1951'

1 030.

234. Srown¡ J.J., and Newbold., G.T.r lQþem.Qgt 1952t 4397. 235. ã. seekfesr L.r þ,.::jlIry,@.¡ 1924t 43¡ 329. b. Ðunet, A., and. V/il-lenart¡ 4., @, 19481 12¡

1081. 236. Rower F.M., and. Osborn, lll., ![þgþ¡ 1947, 829. 237. à. Buu-Hoi, N.P., and Lin, C.K.r Compt.rend.. ¡ 1939, Æ-, 221. b. Shemyakin, Iv[.M. r @¡ 1943t 1Å¡ 29O. et Wheeler¡ D.D,r Young¡ D.C.¡ and. &tey, Ð.S.r JlQgg,¡[þgr

1957 ¡ 22, '47. d.. Renson, M., @¡ 1961r -?9r 77. 238. Rod-da¡ H.J., and. Trett, V., unpublished results.

239. Il{arkruald, 14I.1 and- Meyer, 8., Chem.Ber.r 1900r 3f,r 1885,

240. d. Kunze¡ lV., G.P., 951 1993/1956. b. Kunze¡ W.¡ G.P. t 951r992f1956. 241. ÀLbert, it., trHeterocyclic Compoundsrr, Atblone Pressr London, 1959t

P. 52.

242. Kanda¡ Y., antt lilashima, M. r t 1950, !, t83; Chem.Abs. ¡ 1952, Æ., 9989, 243. Cheinker, Yu.N., Gortlnskaya¡ l[.V. r and' Sycheva¡ T.P., J:$!4

-P.!ys-r 1958, 55, 217. 246

244. 3adger¡G.I\tr.,McCarthy¡I.J.'and'Rod.d'a'H.J..@, 1954;964. rtlonisation 245. Alberto 4., anfl Serjeant, E.P.r Constants of Acid's

and. Basesrr, Methuen, Londont 1962.

246. Teague, P.C.r and. Shortr !V.A.t Ors.S¡¡nth., 1953, 3)r 50.

247. Katritzky, 4.R., Beard¡ J.A.T. r and' Coats, N'4.' J. Chem. Soc . 1959 ¡

3680.

249. Stix, lV., and. Bulgatsch, S.A.r Chen.Ber' ¡ 1932t fi-, 11'

249. Skraup¡ 2.H., Monatsh, lBBl; ?t 148.

250. Dox, A.Itrl'., J.Amor.Chem.Soc. t 1915, 3J, 1949. 251. FeIs, 8., @þa, 1904, 3J, 2140. 2r2. 3Írkofer, L., and Kaiserr C., Chem.Ber. ¡ 1957, Ð., 2933' 2r3. Blanchard, K.C., DeaTborn, 8.H., Lasagna¡ Ir.C.r and. Buhle, Ð.L.t Bulf .Johns Hopkins Hosp., '1952, 91, 330.

254. Gabriel¡.S.r'and. Colman¡ J., !!"t.Bur. I 1)O2t þt 2B4Z'

255. voge1, A.I., ilA Textbook,of PractÍcaI organic chenistryt'r longmans¡ Lond.on, lrd ed., p. 870.

256. Vogel, 4.I., rrA Textbook of Practical Organic Chemistryil, Longmanst London, 3rd ed.., P. 330.

257. Vogel, 4.I., rrA Textbook of Practical. Organic Chemistryrr, Longmanst Lond.on¡ lrd ed.1 P, 973.

258. Skraupl 2.H., Chem.Ber., 1882, 15, 1507.

259. êo vogel, 4.I., rrA Textbook of P¡actÍcal Organic chemistryrrl Longmans, Lond.on, 3rd. ed-., P. 810. b. Vogelr 4.I., rrA Textbook of Practical Organic Chemistryrr¡ Longmans, Lond.on¡ 3rd. ed.., p. B0B. -247-

c. Lynch¡ B.M.r and Pausacker¡ K.H.r J'Chem'Soc', 1955, 1525' rrorganic 260. Mozingo, R., in synthesesrt, Horning¡ E.c.r ed..r lviley¡

Nevr Tork, 1955t Collective Vo1. 3r p' 686'

261. Sato¡ T.¡ and tr[ishima¡ H.r U.S.P.r 218941953/1959'

262. I'anta, P.E.r J.Amer.Chem.Soc. t 1953¡ l5¡ 737.

263. PelLízzarir G. , G^uzettul 19O9t p: 536.

264. Jerchel, D., and Jacobs, 'll.r 4!B.g:I::@., 1954, Ø.¡ 298'

265, Rao, R.P. r Ph.D. Thesis, University of Ad.elaid'e¡ 1965' 266. Bain, 8.M., and. Saxtonr J.8., lQlg.Qggt 1961, 5216'

267. Kind.l,y supplleil. by Dr. \ï.L.X'. Armarego.