The Chemistry of Heterocycles

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

The Chemistry of Heterocycles, (Second Edition). By Theophil Eicher and Siegfried Hauptmann, Wiley-VCH Veriag GmbH, 2003 1 110 5 Five-Membered Heterocycles

The indole ring system forms the basis of several pharmaceuticals, for instance the anti-inflammatory indomethacin 54 and the antidepressant iprindole 55:

MeO,

I CH2— C H 2— C H 2— N M e 2

Indigo and other dyes (see p 81) which contain the chromophore 56

x - ,X = N H o r S , ( E ) - o r ( Z ) - ,

56 are known as indigoid dyes, and are vat dyes. These water-insoluble compounds are reduced by sodium dithionite and sodium hydroxide and applied as vat dyes, whereby they become soluble as disodium dihydro compounds, e.g.:

^2H,2NaOH

-2H20

Before the availability of sodium dithionite (1871), the reduction of indigo was brought about by bacte- ria with reducing properties (fermentation vat). The vat of indigo has a brown-yellow colour. The cloth is dipped in the vat and then exposed to air to allow reoxidation to indigo which is precipitated and finely distributed onto the fibre. A consequence of this process is the low rubbing fastness of the dyes. It causes the faded appearance of indigo-dyed jeans and makes possible the manufacture of 'faded jeans'. Since the seventies, indole compound5.14s Isoindolehave lost their importance as textile dyes. They have, however, found application in other fields, e.g. in polaroid photography. [A-C] The name isoindole is admissible for benzo[c]pyrrole5.15. AlthoughCarbazolisoindolee has an ortho-quinonoid 111 structure, it can be isolated; it is characterized spectroscopically and chemically: 5.14 Isoindole

CO2 + CH3OH

2-(Methoxycarbonyloxy)-l,3-dihydroisoindole (obtained from 2-hydroxy-l,3-dihydroisoindole and 2-(Methoxycarbonyloxy)-1,3-dihydroisoindole (obtained from 2-hydroxy-1,3-dihydroisoindole and The name isoindole is admissible for benzo[c]pyrrolemethyl . (4-nitrophenyl)carbonateAlthough isoindole has a)n wa ortho-qui-s pyrolysed in vacuo at 500°C and isoindole condensed on a cold- nonoid structure, it can bemethyl isolated;( 4it- initrophenyl)carbonate)s characterized spectroscopicallwasy pyrolyzedand chemicallinyvacuo [56]: at 500 °C and isoindole condensed on a cold-finger condenserfingefilledr condensewith liquidr fillenitrogend with .liquid nitrogen. Isoindole crystallizes in colourless needles, darkens at room temperature and polymerizes. Solutions in dichloromethane kept under nitrogen are more stable. Isoindole crystallizesTheiny colorlessgive a redneedles, colour witdarkensh EHRLICH'at roomS reagentemperaturet and formand thpolymerizese correspondin. Solutionsg DIELS-ALDEin R adducts dichloromethane kept(endo:exounder nitrogen= 2:3; seeare p 56more) witstableh Af-phenylmaleinimide. . Isoindoles substituted on the pyrrole ring are thermally more stable and can, for instance, be prepared from 2-substituted 1,3-dihydroisoindol-l-ones They give a red colorby thwithe followinEHRLICH'Sg route: reagent and form the corresponding DIELS-ALDER adducts (endo:exo = 2:3) with N-phenylmaleinimide.

2 N_R1 R*M9Br> r^yVRl ^H^ ^X^/ -MgBrCI -H20

A tautomeric equilibrium exists between isoindoles unsubstituted in the 2-position and the corresponding 1//-isoindoles:

Isomerizations in which an H-atom changes its position in a heterocyclic system are known as annular tautomerisms. This is a special case of prototropy (prototropic rearrangement) [57]. For isoindole, the position of the equilibrium depends to a large extent on the type of the substituent in the 1- and/or 3- position [58]. The 1-phenyl compound exists in the 2//-form and couples with benzenediazonium chlo- ride in the 3-position.

5.15 Carbazole

The numbering of carbazole (benzo[6]indole) predates the introduction of systematic no- A,B menclature and is retained for historical reasons. Carbazoles behave like 0,0 -disubstituted diphenylamines. However, the basicity of carbazole, pKa = -4.94, is much lower than that of diphenylamine (pKa = 0.78), and also lower than that of indole and pyrrole. As a consequence, carbazole is insoluble in dilute acids but only soluble in coned H2SÜ4 with protonation of the N-atom. On pouring the solution into water, carbazole precipitates without polymerization. 5.15 Carbazole 111

CO2 + CH3OH

5.15 Carbazole 111 2-(Methoxycarbonyloxy)-l,3-dihydroisoindole (obtained from 2-hydroxy-l,3-dihydroisoindole and methyl (4-nitrophenyl)carbonate) was pyrolysed in vacuo at 500°C and isoindole condensed on a cold- finger condenser filled with liquid nitrogen. Isoindole crystallizes in colourless needles, darkens at CO2 + CH3OH room temperature and polymerizes. Solutions in dichloromethane kept under nitrogen are more stable. They give a red colour with EHRLICH'S reagent and form the corresponding DIELS-ALDER adducts (endo:exo = 2:32-(Methoxycarbonyloxy)-l,3-dihydroisoindol; see p 56) with Af-phenylmaleinimidee . (obtaineIsoindoled fros substitutem 2-hydroxy-l,3-dihydroisoindold on the pyrrole rine g anarde methyl (4-nitrophenyl)carbonate) was pyrolysed in vacuo at 500°C and isoindole condensed on a cold- thermally more stable and can, for instance, be prepared from 2-substituted 1,3-dihydroisoindol-l-ones finger condenser filled with liquid nitrogen. Isoindole crystallizes in colourless needles, darkens at by the following route: Isoindoles substituted rooonm thetemperaturpyrrolee and ringpolymerizesare .thermally Solutions in moredichloromethanstablee kepandt undecan,r nitrogeforn instance,are more stablebe. prepared from 2-substitutedThey giv1,e3 -adihydroisoindol red colour with EHRLICH'-1-onesS reagenby thet anfollowingd form the routecorrespondin. g DIELS-ALDER adducts (endo:exo = 2:3; see p 56) with Af-phenylmaleinimide. Isoindoles substituted on the pyrrole ring are thermally more stable and can, for instance, be prepared from 2-substituted 1,3-dihydroisoindol-l-ones A tautomeric equilibrium exists between isoindoles unsubstituted in the 2-position and the by the Nfollowin_R1 g routeR*M: 9Br> r^yVRl ^H^ corresponding 1H-isoindoles: ^X^/ -MgBrCI -H20

N_R1 R*M9Br> r^yVRl ^H^ A tautomeric equilibrium exists between isoindoles unsubstitute^X^/ d in th-MgBrCe 2-positioI n and the corresponding 1//-isoindoles: -H20

A tautomeric equilibrium exists between isoindoles unsubstituted in the 2-position and the corresponding 1//-isoindoles:

IsomerizationsIsomerizationin whichs in whican Hh- atoman H-atochangesm changeitss itsposition position inin aa heterocycliheterocyclicc systesystemm are knoware nknown as annularas annular tautomerismstautomerisms.. ThiThiss isis aa speciaspeciall cascasee of prototropof prototropyy (prototropi(prototropicc rearrangementrearrangement)) [57]. Fo. r isoindole, the position of the Isomerizationequilibriums dependin whichs atno H-atoa largm echange extenst itos npositio the typn ine ao heterocyclif the substituenc systemt arine thknowe 1n- aand/os annularr 3- position [58]. Thtautomerisms.e 1-phenyl Thicompouns is a speciad existl cass ei no fth prototrope 2//-fory m(prototropi and couplec rearrangements with benzenediazoniu) [57]. For isoindolem chlo, the- For isoindole, the positionpositioofn theof thequilibriume equilibrium dependdependss to a tolargae largeextent oextentn the typone ofthe the typesubstituenof thet in thsubstituente 1- and/or 3- ride in the 3-position. in the 1- and/or 3-positionposition. [58]The. Th1e -1-phenyphenyll compouncompoundd exists iexistsn the 2//-forin mthe and couple2H-forms with andbenzenediazoniucouplesmwith chlo- benzenediazonium chlorideride in inthethe 3-position3-position. . 3 5.15 Carbazole 5.15 Carbazole

The numberinA,B Thg eo numberinf carbazolg oef (benzo[6]indolecarbazole (benzo[6]indole) predate) predates the s introductiothe introduction onf osystematif systematicc nono-- A,B menclature anmenclaturd is retainee andd fois rretaine historicad forl historica reasonsl .reasons. Carbazoles behave like 0,0 -disubstituted diphenylamines. However, the basicity of carbazole, pKa = Carbazoles behave like 0,0 -disubstituted diphenylamines. However, the basicity of carbazole, pKa = -4.94, is much -4.94lowe, ri stha mucn htha lowet orf thadiphenylaminn that of diphenylamine (pK =e 0.78)(pKa =, 0.78)and ,als anod lowealso lower thar ntha than that ot fo findol indolee anand pyrrole. As a consequence, carbazole is insolubla e in dilute acids but only soluble in coned H2SÜ4 with pyrrole. As a consequenceprotonation o, fcarbazol the N-atome i.s Oinsolubln pourineg ithn edilut solutioe acidn intso buwatert onl, carbazoly soluble eprecipitate in coneds H2SÜwithou4t polywith- protonation of merizationthe N-atom. . On pouring the solution into water, carbazole precipitates without polymerization. 5.15 Carbazole 111

CO2 + CH3OH

2-(Methoxycarbonyloxy)-l,3-dihydroisoindole (obtained from 2-hydroxy-l,3-dihydroisoindole and methyl (4-nitrophenyl)carbonate) was pyrolysed in vacuo at 500°C and isoindole condensed on a cold- finger condenser filled with liquid nitrogen. Isoindole crystallizes in colourless needles, darkens at room temperature and polymerizes. Solutions in dichloromethane kept under nitrogen are more stable. They give a red colour with EHRLICH'S reagent and form the corresponding DIELS-ALDER adducts (endo:exo = 2:3; see p 56) with Af-phenylmaleinimide. Isoindoles substituted on the pyrrole ring are thermally more stable and can, for instance, be prepared from 2-substituted 1,3-dihydroisoindol-l-ones by the following route:

N_R1 R*M9Br> r^yVRl ^H^ ^X^/ -MgBrCI -H20

A tautomeric equilibrium exists between isoindoles unsubstituted in the 2-position and the corresponding 1//-isoindoles:

5.15 Carbazole 5.15 Carbazole

[A,B] The numbering of carbazole (benzo[b]indole) predates the introduction of systematic nomenclatureThe numberinand gis oretainedf carbazolefor (benzo[6]indolehistorical reasons) predate.s the introduction of systematic no- A,B menclature and is retained for historical reasons. Carbazoles behave like 0,0 -disubstituted diphenylamines. However, the basicity of carbazole, pK = Carbazoles behave like o,o’-disubstituted diphenylamines. However, the basicitya of carbazole, pKa = - -4.94, is much lower than that of diphenylamine (pKa = 0.78), and also lower than that of indole and 4.94, is much lower than that of diphenylamine (pKa = 0.78), and also lower than that of indole and pyrrolepyrrole. As. a consequence, carbazole is insoluble in dilute acids but only soluble in coned H2SÜ4 with protonation of the N-atom. On pouring the solution into water, carbazole precipitates without polymerization. As a consequence, carbazole is insoluble in dilute acids but only soluble in coned H2SO4 with protonation of the N-atom. On pouring the solution into water, carbazole precipitates without polymerization.

The NH-acidity of carbazole pKa = 17.06 corresponds approximately to that of indoles and pyrroles. For this reason, carbazole is convertible into N-metallated compounds which can be subjected to electrophilic substitution on nitrogen. Carbazole reacts with electrophiles faster than benzene. Substitution occurs regioselectively in the 3- position, e.g. in the VlLSMElER-HAACK formylation. There are very few addition and ring-opening reactions of carbazoles. 4 112 5 Five-Membered Heterocycles

The NH-acidity of carbazole pKa = 17.06 corresponds approximately to that of indoles and pyrroles. For thi11s reason2 , carbazole is convertibl5 e intFive-Membereo N-metallated compoundHeterocycles swhich can be subjected to electrophilic substitution on nitrogen. Carbazole reacts with electrophiles faster than benzene. Substitution occurs regioselectively in the The NH-acidity of carbazole pKa = 17.06 corresponds approximately to that of indoles and pyrroles. 3-positionFor thi, e.gs reason. in th,e carbazol VlLSMElER-HAACe is convertiblK formylatione into N-metallate. d compounds which can be subjected to elec- Thertrophilie are verc substitutioy few addition on nitrogenn and ring-openin. g reactions of carbazoles. Carbazole reacts with electrophiles faster than benzene. Substitution occurs regioselectively in the 3-positionort/zo-Substitute, e.g. in thde bipheny VlLSMElER-HAACl derivativeK formylations are a startin. g point for the synthesis of carbazoles, e.g.: There are very few addition and ring-opening reactions of carbazoles.

ort/zo-Substituted biphenyl Aderivative orhv s are a starting point for the synthesis of carbazoles, e.g.: [C] ortho-Substituted biphenyl derivatives are a starting point for the synthesis of carbazoles, e.g.:

A orhv

P(OEt)3

Thermolysis orThermolysiphotolysiss orof photolysi2-azidobiphenyls of 2-azidobiphenyproducesl producea nitrene,s a nitreneas ,does as doedeoxygenations deoxygenation ofof 2-nitrobi2- - nitrobiphenyl withphenytriethyllThermolysi with triethyphosphites olr phosphitephotolysi. Thes. nitrene oThf 2-azidobiphenye nitrencyclizese cyclizel immediatelyproduces immediatels a nitrenetoy tgiveo, agivs doeecarbazole carbazoles deoxygenatio.. CarbazolesCarbazolen of 2-nitrobis can als- o can also be madebe madbyphenyecyclodehydrogenation by lcyclodehydrogenatio with triethyl phosphiteofn. Thodiphenylaminesf ediphenylamines nitrene cyclizes. .immediately to give carbazole. Carbazoles can also be made by cyclodehydrogenation of diphenylamines.

-H2

This reaction can be carried out photochemically or with palladium(II) acetate in acetic acid. This reaction can be carried out photochemically or with palladium(n) acetate in acetic acid. This reaction can be carried out photochemically or with palladium(n) acetate in acetic acid. 5

CarbazolCarbazole forme forms water-insolubls water-insoluble crystale crystals so fo fm mpp 245°C 245°C,, bbpp 355°C,, anandd occur occurs sin i nth eth anthracite anthracite e fractiofraction of coan ofl coatar.l tar.

A fewA alkaloid few alkaloids ares deriveare derived frod mfro carbazolem carbazole, e.g, e.g. murrayanin. murrayaninee ll (l-methoxycarbazole-3-carbaldehyde(l-methoxycarbazole-3-carbaldehyde) ) and ellipticinand ellipticine 2, whice 2, which is ha icarbazols a carbazole systee system mwit with ha afuse fusedd pyridinpyridine ring.. EllipticinEllipticine eis ions one oef othf eth sube sub- - stancestances whics hwhic canh intercalatcan intercalate inte oint humao human DNAn DNA. Th. The emolecul moleculee iiss insertedd betweebetween ntw two opaire paired basesd bases. . EllipticinEllipticine derivativee derivatives ares approveare approved ind somin some countriee countries sfo for rus usee aass cytostaticytostaticc agentagents s[59] [59]. . PharmaceuticalPharmaceuticals containins containing a gcarbazol a carbazole systee systemm ar are erare rare, ,bu butt ononee examplee oof fthes these eis i ths the beta-blockee beta-blocker r carazolocarazolol 3 [l-(carbazol-4-yloxy)-3-(isopropylamino)propan-2-ol]l 3 [l-(carbazol-4-yloxy)-3-(isopropylamino)propan-2-ol]:: [D] Carbazole forms water-insoluble crystals of mp 245 °C, bp 355 °C, and occurs in the anthracite fraction of coal tar.

A few alkaloids are derived from carbazole, e.g. murrayanine 1 (1-methoxycarbazole-3-carbaldehyde) and ellipticine 2, which is a carbazole system with a fused pyridine ring.

Ellipticine is one of the substances which can intercalate into human DNA. The molecule is inserted 5.15 Carbazole 113 between two paired bases. Ellipticine derivatives are approved in some countries for use as cytostatic agents.

Pharmaceuticals containing a carbazole system are rare, but one example of these is the beta- blocker carazolol 3 [1-(carbazol-4-yloxy)-3- (isopropylamino)propan-2-ol]: O-CH2—CH-CH2—NH-CHMe2

The textile dye Sirius Light Blue 4 is produced by a double cyclocondensation of 3-aminocarbazole with chloranil followed by sulfonation:

Carbazole is vinylated in the 9-position by acetylene. The resulting polymer 5 (poly-7V-vinylcarbazole) proves to be a photoconductor:

Photoconductors are substances which, upon irradiation, increase their electric conductivity [60]. They find use in electrophotography as well as in copying processes. 5.15 Carbazole 113

5.15 Carbazole 113

O-CH2—CH-CH2—NH-CHMe2

The textile dye Sirius Light Blue 4 is produced by a double cyclocondensation of 3-aminocarbazole with chloranil followed by sulfonation:

The textile dye Sirius Light Blue 4 is produced by a double cyclocondensation of 3-aminocarbazole with chloranil followed by sulfonation: The textile dye Sirius Light Blue 4 is produced by a double cyclocondensation of 3-aminocarbazole with chloranil followed by sulfonation:

Carbazole is vinylated in the 9-position by acetylene. The resulting polymer 5 (poly-7V-vinylcarbazole) proves to be a photoconductor: Carbazole is vinylated in Carbazolthe 9-eposition is vinylatedby in thacetylenee 9-position. byThe acetyleneresulting. The resultinpolymerg polyme5r 5 (poly(poly-7V-vinylcarbazole-N- ) vinylcarbazole) proves to be aprovephotoconductors to be a photoconductor: :

Photoconductors are substances which, upon irradiation, increase their electric conductivity. They find use in electrophotographyPhotoconductoras wells asarein substancecopyings whichprocesses, upon. irradiation, increase their electric conductivity7 [60]. They find usePhotoconductor in electrophotographs are substancey as wels whichl as i,n upo copyinn irradiationg processes, increas. e their electric conductivity [60]. They find use in electrophotography as well as in copying processes. 114 5 Five-Membered Heterocycles 114 5 Five-Membered Heterocycles 5.16 Pyrrolidine 5.16 Pyrrolidine

5.16 Pyrrolidine The pyrrolidine molecule is practically without strain, nonplanar and conformationally mobile. [A] The pyrrolidine moleculeAs isinpractically the case witwithouth Thtetrahydrofurae strain,pyrrolidinnonplanarne (semolecule p and67)e ,i conformationallysth practicalle twist any dwithou envelopmobilet straine .conformationAs, nonplanain rs anared preconformationall- y mobile. the case with tetrahydrofuran,ferred. The activatiothe twistn energandAyenvelopes foinr thpseudorotatioe casconformationse withn tetrahydrofurais 1.3 kareJ moHpreferredn. Th(see chemica.p The67), activationthl eshift twiss ti nan thde NMenvelopR spece conformation- s are pre- 114 energy5 for pseudorotationFive-Memberetra lieis ind1 th .3Heterocyclee kJregiomoln- 1characteristiferred. s . The cactivatio for cycloalkanen energys foanrd pseudorotatiodialkylaminesn. is 1.3 kJ moH. The chemical shifts in the NMR spectra lie in the region characteristic for cycloalkanes and dialkylamines. The chemical shifts1 in the NMR spectra lie in the13region characteristic for cycloalkanes and dialkylamines. H-NMR (CDCI3) C-NMR (CDCI3) 5.16 Pyrrolidine 1 13 H-NMR (CDCI3) C-NMR (CDCI3)

H-2/H-5: 2.75 C-2/C-5: 47.1 H-3/H-4: 1.53 H-2/H-5: 2.75 C-3/C-4: 25.7 C-2/C-5: 47.1 H-3/H-4: 1.53 C-3/C-4: 25.7 Pyrrolidines and TV-substituted pyrrolidines undergo reactions typical of secondary or tertiary [B] Pyrrolidines and N-substituted pyrrolidines undergo reactions typical of secondary or tertiary The pyrrolidine molecule is practically without alkylaminesstrain, nonplana. Theyr ancaPyrrolidinedn conformationallbe alkylateds an,d quaternized TV-substitutey mobile,. acylated pyrrolidined and nitrosateds undergo. Threactione basicits typicay andl nuof- secondary or tertiary As in the case with tetrahydrofuraalkylamines. Theyn (seecan p 67)be ,alkylated, the twistquaternized and envelop, acylatede conformationand nitrosateds are pre. - cleophilicity of pyrrolidinealkylaminess are, however. The, greatey canr thabe nalkylated those of, diethylaminquaternizede, (pyrrolidinacylated ane dpK nitrosateda = 11.27., The basicity and nu- ferred. The activation energy for pseudorotation is 1.3 kJ moH. The chemical shifts in the NMR spec- The basicity and nucleophilicitydiethylamineof pKpyrrolidinesa = cleophilicit10.49). areBecausygreater ofe pyrrolidine of thanthese thosepropertiess areof, howeverdiethylamine, pyrrolidin, greatee (pyrrolidineisr verthayn suitablthosep Koeaf fo=diethylaminr the conversioe (pyrrolidinn e pKa = 11.27, tra lie in the region characteristi11.27c fo, diethylaminer cycloalkanesp anK d =dialkylamines10.49). Because. of these properties, pyrrolidine is very suitable for the of carbonya l compounddiethylamins into enaminese pKa := 10.49). Because of these properties, pyrrolidine is very suitable for the conversion conversion of carbonyl compounds into enaminesof carbony:l compounds into enamines: 1H-NMR (CDCI ) 13C-NMR (CDCI ) 3 3 o 1 'I 29 R— CH 2—C-R + o 8 R1— CH —C-R'I 29 + H-2/H-5: 2.75 C-2/C-5: 47.1 2 H-3/H-4: 1.53 C-3/C-4: 25.7

Pyrrolidines and TV-substituted pyrrolidines undergPyrrolidino reactione ansd TV-substitutetypical of secondard pyrrolidiney ors tertiarare producey d commercially by ring transformation of alkylamines. They can be alkylated, quaternizedtetrahydrofura, acylated annd witnitrosatedh Pyrrolidinammoni. Tha eoe r an basicitprimard TV-substituteyy amineand nus -da tpyrrolidine 300°C on aluminius are producem oxidd ecommerciall catalysts. y by ring transformation of TV-Substituted pyrrolidines tetrahydrofuraare also accessibln wite bhy ammoni photodehydrohalogenatioa or primary aminen so af tTV-alkyl-TV-chloroamine 300°C on aluminium oxids e catalysts. cleophilicity of pyrrolidines are, however, greater than those of diethylamine (pyrrolidine pKa = 11.27, (HOFMANN-LÖFFLERTV-Substitute reaction): d pyrrolidines are also accessible by photodehydrohalogenation of TV-alkyl-TV-chloroamines diethylamine pKa = 10.49). Because of these properties, pyrrolidine is very suitable for the conversion of carbonyl compounds into enamines: (HOFMANN-LÖFFLER reaction): o ' —-HO -, — * o o o ' —-HO -, — * o 1 'I 29 R— CH 2—C-R + + 20H ! -2H20 ! -CI0 + 20H ! -2H20 hv +C| ! -CI0 0 '""** (le^ ------** rI©^ I ------+• © RHN;~ ' -ci- RHN- ' hv RH2N -CH2 RH2N CH+C|2— ci Pyrrolidine and TV-substituted pyrrolidines are produced ccommercialli y by 0rin g transformatio '""** n o(fle^ ------** rI©^ I ------+• © RHN;~ ' -ci- RHN- ' RH2N -CH2 RH2N CH2— ci tetrahydrofuran with ammonia or primary amines at 300°C on aluminium oxidci e catalysts. TV-Substituted pyrrolidines are also accessible by Thphotodehydrohalogenatioe reaction is first carriend oouf tTV-alkyl-TV-chloroamine in acid solution. The photolysis s of the TV-chloroammonium ions pro- (HOFMANN-LÖFFLER reaction): duces an aminium radicaThe reactiol ion whichn is ,firs byt abstractiocarried oun t oifn a acin H-atod solutionm from. Th thee photolysimethyl groups of, thise converteTV-chloroammoniud m ions pro- into an alkyl radicalduce. Thse a nlatte aminiur initiatem radicas a chail ion whichreactio, nb yb yabstractio abstractinn go f aa nCl-ato H-atomm forfromm ath nee wmethy TV-l group, is converted into an alkyl radical. The latter initiates a chain reaction by abstracting a Cl-atom form a new TV- o ' —-HO -, — * o

+ 20H ! -2H20 ! -CI0 hv +C| 0 '""** (le^ ------** rI©^ I ------+• © RHN;~ ' -ci- RHN- ' RH2N -CH2 RH2N CH2— ci ci

The reaction is first carried out in acid solution. The photolysis of the TV-chloroammonium ions produces an aminium radical ion which, by abstraction of an H-atom from the methyl group, is converted into an alkyl radical. The latter initiates a chain reaction by abstracting a Cl-atom form a new TV- 114 5 Five-Membered Heterocycles

5.16 Pyrrolidine

The pyrrolidine molecule is practically without strain, nonplanar and conformationally mobile. As in the case with tetrahydrofuran (see p 67), the twist and envelope conformations are pre- ferred. The activation energy for pseudorotation is 1.3 kJ moH. The chemical shifts in the NMR spectra lie in the region characteristic for cycloalkanes and dialkylamines.

1 13 H-NMR (CDCI3) C-NMR (CDCI3)

H-2/H-5: 2.75 C-2/C-5: 47.1 H-3/H-4: 1.53 C-3/C-4: 25.7

Pyrrolidines and TV-substituted pyrrolidines undergo reactions typical of secondary or tertiary alkylamines. They can be alkylated, quaternized, acylated and nitrosated. The basicity and nu- cleophilicity of pyrrolidines are, however, greater than those of diethylamine (pyrrolidine pKa = 11.27, diethylamine pKa = 10.49). Because of these properties, pyrrolidine is very suitable for the conversion of carbonyl compounds into enamines:

o 1 'I 29 R— CH 2—C-R +

[C] Pyrrolidine andPyrrolidinN-substitutede and TV-substitutepyrrolidinesd pyrrolidineare produceds are producecommerciallyd commerciallby ringy btransformationy ring transformatioof n of tetrahydrofuran withtetrahydrofuraammonianor witprimaryh ammoniaminesa or primarat 300y °amineC onsaluminium at 300°C ooxiden aluminiucatalystsm oxid. e catalysts. TV-Substituted pyrrolidines are also accessible by photodehydrohalogenation of TV-alkyl-TV-chloroamines N-Substituted(HOFMANN-LÖFFLEpyrrolidines Rare reaction)also: accessible by photodehydrohalogenation of N-alkyl-N- chloroamines (HOFMANN-LÖFFLER reaction):

o ' —-HO -, — * o

+ 20H ! -2H20 ! -CI0 hv +C| 0 '""** (le^ ------** rI©^ I ------+• © RHN;~ ' -ci- RHN- ' RH2N -CH2 RH2N CH2— ci ci The reaction is first carried out in acid solution. The photolysis of the N-chloroammonium ions produces anTheaminium reaction radicalis first carrieion which,d out inby aciabstractiond solution. Thofe anphotolysiH-atoms ofromf the TV-chloroammoniuthe methyl group,m ionis s pro- converted intoduceans aalkyln aminiuradicalm radica. l ion which, by abstraction of an H-atom from the methyl group, is converted into an alkyl radical. The latter initiates a chain reaction by abstracting a Cl-atom form a new TV- The latter initiates a chain reaction by abstracting a Cl-atom form a new N-chloroammonium ion. After addition of a base, the cyclodehydrohalogenation occurs via the corresponding �- chloroalkylamine involving an intramolecular nucleophilic substitution. 9 5.16 Pyrrolidine 115

chloroammonium ion. After addition of a base, the cyclodehydrohalogenation occurs via the corre- [D] Pyrrolidine is a colorless,spondinwaterg £-chloroalkylamin-soluble liquide involvinof ga anpenetrating intramolecularamine nucleophili-likec substitutionodor, of. bp 89 °C. It fumes in air owing to salt formation with carbon dioxide. Pyrrolidine is a colourless, water-soluble liquid of a penetrating aminelike odour, of bp 89°C. Pyrrolidin-2-one, often called pyrrolidoneIt fumes in air, owinis theg tolactam salt formationof 4- aminobutyricwith carbon dioxideacid. . Pyrrolidone is prepared from butano-4-lactone andPyrrolidin-2-oneammonia at ,250 often° Ccalle. Itd ispyrrolidonecolorless,, is thwatere lacta-msoluble, of 4-aminobutyriof mp c25 acid°C. Pyrrolidonand bp e250 is pre- °C (decomp). Pyrrolidone pareis vinylatedd from butano-4-lactonby acetylenee and .ammoniPoly-a( Nat -250°Cvinylpyrrolidone). It is colourless, haswater-solubleproved, ousefulf mp 25°Cas anad bp plasma substitute in blood transfusion250°C (decomp). . Pyrrolidone is vinylated by acetylene. Poly-(7V-vinylpyrrolidone) has proved useful as a plasma substitute in blood transfusion. 1-Methylpyrrolidin-2-one l-Methylpyrrolidin-2-onis a colorless, watere -solubleis a colourlessliquid,, water-solublbp 206 °eC, liquidmade, bp from206°Cbutano, made -fro4-mlactone butano-4- lactone and methylamine. It is used as a solvent, for instance for the industrial extraction of acetylene and methylamine. As a solventfrom gaissused mixturesthe. industrial extraction of acetylene from gas mixtures. Proline (pyrrolidine-2-carboxylicProlineacid), (pyrrolidine-2-carboxyliis one of the 20c acid)essential, is one of aminothe 20 essentiaacidsl .amino acids.

nH j..I . / \\ ^" / \\ Q"

1 2 (SAMP) 3 4

20 (S)-(-)-Proline 1, colorless crystals, mp 220°C, [�] D -80 (water), occurs abundantly in collagen. It is produced by acid-catalyzed(*S)-(-)-Prolmhydrolysise 1from, colourlesgelatins crystals. , mp 220°C, [tf]20D -80 (water), occurs abundantly in collagen. It is produced by acid-catalysed hydrolysis from gelatine. Piracetam 3 is medicinally usedPiracetaasmanticonvulsant 3 [60a] is medicinallandy useantiepilepticd as anticonvulsan. Levetiracetamt and antiepileptic4.is Levetiracetaa chiralmsecond 4 is a chira- l generation analogue of 3second-generatioproviding an analoguusefule oalternativef 3 providing a forusefuadjunctivel alternative fortherapy adjunctiveto therapconventionallyy to conventionally anticonvulsants, e.g. benzodiazepinesanticonvulsants., e.g. benzodiazepines. 10 The designation 'chiral pool' was introduced to denote an available source of enantiomerically pure natural products. These include the (

chloroammonium ion. After addition of a base, the cyclodehydrohalogenation occurs via the corresponding £-chloroalkylamine involving an intramolecular nucleophilic substitution.

Pyrrolidine is a colourless, water-soluble liquid of a penetrating aminelike odour, of bp 89°C. It fumes in air owing to salt formation with carbon dioxide. Pyrrolidin-2-one, often called pyrrolidone, is the lactam of 4-aminobutyric acid. Pyrrolidone is prepared from butano-4-lactone and ammonia at 250°C. It is colourless, water-soluble, of mp 25°C and bp 250°C (decomp). Pyrrolidone is vinylated by acetylene. Poly-(7V-vinylpyrrolidone) has proved useful as a plasma substitute in blood transfusion. l-Methylpyrrolidin-2-one is a colourless, water-soluble liquid, bp 206°C, made from butano-4- lactone and methylamine. It is used as a solvent, for instance for the industrial extraction of acetylene from gas mixtures. Proline (pyrrolidine-2-carboxylic acid), is one of the 20 essential amino acids.

nH j..I . / \\ ^" / \\ Q"

1 2 (SAMP) 3 4

(*S)-(-)-Prolme 1, colourless crystals, mp 220°C, [tf]20D -80 (water), occurs abundantly in collagen. It is produced by acid-catalysed hydrolysis from gelatine. Piracetam 3 [60a] is medicinally used as anticonvulsant and antiepileptic. Levetiracetam 4 is a chiral second-generation analogue of 3 providing a useful alternative for adjunctive therapy to conventionally anticonvulsants, e.g. benzodiazepines. The designation 'chiral pool' was introduced to denote an available source of enantiomerically pure natural productsThe. designatioThese includen 'chiral thepool(' Swa)-aminos introduceacids,d to denotas welle an asavailabl(S)-elactic sourceacid, of enantiomericall(S)-malic acid,y pure(R,R)- tartaric acid andnatura�-lD products-glucose. Thes. e include the (

The ketone 5 reacts with SAMP to give hydrazone 6. The possibility of internal asymmetric induction exists in 6, so that the following alkylation (action of lithium diisopropylamide in diethyl ether, followed by 1-iodopropaneThe ketonat -110e 5 °reactC) occurss with SAMdiastereoselectivelyP to give hydrazone. 6. The possibility of internal asymmetric induction exists in 6, so that the following alkylation (action of lithium diisopropylamide in diethyl ether, fol- In the final step, the auxiliary SAMP is hydrolytically removed from 7. Thereby, the �-alkylated ketone 8 is formed with ee = 99.5%. The use of RAMP as auxiliary would thus produce the (R)-enantiomer of 8.11 116 5 FJve-Membered Heterocycles

Although itloweappearsd by 1-iodopropanto be aneenantioselective at -110°C) occurs diastereoselectivelysynthesis, it is. inIn factthe finaa lmulti step,- thstepe auxiliarsynthesisy SAMPin iswhich steps 6 → 7hydrolyticallrepresenty aremovediastereoselectived from 7. Therebyreaction, the a-alkylate. Nowadaysd ketonechiral 8 is formeauxiliariesd with eeare = 99.5%at our. Thdisposale use for the approachof RAMto theP amosts auxiliarvariedy woulsyntheticd thus producproblemse the (T^-enantiome. r of 8. Although it appears to be an enantioselective synthesis, it is in fact a multistep synthesis in which 4-Hydroxyprolinesteps 6 -9> 7is represena proteinogenict a diastereoselectivaminoe acid,reactionoccurring. Nowadaymainlys chiral auxiliariein collagens are. aItt oucanr disposabe separatedl for from the hydrolysisthe approacproductsh to the mosoft gelatinvaried syntheti. c problems.

Several alkaloids4-Hydroxyprolinare derivede 9 is afrom proteinogenipyrrolidine,c amineo. gacid. hygrin, occurrin10g, mainla minory in collagenalkaloid. Ioft cathen becoca separateplant,d as well as nicotinefrom .the hydrolysis products of gelatine. Several alkaloids are derived from pyrrolidine, e.g. hygrin 10, a minor alkaloid of the coca plant, as well as nicotine (see p 305). The vasodilator buflomedil 11 and the antihypertensive captopril 12 are drugs containing a pyrrolidine ring.

H3CO O

xx)H

9 10 11 12

The vasodilator buflomedil 11 and the antihypertensive captopril 12 are drugs containing a pyrrolidine 12 ring.

5.17 Phosphole

Phosphole polymerizes rapidly. 1 -Substituted phospholes are thermally more stable. X-Ray studies of 1-benzylphosphole show that the molecule is not planar and that phosphorus retains its pyramidal structure [63].

P N = CH2— P h

Consistent with this finding, the NMR spectra show that phosphole has a lower aromaticity than furan.

Phospholes are weak bases and react with strong acids to give phospholium salts. The cleavage of the exocyclic P-C bond by lithium in boiling THF is an interesting reaction of 1-phenyl- and 1-benzylphosphole. 116 5 FJve-Membered Heterocycles

lowed by 1-iodopropane at -110°C) occurs diastereoselectively. In the final step, the auxiliary SAMP is hydrolytically removed from 7. Thereby, the a-alkylated ketone 8 is formed with ee = 99.5%. The use of RAMP as auxiliary would thus produce the (T^-enantiomer of 8. Although it appears to be an enantioselective synthesis, it is in fact a multistep synthesis in which steps 6 -> 7 represent a diastereoselective reaction. Nowadays chiral auxiliaries are at our disposal for the approach to the most varied synthetic problems.

4-Hydroxyproline 9 is a proteinogenic amino acid, occurring mainly in collagen. It can be separated from the hydrolysis products of gelatine. Several alkaloids are derived from pyrrolidine, e.g. hygrin 10, a minor alkaloid of the coca plant, as well as nicotine (see p 305). 116 5 FJve-Membered Heterocycles lowed by 1-iodopropane at -110°C) occurs diastereoselectively. In the final Hstep3CO, the auxiliarO y SAMP is hydrolytically removed from 7. Thereby, the a-alkylated ketone 8 is formed with ee = 99.5%. The use of RAMP as auxiliary would thus producxx)e thHe (T^-enantiomer of 8. Although it appears to be an enantioselective synthesis, it is in fact a multistep synthesis in which steps 6 -> 7 represent a diastereoselective reaction. Nowadays chiral auxiliaries are at our disposal for the approach to the most varied syntheti9 c problems. 10 11 12

4-Hydroxyproline 9 is a proteinogenic amino acid, occurring mainly in collagen. It can be separated from the hydrolysis products of gelatine. Several alkaloidThse ar vasodilatoe derived fror mbuflomedi pyrrolidinel ,1 e.g1 an. hygrid thne 10antihypertensiv, a minor alkaloied captopriof the cocl a1 plant2 are, adrugs s containing a pyrrolidine well as nicotine ring(see .p 305).

H3CO O

5.1xx)7H Phosphole

9 10 11 12

The vasodilator buflomedil 11 and the antihypertensive captopril 12 are drugs containing a pyrrolidine ring. 5.17 PhospholePhosphole polymerizes rapidly. 1 -Substituted phospholes are thermally more stable. X-Ray studies of 1-benzylphosphole show that the molecule is not planar and that phosphorus re- [A-C] Phosphole polymerizes rapidly. 1-Substituted phospholes are thermally more stable. X-Ray studies oftain1s-benzylphosphole its pyramidal structurshowe that[63]the. molecule is not planar and that phosphorus retains its 5.17 pyramidalPhospholstructuree .

P N = CH2— P h

ConsistentPhospholwithe polymerizethis finding,s rapidlythe. NMR1 -Substitutespectrad phospholeshow thats phospholeare thermallyhas morae lowerstable.aromaticity X-Ray than furan. studiesConsisten of 1-benzylphospholt with thise findingshow tha, tth thee NM moleculR spectre is noat shoplanawr thaandt phospholthat phosphorue hass rea -lower aromaticity than furan. tains itPhospholess pyramidal structurare weake [63]bases. and react with5.17strong acidsPhospholto givee phospholium salts. The cleavage of11the7 exocyclicPhospholeP-C bonds areby wealithiumk baseins anboilingd react THFwith stronis ang acidinterestings to givereaction phospholiuof m1- phenylsalts. -Thande cleavag1- e of the benzylphosphole. exocyclic P-C bond by lithiuPm in boiling THF is an interesting reaction of 1-phenyl- and 1-benzyl- N phosphole. = CH2— P h

ConsistenTheThte wit phospholephospholh this findinge anionanio, thne isi sNM planar,planarR spectr,aromatic aromatia showc andtha antd phospholiso iso-^-electroni-�-electronice has a lowecwith witr aromaticitfuranh furaandn any thathiophened nthiophene furan. . .

PhospholePhospholes are weask ar basee accessibls and reacet witby h[4+1 stron]g cycloadditioacids to give phospholiun of buta-l,3-dienem salts. Thes cleavagwith alkyle of th- eor aryldibromophos13 - exocycliphanec P-Cs followebond by dlithiu by dehydrobrominationm in boiling THF is an. interesting reaction of 1-phenyl- and 1-benzylphosphole.

2 RX\ R base

Summary of the general chemistry of five-membered heterocycles with one heteroatom: • The parent compounds of the monocyclic five-membered heterocycles with one heteroatom are aromatic. When considering the three most important systems only, it appears that the aromaticity increases as follows: furan < pyrrole < thiophene (< benzene). This sequence also applies to the respective benzo[6] condensed systems. • Because of their aromaticity, these compounds undergo electrophilic substitution, with the r e a c t i v i t y decreasing in the following order: pyrrole > furan > thiophene (» benzene). Substitution occurs regioselectively in the 2-position. The corresponding benzo[&] condensed systems react more slowly. Substitution occurs on the five-membered ring, but in this case, the regioselectivity is reduced. • The reactivity as 1,3-dienes in [4+2] cycloadditions is greatest for fiiran which is also the system most liable to undergo ring-opening. • The benzo[6] condensed systems do not react as 1,3-dienes but undergo [2+2] cycloadditions. • The benzofc] condensed systems have o-quinonoid structures. Their resonance energy is, therefore, lower than that of the corresponding benzo[Z?] condensed systems. The compounds prove to be reactive 1,3-dienes. • Some heterocycles are accessible by cyclodehydration, namely: — furans from 1,4-dicarbonyl compounds — benzo[&]furans from a-phenoxycarbonyl compounds — benzo[£]thiophenes from or-(phenylsulfanyl)carbonyl compounds — indoles from TV-acyl-o-toluidines or «-arylamino ketones — dibenzofurans from 2,2'-dihydroxybiphenyls — tetrahydrofurans from 1,4-diols 5.17 Phosphole 117

The phosphole anion is planar, aromatic and iso-^-electronic with furan and thiophene.

Phospholes are accessible by [4+1] cycloaddition of buta-l,3-dienes with alkyl- or aryldibromophosphanes followed by dehydrobromination.

R\ R2 Phospholes are accessible by [4+1] cycloaddition of buta-1,3-dienes with alkyl- or X base aryldibromophosphanes followed by dehydrobromination.

Summary of the general chemistry of five-membered heterocycles with one heteroatom: • The parent compounds of the monocyclic five-membered heterocycles with one heteroatom are aromatic. When considering theSummarthree ymost of theimportant general chemistrsystemsy of only,five-membereit appearsd heterocyclethat thes witaromaticityh one heteroatom: increases as follows: furan < pyrrole < thiophene (< benzene). This sequence also applies to the • The parent compounds of the monocyclic five-membered heterocycles with one heteroatom are respective benzo[b] condensed systems. aromatic. When considering the three most important systems only, it appears that the aromaticity increases as follows: furan < pyrrole < thiophene (< benzene). This sequence also applies to the re- • Because of their aromaticity, thesespectivcompoundse benzo[6] condenseundergod electrophilicsystems. substitution, with the reactivity decreasing in the following order: pyrrole > furan > thiophene (» benzene). Substitution occurs regioselectively in the 2-position•. TheBecauscorrespondinge of their aromaticitybenzo[, thesb] econdensed compounds undergsystemso electrophilireact morec substitutionslowly., with the r e a c t i v i t y Substitution occurs on the five-membereddecreasinring,g in thbute followinin thisgcase, order: thepyrrolregioselectivitye > furan > thiophenis reducede (» benzene). . Substitution occurs regioselectively in the 2-position. The corresponding benzo[&] condensed systems react more slowly. Substitution occurs on the five-membered ring, but in this case, the regioselectivity is reduced. • The reactivity as 1,3-dienes in [4+2] cycloadditions is greatest for furan which is also the system most liable to undergo ring-opening. • The reactivity as 1,3-dienes in [4+2] cycloadditions is greatest for fiiran which is also the system most liable to undergo ring-opening. • The benzo[b] condensed systems• Thdoe notbenzo[6react] condenseas 1,3-ddienes systemsbut do noundergot react as[ 21,3-diene+2] cycloadditionss but undergo. [2+2] cycloadditions. 14 • The benzofc] condensed systems have o-quinonoid structures. Their resonance energy is, therefore, lower than that of the corresponding benzo[Z?] condensed systems. The compounds prove to be reactive 1,3-dienes. • Some heterocycles are accessible by cyclodehydration, namely: — furans from 1,4-dicarbonyl compounds — benzo[&]furans from a-phenoxycarbonyl compounds — benzo[£]thiophenes from or-(phenylsulfanyl)carbonyl compounds — indoles from TV-acyl-o-toluidines or «-arylamino ketones — dibenzofurans from 2,2'-dihydroxybiphenyls — tetrahydrofurans from 1,4-diols • The benzo[c] condensed systems have o-quinonoid structures. Their resonance energy is, therefore, lower than that of the corresponding benzo[b] condensed systems. The compounds prove to be reactive 1,3-dienes.

• Some heterocycles are accessible by cyclodehydration, namely: — furans from 1,4-dicarbonyl compounds — benzo[b]furans from �-phenoxycarbonyl compounds — benzo[b]thiophenes from �-(phenylsulfanyl)carbonyl compounds — indoles from N-acyl-o-toluidines or �-arylamino ketones — dibenzofurans from 2,2'-dihydroxybiphenyls — tetrahydrofuransfrom 1,4-diols

• Cyclocondensation is an important synthetic method starting from: — 1,4-dicarbonyl compounds (thiophenes, pyrroles) — �-halocarbonyl compounds and �-keto carboxylic esters (furans, pyrroles) — �-amino ketones and �-keto carboxylic esters (pyrroles) — 1,3-dicarbonyl compounds or �-chlorovinylcarbonyl compounds (thiophenes, selenophenes, tellurophenes) — carbonyl compounds and CH-acidic nitriles (aminothiophenes)

15 • Indoles are obtained by specific cyclizations (FISCHER synthesis, REISSERT synthesis, BATCHO- LEIMGRUBER synthesis, NENITZESCU synthesis), as are carbazoles from biphenylene or diphenylamines and pyrrolidines (HOFMANN-LÖFFLER reaction).

Ring transformations make possible the preparation of furans, thiolane, pyrrolidine and pyrrolidin-2- one.

The importance of five-membered heterocycles with one heteroatom, of the benzo and dibenzo condensed systems and of the partially or completely reduced compounds as natural products, pharmaceuticals, and starting materials or auxiliaries for syntheses is much greater than for three- or four-membered heterocycles, apart from oxirane.

16 118 5 Five-Membered Heterocycles

• Cyclocondensation is an important synthetic method starting from: — 1,4-dicarbonyl compounds (thiophenes, pyrroles) — or-halocarbonyl compounds and /?-keto carboxylic esters (furans, pyrroles) — cir-amino ketones and /?-keto carboxylic esters (pyrroles) — 1,3-dicarbonyl compounds or /?-chlorovinylcarbonyl compounds (thiophenes, selenophenes, tellurophenes) — carbonyl compounds and CH-acidic nitriles (aminothiophenes) • Indoles are obtained by specific cyclizations (FISCHER synthesis, REISSERT synthesis, BATCHO- LEIMGRUBER synthesis, NENITZESCU synthesis), as are carbazoles from biphenylene or diphenylamines and pyrrolidines (HOFMANN-LÖFFLE118R reaction). 5 Five-Membered Heterocycles • Ring transformations make possible the preparation of furans, thiolane, pyrrolidine and pyrrolidin- 2-one. • Cyclocondensation is an important synthetic method starting from: — 1,4-dicarbonyl compounds (thiophenes, pyrroles) • The importance of five-membered heterocycle— sor-halocarbony with one heteroatoml compound, ofs thaned benz /?-ketoo an carboxylid dibenzc oester cons- (furans, pyrroles) densed systems and of the partially or completel— cir-aminy reduceo ketoned compounds and /?-kets aos carboxylinatural productsc esters (pyrroles, pharma)- ceuticals, and starting materials or auxiliarie—s fo1,3-dicarbonyr synthesesl icompounds much greates or /?-chlorovinylcarbonyr than for three- or lfour compound- s (thiophenes, membered heterocycles, apart from oxirane. selenophenes, tellurophenes) — carbonyl compounds and CH-acidic nitriles (aminothiophenes) • Indoles are obtained by specific cyclizations (FISCHER synthesis, REISSERT synthesis, BATCHO- LEIMGRUBER synthesis, NENITZESCU synthesis), as are carbazoles from biphenylene or diphenylamines and pyrrolidines (HOFMANN-LÖFFLER reaction). 5.18 1,3-Dioxolane • Ring transformations make possible the preparation of furans, thiolane, pyrrolidine and pyrrolidin- 2-one. • The importance of five-membered heterocycles with one heteroatom, of the benzo and dibenzo condensed systems and of the partially or completely reduced compounds as natural products, pharma- 5.18 1,3-Dioxolane ceuticals, and starting materials or auxiliaries for syntheses is much greater than for three- or four- 1,3-Dioxolanes can be viewed as cyclimemberec acetald heterocycless or ketals,. aparThe t rinfrogm isoxirane nonplana. r and confor- 1,3-Dioxolanes can be mationallviewed asy mobilecyclic. acetals or ketals. The ring is nonplanar and conformationally mobile. 1,3-Dioxolanes are prepared by Cyclocondensation of aldehydes or ketones with 1,2-dioles in benzene 1,3-Dioxolanes are prepared by Cyclocondensation of aldehydes or ketones with 1,2-dioles in benzene and with/?-toluenesulfonic acid as catalyst: and with p-toluenesulfonic acid as catalyst. Quantitative5.18yields 1,3-Dioxolanare realized bye removing the resulting water by azeotropic distillation.

H2O

1,3-Dioxolanes are stable to bases. They are hydrolyzed by dilute acids even at room temperature in a Quantitative yields are realized by removing the resultin1,3-Dioxolaneg water bys azeotropican be viewec distillationd as cycli.c acetals or ketals. The ring is nonplanar and confor- reversal of their formation. The conversion of aldehydes and ketones into 1,3-dioxolanes is one of the mationally mobile. most important methods for the protection of the carbonyl function in multistep syntheses. 1,3-Dioxolanes are stable to bases. They are5.1 hydrolyse9 d1,2-Dithiol by dilutee acid s even at room temperature in a119 It is also the standardreversal omethodf their formationfor blocking. The twoconversiovicinaln1,3-Dioxolane ocisf aldehyde-positionedss anaredhydroxy prepareketoneds groupsbinty oCyclocondensatio 1,3-dioxolanein a carbohydrate,s ni so fon aldehydee of thes or ketones with 1,2-dioles in benzene via reaction withmosacetone,t importanet .methodg.: s for the protection anofd th with/?-toluenesulfonie carbonyl function ci naci multisted as catalystp syntheses: . It is also the standard method for blocking two vicinal czs-positione2 CH3COCH3d ,hydrox ( y groups in a carbohydrate, via reaction with acetone, e.g.: OH H H2O

ß-D-fructopyranose 2,3:4,5-di-O-isopropylidene- 17 Quantitative yields are realizeß-D-fructopyranosd by removine g the resulting water by azeotropic distillation.

1,3-Dioxolanes are stable to bases. They are hydrolysed by dilute acids even at room temperature in a Halogens react with 1,3-dioxolanes vireversaa l,3-dioxolan-2-yliul of their formationm salt. Ths teo conversiogive /?-haloalkyn of aldehydel formatess an:d ketones into 1,3-dioxolanes is one of the most important methods for the protection of the carbonyl function in multistep syntheses. It is also the standard method for blocking two vicinal czs-positioneH d hydroxy groups in a carbohydrate, via reaction with acetone, e.g.:

1,3-Dioxolane, a colourless liquid, bp 78°C, is soluble in water. (4R,5R)- and (4S,55)-2,2-Dimethyl-a,a,a',a'-tetraphenyl-l,3-dioxolane-4J5-dimethanol were prepared from enantiomeric methyl tartrates as follows:

HOCOOMe rno^ylo H3C Y"H BF3-etherate O^COOMe +4PhMgBr

(R,R)-(+)-dimethyl tartrate pph

iw>.X

(4R,5R)-(-)-enantiomer

The compounds form chiral metal complexes as well as chiral clathrates and can be used as auxiliaries for asymmetric syntheses [64].

5.19 1,2-Dithiole

1,2-Dithiole is not a cyclic conjugated system. However, the 1,2-dithiolylium ions derived from it are aromatic. For instance, the corresponding salts are obtained from 1,3-dicarbonyl compounds and disul- fane in acid solution: 5.19 1,2-Dithiole 119 5.19 1,2-Dithiole 119

2 CH3COCH3 , ( 2 CH3COCH3 , (

OH H OH H

ß-D-fructopyranose 2,3:4,5-di-O-isopropylidene- ß-D-fructopyranose 2,3:4,5-di-O-isopropylidene- ß-D-fructopyranose ß-D-fructopyranose

Halogens react with 1,3-dioxolaneHalogens svi reaca l,3-dioxolan-2-yliut with 1,3-dioxolanems saltvia sl,3-dioxolan-2-yliu to give /?-haloalkyml formatessalts to giv: e /?-haloalkyl formates: Halogens react with 1,3-dioxolanes via 1,3-dioxolan-2-ylium salts to give �-haloalkyl formates: H H

1,3-Dioxolane1,3-Dioxolane, a colourles, ascolorless1,3-Dioxolane liquid, bp liquid,78°C, a, colourlesisbp solubl78se° C,liquidin wateris,soluble bp. 78°C,in is watersoluble. in water. (4R,5R)- and (4S,55)-2,2-Dimethyl-a,a,a',a'-tetraphenyl-l,3-dioxolane-4(4R,5R)- and (4S,55)-2,2-Dimethyl-a,a,a',a'-tetraphenyl-l,3-dioxolane-45-dimethanol were Jpre5-dimethano- l were pre- (4R,5R)- and (4S,5S)-2,2-Dimethyl-�,�,�',�'-tetraphenyl-1J ,3-dioxolane-4,5-dimethanol were prepared pared from enantiomeric methyparedl tartratefrom enantiomeris as followsc :methyl tartrates as follows: from enantiomeric methyl tartrates as follows:

COOMe rno^ylo HOCOOMeH C HOY"H BFrno^yl-etherato e O^COOMe H3C Y"H 3 BF3-etherate O^COOM3 e +4PhMgBr +4PhMgBr

(R,R)-(+)-dimethyl tartrate (R,R)-(+)-dimethyl tartrate pph pph iw>.X iw>. X The compounds form chiral metal complexes as well as chiral clathrates and can be used as auxiliaries for asymmetric syntheses.

(4R,5R)-(-)-enantiomer (4R,5R)-(-)-enantiomer 18 The compounds form chiral metal complexes as well as chiral clathrates and can be used as auxiliaries The compounds form chiralfo metar asymmetril complexec syntheses as wels [64]l as .chiral clathrates and can be used as auxiliaries for asymmetric syntheses [64].

5.19 1,2-Dithiole 5.19 1,2-Dithiole

1,2-Dithiole is not a cyclic conjugated system. However, the 1,2-dithiolylium ions derived from it are 1,2-Dithiole is not a cyclic aromaticconjugate. Fod rsystem instance. However, the correspondin, the 1,2-dithiolyliug salts are mobtaine ions dderive from d1,3-dicarbony from it are l compounds and disul- aromatic. For instance, the correspondinfane in acid solutiong salts :are obtained from 1,3-dicarbonyl compounds and disul- fane in acid solution: