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1. General Information 1.1. Recommended Textbooks 1.2

1. General Information 1.1. Recommended Textbooks 1.2

1. General Information Two Hetero-atoms:

1.1. Recommended textbooks N N N 1. 'Heterocyclic Chemistry', T.L. Gilchrist, 2nd Edition, Longman, 1992. N O S H 2. 'Heterocyclic Chemistry', J.A. Joule , K. Mills and G.F. Smith, Third Edition, Chapman thiazole and Hall, 1995. (1,3-diazole) (1,3-oxazole) (1,3-thiazole) 3. 'Aromatic Heterocyclic Chemistry', D. T. Davies, Oxford Chemistry Primers, 1992.

1.2. Nomenclature N N N N O S The heteroaromatics are typically described by trivial names and for the purposes of this H lecture course these will suffice. For those interested in the authoritative method of naming pyrazole isothiazole such compounds they are referred to the recommendations published by the International (1,2-diazole) (1,2-oxazole) (1,2-thiazole) Union of Pure and Applied Chemistry which have been summarised in a review article [McNaught, A.D. Adv. Heterocycl. Chem. 1976, 20, 175]. A method which is in more common use and which comprises a hybrid of trivial and systematic names made up of 6-Membered Rings standard prefixes and suffixes has been described (the Hantzsch-Widman system). A good One Hetero-atom: introduction to this system can be found in Gilchrist, Chapter 11, pp 369. Except for the isoquinolines, numbering always starts from the heteroatom (as shown below for ). The most frequently encountered heteroaromatic systems are: NOS ++X- X- 5-Membered Rings One Hetero-atom: pyrilium thiapyrilium (azine) (oxinium) (thiinium)

4 3

5 1 2 N OS H N pyrrole N (azole) (oxole) (thiole) quinoline isoquinoline (benzo[b]azine) (benzo[c]azine)

N OS H (benzo[b]azole) (benzo[b]oxole) (benzo[b]thiole)

5 6 2. Introduction 2.2. Background and context 2.1. A few examples of important heteroaromatics About one-half of all known compounds contain a heterocyclic ring, and many of these, an aromatic heterocyclic ring. Heteroaromatics are found in very many of the products of both O NH2 NH2 primary and secondary metabolism as well as in many synthetic compounds of commercial H N N N N NN interest such as drugs, pest control agents, colouring agents, flavourings. They comprise the N basic building blocks for many new materials such as porphyrazines and semi-conducting N N O N N N S OH polymers, and as ligands for homogeneous asymmetric . Thus they are of vital N H Cl- adenine importance and (still) represent a very active area of current research. nicotine caffeine thiamin - vitamin B (RNA/DNA) 1 R O OMe 2.3. Ring Synthesis S Cl OH 2.3.1. General Comments N O N There are a (seemingly overwhelming) number of methods (each of which generally has it H N OOHO own name) for the construction of heteroaromatic ring systems, but the heteroaromatics are

R = H; epothilone A Roseophilin: exhibits submicromolar typically synthesised by the pertinent use of a small family of well known reaction types: R = Me; epothilone B cytotoxicity against several human more active than taxol cancer cell lines and much easier to make! 1. Aldol Reactions 2. Michael Additions N O NHNH2 3. Enamine Reactions NO2 2Br- 4. Condensation Reactions Me NS 2 NNHMe N O H Isoniazid: Ranitidine: extremely successful drug used N 2.3.2. Type I and Type II used for treatment for treatment of stomach ulcers of tuberculosis paraquat: As far as disconnection strategies go almost every angle has been explored, but the majority used as a herbicide of the most efficient syntheses can be classified as either "Type I" or Type "II":

H Pr Pr H Type I C4 fragment + X (for a five membered ring) N N O N N N Pr C5 fragment + X (for a six membered ring) O O N NMe2 NN N Zn N PPh2 NMe Type II C2 fragment + C2X (five) Pr 2 MeO OMe N N N O C3 fragment + C2X (six) N N atropisomeric P-N In these cases, X is a heteroatom and usually a , hence the C-fragments must be chelating ligand for Pr Pr electrophilic. Ligand for the osmium catalysed asymmetric catalysis Sharpless Asymmetric dihydroxylation seco-Porphyrazine: Efficient 1 2.4. General properties of 5-membered rings O2 Photosensitizer Furan, thiophene and pyrrole are aromatic by virtue of their planarity and the uninterrupted Bu Bu Bu Bu cycle of p-orbitals containing six electrons: four from the two double bonds and two from a

SiMe3 lone pair of the heteroatom (i.e. obeys Hückel's 4n + 2 rule). However, the extent of Me3Si SSS S S S B (as determined by resonance energies, see below) for these compounds is SSS S S S SiMe Me3Si 3 different from that of (which undergoes electrophilic substitution reactions) and this Cr(CO)3 Bu Bu Bu Bu "borabenzene" is the determining factor in their chemistry (vide infra). An example of an orthogonally fused conjugated oligomer comprised of thiophene units as a potential molecular scale electronic device

7 8 Resonance Energies (experimental and theoretical values): 3. Furan (read this before lecture 2) Furan 88 KJmol-1 3.1. General Pyrrole 100 KJmol-1 The aromatic furan system is a familiar motif in many natural products, occurring widely in Thiophene 130 KJmol-1 secondary plant metabolites. The extremely important Vitamin C (ascorbic acid) is formally Benzene 151 KJmol-1 a 1,2,3-trihydroxyfuran, but assumes a tautomeric lactone form. [This is a first clue towards the somewhat "lacklustre" aromaticity displayed by ]. Furan is derived commercially

from the decarbonylation of furfuraldehyde which in turn is readily available from the action Electron Distribution / Polarisation of mineral acids on vegetable matter (e.g., oats, maize etc) and hence the name furan (furfur

is Latin for bran). σ-framework: π-framework: inductive effects mesomeric effects HO OH (weak) (strong) X HO CHO O O O Overall C-framework is electron rich, the heteroatom (X) is electron deficient HO H

Furfuraldehyde Vitamin C Reactivity

Consideration of the electron distribution within the π-framework shows that the 5-membered heteroaromatics should be susceptible to electrophilic substitution processes. Indeed, they undergo electrophilic substiution much more readily than benzene and attack is predominately in the 2-position (due to relative stabilities of Wheland 3.2. Physical and spectroscopic properties intermediates). Low boiling (b.p. 31˚C), toxic liquid. Planar with 6π-electrons and hence aromatic. Bond Other facets of their reactivity, including metallation, which are generally not lengths show intermediacy between single and double bonds characteristic of aromatics (cf available to benzene derivatives will be examined later in the course. typical bond lengths: C-C single bond, 1.53Å, isolated C=C bond, 1.34Å; aliphatic C-O

bond, 1.43Å; benzene C-C bond 1.39Å).

J = 3.3 Hz 1.44Å H H δH = 6.19 ppm dipole moment: 1.35Å J = 1.8 Hz 0.72 D (due to lone pair on oxygen) H O δH = 7.26 ppm

1.37Å

Chemical shifts consistent with aromatic compound but resonances at somewhat higher field as expected from increased electron density on atoms.

9 10 3.3. Syntheses and Reactivity 3.3.1. Paal-Knorr (Type I) Syntheses: Two classical methods: 1. Paal-Knorr Synthesis (Type I). Very general "H+" OH Involves the dehydration of 1,4- compounds (γ-hydoxy-α,β-unsaturated R R R O enones can also be employed) under non-aqueous acidic conditions. R O R O O OH R + H 2. Feist-Benary Synthesis (Type II). Very general Involves an aldol addition of a (deprotonated) 1,3-dicarbonyl compound to an α- -H2O halocarbonyl moiety followed by subsequent ring closure.

Commercial process: R R O + H+ Xylose H Oat Husks fufuraldehyde Many products (pentoses) steam distill 3.3.2. Feist-Benary (Type II) Miscellaneous methods: There are many, many, other elegant and efficient routes to access furans (browse through any recent copy of the journal Heterocycles) and these cannot be discussed at length H EtO C OH here. Some representative examples will be given. EtO2C EtO2C OH 2 O "OH-" H Reactivity of furans: O O Cl O Due to the relatively small aromatic stabilisation in furan [resonance energy 88 Cl -1 KJmol ] the chemistry of furan is not only that of electrophilic substitution but also that of -H2O the other functionalities: enol ether and chemistry. EtO2C

"normal" electrophilic substitution 2-substituted furans O O

but enol ether chemistry ring opened adducts/polymeric material EtO CR EtO2C 2 O RCl - EtO C R EtO2C R "OH " 2 -H2O O O O OH diene chemistry O O O bicyclic adducts e.g., Diels-Alder O

11 12 3.3.3. Representative example of a curious furan synthesis: 3.4.2. Nitration

+ PPh AcONO2 O 3 NO2 NO2 EtOHC CHPPh3Br O O AcO O O - H H OH NaH OEt AcO O py - Ph3PO - EtOH

NO O 2 O 3.4.3. Sulphonation 3.3.4. Miscellaneous

N O BF 3 SO Et Et 3 O Et O OH O HO S SO H O 3 O 3

3.4. Reactivity 3.4.4. Halogenation 3.4.1. SEAr Recap Reactions with Cl2 or Br2 result in polyhalogenation. Mild reaction In the absence of a nucleophile Wheland intermediates loose a proton conditions required to give the re-aromatised products. -HBr Electrophilic aromatic substitution on furan requires very mild non- Br2/dioxane Br acidic reagents. 0 + - O C Br H Br 1. Nitration using NO2BF4 or AcONO2 O O O 2. Sulphonation with py/SO3 complex 3. Halogenation 4. Alkylation not generally practicable 5. Acylation (Vilsmeier-Haack formylation) or using RCOCl in the presence of mild Lewis acids such as BF3, SnCl4 6. Electrophilic metallation using mercury salts Hg(OAc) or HgCl 2 2

13 14 3.4.7. As a diene 3.4.5. Formylation (Vilsmeier-Haack) Furan will react with reactive dienophiles in a Diels-Alder fashion (reversible)

Cl- O N O N N O O O P O Cl Cl OPOCl Cl O O O Cl 2 O Vilsmeier-Hack O reagent O O O exo (thermodynamic) product formed preferentially N H N N useful for syntheses of benzene derivatives O O Cl O Cl Cl + H HO H O H R R R R N N R R O O O H O OH OH2 H+ CO2Me O CO2Me 3.4.6. Metallation CO2Me O CO2Me OAc H CO2Me HgOAc CO2Me Hg OH O OAc O H

I2 I O

HgOAc O R

RCOCl O O ipso substitution

15 16 3.4.8. Miscellaneous 3. Subjected to electrophilic attack in the presence of a nucleophile then an addition reaction is expected. Thus Br2/MeOH yields:

1. Enol ether chemistry: polymerises with conc. H2SO4 and AlCl3 Br2/MeOH MeO OMe H O O O H+ O H OO

O O and again…. O Br Br Br MeO Br O O 2. Ring opens in hot aqueous mineral acid. MeOH

H+ H H H MeO O OMe MeO O H O O O O O MeOH

H

O O O OH

17 18 4. Pyrrole and Thiophene 4.3. Synthesis of : 4.1. General (read this before lecture 3) Three classical methods: and pyrroles are also extremely important compounds - vital for the chemistry of life. For instance, a unit is contained in Biotin (Vitamin H) and is one of 1. Paal-Knorr Synthesis (Type I). the chief components in yeast and eggs. For the pyrroles, the classic examples are that of As for furans, but involves the reaction of 1,4-dicarbonyl compounds with haem, a and vitamin B12. Pyrrole was first isolated in 1857 and its name derives or primary . Gives 2,4-disubstituted or 1,2,4-trisubstituted pyrroles. from the Greek for red - referring to the bright red colour which pyrrole imparts to pinewood shavings when moistened with concentrated (!). The name thiophene was 2. Knorr Synthesis (Type II). coined by Victor Meyer in 1882 to highlight its apparent similarity to benzene (theion is Condensation between α-aminoketones and β-ketoesters. Gives 3-substituted pyrroles greek for sulphur): it was discovered as a contaminant of -tar benzene. after hydrolysis and .

3. Hantzsch Synthesis (Type II). Involves reaction between enaminoester and an α-chloroketone. Gives 2,5- O N N disubstituted pyrroles after hydrolysis and decarboxylation. HN NH Mg H H N N OH 4.3.1. Paal-Knorr (Type I) S O Biotin MeO C (Vitamin H) 2 OO R R NH3

O O N H 4.2. Physical and spectroscopic properties (eg. R = H) R'NH2 Both are liquids (thiophene, b.p. 84 ˚C; pyrrole, b.p. 139 ˚C). Both are expected to be N aromatic since they comply with Hückel's rule. The bond lengths and 1H NMR shifts are R' consistent with this expectation. Thiophene displays a dipole moment of 0.52 D towards the heteroatom by virtue of its lone pair whereas pyrrole (where the lone pair is directly involved in the π-cloud) shows a dependent dipole moment of approx. 1.55 D away from the heteroatom.

J = 3.3 Hz J = 2.1 Hz 1.42Å 1.42Å

H H δH = 6.87 ppm δH = 6.05 ppm H H 1.37Å J = 5 Hz 1.38Å J = 2.7 Hz H S δH = 6.99 ppm N H δH = 7.70 ppm H

1.71Å 1.37Å

19 20 method for protecting primary amines: 4.3.3. Hantzsch (Type II) Modification of Feist-Benary H+ H+ OH H2NOH CO2Et N Cl CO2Et Cl CO2Et N N N NH3 R' R' R' H O OO OH2N H2N - H O HO OH OH 2 CO2Et HO NH2 N N N H NR' NR' N H H H H

HO OH 4.3.4. Commercial process R'NH2 N N

"Al" NH3 O gas phase N H

4.3.2. Knorr (Type II) 4.3.5. Miscellaneous Barton-Zard pyrrole synthesis CO Et 2 O CO2Et KOH NO2 NO2 R NO2 EtO C 2 N R base R EtO2CNH2 O H

EtO2C KOH EtO CN N H 2 EtO2C N C C O CO2Et HO CO2Et CO2Et H R EtO CN EtO2C N EtO C N R R NO2 2 2 H

EtO C 2 N EtO2C N EtO2C N H

21 22 4.4. Reactivity 4.4.1. With (read also this for lecture 3) More like furan than benzene (resonance energy for pyrrole 100 KJmol-1). Very electron 4.4.1.1. Nitration rich and so very reactive to electrophiles (approx. 106 more reactive than furan) but the presence of the N-H group provides additional scope for reactivity. Hence a more varied and NO2 complex chemistry than furan. AcONO2 AcOH 0 1. Electrophilic reagents: -10 C NO As for furan. Sensitive to acid therefore mild reagents used (as per furan). 2- N N 2 N Substituted adducts. H H H 51% 13% 2. reactions (Reimer-Tiemann reaction) Reacts with electrophilic (e.g. :CCl2). Product distribution dependent on reaction conditions. 4.4.1.2. Sulphonation as with furan and thiophene 3. Metallation: Pyrrole itself is a weak acid (pKa 17.5) and the N-H is readily deprotonated. The 4.4.1.3. Halogenation resulting pyrryl anions are ambident and their reactivity is cation dependent. Monohalogenation is difficult and requires controlled conditions. "Ionic" salts (K+, Na+) react with electrophiles at whilst salts with more covalent character (Li+, MgX+) react with soft electrophiles (carbon, sulphur, ) at the 2- Br Br SO Cl position (i.e. on carbon) but with hard electrophiles at nitrogen. Br2 2 2 00C 00C N-Protected pyrroles are readily deprotonated by strong lithium bases in the 2- Br Cl position and can be quenched with electrophiles giving 1,2-substituted pyrroles. The N Br N N N deprotonation can be deflected to the 3-position by judicious choice of a large protecting H H H H only monoproduct group (e.g. triisopropylsilyl) on the nitrogen.

4.4.1.4. Acylation 4. Reaction with dienophiles: Pyrrole itself rarely undergoes direct Diels-Alder reactions; the usual result is 2- Ac2O substitution (via an electrophilic substitution pathway) because the dienophile simply acts as 2000C without catalyst an . N-Acylated pyrroles, however, are less electron rich and less "aromatic" and give normal Diels-Alder adducts. N N H H O 5. Condensations: The nucleophilic pyrrole ring reacts readily with and under acidic Reacts with Vilsmeier-Haack reagent (formylation) and in the catalysis to form di-, tri- and tetrapyrrolic oligomers. The macrocyclic tetramers are and with other acylating reagents. especially stable and form planar species which accomodate a wide range of metal ions at their core (vide supra, introduction, lecture 1).

23 24 4.4.1.5. Condensation with Aldehydes and Ketones 4.4.2. With Carbenes Reimer-Tiemann Reaction OH H OH O H Cl N N H N H H H N CCl2 N CCl H H 2 N H H CHCl /NaOH 3 hydrolysis

N N H N H H H HN HN N N H H O

But under non-aqueous conditions: R RCHO "H+" N Cl N H Cl H NH N Cl CCl2 NH HN R R N N H H N H N HN HCCl /NaOH N 3

R 4.4.3. Reactions with Bases The NH proton is relatively acidic (pKa 17.5) and can be removed with bases:

N H

NaNH2 RMgBr BuLi

N N N Na MgBr Li "salt-like" "covalent" "in-between"

25 26 4.5. Synthesis of thiophenes E+ (read this for lecture 4) Two classical methods: N N Na E E = MeI, RCOCl etc. 1. Paal Synthesis (Type I). E+ Similar to the Paal-Knorr for furan in that a 1,4-dicarbonyl compound is involved. E The sulphur atom derives from P2S5 or (more recently) Lawessons reagent. Gives 2,5- N N H disubstituted adducts. MgBr 2. Hinsberg Synthesis (Type II). Very general Involves two consecutive aldol type additions between 1,2-dicarbonyl compounds R hydr. H R and thiodiacetates. R MgBr N Cl O N N O H Commercial process: MgBr MgBrO MgBr Simply by pyrolysis of (C4)with sulphur (S8) N-substituted pyrroles As with furan there are many other notable methods for the synthesis of thiophenes. BuLi / r.t. E+ Li E N N N

R R R

4.4.4. With Dienophiles Mainly Michael adducts, and only Diels-Alder reactions with electron withdrawing substituents on N.

MeO2C CO2Me N

N CO Me 2 CO Me 2 CO2Me CO2Me

27 28 4.5.1. Paal-Knorr (Type I) 4.5.2. Hinsberg (Type II)

R R R R P2S5 t-BuOK R R R R O O O S O HO C 2 S CO2Me MeO C 2 S CO2Me

S R S O O R MeO P P OMe Lawessons Reagent O R O O S R R S O O R S CO2Me S S MeO2C CO2Me MeO2C CO Me H S S S S 2 MeO P P OMe Ar P PAr S R S S S R R O O R O

HO2C CO2Me HO C S 2 S CO2Me R R

S S S S S S O O Ar P Ar P Ar P PAr Ph P PPh S O S O 3 S 3

driving force is the formation of the particularly strong P=O double bond. 4.5.3. Commercial process

6000C S8

S

29 30 4.5.4. Miscellaneous In summary: Thiophenes are more stable to acid than furans and pyrroles. Enol ether chemistry is absent in thiophenes due to their highly aromatic character and thus mainly substitution chemistry is Ph observed. Thiophenes are much more reactive than benzene. 1,3-thiazole N Ph R R' N retro DA DA 4.6.1. With Electrophilic Reagents S S + PhCN R R' S 4.6.1.1. Nitration RR' driving force is greater degree of resonance stabilisation (aromaticity) AcOH NO2 HNO3

NO 4.6. Reactivity S or S 2 S (read this before lecture 4) + - NO2 BF4 2 60% 10% Thiophene is somewhat less reactive (10 ) than furan towards electrophiles (and much less 4 reactive than pyrrole), but it is still much more reactive than benzene (approx. 10 ). By less selective than pyrrole or furan -1 virtue of it high resonance energy (130 KJmol ) it is the most aromatic of the five-membered heteroaromatics and undergoes electrophilic substitution rather than addition/ring opening 4.6.1.2. Sulphonation and there is no behaviour as an enolthioether or diene (contrast with furan). Thiophene is as with furan and pyrrole stable to aqueous mineral acids but not to 100% sulphuric acids or strong Lewis acids, exemplified by aluminium(III) chloride. Electrophilic substitution occurs in the 2-position (as for furan) with high positional selectivity. SO3H 1. Electrophilic Reagents: S

Mild electrophilic reagents are used (as for furan) but the acidity is less critical.

4.6.1.3. Electrophilic Metallation (Mercuration) 2. Nucleophilic reagents: as with furan but more difficult to stop reaction at the Thiophenes do not react by nucleophilic substitution or addition [ring is already electron rich, and a relatively stable aromatic system] but are much more acidic than furans (pKas: monosubstituted stage. thiophene 33.0; furan 35.6) and are subject to deprotonation in the 2-position with strong base (e.g., n-BuLi, t-BuLi and LDA). These α-metallated species react readily with electrophiles to give 2-substituted thiophenes. Metallation at the 3-position can be achieved AcOHg HgOAc by suitable substitution and/or directing groups. S

3. Reaction at sulphur: Due to its position in the periodic table, the sulphur atom in thiophene derivatives (unlike nitrogen and oxygen in pyrrole and furan respectively) can "expand its octet". Thus thiophene has chemistry associated with the heteroatom.

31 32 4.6.2. Reaction with Bases

n-BuLi E+ THF o -20 C Li E 4.6.1.4. Halogenation S S S Li E Br n-BuLi THF o -70 C (R) S S S S warm up I2 Br2

aq. HNO3 2x Br2/48% HBr 48% HBr R R 900C -10 to +100C -25 to -50C R'X

I Br Br Br SLi SR' S S S z-ene-yne yields polyhalogenated species unless controlled 4.6.3. Reaction at Sulphur 4.6.1.5. Acylation Proceeds easily under the usual Friedel-Crafts conditions but only E OO requires mild Lewis acids such as SnCl4 to proceed. Also reacts with S m-CPBA Vilsmeier-Haack reagent (POCl3/DMF) similarly to Furan. E S S 4.6.1.6. Aminomethylation (Mannich) O O

37% aq. CH2O + - o NH 4 Cl /60 C E NH2 "Eschenmoser Salt" + SS Me2 NCH2 I + Me2 NCH2 "Mannich Salt" NHMe22 + if E is a good leaving group aromatisation will follow Me2 NCH2 Cl S

33 34 4.6.4. Reducing Reagents 5. Indole 5.1. General Raney-Nickel (read before lecture 5) The Indole unit is found in over a thousand naturally occurring (indole) alkaloids and many R R H2 R R S of these have important physiological activity. The name indole derives from indigo (a blue- purple dye imported from India). Chemical degradation of indigo leads to oxygenated which were named indoxyl and ; indole itself was first prepared in 1866 by zinc dust of oxindole. Most indole alkaloids are derived from the naturally 4.6.5. Analytical Detection occurring amino acid, (S)-tryptophan and an example is the hallucinogen compound psilocin, extracted from Mexican mushrooms by the Aztecs from as early as 1500 BC (although they certainly didn't know - nor care (!) - which chemical was responsible).

O HO H HO NMe S NH2 2 S S OH O O O CO2H N N N H H H N N H H O (S)-tryptophan psilocin NH S S 5.2. Physical and spectroscopic properties S O Colourless, crystalline solid; m.p. 52 ˚C; Oxidises in air, resonance energy 196 kJ mol-1 HN N -1 O H (most of which is accounted for by the benzene ring and cf naphthalene 241 kJ mol ). Has a blue persistent faecal odour - used, in high dilution in perfumery!

1.44Å

H δH = 6.34 ppm 1.36Å

N H δH = 6.54 ppm H 1.37Å 1.38Å δH = 7.00 ppm

5.3. Syntheses 1. Fischer Indole Synthesis (Type II) Condensation/rearrangement of an aryl and a (not applicable to aldehydes). Substituted generally work well, but m-substituted substrates give rise to mixtures of products. Very general and much used.

35 36 2. Reissert Synthesis 5.3.2. Reissert Deprotonation at the (most acidic) benzylic site in an o-methylnitrotoluene and ensuing condensation with ethyl oxalate. Dissolving metal reduction then completes the 1. EtONa CO2Et synthesis. Sn/HCl O NO 2. 3. Azidocinnamate Synthesis 2 O NO2 Unusual in that the aryl-nitrogen bond is not initially present. Involves EtO OEt condensation between an azidoester (acidic methylene protons) and an arylaldehyde. A O nitrene is formed on heating which inserts into an aryl C-H bond thus giving 2-substituted CO2Et indoles. O NH 5.3.1. Fischer 2 1. hydr. CO Et "H+" 2 N 2. decarb. N H NHNH2 O N H H

5.3.3. Azidocinnamate

O

CO2Et CO2Et base heat

N3 N3 R R Japp-Klingeman hydrazone synthesis CO2Et

CO Et insertion 2 N N CO2Et H R NaNO2 - R HCl OH nitrene N + NH2 N2 N H CO2Et O

37 38

5.4. Reactivity 5.4.1. 2- vs 3-Position (read before lecture 5) Because of the presence of a carbocyclic aromatic ring which accounts for most of the E E + "aromaticity" of the system, indole can be considered to behave as a benzene + an enamine. E Consequently, indoles are unstable to acid and very susceptible to electrophilic attack.

N N N 1. Electrophilic substitution. H H H The pyrrolic ring in indole is electron rich and electrophilic substitution occurs preferentially in this ring (rather than the benzene ring). However, in direct contrast to E pyrrole, substitution occurs at the 3-position. This is a consequence of the stabilities of the E+ Wheland intermediates where attack in the 2-position leads to loss of aromaticity in the N N H H benzenoid ring. When the indole is already substituted in the 3-position then apparent 2- substitution occurs but these products (normally) derive from a migration after initial attack at the 3-position. 5.4.2. With Electrophiles 5.4.2.1. Nitration 2. Metallation. Indole, like pyrrole, is a weak acid and can be readily N-deprotonated (pKa NO2 16.2). As for pyrrole, the resulting anions are ambident and for similar reasons attack of soft PhCO NO electrophiles on covalent salts occurs at the 3-position. N-Protected indoles lithiate 2 2 regioselectively at the 2-position and react readily with suitable electrophiles. N N H H : Mild conditions required using benzoyl (PhCOONO2) Chemistry is typically that of a diene in Diels-Alder reactions such that the aromaticity of the benzenoid ring is regained. 5.4.2.2. Sulphonation

as with furan and pyrrole using pyridine/SO3 complex

NH SO3H

NSO3 N N H H

39 40

5.4.2.3. Halogenation 5.4.2.5. Alkylation Mild conditions required. Haloderivatives are not very stable.

IBrMeI 1100C MeI py DMF / KOH Br I2 2 N N N r.t. 00C H H H N N N H H H

5.4.2.4. Acylation H Reacts with Vilsmeier and Mannich reagents, the former being the N N most efficient route to 3-formylindoles. H H Rearrangement related to Wagner-Meerwein called Plancher rearrangement. NMe2 NMe3

CH2O 5.4.2.6. With Diazonium Salts Me2NH MeI NPh N N N N H H H + - CN PhN2 Cl

CN N N H H

N N H H 5.4.2.7. With Michael Acceptors

EWG EWG

N N EWG = NO2, CN, COMe etc. H H

41 42 5.4.3. Reactions with Bases (Metallation) If nitrogen substituted:

BuLi E+ Li E K N N N Reacts N preferentially on H nitrogen with + (hard!) 1. BuLi 1. E Li E electrophiles 2. CO2 NaNH2 RMgBr BuLi N N 2. work up N H H

O MgBr O N N N Reacts K(Na) Li preferentially at Li E MgBr (Zn) C-3 Br

+ BuLi E MeI Li N N N N N Reacts on C-3 K(Na) Me or nitrogen Me depending on metallation at C-3 via metal-halide exchange MeI conditions

N N H MgBr

43 44 5.4.4. In 6. Pyridine 6.1. General ON O (read this before lecture 6) N Pyridine and the methylpyridines (collidines, lutidines) are available on a large scale from the C [3+2] carbonisation of coal. contains about 0.2% of a mixture of pyridine bases which are N N readily extracted with acid and then separated. As for the five-ring heterocycles they are H H familiar motifs in a large number of natural products. For instance, pyridoxol (Vitamin B6) (R = CH2OH, below) occurs in yeast and wheatgerm, and is an important food additive. Related compounds are pyridoxal (R = CHO) and pyridoxamine (R = CH2NH2). The 5- DA phosphate of pyridoxal is a co-enzyme in the decarboxylation and transamination reactions of α-amino amids. Pyridine, like pyrrole, was first isolated from bone pyrolysates. The name N derives from the Greek for fire 'pyr' and the suffix 'idine' was given for all aromatic bases at N H H the time it was named.

R [2+2] HO OH

N NNNN N H H pyridine 2,4,6-collidine 2,6-lutidine reacts with electron-deficient (inverse electron demand)

6.2. Physical and spectroscopic properties Colourless liquid, characteristic odour, b.p. 115˚C, weakly basic (pKa 5.2) with a resonance energy of 117 kJ mol-1

δH 7.10 J 8Hz 1.39Å H δ 6.78 H H Inductive (σ) and 1.39Å J 5Hz mesomeric (π) dipole NHδH 8.56 in same direction

1.34Å basic lone pair

45 46 6.3. Syntheses 6.3.2. Hantzsch

1. Kröhnke Synthesis (Type I) O R O O R O The reaction of a 1,5-dicarbonyl compound with ammonia to reveal a 1,4- O dihydropyridine which is oxidised to a pyridine. The pyridine system can be formed directly EtO OEt EtO OEt either by introducing unsaturation into the dicarbonyl backbone or by judicious use of hyroxylamine (which eliminates water). O O OO

NH3 NH 2. Hantzsch Synthesis 3 Condensation of 2 moles of a 1,3-dicarbonyl compound with one equivalent of an and one equivalent of ammonia followed by oxidation. Very general and much O R O O R O used. [O] EtO OEt EtO OEt 3. Oxazole Synthesis An example of the use of a pericyclic reaction in heterocyclic synthesis: these N N H often start from another (less aromatic) heteroaromatic as here. This is a versatile synthesis the outcome of which depends on the exact functionality present. 6.3.3. Oxazole (via )

Y Y Y 6.3.1. Kröhnke X H H X HO X H O O H [O] NH3 N N N N N O O H Y X NH3 N O O N directly from unsaturated 1,5-dicarbonyl compounds

47 48 6.4. Reactivity 6.4.1. Basicity (read this before lecture 6) Pyridine has a high resonance energy (117 kJ mol-1) and its structure resembles that of benzene quite closely. The presence of the nitrogen atom in the ring does, of course, represent a major pertubation of the benzene structure. The lone pair orthogonal to the π- system provides a site for alkylation and protonation which has no analogy in benzene. N N N N Many of the properties of pyridine are thus those of a tertiary and the aromatic sextet is not involved in these reactions. The other major influence of the nitrogen atom is to distort the electron distribution both in the π-system and in the σ-bonds (by an inductive effect). This confers on the system some of the properties which are associated with conjugated or conjugated carbonyl compounds . N We can therefore expect to find reactions of which show analogies to three N 5.2 types of model systems:

A. Benzene: substitution reactions and resistance to addition and ring opening 6.4.2. With Electrophiles

B. Tertiary amine: reactions at the nitrogen lone pair, including protonation, alkylation, Much less reactive than E+ acylation, N- formation and co-ordination to Lewis acids. pyridine itself for further

C. Conjugated imines or carbonyl compounds: susceptibility to attack by nucleophiles at electrophilic attack the α and γ positions. N N

E

E H

N

E N H

E H

N

49 50 6.4.2.1. Sulphonation pyridine N- are much more reactive towards electrophiles than pyridine itself: cH2SO4 SO3H HgSO4 E 2200C E H 70% N N E+

6.4.2.2. Halogenation N N N

O O O Br Cl2 Cl AlCl Br2 3 66% oleum 1000C 6.4.4. With Nucleophiles N N N mainly 2-substituion (4-substitution minor product) 86% 33%

6.4.4.1. Amination (Chichibabin)

6.4.2.3. Nitration …but with electron donating groups:

heat H NaNH2 cHNO3 oleum H H NO2 0 N N NN 100 C NH2 H

N N + 90% H N O H N NNH NNHNa 6.4.3. Reactions at Nitrogen 2 6.4.3.1. Alkylation also with OH to give pyridones

N MeI SO3 RCO3H RCOCl

NN NN

O SO3 O R pyridine N-oxide

51 52

6.4.4.2. Alkylation/Arylation

[O] RLi H N N NR R Li+

[O] RMgBr H N N NR R

base E+ E N N N E

base E+

N N N

2- and 4-methyl pyridines can be deprotonated with strong bases and undergo enolate-type chemistry.

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