{CFO RD € HEMIS TRY RIMERS Aromatic Heterocyclic Chemistry David T. Davies a eS | zm Ne Oo? OXFORD SCIENCE PUBLICATIONSContents eon eH awn — Introduction Pyrroles, thiophenes, and furans Oxazoles, imidazoles, and thiazoles Isoxazoles, pyrazoles, and isothiazoles Pyridines Quinolines and isoquinolines Indoles Five-membered ring heterocycles with three or four heteroatoms ‘Six-membered ring heterocycles containing one oxygen atom Pyrimidines Answers to problems Index 10 20 28 35 53 61 67 3 8 871. Introduction 1.1 Heterocyclic chemistry Heterocyclic chemistry is a large and important branch of organic chemistry. Heterocycles occur in nature, for instance in nucleic acids (see Chapter 10) and indole alkaloids (see Chapter 7). Synthetic heterocycles have widespread uses as herbicides (e.g. 1.1), fungicides (e.g, 1.2), insecticides (e.g. 1.3), dyes (e.g. 1.4), organic conductors (e.g. 1.5), and, of course, pharmaceutical products such as the anti-ulcer drug 1.6. \) POE), ae sown Ie! Ree ” ew te AA PER at co 12 13 BS 4 s. s N gf ae Od ic s Ss ie fea % Ls 16 1.2 Aromaticity and heteroaromaticity Any ring system containing at least one heteroatom (ie, an atom other than carbon — typically nitrogen, oxygen, or sulphur) can be described as heterocyclic. This broad definition encompasses both aromatic heterocycles (such as pyridine 5.1) and their non-aromatic counterparts (piperidine 1.7). N H 47 Aromatic heterocycles are described as being heteroaromatic, and we shall concentrate on these systems in this book at the expense of more saturated systems. Let us now consider the concept of aromaticity with regard to benzene. sa The compound numbering system in this chapter is not as odd as it might seem. For more on compound 5.1 see Chapter 5, etc.2 Introduction a H #. H H. H #. H — x H H H # H H H 18a 18 ‘The carbon atoms in benzene are sp? hybridised, and the hydrogen atoms are in the same plane as the carbon atoms. The remaining six p orbitals are at right angles to the plane of the ring and contain six m electrons. Benzene fulfils the Hlickel criteria for aromaticity as applied to cyclic polyenes containing 4n + 2 electrons (where n=1 in this case) in filled p orbitals capable of overlap. ‘Although two mesomeric representations 1.8a,b can be drawn for benzene, this does not imply two rapidly-interconverting forms. Rather, the six 1 electrons are delocalised in molecular orbitals resulting in an annular electron cloud above and below the plane of the ring. Benzene can also be represented by structure 1.9, which emphasises the cyclical arrangement of electrons. In agreement with this theory, the carbon-carbon bond lengths are all equivalent (0.14 nm) and intermediate between that of a single (0.154 nm) and double (0.133 nm) carbon-carbon bond. The extra thermodynamic stabilisation imparted to benzene by this phenomenon of electron delocalisation, called ‘resonance’, can be determined indirectly. Real, delocalised benzene is thermodynamically more stable than a theoretical cyclohexatriene molecule (ie. non-delocalised structure 18a) by around 150 kJ mol"! How does this concept of aromaticity apply to typical heterocycles such as pyridine 5.1 and pyrrole 2.1? Pyridine can formally be derived from benzene by replacement of a CH unit by an sp? hybridised nitrogen atom. ‘Consequently, pyridine has a lone pair of electrons instead of a hydrogen atom, However the six electrons are essentially unchanged, and the pyridine is a relatively aromatic heterocycle. e © N H a a A difficulty arises with five-membered heterocycles such as pyrrole, which at first sight would appear to have only four 7 electrons, two short of the 4 +2 Hiickel criteria for aromaticity. The nitrogen atom is sp? hybridised and formally contains a lone pair of electrons in the remaining p orbital at right angles to the ring. However, the system is delocalised, as shown below. a = . a * (32 Somme —~ o£) —~ OS c ; oo aAromatic heterocyclic chemistry 3 | Thus, delocalisation of the nitrogen lone pair completes the sextet of electrons required for aromaticity. These two examples illustrate the point that certain heterocycles (closely analogous to benzene and naphthalene) such as pyridine 5.1, pyrimidine 10.1, and quinoline 6.1 are aromatic ‘by right’ whereas other heterocycles such as pyrrole 2.1, imidazole 3.2, and triazole 8.7 have to ‘eam’ aromaticity by delocalisation of a lone pair of electrons from the heteroatom. N N A A> S r r ms oO of oF & & & N N N’ H H a SA 104 61 24 32 a7 ‘What are the consequences of this concept of lone pair delocalisation for a related series of heterocycles such as pyrrole 2.1, thiophene 2,2, and furan 2.3? As delocalisation results in electron loss from the heteroatom concerned, the extent of delocalisation (and hence aromaticity) will vary with the electronegativity of the heteroatom. The highly electronegative oxygen atom in furan holds on to electron density more strongly than the heteroatom in thiophene or pyrrole. Furan is generally considered to have a non-aromatic electron distribution fairly close to that depicted by structure 2.3. Fm meeapiermes oy N’ 8 ‘0 a H a 3 23 In fact the thorny problem as to how aromatic is a particular heterocycle or For @ review on the concept of series of heterocycles has been a preoccupation of physical organic chemists ne ane see for'some time. Bond lengths, heats of combustion, spectroscopic data, and ‘theoretically-calculated resonance energies have all been invoked, but an ‘absolute measure of aromaticity remains elusive. Nevertheless, trends segarding relative aromaticity will be alluded to in this text as they arise, 1.3 Synthesis of heterocycles are many syntheses of the major heterocycles and they are often jlementary in that they afford different substitution patterns on the ring. of the synthetic methods we shall examine are fairly classical (indeed are decidedly ancient!) although many of the specific examples are quite sm. Many classical syntheses of heterocycles revolve around the sation reaction in its various guises. Let us consider the mechanism of simple acid-catalysed condensation, that of generalised ketone 1.10 and ne 1.11 to give imine 1.12. Protonation of the ketone oxygen atom activates the ketone to philic attack by the amine. Loss of a proton from 1.13 produces intermediate 1.14. A second protonation, once again on the oxygen affords 1.18, which on loss of a water molecule and a proton gives the4 Introduction The symbol = denotes a disconnection, an analytical process in which a structure is transformed into a suitable precursor imine 1.12. All these steps are reversible, but in practice if water can be removed from the equilibrium (for instance by azeotropic distillation) then such reactions can be forced to completion. This type of reaction occurs many times in this text, but in future will not be presented in such detail. The student is strongly advised to work through, using pen and paper, the mechanism shown below and the many subsequent mechanisms. Confidence with reaction mechanisms will facilitate understanding of heterocyclic chemistry and organic chemistry in general. R es He Ho + BN-R a 110 R; 1m = fe? Cw; eae eS ® x H;N-Ry i 13 114 1s The disconnection approach to synthesis essentially involves working backwards from a target compound in a logical manner (so-called retrosynthesis), so that a number of possible routes and starting materials are suggested. This approach has been applied mainly to alicyclic, carbocyclic, and saturated heterocyclic systems. Retrosynthetic analyses are presented in this text not as an all-emibracing answer to synthetic problems, but rather as an aid to understanding the actual construction of unsaturated heterocycles. Returning to the condensation presented above, this leads to an important disconnection. The imine-like linkage present in several heterocycles (generalised structure 1.16) can arise from cyclisation of 1.17, containing amino and carbonyl functionalities. SL, Li, RS N 116 Now consider condensation of ammonia with ketoester 1.18. The isolated product is not imine 1.19 but the thermodynamically more stable enamine fautomer 1.20 which has 2 conjugated double bond system and a strong intramolecular hydrogen-bond. Although not a heterocyclic example, 1.20 illustrates that an enamine-like linkage, as in generalised heterocycle 1.21, is also accessible by a condensation reaction. ont COE NH, COE 2 — ae ° ier mt 119 H 1% LisAromatic heterocyclic chemistry 5 Ina retrosynthetic sense, formal hydrolysis of the carbon-nitrogen bond of 1.21 reveals enol 1.22 which would exist as the more stable ketone tautomer 1.23. Note that in the hydrolytic disconnection step the carbon becomes attached to a hydroxy group and the nitrogen to a hydrogen atom — there is no change in the oxidation levels of carbon or nitrogen, 'N R ‘on NH R 0 NH H Lat a2 423 Unlike our initial imine disconnection which is restricted to nitrogen heterocycles (with one or two specific exceptions such as pyrylium salts, see Chapter 9), the heteroatom in the enamine or enamine-like disconnection could be divalent. Therefore this disconnection is also applicable to oxygen- and sulphur-containing heterocycles, typified by 1.24 and 1.25. ot = 0. R~ ‘on ~OH R“No ~oH a TL) = 1. Rg R~ oH ~SH we Let us see how this disconnection approach can rationalize the synthesis of ole 2.16. (\N = (1 (Ya a= OH Ni > wm > oH 4d 216 + NH, 1.26 Retrosynthetic analysis suggests a double condensation between diketone and ammonia. Pyrrole 2.16 can actually be prepared if this way - see 22. Another aid to understanding heterocyclic synthesis in general is the fact a large number of five- and six-membered heterocycles can be constructed various combinations of small acyclic molecules by complementary ing of nucleophilic and electrophilic functionality. ec ec ‘ce 12% 0 0 cess) NH a to the symthesis of pyrrole 2.16, diketone 1.26 can be regarded as a ‘bon bis-clectrophilic fragment and ammonia, in this instance, as a leophilic nitrogen fragment. Ammonia can form up to three bonds in ilic manner.6 introduction {n this particular instance the correct oxidation level automatically results from the condensation reaction, giving pyrrole 2.16 directly. In other cases cyclisation does not afford the correct oxidation level and an unsaturated system has t0 be oxidised to achieve aromaticity, For instance, 1,5-diketones 1.27 react with ammonia to give dihydropyridines 1.28 which can be oxidised to pyridines 1.29. pia Rana 47 128 129 Examples of this cyclisation-oxidation strategy include the synthesis of pyridotriazine 5.32 (page 42) and syntheses of quinolines and isoquinoline (Chapter 6). Some examples of nucleophilic and electrophilic fragments are shown in Table 1.1. Several points arise from the table. Consider acylating species such as acid chlorides. Acylation of diamine 1.30 initially gives amide 1.32 which undergoes a condensation to produce benzimidazole 1.32. The carbonyl moiety is acting exclusively as an electrophilic centre. Seer ah OC However, delocalisation of the nitrogen lone pair in the amide linkage (see mesomeric representations 1.33a,b) produces a nucleaphilic oxygen atom which can react with electrophiles as shown. i sla BA ae ON Ry . 13a H 133b ; ee Ry, ——> 2S Kh ea?Aromatic heterocyclic chemistry 7 ‘Nacleophlic fragments Table Lt [No.of ring atoms 1 Nis, #038 (see Chapers2 and 5) 2 HGN-NH:,HAN-OB (see pyrarale and isoxazole synthesis, Chapter) NH, NH Na, NH NH 3 sAm ste sy ww, oA, (se thiazole syst, Chapter 3, and pyrimidine syhess, Chapter 10) co (see quinoline synthesis, Chapter 6) co wit, Ni, ‘4 ik (ee bersimidazole synthesis, Chaper 1) NH, 5 te (see isoquinoline synthesis, Chapter 6) Electrophilic fragments No. of ring atoms ce (0 = leaving group, ep. Cl- 200 beraimidezole sychesit, Chapter 1 s 4 ROX and isoquinoline synhesis, Chapter 6 ° ° 2 ‘Ah ton {see thiazole synthesis, Chapter 3) x ns ° ° 3 mR re (see quinoline synthesis, Chapter 6) Ry Rp = alkyl or O-allyl Ne (see pyrazole and isoxazole synthesis, Chapter 4, and pyrimidine syshesi, Chapter 10) « rye (see pyrrole, thiophene, and furan syntheses, Chapter 2) lwcleophiic/ Eieetrophilic frazments {nof ring atoms om a Jk. (see Chapter I and oxazole synthesis, Chapter 3) pe ° aye (see Chapter 1 and coumarin synthesis, Chapter 9) o7*R © as (tee axanolesyuhess, Chapter 3, and Knorr pyrrola 4 < synthesis, Chapter 2)8 Introduction ‘The reaction of an acylating species Amides can cyclize in this manner as, for example, in the acylation of amino with a nucleophile is shown below. acids 1.34 to afford oxazolidinones 1.35. 00 ° ee gon, ra ot Rp Sh R°RX R Ree “em NH 134 1.38 e0y x) no Siee ‘Acylating species are thus included in both electrophilic and je nucleophilic/electrophilic categories in Table 1.1. For a related example see the synthesis of oxazoles in Chapter 3. ° 1,3-Dicarbonyl compounds, such as malonate derivatives, can also be J classified under two calegories. As well as reacting simply a» a tuee-atom ee bis-clectrophilic fragment (as in the synthesis of barbiturate 10.25 (page 77), an alternative reactivity is available. Condensation (by nucleophilic attack) of the active methylene carbon and electrophilic reaction at just one of the carbonyl groups is 2 peo-atom nucleophilic/electrophilic profile, as seen in the preparation of coumarin 9.16. For the sake of simplicity in this toxt ° the two-stage process is abbreviated 5 thus: “I Ot Br OK COE + = es oar She 9.16 ° ey oy | 6, = OE: me a B0~So ee “These concepts of retosynthesis and heterocycle construction will help put ‘the syntheses encountered in the following chapters into a broader perspective. 1.4 References Textbooks Acheson, RM. (1967). Am introduction to the chemistry of heterocyclic compounds, (2nd eda). Wiley, New York. Paquette, L.A. (1965). Principles of modern heterocyclic chemistry. Benjamin, New York. Joule, J.A. and Smith, GE. (1979). Heterocyclic chemistry, (2nd edn). Van Nostrand Reinhold, New York. Gilchrist, T.L. (1985). Heterocyclic chemistry. Longman, Harlow.Aromatic heterocyclic chemistry 9 first two (Acheson and Paquette) are still very good texts even today. OF ‘more recent pair, both are warmly recommended. Joule and Smith is sibly a more introductory text than Gilchrist, which contains many al references and is pitched at the advanced undergraduate/postgraduate el. See Gilchrist for a discussion of the nucleophilic/electrophilic jent approach to heterocyclic synthesis. arren, S. (1978). Designing organic syntheses, p.1S0-172. Wiley, Chichester. farren S. (1982). Organic synthesis - the disconnection approach, p. 3260-345. Wiley, Chichester. ference books and series fey, S. (ed.) (1973 — 1986). Heterocyclic compounds (Vols. 4A — 4K of ‘odd’s chemistry of carbon compounds). Elsevier, Amsterdam. field, R.C. (ed.) (1950 - 1967). Heterocyclic chemistry, Vols. 1-9, filey, New York. itzky, A.R. and Boulton, A.J. (ed.) (1963 ~ 1989). Advances in teracyclic chemistry, Vols. | 45. Academic Press, Orlando. itzky, A.R. and Rees, C.W. (ed.) (1984). Comprehensive heterocyclic -mistry, Vols. 1 ~ 8. Pergamon Press, Oxford. itzky, AR. et al, (1991). Heterocycles, 32, 127-161. mes, P.G. (ed.) (1979). Heterocyclic chemistry (Vol. 4 of ‘omprehensive organic chemistry, ed. D. Barton and W.D. Ollis). on Press, Oxford, ‘burger, A. and Taylor, E.C. (ed.) (1950 ~ 1990). The chemistry of ‘erocyclic compounds. Wiley Interscience, New York. ‘of these sources contain excellent reviews on virtually every aspect of vyclic chemistry. In particular, Katritzky and Rees is a thoroughly hensive work. For those particularly interested in the synthesis of oles as pharmaceutical agents see: , D. and Mitscher, L.A. (1977, 1980, 1984, and 1990). Organic istry of drug synthesis, Vols. 1 — 4. Wiley, New York. imental references is introductory text there is little detail regarding solvents, yields, ip procedures, etc. However, several chapters reference a relevant ental procedure (taken from Organic syntheses or Vogel) which the it is strongly encouraged to read. For an excellent selection of ental procedures for the synthesis of heterocycles see: , BS., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989). el’s textbook of practical organic chemistry (Sth edn), 1127 - 1194. Longman, Harlow.The numbering of heterocycles generally starts at the heteroatom =H ape H Under extreme conditions of ‘acidity pyrrole is protonated, but atthe C2 position. Q NO Ww Na Note that protonation of the yrroie nitrogen would lead to a on-aromatic cation. 2. Pyrroles, thiophenes, and " furans 2.1 Introduction Pyrroie 2.1, thiophene 2.2, and furan 2.3, are five-membered ring heteroaromatic compounds containing one heteroatom. They derive their aromaticity from delocalisation of a lone pair of electrons from the heteroatom. Consequeatly the lone pair is not available for protonation and E ‘The basis and exteat of their aromaticity is discussed in Chapter 1. In summary, the capacity for the lone pair on a particular heteroatom to be delocalised is inversely related to the electronegativity of the heteroatom, For instance, farsa is the least aromatic of the trio because oxygen has the _gzestest clectroncgativity and hence mesomeric representations 2.4b-e make ‘elatively less of = contabetion to the electronic structure of furan than they do i the cases of pyrmole and thiophene. The order of aromaticity is furan < pyre < thiophene We shall see later how this variation in aromaticity ‘affects the reactivities of these three related heterocycles. é = 9, 6 ee 3 05 43 3 6 ° — ll A small number of simple pysvoles such as 2.5 and 2.6 occur naturally. Far more important are the tetramic pyrrole derivatives (porphyrins) such as chlorophyll-a 2.7 and haem 28.Aromatic heterocyclic chemistry 11 Chlorophyi-a is a plant pigment involved in the crucial photosynthetic process in which the energy of sunlight is harnessed to incorporate carbon sloxide into plant metabolism. Haem, however, is fundamental to mammaitan biology, being the coxygen-binding component of haemoglobin. Oxygen absorbed from the air is transported around the body while temporarily co- ordinated to the iton atom of Acetylenic thiophene 2.9, found in some species of higher plants, is one M@etnoalgbin. which occurs in the ‘of the few naturally-occurring thiophenes. However, the thiophene ring is used in several important pharmaceutical products, such as the penicillin antibiotic 2.10. cont 4 z rm Or 5 Ess Bye LOK oO ton 210 In contrast to the pyrrole and thiophene series, the furan nucleus occurs in Terpenes are plant-derived ‘many plant-derived terpenes such as 2.11. The most important furan- ae proces cones te! of ‘containing drug is 2.12, which reduces gastric acid secretion and is important hydrocarbon teoprene, in the treatment of ulcers. NOs (ae 2a . Synthesis of pyrroles, thiophenes, and furans fe shall first examine a general synthesis applicable to all three cles, then consider two specific syntheses of pyrroles. Retrosynthetic cleavage of a carbon-heteroatom bond in 2.13 gives enol 14 which is equivalent to ketone 2.15. Repeating the process gives us a licarbonyl compound and the heteroatom-containing fragment such as a amine or hydrogen sulphide.12 Pyrroles, thiophenes, and furans fame hth. mdf ety 213 Pe + RNHSH,S.H,0 ‘The forward process is known as the Paal-Knorr synthesis. This is a very straightforward synthesis limited only by the accessibility of the 1,4- dicarbonyl precursors. _=n0, er ‘The mechanism is ilustrated by wry the proparaton of 2aimehy x) pyrrole 2.16 and i simply two IV =e Do LN 1? A. = ee — 44) a a consecutive condensations. %, mde. 246 The Paal-Knorr synthesis can similarly be applied to thiophenes, e.g. compounds 2.17 - 2.20. 0 0 s 00 . 217 218 Orme eis onan £3 0 6 Bison ie yA Pa\ CO;Me 219 ae When hydrogen sulphide is the heteroatom source the mechanism is similar to the pyrrole case. > eG = En Qa However, the situation is slightly different when phosphorus (V) sulphide is used. This reagent converts ketones to thioketones, by exchange of a phosphorus-sulphur double bond with a carbon-oxygen double bond. ox Riek) {ao c: ra oe e «=.Aromatic heterocyclic chemistry 13 For instance, in the synthesis of 2.19, the 1,4-diketone is converted into the corresponding 1 ,4-dithioketone followed by loss of hydrogen sulphide. P&S, —ns ‘The mechanism of the cyclisation ni pn tend pet ok, ROA 219 ie ‘Our retrosynthetic analysis of the Paal-Knorr synthesis leads to a problem ‘when applied to furan, as it implies addition of a water molecule, followed by elimination of two water molecules. In practice, simple dehydration of a 1,4- | dicarbonyl compound leads to furans as in the preparation of 2.21. | HPO, ~H,O | IAs I e' atoohm mm AOt mAyBor AG aa ‘Returning again to pyrroles, probably the most widely-used method for ‘their preparation is the Knorr pyrrole synthesis, which is the condensation of ketone 2.22 with an o-aminoketone 2.23 to give pyrrole 2.13, via enamine 2.24, A reasonable mechanism is shown below, although none of the intermediates is isolated, Blew oie] te RNo HAN ~R, Re aan 22 oe 224 Ry Rs OH i \, = Bre The 4 The c-aminoketones are often prepared by nitrosation of an active thylene group followed by reduction of the oxime to the amine (e.g. 2.25 2.26 to 2.27). 4 ° ° 9 L Conk P0808 — G08 wae = aa ie Pe iets Y —* *tngo, ‘AcOH AN, “I Ni A (orn “a 227 As a-aminoketones are prone to self-condensation (see page 22 for a ussion of -aminoketones), the initial condensation step is facilitated by 2 in 2.22 being an electron-withdrawing group. This enhances the philic nature of the ketone carbonyl group thereby increasing the rate the desired reaction, and favours enamine tautomer 2.24 over the imino14 Pyrroles, thiophenes, and furans \ The Knorr pyrrole synthesis ‘consists of a ketone and amine ‘condensing to give an enamine, followed by intramolecular ‘cyclisation of this enamine onto the remaining ketone. Note that pyrrole reacts with electrophiles on carbon, like an enamine. tautomer because of conjugation with the electron-withdrawing group. A selection of Knorr pyrrole syntheses, showing the key intermediate enamines, is shown below. 5. ae ° aes > Sa. Be 1, mes) ES COB CoH on 4 ee eos at ogee BN coe Op N Ph — Pa Oh ¢ de aie eA tS 2 23 Electrophilic substitution of pyrrole, thiophene, and furan All three heterocycles undergo aromatic substitution reactions, though their reactivities vary considerably. Let us consider a generalised mechanism and how the ees Soy of the two possible intermediates affects the position of @ e PES & FO. ’ ae gh oo : Slag XeNHSO 2.29 ‘The intermediate derived from attack at the C2 position has greater delocalisation of the positive charge (mesomeric forms 2.28a,b,c) than that derived from attack at the C3 position (mesomeric forms 2.29a,b). As the charge is more extensively delocalised in the former, this intermediate is at lower energy. This in turn is reflected in a lower activation energy for this pathway and manifested in a selectivity for electrophilic substitution at the 2 position over the C3 position. The actual isomer ratio depends on the heterocycle, the electrophile, and the precise conditions, although in many ‘cases such reactions are virtually regiospecific, and only the C2 substitutionAromatic heterocyclic chemistry 15 products are isolated. Very reactive electrophiles (such as the nitronium ion ‘NO>7+) exhibit lower selectivity because they tend to be less discriminating ‘28 to where they attack the heteroaromatic nucleus. The ease of electrophilic substitution is pyrrole > furan > thiophene > ‘benzene. Pyrrole is extremely reactive towards electrophiles while thiophene, the most aromatic of the trio, is much less reactive. At a very rough ‘approximation, the reactivity of thiophene is of the order of a heteroatom- substituted benzene derivative such as phenol. Despite large differences in the rates of electrophilic substitutions there are some important aromatic substitution reactions common to all three heterocycles. The Vilsmeier reaction is the formylation of reactive aromatic compounds ‘by using a combination of phosphorus oxychloride and N,N- dimethylformamide, followed by a hydrolytic workup. OY 7\ 1, Me;NCHO/ POC! ee a 2. 0 x X=NHS,O H The reaction proceeds by formation of the electrophilic Vilsmeier complex 2.30, followed by electrophilic substitution of the heterocycle. The formyl “sroup is generated in the hydrolytic workup. Pyrrole, thiophene, and furan all ‘endergo this formylation which is highly selective for the C2 position. To give a quantitative feel for these differences in reactivity, data for the bromination of three representative derivatives are shown below. All three heterocycles undergo sulphonation with the pyridine-sulphur “oxide complex. This behaves like a mild source of sulphur trioxide, ‘bling the sulphonation to be carried out under essentially neutral ditions. i \ x X=NHSO Furan and pyrrole are not stable to mineral acids, but acetyl nitrate can be for the nitration of all three heterocycles. [\ ou 0" Prvpi —-& =e Dro, ag’ ‘x7 SOs16 Pyrroles, thiophenes, and furans ‘The formation of 2.82 raises an Whilst the mechanism shown above applies to pyrrole and thiophene, the er coral Fo vomatio itration of furan with acetyl nitrate gives the 2,5-addition product 2.32, and the driving force ore arising from attack of acetate jon on the intermediate cation 2.31. Treatment ‘aromatice’ by lass af a proton is «of 2.32 with pyridine eliminates the elements of acetic acid producing not very strong, cation 2.31 can _nitrofuran 2.33. be intercepted to give 2.82, This behaviour is not observed with a pystole and thiophene. Thiophene, alkyl-substituted furans, and especially pyrrole, undergo ‘Mannich reactions. ain : a > oe “Ths involves condensation of the heterocycle, formaldehyde, and an amine (esually a secondary amine) to give an aminomethyl derivative. AcOH 8. 2. Mesu+co —S + CH= NM, “orc ‘The Friedel-Crafts acylation and alkylation reactions are fundamental processes in aromatic chemistry. Pyrroles and furans are not stable to the Lewis acids necessary for these reactions, but thiophentes are stable to Lewis ‘acids, and do undergo Friedel-Crafis acylation and alkylation. OY PRCOCL (\_o s ar Ph 20, Oi Ss ‘Sach, ee enh ts Position when both the C2 and C5. a -Aromatic heterocyclic chemistry 17 The reactivity of all three heterocyles is considerably reduced when celectron-withdrawing groups are present on the ring. This is important in the synthesis of pyrrole derivatives as it adds chemical stability to the ring, ‘enabling reactions to be performed in the presence of Lewis acids. NO NO. i \ tebe f ll y BF:0E; - ° ‘The regiochemistry of these » oe mee ccay eared eee Onde 0 ers ‘NO, BFE” om, ‘NO, 4 a e cee oD. : ca Pee. oO. ce} H H a peer a 0" NO, *O Anion chemistry of pyrroles, thiophenes, and furans Pyrrole has a weakly acidic hydrogen atom attached to the nitrogen (pKa= -5) and can be deprotonated by strong bases. The sodium and potassium are ionic in character and the naked anion tends to react on nitrogen as in preparation of N-methyl pyrrole 2.34. The corresponding magnesium ative 2.35 has more covalent character and tends to react more on carbon nitrogen, as in the preparation of pyrrole aldehyde 2.36 O me, O =. O aw Me N e one it D — pod Oy a 235 a.” yl pyrrole 2.34, thiophene, and furan can be metallated at the C2 with alkyl lithium reagents. This position is more activated to ation than the C3 position because of the electron-withdrawing ive effect of the heteroatom. The nucleophilic 2-lithio species can then with various electrophiles, as in the preparation of 2.37, 2.38,18 Pyrroles, thiophenes, and furans and 2.39. Let us see how this methodology can be applied to the synthesis of 2.42, a furan-containing mimic of a long-chain fatty acid. Deprotonation of furan and alkylation produces 2.39. A second deprotonation at the C5 position and alkylation gives bromide 2.40. Displacement of the bromide affords nitrile 2.41, and acidic hydrolysis yields the target furan 2.42, e ome a (coe Me 237 ‘The precise nature of the carbon— lithium bond is beyond the scope of this book. Organolithium intermediates are here Fr) ous 2 HOO 6 represented as carbanion and — eli rine s Ee cation to emphasise differences in s Boe Properties and reactivities as 22 2.38, Compared with fll covalent bonds. “The alky! group atthe C2 poston BuLi/CHICHDRe Bul BUCH BE is not deprotonated in the second aaa! ) —__—*i allylation ° cH) cee, (apex 23 239 240 N Note the use of “CN as a synthon r HC1/#,0 \ econ ae eaycon oF ee (cayeen ne 2st E ; — 243 Tricyclic pyrrole derivative 2.43 is a drug currently under development for the treatment of schizophrenia. It is prepared by a Knorr pyrrole synthesis. ‘What are the structures of the two starting materials required, and that of the termediate enamine? 2. Why is pyrrole aldehyde 2.44 less reactive to nucleophiles than, say, benzaldehyde? Why is pyrrole alcohol 2.45 readily polymerised on exposure to acid’Aromatic heterocyclic chemistry 19 ._Nitration of furan with nitronium tetrafluoroborate produces nitrofuran 33 directly. Contrast this result to the two stage reaction necessary with yl nitrate, page 16. Explain these observations. eo O _NoaBr. i" 0" 0” 22 233 What is the mechanism of this reaction? CS a aS 2 3 References in, F.M. (1982). Adv. heterocyclic chem., 30, 167; 31, 237 (furans), owitz, S. (ed.) (1985). In Thiophene and its derivatives (The istry of heterocyclic corapounds ed. A. Weissburger and E.C. Taylor], . 44). Wiley Interscience, New York. iss, B.S., Hannaford, A.J., Smith, P.W.G, and Tatchell, A.R. (1989). Vogel's textbook of practical organic chemistry (Sth edn), p.1148 (preparation of pyrrole 2.16). Longman, Harlow. son, A.H. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (ol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis) (pyrroles). Pergamon Press, Oxford. R.A. (ed.) (1990). In Pyrroles (The chemistry of heterocyclic compounds (ed. A. Weissburger and E.C. Taylor], Vol 48, Part 1), Wiley Interscience, New York. R.A. and Bean, G.P. (1977). The chemistry of pyrroles. Academic Press, London. , B. and Moodie, ILM. (1970). Org. syn., $0, 104 (C2 metallation of thiophene). itzky, A.R. and Rees, C.W. (ed.) (1984). Comprehensive heterocyclic chemistry, Vol. 4, Part 3 (five-membered rings with one heteroatom). Pergamon Press, Oxford. -Cohn, O. (1979). In Heterocyclic chemistry (ed. P.G. Sarnmes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis), p.737 (thiophenes). Pergamon, Press, Oxford. ent, MV. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and WD. Ollis), p.693 furans). Pergamon Press, Oxford, in, R.M., Ryskiewicz, E.E., and Willard, C. (1963). Organic “syntheses, Coll. Vol. IV, 831 (Vilsmeier formylation of pyrrole).The biosynthesis of histamine involves decarboxylation of the amino acid histidine. 3. Oxazoles, imidazoles, and thiazoles 3.1 Introduction Oxazole 3.1, imidazole 3.2, and thiazole 3.3 are the parent structures of a related series of 1,3-azoles containing a nitrogen atom plus a second heteroatom in a five-membered ring 2 12 fied sl 2 2 lS: °% x si = 3 ‘They are isomeric with the 1,2-azoles isoxazole, pyrazole, and isothiazole (see Chapter 4). Their aromaticity derives from delocalisation of a lone pair from the second heteroatom, 3.4a-e. = ~~ ex =x sr eee 3 0 — Cie z s g 5 34a 3b Be 34d Be X=ONES ‘The imidazole ring occurs naturally in histamine 3.5, an important mediator of inflammation and gastric acid secretion. A quatemnised thiazole ring is found in the essential vitamin thiamin 3,6, There are few naturally occurring oxazoles, apart from some secondary metabolites from plant and fungal sources. NH, a & F~N i 2 q iv ea allt m 35 36 Oxazole, imidazole, and thiazole can be formally derived from furan, pyrrole, and thiophene respectively by replacement of a CH group by a nitrogen atom at the 3 position. The presence of this pyridine-like nitrogen deactivates the 1,3-azoles towards electrophilic attack and increases their susceptibility towards nucleophilic attack (see later). These 1,3-azoles can be viewed as hybrids between furan, pyrrole, or thiophene, and pyridine.Aromatic heterocyeli¢ chemistry 21 Imidazole (pXs=7.0) is more basic than oxazole (pK a=0.8) or thiazole The statement that oxazole has a (pK,=2.5). This increased basicity arises from the greater clectron-releasing Ka of 0.8 means that the capacity of two nitrogen atoms relative to a combination of nitrogen and a _Protenated form of oxazole is a heteroatom of higher electronegativity. Also note that a symmetrical Ye Sone 256. q ‘Therefore oxazole the fr resonance-stabilised cation 3.7a,b is formed. a ea ped Eioed, @ rs er oa (ye ye) a H xe sa 3 Furthermore, certain substituted imidazoles can exist in two tautomeric : Se 38 39 instance, the imidazole shown above exists as a rapidly equilibrating ixture of 4-methyl 3.8 and S-methyl 3.9 tautomers, and is referred to as 5)-methylimidazole. Tt must again be stressed that tautomerisation and nance afe totally different. Mesomeric representations 3.7a,b are not mnverting like tautomers 3.8 and 3.9; this is simply a means to describe intermediate hybrid structure. Synthesis of oxazoles synthetic cleavage of the carbon-oxygen bond in generalised oxazole produces iminoalcohol 3.11 (better represented in the artide form By Na? er ig => af % et 1. R07 [OH J Siam ‘oH oO 312 au su L ty m a — xt ig . . Re Ce as sat i 1.12), Simiar tautomerisation of the enol group gives an actual ediate 3.13, and disconnection of the amide linkage seveals sketonte 3.18 and an acylating species 3.14 such as an acid chloride. The ard process, cyclocondensation of amides 3.13 to yield oxazoles 3.46, is as the Robinson-Gabriel synthesis.22 Oxazoles, imidazoles, and thiazoles Nu; pe: Ba, eee 2 ma) oS U3 ae a is ne In practice the dehydration can be achieved with a broad range of acids or acid anhydrides, such as phosphoric acid, phosphorus oxychloride, phosgene (COCIg), and thionyl chloride. An example of the mechanism is shown below for thiony] chloride and involves activation of the amide to imidoly! halide 3.16 then intramolecular attack by the enolic form of the ketone. 8 |. NY_LRs NBs NUR -nar, N y Seo, amemees ST 0.7% wie Soi ee, = Lady As as 4) &) = aw ‘The aminoketones themselves can be prepared by a number of methods. A typical route is illustrated by the synthesis of anti-inflaramatory drug 3.23. Br, ae “Naty = Gia se ao ‘0 ais Pir 3.20 ° ot Aeop [PROP Ph WT et LN:OH Ws. = qt 323 a2 Drugs which reduce intammation —Bromination of Ketone 3.17 gives 3.28 which can be converted to azide 3.19, ‘are often used to treat the Hydrogenation of 3.19 in the presence of hydrochloric acid affords errno mate: aminoketone hydrochloride salt 3.20. Such aminoketones are often isolated as the corresponding salts because the free aminoketones are prone to dimerisation, having both nucleophilic and electrophilic centres. (For a common alternative preparation of aminoketones, see the Knorr pyrrole synthesis, Chapter 2.) Liberation of the free base of 3.20 in the presence of the acid chloride affords amide 3.21 which is cyclised to oxazole 3.22. Ester hydrolysis then affords the biologically-active carboxylic acid 3.23. 3.3. Synthesis of imidazoles Although there are several ways of preparing imidazoles, there is no one outstanding method. One useful synthesis is the condensation of a 1,2Aromatic heterocyclic chemistry 23 Sicarbonyl compound with ammonium acetate and an aldehyde, as in the Preparation of imidazole 3.25. ‘McO. a ie Oe eee F r% Lh RR OO ‘MeO’ tas F ‘A reasonable rationalisation is a cyelocondensation type of process to give followed by irreversible tautomerisation to 3.25. e e RO © @ 6 R UNH mua" Ri bea 8 OA Ae OI Geen cei KE cate Ro Ry Sw Rw @ < R, RL RN ff iN =N NR; Th, — Oe om Spi. oye Ry Xa a; Ls 325 324 formally to enol 3.27 which is equivalent to ketone 3.28. This can be ived from haloketone 3,29 and thicamide 3.30. v3 OH R, O NH. RO NE Bo SO = Ne Rie 82 oR, Ry a ROX Bian, 3.26 327 3.28 3.29 3.390 X=O.Brd ‘The forward process is the Hantasch synthesis of thiazoles which, despite antiquity (it is around 100 years old), is still very widely used. ° Mh Lact ws at oo mae ee oN ‘Thiocarbony compounds are ‘Much more nucleophilic than 331 carbonyl compounds because ‘The mechanism for the formation of thiazole 3.31 involves initial ofthelower th lic attack by sulphur followed by a cyclocondensation, cf sulphur as compared to24 Oxazoles, imidazoles, and thiazoles ‘As with pyridine, not only does the electronegative nitrogen atom withdraw electron density from the ring, but under the acidic conditions of many electrophiic reactions the azole nitrogen is protonated. The azolum cation is relatively inet to further attack by a positively charged electrophile. EN x OHH Le wt HON yao N arg a TE TK ‘The thioamides themselves are conveniently prepared from the corresponding, amides by treatment with phosphorus (V) sulphide (see the Paal—Knorr synthesis of thiophenes, Chapter 2, for this type of conversion). A variation of the Hantzsch reaction utilises thioureas, where R3 in 3.30 is a nitrogen and not a carbon substituent. For instance, thiourea itseif is used in the ‘preparation of 2-aminothiazoles such as 3.32, 3.5 Electrophilic substitution reactions of oxazoles, imidazoles, and thiazoles The 1,3-anples are not very reactive towards electrophilic attack due to the deactivating effect of the pyridine-like nitrogen. However, electron-donating groups can facilitate electrophilic attack, as in the preparation of oxazoles 3.34 and 3.35. Dimethylamino oxazole 3.33 is essentially functioning like ap enamine in this reaction. 0 Lay ators v3 — CF 003 — MeN Po” >F 33s a ae No, “soe Imidazole can be nitrated under forcing conditions, nitration remarkably occurring on the imidazolium cation 3.7a,b, giving nitroimidazole 3.36 after loss of two protons. NO; x a CS wax vy 3.36 5 fe Tae e ra ml Le oA MQ om ° “TS. KES a OS Sara xe %Aromatic heterocyclic chemistry 25 3.6 Anion chemistry of oxazoles, imidazoles, and thiazoles C2 position of 1,3-azoles is particularly electron-deficient because of the ctron-withdrawing effect of the adjacent heteroatoms. The acidity of the ‘protons at this position is such that deprotonation can be achieved with ig bases to give nucleophilic carbanions 3.37 which can be quenched ith electrophiles producing substituted 1,3-azoles 3.38. lS mBoLi Oe ue ® ON 338 x Xs * Ne ilarly, alkyl groups at the C2 positions (but not the C4 or CS positions) There is @ useful analogy be deprotonated giving carbanions 3.39a,b which can also be quenched _Petween resonance-stabilised a o anion 8.98a,b and an ester ith electrophiles to afford 1,3-azoles 3.40. enolate anion. Note that in both cases the negative charge can be Ee ee Bato hither penton Cs) Coe a OOM Ou ° a es cA a ae examples of both the above types of reactivity are given below of 7 C3 pa kee rots waned Ny CPhs ch; H x N i) 2, T i f 2CHCHO : ™ anaro a a L nBoLt ry y |. n-BuLi \ Ph Ph oN 2Pp,CO ” Pho’ Ph 3,.HC1/ 1,026 Oxazoles, imidazoles, and thiazoles ‘Once again this reactivity parallels certain features of carbonyl ‘chemistry. Compare the reaction of aniline with chloroformates, below. ° AD | ENP ° ape H 3.7 Nucleophilic aromatic substitution of oxazoles, imidazoles, and thiazoles We have previously discussed the reduced reactivity to electrophiles of oxazole, imidazole, and thiazole, as compared to furan, pyrrole, and thiophene, which results from the presence of the pyridine-like nitrogen atom. This behaviour is paralleled by increased reactivity to nucleophiles. ‘Nucleophilic attack on furan, pyrrole, and thiophene derivatives only occurs when an additional activating group is present, as in the displacement reaction giving thiophene 3.41. co =, th, \ OY i \ Cg Ss on’ NGS 20 341 ‘The nitro group plays a key role as an electron-acceptor in this reaction, which also illustrates the fact that imidazole is a good nucleophile. However, no activation is necessary with 2-halo-1,3-azoles, which can react with nucleophiles, as shown by the preparations of 3.42 and 3.43. ans a i ae Ir cla —cl wa A eae HNPh Os Cy 2% oO se eee oe 3.8 Problems 1. Suggest a synthesis of oxazole 3.33. i coe Se 33 2. A less general synthesis of oxazoles is the condensation of bromoketones with amides. What is the mechanism for the formation of oxazole 3.44? How does 3.44 relate to the oxazole which might be prepared from the same bromoketone by conversion to the corresponding aminoketone, N- formylation, and cyclocondensation?Aromatic heterocyclic chemistry 27 Carboxylic acid 3.46 has been extensively used in the preparation of i-synthetic penicillins and cephalosporins. Devise a synthesis of 3.46 ester 3.45. coe co, Monee money soon, sas References ipbell, M.M. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) ‘ol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. |. p- 962 (oxazoles) and p. 967 (thiazoles). Pergamon Press, Oxford. iss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989). Vogel's textbook of practical organic chemistry (Sth edn), p.1153 {preparation of aminothiazole 3.32). Longman, Harlow. immett, M.R. (1970). Adv. heterocyclic chem., 12, 103 (imidazoles). immett, M.R. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) fal. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. is), p.357 (imidazoles). Pergamon Press, Oxford. immett, M.R. (1980). Ady. heterocyclic chem., 27, 241 (imidazoles). in, R. and Terai, B. (1974). Adv. heterocyclic chem.,17, 99 (oxazoles). get, J.V. (1979), In Thiazole and its derivatives (The chemistry of heterocyclic compounds [ed. A. Weissburger and E.C. Taylor], Vol. 34). Wiley Interscience, New York. hi, LJ. (1986). In Oxazoles (The chemistry of heterocyclic compounds fed. A. Weissburger and E.C. Taylor], Vol. 45). Wiley Interscience, New York. i, LJ. and Dewar, M.J.S. (1975). Chem. rev. ,75, 389 (oxazoles).4. lsoxazoles, pyrazoles, and isothiazoles Isoxazole 4.1, pyrazole 4.2, and isothiazole 4.3 are the parent structures of the 1,2-azole family of heterocycles, having a nitrogen atom plus one other heteroatom in a 1,2-relationship in a five-membered ring. 43 So a \ au 2 ¢ N2 sf N2 ‘ N’ 8 i H 1 an 42 43 The aromatic sextet is completed by delocalisation of the lone pair from the second heteroatom, 4.4a-e. Consequently, as in pyridine, the nitrogen atoms of the 1,2-azoles have a lone pair available for protonation, However the 1,2- azoles are significantly less basic than the 1,3-azoles because of the electron- withdrawing effect of the adjacent heteroatom. Isoxazole and isothiazole are essentially non-basic heterocycles (pX,s <0), and even pyrazole (PK=2.5) is a much weaker base than the corresponding 1,3-azole imidazole (pK, 7). Oo g ( é \ 4 ols Nae LN we GN a (Ne <> 4, x @ c e @ 44a 4.4b 44e 44d ade X=ONHS As with substituted imidazoles, substituted pyrazoles may exist as a mixture of tautomers. 5-Methyl pyrazole 4.5 and 3-methyl pyrazole 4.6 exist as a rapidly equilibrating mixture in solution. as oS ke Na “a re 46 Although there are a few examples of naturally-ocourring 1,2-azoles, many totally synthetic derivatives have found pharmaceutical application.Aromatic heterocyclic chemistry 29 A Synthesis of isoxazoles and pyrazoles synthetic disconnection of generalised 1,2-azole 4.7 gives initially 4.8 ich would exist as ketone 4.9. This in tum is clearly derived from 1,3- ne 4,10. R Bae ‘ AL HNOH JORG e 442 HANNE, ROH doy ene! 413° H,NSH 48 49 410 in practice hydroxylamine and hydrazine are very reactive nucleophiles, far more so than might be expected from consideration ot simple physical is analysis suggests that condensation of 4.10 with hydroxylamine 4.11, parameters. The inceased rine 4.12, or thiohydroxylamine 4.13 should give the corresponding "uCleophilicty of a heteroatom azole, This approach represents an important route 10 isoxazoles and When bonded to @ second les, but thiohydroxylamine 4.13, although known, is far too unstable _ Pereosiom is known as the synthetic purposes. The synthesis of isothiazoles will be mentioned later, 100% FOC 2 Saran mechanism of the forward process is illustrated by the preparation of Yerms of frontier obitals see Fleming, 1976. # Y —#0 i HO. ne. a Jt ‘0 414 Note that if hydroxylamine or a substituted hydrazine is condensed with an symmetrical diketone (4.10, where Rj and R3 are different) then a joisomeric mixture of isoxazoles or pyrazoles may result. However a le regioisomer may predominate where there is an inherent bias. oo The general reactions of HyNOH ws HOH | ae at R, o oO and HoNNHR with unsymmetrical NNER Ry Ry Rs diketones are shown here. Ry xR i + ae R RONT RN R instance, the preparation of isoxazole 4.17 is virtually regiospecific ause the reaction commences with the more nucleophilic heteroatom (i.e. trogen) attacking the more electrophilic ketone (activated by the electron ithdrawing inductive effect of the adjacent ester group). The reader is -ouraged to consider the regiochemical bias in the preparation of isoxazole 13 and pyrazole 4.16.30 Isoxazoles, pyrazoles, and isothiazoles es con : ea ne ‘The other important isoxazole synthesis involves the concerted [3+2] cycloaddition reaction of nitrile oxides 4.18 with cither alkynes 4.19 or alkyne equivalents 4.20. i PAP eM = * me 1% xh } Me To Ro Rt ‘X=OAc,NMe,,NO, A wide range of nitrile oxides is known (R3 = H, aryl, alkyl, ester, halide, etc). The method of choice for the preparation of simple nitrile oxides (R3 = alkyl, aryl) is oxidation of the corresponding oxime: OH P A SO es ., e HO, Be i PD, ee N-0 il 438Aromatic heterocyclic chemistry 31 Several oxidising agents can be used (lead tetraacetate, N- ‘bromosuccinimide, chlorine, etc). A mechanism is illustrated below for alkaline sodium hypochlorite. ¥O) RS wou x on Bee aan Xa Let us now consider the synthesis of isoxazole 4.28, a drug for the iment of bronchial asthma. The most direct preparation of isoxazolyl Ketone 4.24 is the cycloaddition of unstable bromonitrile oxide 4.22 (prepared in situ by dehydrobromination of 4.21) with acetylenic ketone 4.23. )bserve the regioselectivity of this reaction. Both electron-donating and lectron-withdrawing groups on the acetylenic components in such ‘loadditions tend to occur at the C5 position in the final isoxazole and not C4, Bromination of ketone 4.24 affords bromoketone 4.25 which is ~ Bo Br Br en =< me. Br r Soe een ee NY BW oo Ne *o’ Yo’ Br aa ne an as ° a2 a / 2 Br to am wee TT ge I NiBa 0’ 0’ Be on ° Me 428 aar 426 with sodium borohydride to give bromohydrin 4.26. Treatment with a mg base produces epoxide 4.27 via the intermediate alkoxide, and Jleophilic opening of this epoxide at the least sterically hindered position the tanget drug 4.28. Synthesis of isothiazoles thiazoles are usually prepared by routes involving formation of the itrogen-sulphur bond in the cyclisation step. This is often set up by ‘dation of the sulphur atom, as in the conversion of thioamide 4.29 to liazole 4.30. NH, RSafaiy aaa ls bes aa Gagan | a \ | Ps as 7 = ‘a NS Wag a Cee, OX, He a HWA ie32 Isoxazoles, pyrazoles, and isothiazoles NO, i us 5 x See the related preparation of ritroimidazole 3.36. 3 Electrophilic substitution of isoxazoles, pyrazoles, and isothiazoles ‘The presence of a pyridine-like nitrogen in the 1,2-azoles makes them markedly less reactive towards electrophilic substitution than furan, pyrrole, and thiophene, (The same effect was noted for the 1,3-azoles in Chapter 3.) Nevertheless, electrophilic substitution is known in 1,2-azoles, occurring principally at the C4 position. This selectivity is reminiscent of pyridine chemistry where the position meta to the electronegative nitrogen atom is the ‘least deactivated’ (see Chapter 5). Br—Br Be Br Cw Br, H Ca ge De Np tees inlay to We ‘0% BrLBr Br Br Ay X Br, BON -x® q a ty NaOAc™ SNe = aera NY 8 u a Nitration and sulphonation of 1,2-azoles under vigorous conditions are also known, as in the preparation of 4-nitropyrazole 4.31. NO, NQ e oO HNO, Or No; Ht —on® ll ‘ ll : 2 Bs: [ Ne 2H i \ N NW ou NT 43t a H 4 H As we have seen with other electron-deficient heterocycles, the introduction of an electron-donating group promotes electrophilic substitution, as in the facile bromination of aminoisothiazole 4.32. 4.4 Anion chemistry of isoxazoles, pyrazoles, and isothiazoles Isothiazoles and nitrogen-blocked pyrazoles can be deprotonated at the C5 position with alkyl lithium reagents, and the resultant carbanions quenched with a wide range of electrophiles, as in the preparation of 4.33 and 4.34.Aromatic heterocyclic chemistry 33 ° CY, ne, ef mm sae a 3 =O) Ss 433 ° Y eBuli 1 ‘Mel i \ EX sel ee UN Ph mh Ph This useful methodology (complementary to the C4 selectivity of normal lectrophilic substitution) is not applicable to isoxazole chemistry because intermediate anions (such as 4.35) are rather unstable and decompose via -a-nitrogen cleavage. Ph Ph PR Ph mh gy meu? ow Ce i + PREN ° 3 * its 435 ever, alkyl groups at the C5 position of isoxazoles can be deprotonated reacted with electrophiles. : Note the analogy tothe anions Bes =. et, ae, Se ‘0 w e8&-“4 Ph of oR Dimethyl isoxazole 4.14 can be selectively deprotonated at the C5 methyl rr SS up, nearer the more electronegative oxygen atom. Although simple g AN ° tonation cannot afford an entry into C4 substitution in this system, it is sible to generate a carbanion at the C4 position in a roundabout fashion. t t ination of 4.14 affords the C4-functionalised isoxazole 4.36. Metal— OR jogen exchange With n-butyllithium at low temperature (-78°C) generates = imag yanion 4.37 which can be quenched with electrophiles to give isoxazoles one ee e as 4.38. epaat Interestingly, 1, 3, 5-trimethyl ui? pyrazole is deprotonated on the uk Be s CQH 7 N-methyl group, facitating aa ren TX 1.00, TG reaction with electrophiles at this oN oe ASN ee A ‘7 Position. aaa 436 437 438 IG a N Me Problems ld sx Ni Ne a 08 pe HE : SS ~x® _ sat (> ol = (7 s» oy aya % oe @ 08 Ez E B o poy S wl jJ—+- () — ff Ne NO NZ set Ores PO, O- Fel,Aromatic heterocyclic chemistry 39 instance, 4-nitropyridine 5.20 can be prepared from pyridine in three by this methodology. No, No, S HNO, — AS 5 pw (J +> CC 780, % . 0 520 Pyridine N-oxides can also be converted into synthetically useful 2- loropyridines §.21 (see later). Another approach to electrophilic substitution involves the chemistry of idone 5.22 and 4-pyridone 5.23. These are the tautomeric forms of 2- 4-hydroxypyridine respectively. They exist exclusively in the pyridone . the hydrogen atom being attached to the nitrogen atom, not the ‘ygen. Their electronic structures are not adequately described by a single ce representation, the lone pair from the nitrogen atom being delocalised a considerable extent onto the oxygen atom, as in mesomeric on ° Sy ( = (Fs 0 Nn? On no Nees N H sz H 523 ° oe Ss S S q + [ ( J) «+ f{ NSO, ria N NZ H iH H fh H s2z 523aH Both pyridones can react with electrophiles at positions ortho and para to activating oxygen atom. For instance, 4-pyridone reacts with trophiles at the C3 position (the mechanism can be formulated from +T mesomeric representation) to give intermediate 5.24, As with pyridine rides, reaction with phosphorus oxychloride gives useful yyridines 5.25. We shall see the utility of 2- and 4-chloropyridines in next section.40 Pyridines ‘The actual mechanism is rather complicated. Hydrogen gas is ‘evolved, but in reallly free sodium hydride is never generated. See ‘McGill and Rlappa (1988). ay Ge sult, BEN H H \-cr ey) g t oN gues ® Pcl o-a sm fl apa gira E es E A ( — 14 — l “7 N’ N" o i il 525 e H 5.4 Nucleophilic substitution of pyridines Pyridine can be attacked by nucleophiles at the C2/C6 and C4 positions in a | manner analogous to the addition of nucleophiles to a carbonyl group in a 1,2 or 1,4 fashion. Attack at the C3/C5 positions is not favoured because the negative charge on the intermediate cannot be delocalised onto the electronegative nitrogen atom. > xi (ry Oo gf GG Be) AN, . ae. Ss Under conditions of high temperatures the intermediate anion can re- aromatise by loss of a hydride ion, even though it is a very poor leaving group. This is illustrated by the Chichibabin reaction of pyridine and sodamide to produce 2-aminopyridine 5.26. The immediate product of the reaction is 5.27, the sodium salt of §.26, as the eliminated hydride ion is very basic. Protonation of this sodium salt during the aqueous workup then regenerates 5.26. A simplistic rationale is shown below. SS SS DS ‘NaH_(CHa) Or Oe=0 ¥ Gy Nal Ny? Aa woe NZ Ny, KO Nn, ne 526 sar o 8 NH NaAromatic heterocyclic chemistry 41 nucleophilic substitution reactions are much more facile when better wving groups (e.g. halide ions instead of hydride ions) are employed. s ox S in) re —e, WRG e woex @) x x & © ie G23) ssarasese eng lls aasnitms reso w N’ x as X= Nucleophile Nucleophilic substitutions are widely used in pyridine chemistry. Some a RAynZ S ae S i Ne =o) QO HIN(CH,CHCH,)» OC c Na, N’ aie a SEt ea ENN () xn 7s a tO eS a NS nat N ‘ a HINPh SS HNMe Ss SS HNPh SS oe ee (SV ose all a N7 SMe nN’ N a ca un-Ne 8 Ne OMe (S SS HANNE, Sy ipa es (J — | a N” Some N’ n7 Finally, before leaving this section, we shall consider the synthesis of idotriazine 5.32, a potential anti-fungal drug. This synthesis illustrates s of both electrophilic and nucleophilic pyridine chemistry. Nitration of 4-pyridone 5.23 gives 5.28, and reaction with phosphorus ‘chloride affords chloropyridine 5.29. This pyridone-chloropyridine ersion activates the system to nucleophilic attack by hydrazine, affording . The nitro group also facilitates nucleophilic attack by delocalisation of ive charge in the intermediate.42 Pyridines HN-NH cl n/N ‘le re fy Nn NZ sp 520 N-Acylation, reduction of nitro to amino, and condensation produce dihydrotriazine 5.31. This system is readily dehydrogenated with manganese dioxide to afford the fully aromatic heterocycle 5.32. Note how relatively simple chemistry can be used to form a quite complex heterocycle, Wyo ] ; orgs =e ‘N’ Bai N’ ora 5.23 5.28 ‘Hy | PAC , ‘ | : 1 Nv nye ql ° o) ioe acne) NM 5.5 Anion chemistry of pyridines We earlier drew a parallel between nucleophilic attack on the C2/C6 and C4 Positions of pyridine and 1,2 and 1,4 addition of nucleophiles to a carbonyl group. This analogy can be extended to deprotonation of alkyl substituents at the C2/C6 and C4 positions. oars I-23 Just as a carbonyl group stabilises an adjacent negative charge as an enolate anion, so the anion derived from 2-methy! pyridine is stabilised by delocalisation of the negative charge onto the electronegative nitrogen atom,Aromatic heterocyclic chemistry 43 similar argument holds for 4-methyl pyridine. These stabilised anions can react with the usual range of electrophiles. a OL N a i nae SS S Phi ( PACHACI oer Bay ? a ue PAL ~ 1.00; ee Noe 2H yore u® 1e o 4 a ee pA oe eee weg 2G Na® | The negative charge resulting from deprotonation of the ethy! ‘NaNH, (> Mel ( yo methylene group of 5.33 cannot Z eo be delocalised onto the nitrogen w ‘atom. Dialkyl pyridine 5.33 is selectively deprotonated at the C4 alkyl group, trating the greater acidity of this position over the C3 position. With to ring deprotonation, however, there are relatively few examples m for simple pyridines, in contrast to the extensive chemistry developed the five-membered ring heterocycles. This is because the resultant tallic species are good nucleophiles, and because pyridines are also Tate electrophiles, polymerisation problems are often encountered. More ss has been achieved with substituted pyridines having an ortho tivating substituent (e.g. -CONHR, -NHCOR, -OMe, IQNR etc). These substituents increase the rate of kinetic deprotonation stabilise the intermediate organolithium species by coordination. For instance, 4-aminopyridine 5.34 can be converted to amide 5.35 which, treatment with two equivalents of butyl lithium, gives organometallic ies 5.36. Formylation of the more reactive anion (the carbanion) then se- jonation of the amide anion gives 5.37. Acidic hydrolysis removes the ivating group to release pyridine aldehyde §.38,44 Pyridines The metalation proceeds by initial deprotonation of the amide followed by ortho-directed deprotonation at the C3 position to NH, uno NZ~09 produce the pseudo six: membered ring organolithium i SS) sBucoct, i = neBuli Se species 5.36. ye BN 2 Gopiviemy LD) sa 535, ° ur Sate, aaier0 bia NO ano ° SH HCL (cone) ~ ( eae 4 zZ Heat zZ N N’ 538 $37 5.6 Problems 1. What is the mechanism of this reaction? oR Et WOE BOR” ‘EtOH os Hint, Start by acetyating the 2. The condensation of active methyl groups with aldehydes can be catalysed ye poured with acetic anhydride as well as base. Suggest a possible mechanism. cationic species. How can deprotonation afford a Ph rucleoptilic enamine-ike system? 1 S PhCHO SS le ‘Ae, / AcOH lay, N’ N 3. Rationalise the formation of lactone 5.40 from pyridyl amide 5.39. OMe OMe OMe 1.2¢q.n-Boli 4, CS) w, zeMeocaucHo, (So NZ NP BHSO4/ HO 7 ° saxo ° 540 4, Some pyridine N-oxides are not just synthetic intermediates, but are of interest in their own right. For instance, pyridine N-oxide 5.41 is anew drugAromatic heterocyclic chemistry 45 imed to be useful for the treatment of senile dementia, What are the jovitch, R.A. (1974). In Pyridine and its derivatives (The chemistry of heterocyclic compounds [ed. A. Weissburger and E.C. Taylor], Vol. Supplement Parts 1-4), Wiley Interscience, New York. er, V. and Kuthum, J. (1972). Chem. rev.,72, 1 (dihydropyridines). iss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989). Vogel's textbook of practical organic chemistry (Sth edn), p.1168 {preparation of pyridine 5.13). Longman, Harlow. berg, E. (1974). In Pyridine and its derivatives (The chemistry of ‘heterocyclic compounds [ed. A. Weissburger and E.C. Taylor], Vol. 14, arts 1— 4). Wiley Interscience, New York. ill, C.K. and Rappa, A. (1988). Adv. heterocyclic chem., 44, 3. ith, D.M. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis), p.3. Pergamon Press, Oxford.Quinoline and isoquinaline can also be viewed as being formally derived from naphthalene Note the numbering system for isoquinoline 6. Quinolines and isoquinolines 6.1 Introduction Quinoline 6.1 and isoquinoline 6.2 are two isomeric heterocyclic systems, which can be envisaged as being constructed from the fusion of a benzene ring at the C2/C3 and C3/C4 positions of pyridine respectively. They are both ten n-electron aromatic heterocycles, Like pyridine, they are moderately basic (pK, quinoline = 4.9, pKa isoquinoline = 5.1). Indeed quinoline is sometimes used as a high boiling-point (237°C) basic solvent. ed Se, ¥ n?? 3 61 8 62 As with pyridine, the nitrogen atoms of quinoline and isoquinoline each bear a lone pair of electrons not involved in aromatic bonding which can be protonated, alkylated, or complexed to Lewis acids, This chapter should be read in conjunction with the chapter on pyridines as several points discussed at length there are also relevant to the chemistry of quinoline and isoquinoline. 6.2 Synthesis of quinolines and isoquinolines The classical Skraup synthesis of quinolines is exemplified by the reaction of aniline 6.3 with glycerol 6.4 under acidic/oxidative conditions to produce quinoline 6.1. Senn Pea PRNO; ~ = : #80, eS = e ‘At first sight this reaction appears 40 be another one of those ancient heterocyclic syntheses that owe more to alchemy than to logic, but in fact the processes involved are relatively straightforward.Aromatic heterocyclic chemistry 4 on 64 H oA 67 Protonation of glycerol 6.4 catalyses dehydration via secondary carbonium x1 6.5 10 give enol 6.6. Acid catalysed climination af a second water olecule affords acrolein 6.7. Thus glycerol acts essentially as a protected em of acrolein, slowly releasing this unstable c,8-unsaturated aldehyde into perolein is a highly reactive oletin reaction medium. Better yields are realised with this approach than if that is prame ta polymerisation. lin itself is present from the start. The reaction proceeds with a Michael dition of aniline 6,3 to acrolein, producing saturated aldehyde 6.8 which ises via an aromatic substitution reaction to alcohol 6.9. Acid-catalysed =hydration to 6.10 then oxidation yields quinoline 6.1. Nitrobenzene can be ed as a mild oxidant, meres et tele (Gan nf ote On Ve 619 H so ne examples of the Skraup synthesis are shown below. =e as a ‘The key intermediates in the synthesis of isoquinolines are B- ethylamines. For instance, acylation of B-phenylethylamine 6,11 gives sides of general structures 6,12 which can be cyclised with phosphorus chloride 10 produce dihydroisoquinoline 6.13. Better yields are obtained48 Quinolines and isoquinolines with electron-donating groups on the aromatic ring facilitating this aromatic substitution cyclisation. x, COC Buc ‘X = Hlectron-donsting, sn substituent Sy Pa aN a o14 R This dehydrogenation is As in the Skraup quinoline synthesis, loss of two hydrogen atoms is the reverse of a normal necessary to reach the fully aromatic system. However, this is usually hy re ES : bhi Cysegenanoe te cteg accomplished in a separste step, utilising palladium catalysis 19 give ‘out under milder conditions when generalised isoquinoline 6.14. This is known as the Bischler-Napieralski a hydrogen acceptor (such as synthesis. The mechanism probably invalves conversion of amide 6.12 to ‘eyclohexene) is present. protonated imidoyl chloride 6.13 followed by electrophilic aromatic substitution 10 give 6.13. (For a similar activation of an amide to an electrophilic species see the Vilsmeier reaction, Chapter 2.) Non ee -O0 ot wd i os R ous X= Blecwondonatiog subsiuent The Pictet-Spengier synthesis is Closely related to the Bischler—Napieralski synthesis is the Pictet— usually used when the Spengler synthesis, which utilises aldehydes rather than acylating species. tetrahydroisoquinoline oxidation level tequred. Condensation of B-arylethylamines with aldehydes produces imines such as 6.16 which can be cyclised with acid to give tetrahydroisoquinoline 6.17. As ‘ne Bischler—Napicralski synthesis, electron-donating groups (typically methoxy groups) facilitate the cyclisation step. The lower oxidation state of 6.17 as compared to 6.13 is a direct consequence of using a carbonyl group at the aldehyde rather than carboxylic acid oxidation level. Four hydrogen atoms | have to be removed from tetrahydsaisoquinolines by oxidation to produce the fully aromatic isoquinoline, - GIO eas Cane REGAromatic heterocyclic chemistry 49 Electrophilic substitution of quinoline and isoquinoline ‘line and isoquinoline undergo electrophilic substitution reactions more fly than pyridine, though not surprisingly the incoming electrophile the benzenoid ring. As with pyridine, the nitrogen atoms of quinoline isoquinoline are protonated under the typically acidic conditions of tion or sulphonation, making the heterocyclic ring resistant to attack. C5 and C8 positions are most susceptible to electrophilic attack. ce BW EO S sy S pe LJ — C1) ate 78 ye i samt tnt ° a Ey Ss %. SS Cae Ng Ng t oo ‘tack of an electrophile at C5 of protonated quinoline gives cation b which is stabilised by resonance as shown without disturbing the ticity of the adjacent pyridinium ring. However, attack of an hile at C6 produces cation 6.19 which does not possess the same ice stabilisation of cation 6.18a,b. (The student should perform the exercise for the C7 and C8 positions and confirm that the same its can be applied.) SS HNO; S bins BD S-- 89 "GD iN’ a N’ N 61 6.20 NO, 6.21 instance, nitration of quinoline gives an equal mixture of regioisomers and 6.21. However, nitration of isoquinoline is reasonably selective 1) for the C5 position over the C8, affording mainly 6.22. NO, Sy HNO; Sy ZN SO, ZN 62 6.22 Nucleophilic substitution of quinoline and isoquinoline Line and isoquinoline undergo nucleophilic substitution reactions, like‘50 Quinolines and isoquinolines SS) ALKNH,/ Heat Sy ~ SS OO 2 Ote-Gae- N’ N7 NH, n7~c1 N78: 623 6.25 Sok Ss SS : NH Heat 208: ZN 2.Aq. Workup oN ZN gN 624 NH, a 626 O8t For instance, both quinoline and isoquinoline undergo the Chichibabi reaction (with formal hydride elimination, see Chapter 5) to give 2 aminoquinoline 6,23 and l-aminoisoquinoline 6.24 respectively. Haloge: substituents ortho to the nitrogen atoms are easily displaced, as in th Preparations of 6.25 and 6.26. = SS Sy CoS — wo xE : ae : ‘X=Nucleophile get AN Note that nucleophilic displacement in isoquinolines occurs more easily at the Cl position than at the C3 position (even though they are both ortho to nitrogen) because displacement at C3 involves temporary disruption of the benzenoid ring. — . a x or aug ni org ex a 5 6.5 Anion chemistry of quinoline and isoquinoline Alkyl groups at the C2 and C4 positions of quinoline can be deprotonated by strong bases. This is because (as with pyridine) the negative charge on the resultant carbanions can be delocalised onto the electronegative nitrogen atom, as in carbanion 6.27a,b. SON N sam & Coo — ; as ‘ee Such carbanions can be alkylated, acylated, or condensed with aldehydes: 6278 : lL = ; ; : N’ +2. PhCO,Et 'N’ ‘PhAromatic heterocyclic chemistry 51 Ar Z S 1LNHOH ~ —> Ars p-MeOCgH,— wn? ‘AsCHO 7 This type of chemistry is also observed with 1-methyl isoquinoline 6.28. »wever 3-methyl isoquinoline is much less activated because delocalisation charge in 6.29a,b involves disruption of aromaticity of the benzenoid ring. is phenomenon is closely related to the reluctance of 3-halo isoquinolines undergo nucleophilic substitution. ° S Ss A ZN ZN SNe 6298 629 As with pyridine, activated alkyl groups can be condensed with aldehydes der acidic as well as basic conditions, as in the preparation of 6.30 and i Se 630 , mechanistic explanation of such 1 e- CO. wn? ‘Ac,O /Heat N72 a condensations. Problems 628 ‘The synthesis of the important quinolone antibiotic 6.33 is shown. The stages are the Gould—Jacobson quinolone synthesis to give 6.32, and the lacement reaction to afford 6.33. What are the mechanisms of these 252 Quinolines and isoquinolines 2. A synthesis of the naturally-occurring isoquinoline alkaloid 6.34 is shown below. What reagents might be used to aecomplish each transformation? : SOT aI RO bape ‘a a Sep? “Ro. Nth 5ep3"R0 se Step 4 ‘OMe 2 mm, seeps RO. Step 5 NH NH oN HO’ RO RO ee C... Coles R=CHPA 6.7 References Adams, R. and Sloan, A.W. (1941). Organic syntheses, Coll. Vol. I, 478 (areal blood-and-thunder preparation of quinoline). Claret, P.A. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis), p.155 (quinolines) and p.205 (isoquinolines). Pergamon Press, Oxford. Fumiss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989). Vogel ‘s textbook of practical organic chemistry (5th edn), p.1185 (a rather more safety-conscious preparation of quinoline). Longman, Harlow. Grethe, G. (ed.) (1981). In Isoquinotines (The chemistry of heterocyclic compounds (ed. A. Weissburger and E.C. Taylor], Vol. 3, Part 1). Wiley Interscience, New York. Jones, G. (1977, 1990). In Quinolines (The chemistry of heterocyclic compounds [ed. A. Weissburger and E.C. Taylor], Vol. 32, Parts 1, 2, and 3). Wiley Interscience, New-York. Kathawala, G.F., Coppola, G.M., and Schuster, H.F. (ed.) (1989). In Isoquinolines (The chemistry of neterocyclic compounds [ed. A. Weissburger and E.C, Taylor}, Vol. 3, Part 2). Wiley Interscience, New York. Manske, RHF. and Kalka, M. (1953). Organic reactions, 7, 59 (Skraup synthesis), Whaley, W.M. and Govindachari, TR. (1951). Organic reactions, 6, p51 (Pictet-Spengler synthesis).zothiophene 7.3. This chapter will cont the most important member of this series, cat 72 as Indole is a ten-r electron aromatic system. As with pyrrole, delocalisation the lone pair of electrons from the nitrogen atom is necessary for ticity. The single overall electronic structure of indole is not ipletely described by structure 7.1, because this implies localisation of the le pair on the nitrogen atom, Mesomeric representation 7.1a makes a tribution to the electronic structure of indole, as to a lesser extent do eric representations where the negative charge occurs on the benzenoid Z Mg ao 'N’ 'N; | 15 H H 7 71a A consequence of this delocalisation is that the lone pair is not available Protonation under moderately acidic conditions 80, like pyrrole, indole is54 Indoles Neurotransmitters are naturally- ‘occurring substances which effect chemical communication between nerve cells by binding at specific sites on the cell surface called receptors. Historically, interest in indoles arose with the isolation and characterisation of members of the enormous family of indole alkaloids, such as lysergic acid 7.4. Many indole alkaloids possess interesting and sometimes useful biological activities. Although natural product chemistry is still an active area of primarily academic research, considerably more effort is expended nowadays in the preparation of indole derivatives as potential drug candidates. Following on from the observations that certain indole alkaloids or their semi-synthetic derivatives (e.g. lysergic acid diethylamide, LSD 7.5) have potent central nervous system activity, i was established that the simple indole 5-aydroxytryptamine 7,6 is a major neurotransmitter. Many indole derivatives which mimic or block the binding of this neurotransmitter to its receptors have been synthesised and are beginning to find use in the treatment of various psychological disorders. °O x \_ Le HOW Oo Ae 14 Xeon { 7 75 XoNBy . 3 16 7.2 Synthesis of indoles As might be expected for a large branch of heterocyclic chemistry, many syntheses of indoles have been developed. We shall restrict our discussion to ‘two, commencing with the widely-used Fischer synthesis, The Fischer synthesis is the condensation of an ary} ltydrazine with a ketone followed by cyclisation of the resultant hydrazone under acidic conditions to give the corresponding indole, as illustrated by the preparation of 2-phenyl indole 7.9. ° PhoN-N, nena ACH COL # He R Ph ZaCh Nh 19 +H a 78 The actual cyclisation stage is not as imponderable as it appears. The first step is the acid-catalysed equilibration between hydrazone 7.8 and ene hydrazine 7.10. The next step, which is irreversible, is a concerted electrocyclic reaction, forming a strong carbon-carbon bond, and breaking a weak nitrogen-nitrogen bond. The resulting i 7.41 immediately re- aromatises by tautomerisation to aniline 7,12. Finally, acid-catalysed elimination of ammonia forms indole 7.9, reminiscent of the lest step of the Knorr pyrrole synthesis (Chapter 2).Aromatic heterocyclic chemistry 55 a seas Ne en ey Ne Ph -N-N= Ph—-N-N = a? nF 3 Ch — Cox a : x if i ma = ea eo Ne 7 en 4 79 The electrocyclic reaction is very similar to the Claisen rearrangement of Cope rearrangement phenyl allyl ether 7.12 to give phenol 7.13. FQ %-a OS cose: oo a ‘Some examples of the Fischer indole synthesis are shown below, ct oon So O ce fal ‘OMe Aza-Cope rearrangement S FQ fo, eee Sed ‘OMe 7 OMe — Diaza-Cope rearrangement — hyo th dy =O a R mre + SO” —- OO : 714 'NMey MeO. NMe, Ot Lo N-NH, 0! q F F ¥ tg), —— ea N-N 0 Foy gn Toa Ae ee An interesting regioselectivity question arises with the use of symmetrical ketone 7.14 to prepare indole 7.15. Two ene hydrazines 7.16 a € mt w56 Indoles and 7.17 can form, which would give rise to indoles 7.15 and 7.18 respectively. Loe — OE, “ a 3 doce Oolm , x Ho 1.17 (minor ) 718 In such cases the most thermodynamically stable ene hydrazine, i.e. the one with the more highly substituted double bond, forms preferentially. In this particular example there is also extra stabilisation derived from conjugation of the lone pairs of electrons on the sulphur atom with the double bond. This regioselectivity in ene hydrazine formation is then reflected in the egioselectivity of indole formation. The more recent Leimgruber synthesis is illustrated by the aminomethylenation of nitrotoluene 7.19 to give 7.20, followed by hydrogenation to produce indole 7.1. Meo MO aa mo 2 UN. ee OC I pee No, PA/C N’ 19. 720 a The combination of formyl pyrrolidine acetal 7.21 and nitrotoluene 7.19 produces electrophilic cation 7.22 and nucleophilic carbanion 7.23a,b which react together affording enamine 7.20, OY °oMe yo ~ok eo NO;Aromatic heterocyclic chemistry 57 Hydrogenation of enamine 7.20 reduces the nitro group giving aniline 24, then elimination of pyrrolidine produces indole 7.1. Note the similarity this ring closure step to the last step of the Fischer synthesis. In both the eventual C2 carbon atom is formally at the carbonyl oxidation el, even though it occurs as either an imine (Fischer synthesis) or an amine (Leimgruber synthesis). Elimination of ammonia or pyrrolidine spectively is analogous to a condensation process involving elimination of 124 3 Electrophilic substitution of indoles an electron-rich heterocycle, indole easily undergoes electrophilic stitution, However whereas pyrrole reacts preferentially at the C2/C5 itions (see Chapter 2), indole reacts preferentially at the C3 position. a : 2 2 F F -H® al Or Cen Om ri a oy # Z i Z CE ~~”, A xt gees S oe G D nN NOE 7s a explanation is that attack at C2 results in disruption of the aromaticity the benzenoid ring, as in intermediate 7.25. This is therefore a high-energy fate, and this reaction pathway is slower because the first step is rate- termining. Also the C3 selectivity is in accord with the electrophile ‘king the site of highest electron density on the ring. In essence, indole ids to react like an enamine towards electrophiles, with substitution58 indoles This is the reactive electrophilic species of the Mannich reaction. e Cha Nu ‘This is the reactive electrophilic species of the Vilsmeier reaction. He = Nie, d ‘occurring at the C3 position, although substitution occurs at the C2 position ‘when the C3 position is blocked. Indole itself is unstable to the mineral acid conditions for nitration. The nitration of substituted indoles is quite complex and the outcome is dependent ‘on the precise seaction conditions. Like pyrrole, indole readily undergoes the Mannich reaction affording the aminomethyl derivative 7.26. A variety of nucleophiles can displace the amine via an climination followed by a (4-addition reaction, as in the preparation of acetate 7.27. Ww HNMe, 1 xq ‘ACOH w 18 ran? Tone ae OL oor ™ , 8 t a tat The Vilsmeier reaction proceeds extremely well with indoles giving aldehydes such as 7.28. ° 7] POH / CONN, oo oe N 2120 N’ mW Bs 728 Aldehyde 7.28 is another useful synthetic intermediate, readily undergoing condensation reactions with active methylene compounds such as malani¢ acid and nitromethane to produce 7.29 and 7.30, 128 z 129 ¥ Acylation of the C3 position can also be accomplished with acid chlorides, as illustrated in the synthesis of indole 7.34, a drug for the treatment of depression. Reaction of indole 7.31 with oxalyl chloride affords C3- substituted product 7.32 even though the benzene ring is very electron-rich. Conversion to amide 7.33 is followed by reduction with lithium aluminium hydride which removes both carbonyl groups, affording the target indole 7.34.Aromatic heterocyclic chemistry 59 Meco J Meo xJ q ih ae } MeO" 1. LiAIH, MeO" 'N’ Ll 2.40 H 134 133 mZ 7.4 Anion chemistry of indole Treatment of indole (pK q = 17) with strong bases such as butyl lithium, Grignard reagents, or metal hydrides produces the corresponding indolyl anion, which reacts with electrophiles either on nitrogen or at the C3 position. With lithium, sodium, or potassium as counterion the indolyl ‘anion tends to react on nitrogen, as in the preparation of 7.35. However, with ‘magnesium as the counterion the intermediate has an essentially covalent ‘rather than ionic structure, and reaction tends to occur at the C3 position, as in the preparation of 7.36. = fi es jo —» ) as x 4 H Ne Tabi Be liens SANG Pogo eo fr Cer Cio eae yi hae ma When the nitrogen is blocked, deprotonation can occur at the C2 position, jjacent to the electronegative heteroatom. This offers a means of introducing trophiles at this position, complementing the C3 selectivity shown by ical electrophilic substitution. For instance, alcohol 7.37 can be prepared this way using ethylene oxide as the eae60 Indoles 7.5 Problems 1, Devise a synthesis of the antidepressant drug 7.38, “oD NMey 2. The synthesis of amino ester 7.41 is shown below. What is the mechanism of the conversion of 7.39 to 7.40. CO, ~ a eae i, RO cox RO. RO. j ‘NMe, NOs ] Et nickel Eloleleeleew, == ete. N Heat Crs No, % NE Ho 1a 739 H A 740 R = PACH, 3. It was intended to prepare imine 7.43 from indole 7.42 by deprotonation at the C2 position then quenching with benzonitrile followed by an aqueous workup. However, the isolated products were ketone 7.44 and sulphonamide 7.45. Account for this observation an J] a= Bobi j 2. Ph—C=N, ? < N a . aie” o=$=08 i z Za Oude : ze oO 7.6 References Brown, R.T. and Joule, J.A. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis), p.411 (indoles and related systems). Pergamon Press, ‘Oxford. Fumiss, 8.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989) Vogel's textbook of practical organic chemistry (5th edn), p.1161 (preparation of indole 7.9). Longman, Harlow. Houlihan, W.J. (ed.) (1972). indoles (The chemistry of heterocyclic compounds [ed. A. Weissburger and E.C.Taylor], Vol. 25, Parts 1 — 3). Wiley Interscience, New York. Leimgruber, W. (1985). Organic syntheses, 63, 214 (indole synthesis). Robinson, B. (1969). Chem. rev., 69, 227 (Fischer indole synthesis). Saxton, J.E. (ed.) (1979). Indoles (The chemistry of heterocyclic compounds ed. A. Weissburger and E.C, Taylor], Vol, 25, Part 4). Wiley Interscience, New York Sundberg, RJ. (1970). The chemistry of indoles. Academic Press, New York,8. Five-membered ring heterocycles with three or four heteroatoms 8.1 Introduction The broad category of five-membered ring heterocycles containing three or four heteroatoms encompasses many heterocyclic systems. Obviously there is considerable variation in the physical and chemical properties of such a oxadiazole 8.3 is considered to be less aromatic than triazole 8.8 or tetrazole 8.9. New ne Us GX cxstastes 0" ‘07 #2 83 nen v5 uy CON diseases 5 5 as a6 4n-n3 N-N N-N sho Us ae NN‘ tetrazole (07 oxatriazole 8” thiatriazole 2 89 8.10 BL Nevertheless, this collection of heterocycles does share certain characteristics, The trend we have seen of decreasing tendency towards electrophilic substitution on going from furan, pyrrole, and thiophene to the azoles is continued into these series. The presence of additional ‘pyridine-like' nitrogen ‘atoms renders these systems particularly ‘electron-deficient’, and electrophilic substitution is of little importance, Conversely, nucleophilic substitution (which we have seen in earlier ‘chapters on 1,3-azoles and pyridines) does occur in these systems, especially when the carbon atom concemed is between two heteroatoms, as in the displacement reactions of oxadiazole 8.12 and tetrazole 8.13. Note the parallel with furan being uch @ jess aromatic than pyrrole, large group of heterocycles. For instance, with regard to aromaticity, Ghapter 262 Five-membered rings with three or four heteroatoms Once again note the analogy with standard carbony| chemistry. Another similarity with azoles is that there are examples of deprotonation of alkyl substituents between Wo heteroatoms followed by quenching the resultant carbanions with electrophiles, as in the preparation of oxadiazole 8.14. Ring deprotonation is also known with certain members of these series. Carbanion 8.15 is stable at low temperature (-70°C) and can be trapped with electrophiles, but on warming to room temperature it decomposes with ring fragmentation and extrusion of nitrogen. This fragmentation process is reminiscent of the base-catalysed cleavage of isoxazoles (Chapter 4). nN N-N, = NN i UN “on TN me ee a a4 Ph Ph Ph ais Ry i wR y an 8 ue Ste ee a ue aus For simplicity we shall now consider the synthesis of just three members of these series, 1,2,4-oxadiazole 8,3, 1,2,3-triazole 8.7, and tetrazole 8.9. 8.2 Synthesis of 1,2,4-oxadiazoles Disconnection of the C5-oxygen bond in 8.16 leads to iminoalcohol 8.17 which occurs as amide 8.18. Cleavage of the amide linkage leads to an activated carboxylic acid 8.20 plus the heteroatom-containing amidoxime 8.19,Aromatic heterocyclic chemistry 63 : mK Nt pas y, Nog | RK WA, Son on 8.18 cSt) 820 Amidoximes can be prepared by acid-catalysed additon of hydroxylamine to aitriles. HANOH R,—CiN ——> HCL H,N—0H ‘An example of this approach to oxadiazoles is shown by the conversion of ester 8.21 to oxadiazole 8.22, prepared as a potential candidate for the treatment of senile dementia. Simple esters are metabolically unstable in man Because of the high activity of esterases. These enzymes catalyse the hydrolysis of esters to carboxylic acids. A common tactic in drug research ‘when confronted with the problem of metabolic instability of a biologically active ester is to replace the ester group with a small heterocycle (often ‘exadiazole), to try to produce a biologically-active molecule with improved metabolic stability. This concept of replacing fragments of a molecule by groups with broadly similar physicochemical parameters in a systematic manner is known as bioisosteric replacement. In this instance oxadiazole 8.22 can mimic both the physical and biological properties of 8.21, but itis ‘obviously not a substrate for esterases. Ay 08 ne u\ me 0H tear an 8.3 Synthesis of 1,2,3-triazoles These are best prepared by a 1,3-dipolar cycloaddition of an azide and an acetylene, Nady N we ae 180, Cx H For instance, triazole 8.8 itself has been prepared by cycloaddition of ‘nydrazoic acid to acetylene.64 Five-membered rings with three or four heteroatoms 4 Io iS r 3 — Oo ,) Nas Ny Wd w’ 4 I H 4 H Although a simple mechanism can be drawn for this transformation, it is only useful as a 'book-keeping exercise’ to ensure that the correct structure is drawn for the product. In reality the reaction is a concerted process and the usual considerations of nucleophilic and electrophilic attack do not apply. Excellent yields are achieved in these cycloadditions when electron- withdrawing groups are present on the acetylene, as in the preparation of triazole 8.23. COR al B0,C-c=C-co —+ cr Heat CoE N’ a 823 8.4 Synthesis of tetrazoles Tetrazole itself explodes on Tetrazoles of general structure 8.24 can be prepared in a very similar manner heating with loss of two molecules 5 triazoles, except that nitriles are used rather than acetylenes. Once again ona the reaction with azides is a concerted cycloaddition process. vox oy Noy hae Te Ri Let us now consider the synthesis of tetrazole 8.27, an inhibitor of the enzyme omithine decarboxylase, which catalyses the conversion of ornithine 8.25 to diamine 8.26, N oN com Nu, N ee a aaa Nu, ~ Oe 826 Ni 225 a7 ‘The tetrazole moiety is an excellent bioisosteric replacement for a carboxylic acid, being a small, polar, acidic heterocycle. N-N Cho = ye H ° hcAromatic heterocyclic chemistry 65 Tetrazole 8.27 is sufficiently similar to ornithine 8.25 in its physical properties to bind to the active site of the enzyme. However, as it obviously cannot undergo the decarboxylation process, it acts as an inhibitor of the enzyme. The synthesis commences with alkylation of the stabilised carbanion derived from cyanoester 8.29 with iodide 8.28 to give adduct 8.30 cN *B00,8 HN ° ° ° a0 is co,B N 1 —___+ Nhs IW Tae CN ° ( aes = 1a cmap N-N P N ssid Seance Ons 3 ks GoM ne ~~ me | Cycloaddition with sodium azide followed by acidification during aqueous | workup affords tetrazole 8.31. s NaNs N HCL N-N Roe ee we RON RON me? & g2 HP isa) Note that the first-formed product from the cycloaddition is actually the sodium tetrazolate salt 8.32. Protonation affords the neutral tetrazole 8.31. Prolonged acidic hydrolysis accomplishes several transformations: hydrolytic removal of both the phthalimide and acetyl nitrogen protecting groups, and hydrolysis/decarboxylation of the ester. The net result is to produce the target tetrazole 8.27 as its dihydrochloride salt. This tetrazole-assisted decarboxylation is mechanistically very similar to the decarboxylation of malonyl half-esters 8.33. C Hoy ot = 00; © Fe Regen NO eer on 8.33 ee HR66 Five-membered rings with three or four heteroatoms 8.5 Problems 1. Triazoles and tetrazoles can be alkylated on nitrogen under basic conditions, as in the synthesis of the clinically-used antifungal drug 8.35 in which 1,2,4-triazole is alkylated by a chloromethyl ketone and an epoxide, both gobd alkylating agents. What is the mechanism of formation of epoxide 8.34? Of compounds 8.34 and 8.35, which is achiral and which is racemic? N °. 9. vV °. aN, (I Sao a Qn a) F a F F =N. — aa AIC; BN I me 3 (CHy),S=0 ‘a OH N oO NL Dy N, cx Mey) GN wy n= len nN F ‘EN pes K,CO; eh lives 2. What is the mechanism of formation of oxadiazole 8.22? NH ° N aye? me? y ¢ ome a ' — ms ELOH, heat 821 a2 8.6 References Butler, R.N. (1977). Adv. heterocyclic chem., 21, 323 (tetrazoles). Clapp, L.B. (1976). Adv. heterocyclic chem, 20, 65, (1,2,4-oxadiazoles) « Gilchrist, T.L. (1985). Heterocyclic chemistry, p.81 (1,3-dipolar cycloadditions in heterocyclic synthesis). Longman, Harlow. Gilchrist, T.L. and Gymer, G.E. (1974). Adv. heterocyclic chem., 16, 33 (1,2,3-triazoles). Grimmett, MR. (1979). In Heterocyclic chemistry (ed. PG. Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and WD. Ollis), p.357 (triazoles and tetrazoles). Pergamon Press, Oxford.9. Six-membered ring heterocycles containing one oxygen atom 9.1 Introduction The pyrilium cation 9.1, 2-pyrone 9.2, 4-pyrone 9.3, and their benzo-fused analogues the benzopyrilium cation 9.4, coumarin 9.5, chromone 9.6, are the ‘parent structures of a series of six-membered ring heterocycles containing one ‘oxygen atom. The impetus for research in this area comes from the enormous number of plant-derived natural products based on the benzopyrilium, ‘coumarin, and chromone structures. 4 4 a 543 ~ eee CL Ue! ‘0 ° C 19” sa Oar Okog 1°93 Site 5 4 sent Fleder at my Slate ee J 7 22 ° ‘0 8 6! sf net 94 9s 96 The red, violet, and blue pigments of flower petals are called anthocyanins, and are glycosides of various benzopyrilium cations. Delphinidin chloride 9.7, for example, is a blue pigment. Khellin 9.8 is a natural product which has found clinical application in the treatment of bronchial asthma and has been the starting point for the design of many totally synthetic chromones ‘with improved biological properties. oH OMe 0 OH Cr é HO ‘07 a on ‘0 5: 2 @ a’ ae OMe a7 OH 98 Coumarin 9.5 is itself a natural product which occurs in lavender oil and has ‘been found in over sixty species of plants. In natural product chemistry, the acetal formed between an aliphatic or aromatic alcohol and a sugar is termed a glycoside.68 Six-membered ring heterocycles containing one oxygen atom The carbonyl groups of 4-pyrone and 4-pyridone absorb at approximately 1650 cm"! and 1550 cm” respectively. The lower energy of the pyridone absorption reflects greater single bond character, and hence greater delocalisation. The pyrylium cation 9.1 is the oxygen analogue of pyridine and is a six r-electron aromatic system. Nevertheless, being a cation it is reactive towards nucleophiles and is readily hydrolysed to give dialdchyde 9.9. These reactions are reversible, a fact which has been used in a synthesis of 9.1 from 9,9. At low pH (high acidity) the equilibrium lies to the side of the pyrylium species 9.1 but if the medium is basified then hydrolysis of 9.1. occurs to give 9.9. This is because one mole of hydroxide is consumed on going from pyrylium cation 9.1 to neutral aldehyde 9.9. Increasing the hydroxide concentration therefore forces the equilibrium from left to right. ep Bs S ‘Oo oO OL SHO Tats Guinean Hoy oa * In contrast, 2- and 4-pyrones are considered to have relatively little aromatic character. Whereas in an analogous nitrogen series 4-pyridone 5.23 has significant aromatic character (mesomeric representation 5.23a making a considerable contribution to the overall electronic distribution), aromatic mesomeric representation 9.3a makes less of a contribution to the overall electronic structure of 4-pyrone. As with furan, the higher electronegativity of oxygen leads to heterocycles of little aromaticity in cases where delocalisation of electron density from the heteroatom is a prerequisite for that aromaticity. ° 0? ° 0? O- QO] [O-9 93 930 5.23 5.238 Let us now consider the synthesis of a pyrylium salt, a coumarin, and a chromone. 9.2 Synthesis of a pyrylium salt A typical pyrilium salt synthesis is illustrated by the preparation of salt 9.12. The precursor to 9.12 is pyran 9.11, available by dehydration of 1,5- diketone 9.10. Note the similarity of this sequence to the Hantzch pyridine synthesis, Chapter 5. Also, the dehydrative cyclisation of a diketone to oxygen heterocycle 9.11 is reminiscent of furan synthesis, Chapter 2. ° ae pois ka OL Ge “rao,” Sog > Ph S 9.0 gat 912 C10,