Heterocíclos: Reactividade e Síntese

Heterocíclos: Reactividade e Síntese
Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e Síntese Exemplos de heterocíclos saturados Heterocíclos Saturados

Heterocíclos Saturados: Reactividade e síntese
Heterocíclos Química Farmacêutica I Heterocíclos Saturados: Reactividade e síntese Unidades representativas 2

Heterocíclos Química Farmacêutica I Heterocíclos Saturados: Reactividade e síntese Heterocíclos contendo átomo(s) de N são mais básicos e nucleófilos 3

Heterocíclos Química Farmacêutica I Heterocíclos Saturados: Reactividade e síntese Heterocíclos de anéis pequenos sofrem abertura mais facilmente 4

Heterocíclos Química Farmacêutica I Heterocíclos Saturados: Reactividade e síntese Formação de heterocíclos saturados por ciclização intramolecular 5

Heterocíclos Química Farmacêutica I Heterocíclos Saturados: Reactividade e síntese Formação de heterocíclos saturados por ciclização intramolecular 6

Heterocíclos: Reactividade e síntese
Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Formação de heterocíclos insaturados (pirroles) Ciclização de compostos 1,4-dicarbonílicos (síntese de Paal-Knorr) Mecanismo Exemplo: Síntese do antibiótico roseophilin (Trost et al; J. Am :Chem. Soc, 2000, 122, 3801). Método clássico The Paal-Knorr Pyrrole Synthesis is the condensation of a 1,4-dicarbonyl compound with an excess of a primary amine or ammonia to give a pyrrole. The reaction can be conducted under neutral or weakly acidic conditions. Addition of a weak acid such as acetic acid accelerates the reaction, but the use of amine/ammonium hydrochloride salts or reactions at pH < 3 lead to furans as main products (Paal-Knorr Furan Synthesis). 7

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Formação de heterocíclos insaturados (furanos) Ciclização de compostos 1,4-dicarbonílicos (síntese de Paal-Knorr) Mecanismo Passo lento Exemplos: F. Stauffer, R. Neier, Org. Lett., 2000, 2, Hart et al. J. Org. Chem. 1982, 47, 4370, 8

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Formação de heterocíclos insaturados (tiofenos) Ciclização de compostos 1,4-dicarbonílicos (síntese de Paal-Knorr ) Mecanismo (duas possibilidades em aberto) Exemplos: Thiophene synthesis is achieved via a mechanism very similar to the furan synthesis. The initial diketone is converted to a thioketone with a sulfurizing agent, which then undergoes the same mechanism as the furan synthesis. Most sulfurization agents are strong dehydrators and drive completion of the reaction. Early postulates toward the mechanism of the Paal-Knorr furan synthesis suggested that the thiophene was achieved by sulfurization of the furan product. Campaigne and Foye showed that treatment of isolated furans from the Paal-Knorr Furan Synthesis with phosphorous pentoxide gave inconsistent results with the treatment of 1,4-dicarbonyls with phosphorus pentoxide, which ruled out the sulfurization of a furan mechanism and suggests that the reaction proceeds via sulfurization of a dicarbonyl.[6] Mechanism of the Paal-Knorr Thiophene Synthesis Reagents such as phosphorus pentasulfide or Lawesson's reagent act as sulfurizing agents as well as dehydrating agents, allowing a reaction pathway that could lead first to the formation of furans. This hypothesis was tested by Foye (J. Org. Chem., 1952, 17, 1405.) by treatment of different 1,4-dicarbonyl compounds and the corresponding possible furan intermediates (such as acetonylacetone and 2,5-dimethylfuran) with phosphorus pentasulfide. Using the same reaction conditions, the differences in the yields of 2,5-dimethylthiophene excludes the possibility that a predominant reaction pathway could lead through furan intermediates: G. Minetto, L. F. Raveglia, A. Sega, M. Taddei, Eur. J. Org. Chem., 2005, Z. Kaleta, B. T Makowski, T. Soos, R. Dembinski, Org. Lett., 2006, 8, 9

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Formação de heterocíclos insaturados (piridinas) Reacção de quatro componentes (síntese de Hantzsch ) retro-síntese Reacção Mecanismo The idea of coupling two keto-esters together with a nitrogen atom also works for pyridines except that an extra carbon atom is needed. This is provided as an aldehyde and another important difference is that the nitrogen atom is added as a nucleophile rather than an electrophile. These are features of the Hantzsch pyridine synthesis. This is a four-component reaction that goes like this. You are hardly likely to understand the rationale behind this reaction from that diagram so let’s explore the details. The product of the reaction is actually the dihydropyridine, which has to be oxidized to the pyridine by a reagent such as HNO3, Ce(IV), or a quinone. The reaction is very simply carried out by mixing the components in the right proportions in ethanol. The presence of water does not spoil the reaction and the ammonia, or some added amine, ensures the slightly alkaline pH necessary. Any aldehyde can be used, even formaldehyde, and yields of the crystalline dihydropyridine are usually very good. This reaction is an impressive piece of molecular recognition by small molecules and writing a detailed mechanism is a bold venture. We can see that certain events have to happen. The ammonia has to attack the ketone groups, but it would prefer to attack the more electrophilic aldehyde so this is probably not the first step. The enol or enolate of the keto-ester has to attack the aldehyde (twice!) so let us start there. 1010

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Formação de heterocíclos insaturados (piridinas) Reacção de quatro componentes (síntese de Hantzsch ): Passo de oxidação The idea of coupling two keto-esters together with a nitrogen atom also works for pyridines except that an extra carbon atom is needed. This is provided as an aldehyde and another important difference is that the nitrogen atom is added as a nucleophile rather than an electrophile. These are features of the Hantzsch pyridine synthesis. This is a four-component reaction that goes like this. You are hardly likely to understand the rationale behind this reaction from that diagram so let’s explore the details. The product of the reaction is actually the dihydropyridine, which has to be oxidized to the pyridine by a reagent such as HNO3, Ce(IV), or a quinone. The necessary oxidation is easy both because the product is aromatic and because the nitrogen atom can help to expel the hydrogen atom and its pair of electrons from the 4-position. If we use a quinone as oxidizing agent, both compounds become aromatic in the same step. We will show in Chapter 50 that Nature uses related dihydropyridines as reducing agents in living things. 1111

Formação de heterocíclos insaturados (piridinas)
Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Formação de heterocíclos insaturados (piridinas) Síntese de Hantzsch Exemplos e importância das di-hidropiridinas L.-M. Wang, et al. Tetrahedron, 2005, 61, O. De Paolis, J. Baffoe, S. M. Landge, B. Török, Synthesis, 2008, 1212

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Sintese de piridinas a partir de 1,5-dicetonas Sintese de piridinas por ciclização de aldol The Hantzsch synthesis produces a reduced pyridine but there are many syntheses that go directly to pyridines. One of the simplest is to use hydroxylamine (NH2OH) instead of ammonia as the nucleophile. Reaction with a 1,5-diketone gives a dihydropyridine but then water is lost and no oxidation is needed. Another direct route leads, as we shall now demonstrate, to pyridones. These useful compounds are the basis for nucleophilic substitutions on the ring (Chapter 43). We choose an example that puts a nitrile in the 3-position. This is significant because the role of nicotinamide in living things (Chapter 50) makes such products interesting to make. Aldol disconnection of a 3-cyano pyridone starts us on the right path. If we now disconnect the C–N bond forming the enamine on the other side of the ring we will expose the true starting materials. This approach is unusual in that the nitrogen atom that is to be the pyridine nitrogen is not added as ammonia but is already present in a molecule of cyanoacetamide. The keto-aldehyde can be made by a simple Claisen ester condensation (Chapter 28) using the enolate of the methyl ketone with ethyl formate (HCO2Et) as the electrophile. It actually exists as a stable enol, like so many 1,3-dicarbonyl compounds (Chapter 21). What must happen here is that the two compounds must exchange protons (or switch enolates if you prefer) before the aldol reaction occurs. Cyclization probably occurs next through C–N bond formation and, finally, dehydration is forced to give the Z-alkene. 1313

Formação de heterocíclos insaturados (piridinas)
Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Formação de heterocíclos insaturados (piridinas) Síntese de Hantzsch Exemplos e importância das di-hidropiridinas The Hantzsch pyridine synthesis is an old discovery (1882) which sprang into prominence in the 1980s with the discovery that the dihydropyridine intermediates prepared from aromatic aldehydes are calcium channel blocking agents and therefore valuable drugs for heart disease with useful effects on angina and hypertension. Clearly, a modification is needed in which half of the molecule is assembled first. The solution lies in early work by Robinson who made the very first enamines from keto-esters and amines. One half of the molecule is made from an enamine and the other half from a separately synthesized enone. We can use felodipine as a simple example. 1414

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Importância das di-hidropiridinas na natureza These two nucleotides can combine together as a pyrophosphate to give a dinucleotide. Notice that the link is not at all the same as in the nucleic acids. The latter are joined by one phosphate that links the 3′–5′ positions. Here we have a pyrophosphate link between the two 5′-positions. Notice also the positive charge on the nitrogen atom of the pyridine ring. This part of the molecule does all the work and from now on we will draw only the reactive part for clarity. This is NAD+, nicotine adenine dinucleotide, and it is one of Nature’s most important oxidizing agents. Some reactions use NADP instead but this differs only in having an extra phosphate group on the adenosine portion so the same part structure will do for both. NAD+ and NADP both work by accepting a hydrogen atom and a pair of electrons from another compound. The reduced compounds are called NADH and NADPH. The reduction of NAD+ (and NADP) is reversible, and NADH is itself a reducing agent. We will first look at one of its reactions: a typical reduction of a ketone. The ketone is pyruvic acid and the reduction product lactic acid, two important metabolites. The reaction is catalysed by the enzyme liver alcohol dehydrogenase. This is a reaction that would also work in the laboratory with NaBH4 as the reducing agent, but there is a big difference. The product from the NaBH4 reaction must be racemic—no optical activity has been put in from compound, reagent, or solvent. 1515

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Formação de pirazoles e piridazinas a partir de compostos dicarbonílicos piridazinas di-hidropiridazolona 1616

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Formação de pirimidinas a partir de compostos 1,3-dicarbonílicos antibiótico Estratégia Síntese Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections. It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors. Trimethoprim was formerly marketed by GlaxoSmithKline under trade names including Proloprim, Monotrim and Triprim; In Chapter 43 we met some compounds that interfere in folic acid metabolism and are used as antibacterial agents. One of them was trimethoprim and it contains a pyrimidine ring (black on the diagram). We are going to look at its synthesis briefly because the strategy used is the opposite of that used with the pyrimidine ring in Viagra. Here we disconnect a molecule of guanidine from a 1,3- dicarbonyl compound. The 1,3-dicarbonyl compound is a combination of an aldehyde and an amide but is very similar to a malonic ester so we might think of making this compound by alkylation of that stable enolate (Chapter 26) with the convenient benzylic bromide. The alkylation works fine but it turns out to be better to add the aldehyde as an electrophile (cf. the pyridone synthesis on p. 000) rather than try to reduce an ester to an aldehyde. The other ester is already at the right oxidation level. Notice the use of the NaCl method of decarboxylation (Chapter 26). Condensation with ethyl formate (HCO2Et) and cyclization with guanidine gives the pyrimidine ring system but with an OH instead of the required amino group. Aromatic nucleophilic substitution in the pyrimidone style from Chapter 43 gives trimethoprim. 1717

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Formação de isoxazoles e tetrazoles por cicloadição Intramolecular: só um isómero Intermolecular: mistura de isoxazoles isómeros Ex. Aplicação na síntese da Indomethacin (anti-inflamatório não-esteróide) The alkyne is using its HOMO to attack the LUMO of the nitrile oxide (see Chapter 35 for an explanation). If the alkyne has an electron-withdrawing group, mixtures of isomers are usually formed as the HOMO of the nitrile oxide also attacks the LUMO of the alkyne. Intramolecular reactions are usually clean regardless of the preferred electronic orientation if the tether is too short to allow any cyclization except one. In this example, even the more favourable orientation looks very bad because of the linear nature of the reacting species, but only one isomer is formed. 1818

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese 1,2,3-triazoles: uma metodologia click chemistry obtida por cicloadição Example: Drug discovery of HIV protease inhibitors (Sharpless et al. Drug Discovery Today, 2003, 8, 1128) (c) Development of HIV protease inhibitors. HIV protease is responsible for the final stages of virus maturation and, thus, its inhibitors are useful drugs for the treatment of AIDS [33]. The emergence of drug-resistant mutant HIV proteases increases the demand for new inhibitors [34]. Wong et al. prepared two focused libraries of 50 compounds each, based on hydroxyethylamine peptide isosteres (Figure 2c) [35]. Azide-bearing scaffolds 2 and 3, inspired by Glaxo’s Amprenavir ( [36], were united via the new copper-catalyzed process with acetylenes, for library production. These libraries, which were already in aqueous solution from the synthesis step, were used directly, for screening against wild type HIV-1 protease and three mutants (G48V, V82F, V82A). As was predicted by molecular modeling, compounds derived from scaffold 2 did not yield any hits at 100 nM concentration, whereas, scaffold 3 provided four hit compounds with good activity at 10 nM concentration. Two of these compounds strongly inhibited all four proteases tested, with activities in the low nanomolar range (purified compounds). 1919

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Preparação de indóis através da síntese de Ficher Mecanismo Outras alternativas: ex. Buchwald et al. (J. Am. Chem. Soc. 1998, 120, 6621) You are about to see one of the great inventions of organic chemistry. It is a remarkable reaction, amazing in its mechanism, and it was discovered in 1883 by one of the greatest organic chemists of all, Emil Fischer. Fischer had earlier discovered phenylhydrazine (PhNHNH2) and, in its simplest form, the Fischer indole synthesis occurs when phenylhydrazine is heated in acidic solution with an aldehyde or ketone. The first step in the mechanism is formation of the phenylhydrazone (the imine) of the ketone. This can be isolated as a stable compound (Chapter 14). The hydrazone then needs to tautomerize to the enamine, and now comes the key step in the reaction. The enamine can rearrange with formation of a strong C–C bond and cleavage of the weak N–N single bond by moving electrons round a six-membered ring. Next, re-aromatization of the benzene ring (by proton transfer from carbon to nitrogen) creates an aromatic amine that immediately attacks the other imine. This gives an aminal, the nitrogen equivalent of an acetal. 2020

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Preparação de quinolinas 2121

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Algumas transformações de heterocíclos por reacções de substituição Piridina é pouco reactiva a substituições electrofílicas aromáticas The lower energy of the orbitals of pyridine’s p system means that electrophilic attack on the ring is difficult. Another way to look at this is to see that the nitrogen atom destabilizes the cationic would-be intermediate, especially at the 2- and 4-positions. An equally serious problem is that the nitrogen lone pair is basic and a reasonably good nucleophile—this is the basis for its role as a nucleophilic catalyst in acylations. The normal reagents for electrophilic substitution reactions, such as nitration, are acidic. Treatment of pyridine with the usual mixture of HNO3 and H2SO4 merely protonates the nitrogen atom. Pyridine itself is not very reactive towards electrophiles: the pyridinium ion is totally unreactive. Other reactions, such as Friedel–Crafts acylations, require Lewis acids and these too react at nitrogen. Pyridine is a good ligand for metals such as Al(III) or Sn(IV) and, once again, the complex with its cationic nitrogen is completely unreactive towards electrophiles. 2222

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Algumas transformações de heterocíclos por reacções de substituição Piridina é pouco reactiva a substituições electrofílicas aromáticas Catalisador eficiente em reacções de acilação DMAP: Um catalisador único 2323

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Algumas transformações de heterocíclos por reacções de substituição Piridinas com grupos doadores já são reactivas a substituições electrofílicas aromáticas Exemplo Óxidos de piridinas já são reactivas a substituições electrofílicas aromáticas Exemplo: Nitração Useful electrophilic substitutions occur only on pyridines having electron-donating substituents such as NH2 or OMe. These activate benzene rings too (Chapter 22) but here their help is vital. They supply a nonbonding pair of electrons that becomes the HOMO and carries out the reaction. Simple amino- or methoxypyridines react reasonably well ortho and para to the activating group. These reactions happen in spite of the molecule being a pyridine, not because of it. 2424

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Algumas transformações de heterocíclos por reacções de substituição Piridina é reactiva a substituições nucleofílicas aromáticas Exemplos By contrast, the nitrogen atom makes pyridines more reactive towards nucleophilic substitution, particularly at the 2- and 4-positions, by lowering the LUMO energy of the p system of pyridine. You can see this effect in action in the ease of replacement of halogens in these positions by nucleophiles. The intermediate anion is stabilized by electronegative nitrogen and by delocalization round the ring. These reactions have some similarity to nucleophilic aromatic substitution (Chapter 23) but are more similar to carbonyl reactions. The intermediate anion is a tetrahedral intermediate that loses the best leaving group to regenerate the stable aromatic system. Nucleophiles such as amines or thiolate anions work well in these reactions. The leaving group does not have to be as good as chloride in these reactions. Continuing the analogy with carbonyl reactions, 2- and 4-chloropyridines are rather like acid chlorides but we need only use less reactive pyridyl ethers, which react like esters, to make amides. The 2- and 4- methoxypyridines allow the completion of the synthesis of flupirtine. 2525

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Algumas transformações de heterocíclos por reacções de substituição Óxido de piridina também é reactiva a substituições nucleofílicas aromáticas The same activation that allowed simple electrophilic substitution—oxidation to the N-oxide— can also allow a useful nucleophilic substitution. The positive nitrogen atom encourages nucleophilic attack and the oxygen atom can be turned into a leaving group with PCl3. Our example is nicotinic acid whose biological importance we will discuss in Chapter 50. The N-oxide reacts with PCl3 through oxygen and the chloride ion released in this reaction adds to the most electrophilic position between the two electron-withdrawing groups. Now a simple elimination restores aromaticity and gives a product looking as though it results from chlorination rather than nucleophilic attack. The reagent PCl3 also converts the carboxylic acid to the acyl chloride, which is hydrolysed back again in the last step. This is a useful sequence because the chlorine atom has been introduced into the 2-position from which it may in turn be displaced by, for example, amines. 2626

vPirrole>vFurano >vTiofeno >vBenzeno
Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Algumas transformações de heterocíclos por reacções de substituição Heterocíclos de cinco átomos são reactivos a substituições electrofílicas aromáticas Mais favorável Just about everything is the other way round with pyrrole. Electrophilic substitution is much easier than it is with benzene—almost too easy in fact—while nucleophilic substitution is more difficult. Pyrrole is not a base nor can it be converted to an N-oxide. We need to find out why this is. The big difference is that the nitrogen lone pair is delocalized round the ring. The NMR spectrum suggests that all the positions in the ring are about equally electron-rich with chemical shifts about 1 p.p.m. smaller than those of benzene. The ring is flat and the bond lengths are very similar, though the bond opposite the nitrogen atom is a bit longer than the others. The delocalization of the lone pair can be drawn equally well to any ring atom because of the fivemembered ring and we shall soon see the consequences of this. All the delocalization pushes electrons from the nitrogen atom into the ring and we expect the ring to be electron-rich at the expense of the nitrogen atom. The HOMO should go up in energy and the ring become more nucleophilic. An obvious consequence of this delocalization is the decreased basicity of the nitrogen atom and the increased acidity of the NH group as a whole. In fact, the pKa of pyrrole acting as a base is about –4 and protonation occurs at carbon. The NH proton can be removed by much weaker bases than those that can remove protons on normal secondary amines. The nucleophilic nature of the ring means that pyrrole is attacked readily by electrophiles. Reaction with bromine requires no Lewis acid and leads to substitution (confirming the aromaticity of pyrrole) at all four free positions. This is a fine reaction in its way, but we don’t usually want four bromine atoms in a molecule so one problem with pyrrole is to control the reaction to give only monosubstitution. Another problem is that strong acids cannot be used. Though protonation does not occur at nitrogen, it does occur at carbon and the protonated pyrrole then adds another molecule like this. Z=NH Pirrole Z=O Furano Z=S Tiofeno vPirrole>vFurano >vTiofeno >vBenzeno 2727

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Algumas transformações de heterocíclos por reacções de substituição Heterocíclos de cinco átomos são reactivos a substituições electrofílicas aromáticas Exemplos An obvious consequence of this delocalization is the decreased basicity of the nitrogen atom and the increased acidity of the NH group as a whole. In fact, the pKa of pyrrole acting as a base is about –4 and protonation occurs at carbon. The NH proton can be removed by much weaker bases than those that can remove protons on normal secondary amines. The nucleophilic nature of the ring means that pyrrole is attacked readily by electrophiles. Reaction with bromine requires no Lewis acid and leads to substitution (confirming the aromaticity of pyrrole) at all four free positions. This is a fine reaction in its way, but we don’t usually want four bromine atoms in a molecule so one problem with pyrrole is to control the reaction to give only monosubstitution. Another problem is that strong acids cannot be used. Though protonation does not occur at nitrogen, it does occur at carbon and the protonated pyrrole then adds another molecule like this. The other simple five-membered heterocycles are furan, with an oxygen atom instead of nitrogen, and thiophene with a sulfur atom. They also undergo electrophilic aromatic substitution very readily, though not so readily as pyrrole. Nitrogen is the most powerful electron donor of the three, oxygen the next, and sulfur the least. Thiophene is very similar to benzene in reactivity. You may be surprised that thiophene is the least reactive of the three but this is because the p orbital of the lone pair of electrons on sulfur that conjugates with the ring is a 3p orbital rather than the 2p orbital of N or O, so overlap with the 2p orbitals on carbon is less good. Both furan and thiophene undergo more or less normal Friedel–Crafts reactions though the less reactive anhydrides are used instead of acid chlorides, and weaker Lewis acids than AlCl3 are preferred. Notice that the regioselectivity is the same as it was with pyrrole—the 2-position is more reactive than the 3-position in both cases. The product ketones are less reactive towards electrophiles than the starting heterocycles and deactivated furans can even be nitrated with the usual reagents used for benzene derivatives. Notice that reaction has occurred at the 5-position in spite of the presence of the ketone. The preference for 2- and 5-substitution is quite marked. 2828

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Algumas transformações de heterocíclos por reacções de substituição Heterocíclos de cinco átomos são reactivos a substituições electrofílicas aromáticas Exemplos: Reacção de Vilsmeier H2O 2929

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Cicloadições (Diels-Alder) com heterocíclos a-pirona Furan is particularly good at Diels–Alder reactions but it gives the thermodynamic product, the exo adduct, because with this aromatic diene the reaction is reversible (Chapter 35). If pyrrole would do a similar thermodynamically controlled exo Diels–Alder reaction with a vinyl pyridine, a short route to the interesting analgesic epibatidine could be imagined, with just a simple reduction of the remaining alkene left to do. The reaction looks promising as the pyridine makes the dienophile electron-deficient and pyrrole is an electron-rich ‘diene’. The trouble is that pyrrole will not do this reaction as it is so good at electrophilic substitution. What happens instead is that pyrrole acts as a nucleophile and attacks the electron-deficient alkene. The answer is to make pyrrole less nucleophilic by acylating the nitrogen atom with the famous ‘Boc’ protecting group (Chapter 24). We will see in the next section how this may be done. A good Diels–Alder reaction then occurs with a alkynyl sulfone. Similar reactions occur with a-pyrones. These are also rather unstable and barely aromatic and they react with alkynes by Diels–Alder reactions followed by reverse Diels–Alder reaction to give benzene derivatives with the loss of CO2 rather than SO2. 3030

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Substituição electrofílica aromática em heterocíclos bicíclicos indole manutenção de aromaticidade perda de aromaticidade 3131

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Substituição electrofílica aromática em heterocíclos bicíclicos Exemplos informação adicional mecanismo In many ways the chemistry of indole is that of a reactive pyrrole ring with a relatively unreactive benzene ring standing on one side—electrophilic substitution almost always occurs on the pyrrole ring, for example. But indole and pyrrole differ in one important respect. In indole, electrophilic substitution is preferred in the 3-position with almost all reagents. Halogenation, nitration, sulfonation, Friedel–Crafts acylation, and alkylation all occur cleanly at that position. This is, of course, the reverse of what happens with pyrrole. Why should this be? A simple explanation is that reaction at the 3-position simply involves the rather isolated enamine system in the five-membered ring and does not disturb the aromaticity of the benzene ring. The positive charge in the intermediate is, of course, delocalized round the benzene ring, but it gets its main stabilization from the nitrogen atom. It is not possible to get reaction in the 2-position without seriously disturbing the aromaticity of the benzene ring. 3232

Heterocíclos Química Farmacêutica I Heterocíclos: Reactividade e síntese Substituição electrofílica aromática em heterocíclos bicíclicos Quinolina Isoquinolina Exemplo Quinoline forms part of quinine (structure at the head of this chapter) and isoquinoline forms the central skeleton of the isoquinoline alkaloids, which we will discuss at some length in Chapter 51. In this chapter we need not say much about quinoline because it behaves rather as you would expect—its chemistry is a mixture of that of benzene and pyridine. Electrophilic substitution favours the benzene ring and nucleophilic substitution favours the pyridine ring. So nitration of quinoline gives two products—the 5- nitroquinolines and the 8-nitroquinolines—in about equal quantities (though you will realize that the reaction really occurs on protonated quinoline. This is obviously rather unsatisfactory but nitration is actually one of the better behaved reactions. Chlorination gives ten products (at least!), of which no fewer than five are chlorinated quinolines of various structures. The nitration of isoquinoline is rather better behaved, giving 72% of one isomer (5-nitroisoquinoline) at 0 °C. 3333

Heterocíclos Química Farmacêutica I
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