Cyclisation electrophilic

The simplest reaction, that between a diketone and a phenol, works best with resorcinol, for the second hydroxyl facilitates the cyclising electrophilic attack. This synthesis can give mixtures with unsymmetrical diketones, and it is therefore well suited to the synthesis of 1-benzopyryliums with identical groups at C-2 and C-4, ° however diketones in which the two carbonyl groups are appreciably different in reactivity can also produce high yields of single products. ... 

All around this chapter, we have seen that a,/J-unsaturated Fischer carbene complexes may act as efficient C3-synthons. As has been previously mentioned, these complexes contain two electrophilic positions, the carbene carbon and the /J-carbon (Fig. 3), so they can react via these two positions with molecules which include two nucleophilic positions in their structure. On the other hand, alkenyl- and alkynylcarbene complexes are capable of undergoing [1,2]-migration of the metalpentacarbonyl allowing an electrophilic-to-nucleophilic polarity change of the carbene ligand /J-carbon (Fig. 3). These two modes of reaction along with other processes initiated by [2+2] cycloaddition reactions have been applied to [3+3] cyclisation processes and will be briefly discussed in the next few sections. 

Naturally we shall need to esterify all the carboxylic acid groupings and we then have an unambiguous condensation between enolisable ester (53) and unenolis-able but more electrophilic (a-diCO) diethyl oxalate (54). Hydrolysis of the esters in (55) and cyclisation occur under the same conditions. 

Either electrophile could be added to BuNHg first in the published synthesis the Michael addition was first (contrast p T 246 ) It is of no importance whether (39) or (41) is formed in the cyclisation l both decarboxylate to (37). 

An alternative route to pyranthrone, involving baking 1,6-dibenzoylpyrene (6.96) with aluminium chloride, was also devised by Scholl (Scheme 6.18). The Scholl reaction is a key step in the synthesis of several polycyclic quinones the cyclisation of 1-benzoylnaphthalene to give benzanthrone (6.73) has already been mentioned. The mechanism of this cyclodehydrogenation reaction may involve an initial protonation step, if traces of water are present, or complexation with aluminium chloride. Electrophilic substitution is thereby... 

Radicals generated at the position (3 to C-F bonds are expected to be more electrophilic than analogous alkyl radicals. Taguchi et al. have explored the scope of cyclisations involving primary and secondary /Tdifluoroalkyl radicals [383]. Difluorotetrahydropyrans and cyclohexanes were prepared Eq. 156 shows an efficient cyclisation. 

If you don t see at once what reagent will be used for the synthon 37, you are not alone. How can we use the other OH group at C-l to make C-2 electrophilic One way to visualise the answer is to imagine what would happen if you actually made the cation 37. It would instantly cyclise 38 to form a three-membered ring 39 that could lose a proton to give the epoxide 40. Epoxides are strained ethers and react with nucleophiles such as amines 41 to give 42 and hence the aminoalcohol 33. 

A dramatic example occurs in the last stage of the production of sildenafil 63 the Pfizer treatment of male erectile dysfunction better known as Viagra . The cyclisation of 62 must involve the attack of the nitrogen atom of one amide on the carbonyl atom of the other (arrows show first stage). This is an exceptionally difficult reaction amides are very poor nucleophiles and very poor electrophiles. Yet this reaction goes in over 90% yield.14 It does so because it is intramolecular. 

Five-membered ring formation is very favourable as the conformation needed 4 is reasonable and transition state and product are unstrained. If you make a molecular model of a long chain and fold it round you will find that the atoms that approach each other have a 1,5-relationship. Folding a chain 12 to form a six-membered ring takes the nucleophile past the electrophile 12a and only when the chain folds up in a chair-like fashion can cyclisation 13 occur. 

When a four-membered heterocycle is cis-fused on the side of another ring, as with syn-44, which we met in chapter 12, cyclisation of the syn-monotosylate 42 in base is very efficient as the, usually unfavourable, conformation 10 is now the only possible one and the nucleophile and electrophile are perfectly arranged 43 for cyclisation. This observation took on a new importance when the anti-cancer compound taxol was discovered as it also has a cis -fused oxetane.6... 

Another advantage of this approach is that we can now use electrophilic substitution on the pyrrole to add the rest of the molecule. So the secondary benzylic alcohol 106 might well cyclise to 105 with Lewis acid catalysis as the cation will be reasonably stable and the reaction is intramolecular. But the Friedel-Crafts alkylation to give 107 will not succeed as the cation would be primary. 

Homoallylic alcohols with a silyl group attached to the terminal alkene carbon were cyclised to oxetanes in high yields by reaction with bis(.sy z-collidine)bromine(l) hexafluoroantimonate (e.g., Equation 31) <2001TL2481>. This reaction exclusively gave the four-membered cyclic ether, with the silyl group directing formation of the electrophilic intermediate for the subsequent 4-fvo-/rrg -cyclization. When the carbon /3 to the silyl group on the double bond was unsubstituted, the reaction was diastereospecific. 

Bromobenzyl 2-fluorophenyl thioether, derived from 2-fluorothiophenol and 2-bromobenzyl bromide, is a source of a benzyne through reaction with /-butyllithium. Simultaneously, the bromobenzyl moiety generates the tethered aryllithium 405 and an intramolecular anionic cyclisation is promoted. The sequence is completed by the addition of an electrophilic species leading to 1-substituted b/Z-dibenzol //]thiopyrans (Scheme 121) <2002CEJ2034>. 

Examples of this cyclisation-oxidation strategy include the synthesis of pyridotriazine 5.32 (page 42) and syntheses of quinolines and isoquinolines (Chapter 6). Some examples of nucleophilic and electrophilic fragments are shown in Table 1.1. Several points arise from the table. 

Bromination of ketone 3.17 gives 3.18 which can be converted to azide 3.19. Hydrogenation of 3.19 in the presence of hydrochloric acid affords 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. 

It is interesting to contrast these double lithiations of secondary N-allyl amides with the double lithiation of a secondary N-silyl amine 59, which leads to vinylic y-lithiation, rather than allylic a-lithiation.41 42 The product 60 cyclises onto carbonyl electrophiles to yield pyrroles such as 61. 

Removal of the amide function is much easier if the reaction is intramolecular, and -CONEt2 amides (sometimes even -CON/-Pr2 amides) may be converted to lactones, lactams and other heterocycles in this way.120 158 Addition of an aldehyde or ketone as an electrophile generates a hydroxyl group (in some cases, atroposelectively, as it happens159 132 - though this is usually irrelevant to the stereochemistry of the product) which cyclises to give a lactone via a benzylic cation in acid. This reaction has found wide use in the synthesis of polycyclic aromatics, particularly alkaloids. 

Rather than fighting against the lack of electrophilicity at the amide carbonyl group, it can be more fruitful to exploit its electron-rich nature in cyclisations onto carbocations. For example, the allyl-substituted amides 174 cyclise to the 6-membered lactones 175 in refluxing 6M HC1.161... 

Secondary amides have the advantage over tertiary amides that they are relatively easy to remove. It is quite difficult to stop the addition products from aldehydes, ketones, amides, epoxides and nitriles cyclising directly to give a variety of lactone derivatives (by attack of OH on the secondary amide) or lactam derivatives (by attack of the secondary amide on the new electrophilic centre).102 Thioamides behave similarly.170... 

Much more versatile than the simple anilines are their anilide derivatives. Pivalanilides, benzanilides and other non199 414 (or scarcely415) enolisable amides 459 are laterally lithiated on treatment with two equivalents of BuLi, and may be quenched with electrophiles to give 461. In the absence of an electrophile, the organolithiums 460 cyclise to indoles 462. 

A similar cyclisation can result from lithiation of an isonitrile lithiation of 463 requires two equivalents of LDA and the organolithium 464 can either be trapped with other electrophiles at low temperature or warmed to give an indole 465.416 417 it is quite clear that isonitriles activate purely by conjugation, and indeed they promote deprotonation of methyl groups para to an isonitrile just as well as ortho. The ease with which isonitriles can be made from formamides suggests that these methods could be rather more widely used than they are. 

Configurationally stable sulfur-substituted organolithiums probably also react with retention. Hoffmann showed that the retro-anionic cyclisation of 17 and electrophilic substitution with Mel of 18 proceeded with overall retention, indicating either double inversion or double retention.16 A tin electrophile behaved similarly. 

Non-heterosubstituted organolithiums usually have low configurational stability, but the very rapid cyclisation of 49 means that - assuming tin-lithium exchange of 48 goes with retention - invertive substitution can be proved.51 Inversion at both nucleophilic and electrophilic centres is a common feature of cyclopropane-forming reactions.7... 

The first cyclisations to be put to synthetic use were those of aryl lithiums onto carbonyl compounds, imines and epoxides. These are known as Parham cyclisations , and the method for transforming an aryl bromide to an aryllithium the Parham protocol , after W. E. Parham, who developed the reaction. We will survey the use of Parham cyclisations in synthesis, before assessing intramolecular attack of other electrophiles. The most important of these are the alkenes, and the usefulness of anionic cyclisations onto unactivated double bonds compares very favourably with radical cyclisations, particularly with regard to stereochemical control. 

With metallic lithium, the problem of alkyllithium addition to the electrophile is avoided, and provided the reacting substituents were arranged cis on the existing five-membered ring, the ketone 94 could be cyclised to a single isomer of the bicyclic 5,5-system 95 in 95% yield.54 The mms-fused system 97 formed in only 44% yield from 96, as a mixture of diastereoisomers - the major product was then simple reduction to the uncyclised alkene 98. 

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