Cyclisation, anionic

The base-catalysed anionic cyclisation of hexynones 5 results in the 4//-pyran 6 and a mixture of E- and Z-dihydropyrans 7 (Scheme 3) <00EJO527>. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

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>. 

Cyclic arylsulfides, such as the heterocycle 60, undergo ring opening with Li and DBB.75 The sequence to 61 illustrates a useful ring expansion. Simple phenylsulfides have also been used as starting materials for anionic cyclisations,76 and functionalised sulfides have been converted to functionalised organolithiums.77 78... 

Carbamates containing unsaturated substituents may undergo enantioselective anionic cyclisations (see also section 7.2.4) for example, 421 is deprotonated enantioselectively by s-BuLi-(-)-sparteine and gives the cyclopentane 422.180... 

Anionic cyclisations of a-alkoxyorganolithiums similarly proceed with retention, in contrast to their [2,3]-sigmatropic rearrangements (see sections 7.2 and 8.4). 

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. 

There is a marked contrast between these rearrangements and two similar classes of reaction. Firstly, anionic cyclisations (see section 7.2) of a-alkoxyorganolithiums such as 32, which proceed with retention.28 Yields in the cyclisation are poor from 33 without the driving force of methoxide elimination, but the methoxy group has no effect on the stereospecificity of the cyclisation. 

The addition of organolithiums to polarised C=X bonds is one of the most widely used ways of making C-C bonds, and (excepting some unusual intramolecular cases) will not be discussed in this book other than to say it is a reliable and successful reaction. With a few exceptions,1 3 stereoselectivity is not a general feature of organolithium addition reactions to C=0 n bonds. Much of this chapter will concern controlled addition of organolithiums to C=C 7i bonds after an overview of carbolithiation, we shall review the development of intramolecular carbolithiation, or anionic cyclisation. 

Intramolecular addition and substitution reactions anionic cyclisation... 

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. 

Anionic cyclisations onto carbonyl compounds and derivatives... 

Cyclisation of iodonitrile 10559 to 107 was an early example of an anionic cyclisation. Slow transmetallation of the choronitrile 108 allowed the BuLi to attack the nitrile instead, leading to a quite different cyclisation product 109. The successful iodine-lithium exchange of primary alkyl iodide 105 to give 106 even with n-BuLi must be driven by the cyclisation itself. 

There is one example, unique for several reasons, of the formation of a four-membered ring by anionic cyclisation onto an oxazoline. Attempted oxazoline-directed lithiation of the styrene 122 gave, instead, the cyclobutane 124 via addition of the alkyllithium to give a benzylic organolithium 123 which cyclises stereoselectively.63 The initial intermolecular carbolithiation proceeds remarkably easily - no additives (such as TMEDA) are required, even with MeLi. 

Anionic cyclisations onto alkyl halides and similar compounds... 

There are nonetheless just a few isolated examples of three- or four-membered ring forming anionic cyclisations curiously it was in fact a three- and a four-membered ring forming reaction which provided the first two pieces of evidence that organolithiums do indeed cyclise onto unactivated double bonds. In 1960, Wittig107 showed that n-BuLi not only added to one of the double bonds of norbornadiene but that the major product of the reaction arose from organolithium cyclisation of the intermediate 201 onto the other double bond. This odd reaction is presumably made possible by the strain already inherent in the bicyclic system. After protonation, the major product was 202. 

With the radical controversy solved, Bailey and others set about the detailed investigation of anionic cyclisation as a synthetic method for the formation of five-membered carbocyclic rings, and we shall divide the remainder of this section, which covers work published between 1987 and 2000, into the main classes of compounds produced by the cyclisation cyclopentanes, furans, pyrrolidines, and polycyclic products. It turns out that organolithiums are unique among the alkali metals in their ability to undergo anionic cyclisation to give cyclopentanes, particularly where primary organometallics are concerned.121... 

Cyclisations of ring-containing starting materials to form bicyclic products 235 and 236 are rather slower, but an effective way to increase the rate of any anionic cyclisation is to add TMEDA 235 is formed in only 15% yield after 4 h at 25 °C without TMEDA, but 62% with. 

Anionic cyclisation can be used to form cyclopropanes when the product cyclopropylmethyllithium can undergo an elimination reaction.140111 The simple primary organolithium 270 requires the presence of TMEDA to cyclise, but gives 88% of vinylcyclopropane. 271 cyclises with moderate stereoselectivity. 

Since the sulfide substituents can be removed reductively, the cyclisations of 273 and 276 are synthetically equivalent to cyclisations onto disubstituted double bonds, giving compounds such as 275.142>143 Like the corresponding cyclisations onto monosubstituted alkenes they are highly stereoselective, with the sense of stereoselectivity being solvent-dependent the products 274 and 277 are trans as shown for a cyclisation conducted in THF in pentane complete cis selectivity is obtained. Similar cyclisations onto vinyl sulfides have been used to explore the stereochemical course of the anionic cyclisation reaction, and are discussed below.146... 

Cyclisation of 298 in pentane leads to a cascade of two very curious anionic cyclisations in remarkably good yield a usually highly unfavourable addition to a 1,2-disubstituted alkene, followed by attack on an aromatic ring with subsequent rearomatisation to give 299.147... 

A problem can arise in anionic cyclisations when the organolithium is formed by tin-lithium exchanges such as these. The product organolithium may become stannylated by nucleophilic... 

The stereochemical contrast between radical and anionic cyclisations provides a useful test of mechanism which has been used on a number of occasions to elucidate the course of reactions whose mechanism is ambiguous. For example the results in table 7.2.2 show that the anionic cyclisation of 352 under certain conditions proceeds without a radical component. However,... 

The first alkyne cyclisations, from 377, 379 and 381, predate the early alkene cyclisations by a couple of years these three date from 1966173 and 1967,174 and illustrate the favourability of both exo and endo-dig cyclisation. All three generate benzylic vinyllithiums (378, 380 and 382), and both aryl (377, 379) and alkyl halides (381) are successful starting materials. Similar organomagnesium cyclisations were described at about the same time.175 However, it is not clear in these reactions how much of the product is due to participation of radicals in the mechanism - alkylbromides undergo halogen-metal exchange with alkyllithiums via radical intermediates (chapter 3).176 If it really is an anionic cyclisation, cyclisation to 378 is remarkable in being endo. Endo-dig anionic cyclisations are discussed below. 

Endo-trig cyclisations are rare for organolithiums, but endo-dig cyclisations are in general more favourable, and 5-endo-dig anionic cyclisations do occur. One possible example is the... 

Anionic cyclisations of yet more stabilised carbon nucleophiles such as enolates fall outside the scope of this book.185... 

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