Intramolecular reactions, cyclisation

Oxidative cyclisations representing intramolecular variant of the Wacker reaction have seen significant developments. The intramolecular oxidative cyclisation of tosylamines was found to be catalysed by the [Pd(TFA)2(IMes)(OH2)] complex (TFA = trifluoroacetate) [42], The presence of a catalytic amount of acetic or benzoic acid leads to improved activity and selectivity (Scheme 10.13). 

Due to its marked atom economy, the intramolecular hydroamination of alkenes represents an attractive process for the catalytic synthesis of nitrogen-containing organic compounds. Moreover, the nitrogen heterocycles obtained by hydroamination/cyclisation processes are frequently found in numerous pharmacologically active products. The pioneering work in this area was reported by Marks et al. who have used lanthanocenes to perform hydroamination/cyclisation reactions in 1992. These reactions can be performed in an intermolecular fashion and transition metals are by far the more efficient catalysts for promotion of these transformations via activation of the... 

This chapter is concerned with reaction rates, equilibria, and mechanisms of cyclisation reactions of chain molecules. A detailed analysis of the historical development of experimental approaches and theories concerning the intramolecular interactions of chain molecules and the processes of ring closure is outside the scope of this chapter. It must be borne in mind, however, that the present state of the art in the field is the result of investigations which have been approached with a variety of lines of thought, methods, and objectives. 

The values of 0(ASD) /2.3O3 R listed in Table 5 are the entropic components of log EM. These are the log EM- alues for ideal strainless cyclisation reactions, i.e. reactions where 0AH° = 0. It is of interest to note that, as far as the entropic component is concerned, symmetry corrected effective molarities on the order of 102 106M are found. This observation leads to the important conclusion that cyclisation reactions of chains up to about 7 skeletal bonds are entropically favoured over reactions between non-connected 1 M end-groups. The intercept of 33 e.u. corresponds to an effective molarity of exp(33/R) or 107 2M, which may be taken as a representative value for the maximum advantage due to proximity of end-groups in intramolecular equilibrium reactions. It compares well with the maximum EM of about 108M estimated by Page and Jencks (1971). 

More direct evidence is derived from investigations of solvent effects on cyclisation reactions (for a short review see Galli et al., 1981). Bruice and Turner (1970) found that transfer from water to 1 M water in Me2SO causes little changes in the EM s for the formation of the 5-membered cyclic anhydrides [31] and [32], This was taken as evidence that solvation phenomena contribute very little to rate enhancements of intramolecular reactions. Similar... 

Lemer and Benkovic examined the possibility of performing an intramolecular cyclisation reaction [30]. They chose the formation of a six-membered lactone ring from a hydroxy ester (12) and observed that only one single enantiomer of the 5-lactone (14) in 94% ee was formed from the corresponding 5-hydroxy ester. Moreover, the stereospecific ring closure reaction was accelerated by the antibody -elicited from the transition-state analog 15- by about a factor of 170. 

Aspartame is relatively unstable in solution, undergoing cyclisation by intramolecular self-aminolysis at pH values in excess of 2.0 [91]. This follows nucleophilic attack of the free base N-terminal amino group on the phenylalanine carboxyl group resulting in the formation of 3-methylenecarboxyl-6-benzyl-2, 5-diketopiperazine (DKP). The DKP further hydrolyses to L-aspartyl-L-phenyl-alanine and to L-phenylalanine-L-aspartate [92]. Grant and co-workers [93] have extensively investigated the solid-state stability of aspartame. At elevated temperatures, dehydration followed by loss of methanol and the resultant cyclisation to DKP were observed. The solid-state reaction mechanism was described as Prout-Tompkins kinetics (via nucleation control mechanism). 

The intramolecular carbon-carbon bond-forming reactions considered in this section are based on the aldol condensation (see Section 5.18.2, p. 799), the Claisen-Schmidt reaction (see Section 6.12.2, p. 1032), the Claisen ester condensation (see Section 5.14.3, p. 736), and the Claisen reaction (see Section 6.12.2, p. 1032). Since these carbonyl addition reactions are reversible, the methods of synthesis are most successful for the formation of the thermodynamically stable five- and six-membered ring systems. The preparation of the starting materials for some of these cyclisation reactions further illustrates the utility of the Michael reaction (see Section, 5.11.6, p. 681). 

An illustrative example of oxirane formation by the action of alkali on a / -halohydrin is to be found in the reaction sequence involved in the Darzens glycidic ester synthesis (Section 5.7.6, p. 598). Three target molecules, namely 2-phenylaziridine (4), methyl (S)-thiiranecarboxylate (5) and cyclooctene sulphide (6), are selected here to exemplify this intramolecular cyclisation reaction type. 

This chapter is about intramolecular reactions and, in particular, about making heterocycles by cyclisation reactions. At the end of the last chapter we mentioned that the synthesis of 76 by reaction of the primary alkyl chloride 74 with MeNH2 was likely to give a poor yield (numbers from chapter 28). The problem is that the product 75 is also a nucleophile and will react at a similar rate with 74 as does MeNH2- The reaction is mtermolecular and so bimolecular. 

Cyclisations are easy. In chapters 7 and 21 we saw that the type of control needed to make open chain compounds is often unnecessary for cyclisations as intramolecular reactions usually take precedence over intermolecular. If, therefore, a difficult step needs to be used in a synthesis, it is good strategy to make it a cyclisation. 

The ability of Sml2 to reduce alkyl halides has been exploited in a number of carbon carbon bond-forming reactions. Radicals generated from the reduction of alkyl halides can be trapped by alkenes in cyclisation reactions to form carbocyclic and heterocyclic rings (see Chapter 5, Section 5.3), and the alkyl-samarium intermediates can be used in intermolecular and intramolecular Barbier and Grignard reactions (see Chapter 5, Section 5.4). The reduction of ot-halocarbonyl compounds with Sml2 gives rise to Sm(III) enolates that can be exploited in Reformatsky reactions (Chapter 5, Section 5.5) and are discussed in Section 4.5. 

One of the main drawbacks of the intermolecular reaction is that to achieve good yields and selectivity it is frequently necessary to run reactions to low conversion rates or use the heteroaromatic base in vast excess. Such a limitation does not apply when conducting reactions intramolecularly and in recent times much attention has been focussed on such variants. A number of synthetically useful orr/jo-cyclisation and j so-substitution reactions have been uncovered providing new routes condensed heteroaromatic ring systems and substituted pyridines. Reactions can be effected at neutral pH and may occur to each of the carbon centres in the pyridine ring system. As these recent advances have not been summarised previously, much of this review will be devoted to the intramolecular reaction. 

Galatsis group [14] reported a study on an NARC sequence involving (i) aldol reactions of enolates derived from the kinetic deprotonation of unsaturated esters, such as 25 and 28, to ketones (Fig. 9) and aldehydes (Fig. 10) followed by (ii) endo-cyclisation via intramolecular iodoetherification. As the enolates used in the study were racemic and the aldol reactions stereorandom, it would be interesting to repeat this work using a chiral auxiliary (e.g. a chiral amide). This should ensure high levels of enantio- and diastereo-selectivity. 

A specifically kinetic effect may derive from the nature of the transition state. For a cydization reaction the transition state is a ring with one partial covalent bond (for example, 5.2). This may be formed almost completely, as in some lactonisa-tions moderately, as in Sn 2-type processes or to a very minor extent, as perhaps in the hard-to-detect cyclisation reactions of acetals (see 3.29, above). Observed EMs for cydization reactions fall in this order [36]. For a general base catalyzed reaction, by contrast, there is no formal equilibrium free energy of cydization, because the product is not a ring rather - at best - a cycle interrupted by an intramolecular hydrogen bond, set up for the reverse, intramolecular general add catalyzed reaction (5.5, Scheme 2.41). In this situation it is clear that stronger... 

A full paper has appeared expanding on the previous report concerning the photo-Fries rearrangements of N-aroylcarbazoles. In polar solvents mixtures of carbazole and both (311) and (312) are obtained, while in non-polar solvents carbazole and low yields of (311) only are isolated instead. An intramolecular cyclisation reaction competed successfully with rearrangement in the case of N-(ortho-chlorobenzoyl)carbazole to yield (313) as the major product. In a report from a different laboratory the photo-Fries rearrangement of N-sulphonylcarbazole is described and the products identified as (314) and (315) in contrast to the results described above, these authors report that N-benzoylcarbazole is photochemically inert. 

Another useful class of reactions which has been successfiilly demonstrated as a continuous SCF process are etherfication/cyclisation reactions, again using acid catalysts [52]. Examples include the formation of asymmetric esters and heterocyclic compounds. Scheme 12.2 shows the intramolecular cyclization of 1,4-butanediol over Amberlyst-15 at 120 bar, 170 °C, which produces the heterocyclic compound tetrahydrofuran (THE). 1,4-Butanediol has a melting point of 16 °C, and so, although not strictly required, a small amount of methanol may be added to the reactants to aid solubility during decompression of the SCF. Adding a cosolvent to the system may also improve solubility in SCCO2 [13]. 

Macrolides and Related Compounds. - Complex phosphonates continue to be used in the construction of carbon skeletons and in cyclisation reactions, as exemplified by the synthesis of didesepoxyrhizoxin, the biogenetic precursor of the antitumour agent rhizoxin, via intramolecular olefination of (225). (+)-Trienomycins A and F, members of a family of ansamycin antibiotics, have been synthesised using a double Wittig reaction of the diphosphonium salt (226) as a key step. The reaction produces a mixture of isomers including 21% of the required (all- ) product. 

When allowance is made for the changes in strain energy and loss of entropy of internal rotations that occur upon cyclisation in intramolecular reactions the variations in effective concentrations previously mentioned may be nicely accounted for [15,16]. 

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