Radical cyclisations

Keywords Block polymers Radical addition Radical cyclisation Radical-polar-crossover Xanthates... 

The endoperoxy hydroperoxide (36) results from the hydroperoxide (35) by sequential peroxy radical generation, (>-exo trig cyclisation and oxygen trapping <96SL349>. 

In other cyclisations to functionalised oxepanes, Rychnovsky and Dahanukar have shown that the epoxide 36 cyclises with BF3 etherate and TMSCN to form the oxepane 37 as single product <96TL339>, and Evans and Roseman have prepared a series of cyclic ethers by radical cyclisation of the acylselenides 38 (Scheme 8) <96JOC2252>. The major product was always the cw-isomer and the best yields were obtained with (TMSjaSiH. 

The secret of the cyclisation is that salt (4) decomposes to radical (5) (and Cl ) which abstracts a hydrogen atom from the fourth carbon atom along the chain (5, arrows) via transition state (6) to give radical (7). This recaptures Cl (from Cl ) to give (8) which cyclises to (3) very easily. 

The cyclisation route gave the highest yield, but (12) is not available and had to be made by a low-yield radical coupling process. 

Radical cyclization of the indole thioesters 107 and 110 with tributyltin hydride and 2,2 -azobisisobutyronitrile (AIBN) gives a mixture of products in each case the 6-< Wo-cyclization product (the indolonaphthyridine, 109 or 112) and the 5-f vv-cyclisation product (the spiro compound 108 or 111) are obtained in approximately equal yield (Equations 22 and 23) <20040L759>. 

The cyclic sulfinates 87 and 88 have been prepared by radical cyclisation of the corresponding haloalkyl ferf-butylsulfinates as shown <06AG(E)633. 

The base-catalysed ring contraction of 1,3-dioxepanes offers an attractive route to 4-formyl tetrahydropyrans (Scheme 14) , whilst fused exo-cyclic dienes 27 result from the radical cyclisation of alkenyl iodides 26 (Scheme 15) <00OL2011>. Intramolecular radical addition to vinylogous sulfonates is highly stereoselective, leading to the ci s-2,6-disubstituted tetrahydropyran (Scheme 16) . 

The adduct formed in the first step (an equilibrium) is highly colored and decomposes either back to reactants or to a reduced species [Fe(CN)5NO]3 and the thiyl radical RS. In the presence of oxygen the reduced species is oxidised back to NP, giving a cyclised oxidation of RS to RS (and disulfide) but, under anaerobic conditions, NP reacts with eventual release of NO [46]. However, in spite of the desired... 

In the past few years, however, very efficient new methods of cyclisation proceeding via radical intermediates have been developed and several reviews [19a] and a comprehensive book by Giese [19b] have been published. Rather than reactions involving the dimerisation of two radicals -as in the Kolbe electrochemical synthesis [20] or the radical induced dehydrodimerisation developed by Viehe [21]-more important are the reactions between a radical with a non-radical species. The advantage of this type of reaction is that the radical character is not destroyed during the reaction and a chain-reaction may be induced by working with catalytic amounts of a radical initiator. However, in order to be successful two conditions must be met i) The selectivities of the radicals involved in the chain-reaction must differ from each other, and ii) the reaction between radicals and non-radicals must be faster than radical combination reactions. 

These methods are usually highly regio- and stereoselective and represent a breakthrough for synthetic chemistry using radicals. Giese quotes, as an example, that the cyclisation of the 5-hexenyl radical 8 affords the primary cyclopentylmethyl... 

According to the Baldwin rules (see Table 6.1), the exo-cyclisation leading to the primary radical (9) is favoured over the enJo-cyclisation which would lead to the more stable secondary radical (10), the stereoelectronic factors playing a fundamental role in the observed selectivity. 

On the other hand, Beckwith rules [22] are useful guidelines for predicting the stereoselectivity in the cyclisation of substituted hexenyl radicals i) 1- or 3-substituted radicals give preferentially cij-disubstituted cyclopentane derivatives and ii) 2- or 4-substituted radicals give mainly rrans-disubstituted derivatives. These rules can be explained in terms of 1,3-diaxial interactions present in a chair-like transition state. Some examples which demonstrate such an effect are [19b] ... 

In fact, the formation of five-membered rings during the radical cyclisation has been used extensively in the past few years for the synthesis of several polyquinanes. 

High stereoselectivity is achieved in radical cyclisations leading to pentagonal rings. 

For the route A, acyl radicals donors like iS are readily generated from acyl selenides (ISa) or acyl cobalt derivatives (iSb) and radicals acceptors 2S are usually multiple bonds as in methyl vinyl ketone (2Sa) -although some homolytic substitutions are possible. On the other hand, nitriles GSal are useful acceptors (3S) in radical cyclisations and 4Sa is an obvious synthon equivalent of radical donor 4S (See Table 7.2). 

Since acetonitrile itself is a poor radical acceptor, strategy B is more suitable for intramolecular cyclisations (Scheme 7.20). 

From an exhaustive retrosynthetic analysis and from the experimental work performed by Curran [29] [32], it was clear that the synthesis of modhephene required an elaborate strategy. In the first place, the tandem radical cyclisation should be conducted individually rather than just in one step since it allows more flexibility. In the second place, Curran s observation that the precursor of modhephene (54) could be the olefmic exocyclic derivative 55 allows the application of a series of heuristic principles already familiar to us, which greatly simplifies the retrosynthetic analysis and leads to diquinane and, finally, through a second radical retroannulation to the very simple cyclopentanone derivative (Scheme 7.24). 

The synthesis of modhephene (54), which proceeds according to plan in an overall yield of >16%, with complete control of relative stereochemistry, demonstrates the ability of radical cyclisations to form propellane systems and generate highly crowded neopentyl quaternary centres. The accepted pathway for the cyclisation of the vinyl trimethylstannane is shown in Scheme 7.25. The chair-like transition state in which the methyl substituent on the radical is pseudoequatorial, accounts for the observed endo stereoselectivity. 

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