Intramolecular radical cyclisations

A conceptually different C-C bond forming reaction involving intramolecular radical cyclisation of allylic esters of bromodifluoroacetic acid was described by Itoh et al. [200]. Reduction to the acetal sets the stage for a tin hydride-mediated cyclisation (Eq. 65). 

Intramolecular free radical addition has been used to prepare the 1,2-thiazepine derivatives 258 and 259 from 257 a further intramolecular radical cyclisation was then used to convert 258 to a new azabicyclic system with a bridgehead nitrogen [01JOC3564],... 

Mohanakrishnan, A.K. and Srinivasan, RC. (1996) Synthesis of 4-substituted-1,2,3,4-tetrahydro-/)-carbolines via intramolecular radical cyclisation and Heck reaction. Tetrahedron Lett., 37, 2659-62. 

The application of intramolecular radical cyclisations in synthetic organic chemistry is a valuable approach to obtain important synthetic targets such as natural product precursors and biologically active substances. The use of carbohydrate starting materials in this field is no exception to this because of their well-defined stereochemistry, highly functionalised nature and availability. 

The stereoselectivity of intermolecular free radical reactions has been reviewed including the use of carbohydrate-based radicals for forming branched-chain sugars. A number of intramolecular radical cyclisations affording C-branched compounds have been reported. A 2-deojgr-2-iodo-glycoside on treatment with Bu3SnH affords a C-2 radical which may cyclise onto an appropriate functional... 

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) . 

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]. 

Scheme 10.11 shows a PRE-mediated 5-exo-trig radical cyclisation in which the controlled thermal formation of active radicals from the dormant alkoxyamine 2 is facilitated by steric compression of the alkoxyamine C—O bond by the bulky N-alkyl and O-alkyl groups [8]. Intramolecular H-bonding between a —CH2—OH and the nitroxyl oxygen of the incipient nitroxide in a six-membered cyclic transition structure further facilitated the dissociation of 2. After cyclisation, the resultant primary cyclopentylmethyl radical was trapped by the free nitroxide to form the new dormant isomerised alkoxyamine 3, which is more stable than 2 since the O-alkyl is now primary. The same reaction using TEMPO as the nitroxide component did not work presumably because the C—O bond in the alkoxyamine precursor is much stronger. 

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. 

Procter has recently shown that radical cyclisation-intramolecular aldol sequences can also be carried out.16 For example, treatment of dialdehydes 26 and 27 with Sml2 results in a sequential cyclisation to give 28 and 29, respectively, as single diastereoisomers in high yield (Scheme 6.11). The diastereo-selectivity of the sequence can be ascribed to the chelation of Sm(III) to intermediates, most notably in controlling the double-bond stereochemistry during the formation of Sm(III) enolate 30.16... 

Oxasilacyclopentanes have been extensively studied over the period reviewed and many different methodologies have been developed for their syntheses. Intramolecular radical cyclizations <2001JOC1%6>, intramolecular silylformylation of silyloxyalkynes promoted by catalysts such as Rh <20010L1303>, Ni <2001TL3259>, hydrosilylation of homo-propargyl hydrodimethylsilyl ethers promoted by solvated Pt-atoms (Equation 49) <1998JOM57>, and also photoin-duced intramolecular cyclisation of alkynyl-substituted pentamethyldisilanes have been reported <1998TL6891>. 

A radical cation is involved in the direct synthesis of chromans by an intramolecular oxidative cyclisation of 3-arylpropanols 32 brought about by a hypervalent iodine(III) reagent <04TL2293> and iodonium species catalyse the intramolecular arylation of alkenes which yields iodo-substituted chromans 33 <04JA3416>. 3-Allenylchroman-4-ols result from a one-pot reaction between salicylaldehydes and 1,4-dibromobut-2-yne in which the intramolecular cyclisation of the intermediate ether is mediated by In metal <04SL45>... 

Previously, tin-ketyl radicals have been added to alkenes only in an intramolecular fashion. [9] In recent publications, however, pinacols and amino alcohols have been prepared by cyclisation of dicarbonyl compounds [10] or keto-oximes [11] with tributyltin hydride. Cyclisation of 1,5-ketoaldehydes 1 and 1,5-dialdehydes with tributyltin hydride yields cw-diols 2 with excellent stereoselectivities, whereas the keto-oxime 4 with four benzyloxy-substituents affords a 58 42 cis trans) mixture. The tran -product was transformed in two more steps to the potent glycosidase inhibitor 1-deoxynojirimycin (6). [lib] The reversibility of both the addition of the tributyltin-radical to the carbonyl group and the intramolecular radical C-C bond formation is believed to be responsible for the high selectivity in the formation of 2. In the cyclisation of 1,5-pentanedial the unhydrolyzed coupling product 3 could be isolated, therefore providing evidence for a new mechanistic variant of the pinacol reaction, in which only 1.2 equivalent of the reducing agent are necessary. 

In the first example, the electronic requirements were investigated with similar outcomes. The final yields of cyclised 34a-c were calculated over two steps, so radical precursors 33a-c were not isolated. However, the cyclised to reduced ratio was in favour of the former. In the second example, an asymmetric synthesis of azaindolines 37a and 37b was successfully achieved by radical cyclisation of enantiomerically pure 36a and 36b. The neutral conditions used preserve the stereogenic centre, demonstrating the potential of this approach. Banerjee (02JCS(P1)1769) reported a study of an intramolecular radical addition of a 2-p37ridyl radical from 38 onto a double bond to produce the tricyclic products 39-41 (Scheme 9). 

Only 5-exo-cyclisation products 56a,b and 57a,b are observed. The presence of the bulky protecting group on the alcohol (TBDMS) slightly increases the cis-trans isomer ratio, as predicted by the Beckwith model (81T3073). In the same paper, the synthesis of ( + )-oxerine has been reported, using an intramolecular radical addition of the 3-pyridyl radical to a terminal alkyne as the key step to give 59 as well as small amounts of the reduced product 60 (Scheme 13). 

An interesting synthesis of pyrazolopyridines has been presented by Alvarez-Builla (02S1093), using an intramolecular radical addition by the 3-pyridyl radical derived from 76a-d (Scheme 14) as well as 2-p5u-azinyl radicals to a p5uidine ring, with subsequent rearomatisation to produce cyclised products 77a-c (Scheme 17). 

In one of the earliest reports on indole radicals, Sundberg (90JOC6028) outlined an intramolecular radical addition of a 3-indolyl radical onto an isolated double bond (for the synthesis of analogues of Iboga alkaloids) to yield 128a-c providing a rare example of an S-endo-trig cyclisation (Scheme 31). 

In early studies on the 4-indolyl radical, Boger (88JA1321) synthesised the antitumour-antibiotic CC-1065, using an intramolecular radical addition to an alkyne in a 5-exo-dig cyclisation (Scheme 36). 

Bennasar M-L, Roca T, Perrando F (2004) Intramolecular reactions of 2-indolylacyl radicals cyclisation upon aromatic rings. Tetrahedron Lett 45 5605-5609... 

If both the radical source and the radical trap are in the same molecule, then an intramolecular atom-transfer radical cyclisation reaction occurs. In 2001, Yang et al. reported the oxazoline 39d-magnesium-catalysed bromine atom-transfer radical cyclisation reaction of unsaturated p-keto ester 49 for... 

In 2014, an intramolecular atom transfer radical cyclisation (ATRC) between a trichloroacetamide and an anisole or enol acetate moiety was applied to the synthesis of highly functionalized 2-azaspiro[4.5]decanes or morphan compounds, respectively, using the second-generation Grubbs catalyst 20. The procedure was further employed to construct the azatricyclic framework of the immunosuppressant FR901483 by the elaboration of its azatricyclic core [eqn (7.15)]. 

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