This review highlights a number of synthetic advances made using radical reactions in the field of organic chemistry during 2002. The development of tin-free radical reactions continues to be the focus of considerable attention. Walton has developed 1-phenylcyclohexa-2,5-diene-1-carboxylates as pro-aromatic sources of clean free radicals.1Treatment of1with a peroxide radical initiator results in formation of the cyclohexadienyl radical2. β-Scission then forms the alkoxycarbonyl radical3and the innocuous biphenyl (Scheme 1). The former extrudes carbon dioxide to generate the desired alkyl radical4, which can be trapped by an internal alkene in good yield. Previous cyclohexadiene precursors have contained an alkyl substituent at the 1-position and have suffered from low yields due to competitive β-scission. This is not observed with1and its analogues as this would result in formation of the energetically unfavourable aryl radical. Good yields could be obtained for intramolecular 5-exocyclisations. Unfortunately, yields for intermolecular reactions were not as satisfactory. This, in conjunction with difficulty in preparing the precursors, limits the scope of this methodology at present.In related research, Studer has utilised a silylated cyclohexadiene to generate silicon-centred radicals that are able to undergo intramolecular hydrosilylation (Scheme 2).2The reaction works for a variety of alkenes but is sensitive to terminal substitution. Remarkably, the methodology allowed the first example of a 5-endo-digradical cyclisation to be achieved, furnishing5in an impressive 55% yield for two steps.Walton has developed an elegant method for the synthesis of lactams utilising the photosensitised decomposition of oxime oxalate amides as a source of clean radicals.3The radical precursors were readily prepared from an oxime and oxalyl chloride followed by treatment with a secondary amine. Cyclisation was achieved by photolysis of the radical precursors6in the presence of 4-methoxyacetophenone (MAP) as a photosensitiser (Scheme 3). Interestingly, if cyclisation resulted in a secondary radical7, hydroxylation was observed, resulting in alcohols8. Presumably the more stable radical has the opportunity to react with oxygen from the solvent.Kim has continued to develop a range of ingenious tin-free radical reactions utilising sulfones as radical reagents and precursors. Alkyl iodides9were found to undergo radical cyanation with toluenesulfonyl cyanide10in the presence of the initiator V-40 [azobis(cyclohexanecarbonitrile), a thermally more stable analogue of AIBN] and methyl allyl sulfone11(Scheme 4).4The methyl allyl sulfone11acts as a source of methyl radicals for the atom transfer process. The initially-formed toluenesulfonyl radical12interacts with11to give the methyl sulfonyl radical13. Whilst13could add to either11or14, neither process is detrimental; addition to11is degenerate whilst addition to the latter regenerates12. Thermal decomposition of13gives the methyl radical14, which undergoes atom transfer with9to give the desired alkyl radical15. Finally, this reacts with10to give product16and regenerate12. Whilst the reaction gave good results with tertiary and benzylic iodides, primary and secondary alkyl halides were far inferior due to the competing direct addition of the methyl radical to toluenesulfonyl cyanide over iodine atom transfer. This limitation could be overcome by employing alkyl tellurides, thus allowing more complex products17to be formed.The inefficiency of iodine atom transfer from primary halides has limited a number of tin-free radical methodologies. As a result other radical precursors have been developed. Kim has used alkyl allyl sulfones (e.g.18) as a source of primary radicals (Scheme 5).5The proposed pathway for the radical chain reaction is analogous to the previous cyanation process (vide supra) and has been used in cyanation, vinylation, allylation and tandem radical reactions (19to20) (Scheme 5).N-Ethylpiperidine hypophosphate (EPHP) has found considerable use as a cheap, clean and convenient alternative to organotin reagents in radical reactions.6,7Jang has developed an environmentally benign intermolecular addition of alkyl halides to electron-deficient alkenes that utilises EPHP in water (Scheme 6).8For hydrophobic substrates the use of a phase transfer reagent was shown greatly to enhance the reaction.Other metal reagents offer advantages over organotin compounds in terms of cost, stability, toxicity and ease of the work-up process. It is impossible to discuss all these studies in detail, and so just one example of each class of reagent is highlighted. Samarium diiodide continues to be a popular single electron transfer reagent.9The intramolecular coupling of aldehydes or ketones to various C&z.dbd;N bonds is a well known transformation. The analogous intermolecular cross coupling is far less successful due to competing homocoupling and simple reduction. Py and Vallée have overcome this limitation by employing nitrones21as the nitrogen component. Both aromatic and aliphatic nitrones reacted efficiently with a variety of aldehydes and ketones22in the presence of samarium diiodide to give products23(Scheme 7).10No side-products from reduction or homocoupling were observed. Surprisingly, evidence suggests that single electron transfer occurs to the nitrone first. When an α-cyclopropylketone was employed, no ring-opening was observed, indicating that the ketyl radical was not an intermediate.Indium shows great potential as a reagent in radical reactions.7,11Baba has shown that indium hydride (Cl2InH), generatedin situby the reduction of a catalytic quantity of indium chloride with sodium borohydride, acts as an efficient radical reagent.12Both intra-24and intermolecular25radical additions could be carried out efficiently (Scheme 8). The mechanism of initiation is unclear, however, the authors believe that homolytic cleavage of the indium hydride bond is responsible and have discounted the participation of an indium(0) species.Naito has utilised indium metal (In(0)) as a radical initiator in the addition of alkyl radicals to both electron-deficient C&z.dbd;N bonds26and alkenes in water.13The reaction proceeds at a slower rate than those initiated by triethylborane but is cleaner, resulting in less side-products, and requires fewer equivalents of the iodide to achieve good yields (Scheme 9). Water was found to be essential for reactivity. The presence of a radical trap stopped the reaction. It should be noted that this is not conclusive proof that the reaction proceeds through a radical addition and thus does not necessarily contradict the previous work (vide supra).Gansäuer has studied a number of common single electron transfer reagents in the reductive ring-opening of epoxides in order to elucidate the reasons that Nugent's titanocene reagent is superior to other reagents.14In a series of comparison experiments between titanocene(iii) chloride, samarium diiodide, chromium(ii) chloride and [V2Cl3(THF)6]2[Zn2Cl6] it became clear that only the titanocene reagent had the required properties of low Lewis acidity, to prevent epoxide opening through either SN2 or SN1 mechanisms, coupled with low reducing power towards the β-metal oxy radical. Intriguingly, CrCl2was the only other reagent that allowed carbon–carbon bond formation, but at present has too low a reactivity to be of any synthetic use. Clearly this is a deficiency that will soon be rectified.Gansäuer has exploited the activity of Nugent's reagent to synthesise bicyclic alkenes with excellent control of the alkene geometry through a tandem ring-opening–cyclisation–intermolecular radical addition process (Scheme 10).15Choice of solvent was critical for the success of the tandem reaction. It was necessary that the solvent had a lower hydrogen donor propensity than THF so that the reactive vinyl radical intermediate was not reduced prior to intermolecular addition. The solvent also had to enable fast reduction of the titanocene(iv) pre-catalyst in order to maintain the catalytic cycle. Ethyl acetate was found to be the optimum solvent. The control of the alkene geometry during the intermolecular addition is thought to arise by the titanium oxygen complex blocking approach of the enone from one face27.A number of examples of manganese(iii) acetate-mediated oxidative free radical reactions of 1,3-dicarbonyl compounds were reported during 2002.16One interesting example was the preparation of macrocycles28in good yields (Scheme 11).17Various diketones29containing a pendant allyl ether substituent could be cyclised with 5 equivalents of Mn(OAc)3in acetic acid at reflux to give the bicyclic compounds28. Surprisingly, the best yield was achieved for the cyclodecane (n= 4) system, which is the hardest ring-size to form by intramolecular cyclisation, whilst formation of cyclopentane derivative (n= 0), a favourable 5-exo-trigprocess, proved impossible.Most manganese(ii)-mediated radical reactions use an excess of the reagent, a property that is unattractive from a practical standpoint. A catalytic variant, employing Mn(OAc)2, Co(OAc)2and oxygen has been developed by Ishii (Scheme 12).18The Mn(ii) is continuously oxidised to the reactive Mn(iii) by the action of a Co(iii)–dioxygen complex; it can then oxidise the diketone to a radical species, which undergoes addition to the alkene. The system works well for a variety of diketones and alkenes. The major limitation is the need for a large excess of the diketone. An impressive example is outlined inScheme 12.An elegant radical cascade employing catalytic palladium(0) and light has been reported by Ryu and Komatsu.19The methodology is analogous to Pd(0) catalysed cascades, resulting in both carbonylation and cyclisation, but, due to its radical nature, functions with alkyl halides instead of aromatic or vinylic halides. Irradiation of a variety of 4-alkenyl iodides30in the presence of Pd(PPh3)4, triethylamine and DMAP under an atmosphere of carbon monoxide initially results in the formation of cyclopentanone31, which can then undergo a second carbonylation process (Scheme 13). The reaction is terminated by addition of an alcohol or a secondary amine to give a variety of esters or amides32. It is postulated that Pd(0) is oxidised to Pd(i) with concomitant formation of the alkyl radical33under the photolysis conditions. Radical carbonylation followed by 5-exo-trigcyclisation then occurs to give31. A second carbonylation generates an acyl radical34which oxidises the Pd(i) to an acylpalladium(ii) intermediate35. Finally reductive elimination in the presence of either alcohol or amine furnishes the product32and regenerates the Pd(0) catalyst. The efficient formation of functionalised ring-systems by the construction of 4 new bonds under mild conditions is extremely attractive.Aminohydroxylation of alkenes offers an attractive route to a variety of biologically important motifs. Göttlich has achieved a catalytic radical aminohydroxylation through a group transfer reaction utilising a copper(i) catalyst in the presence of boron trifluoride etherate (Scheme 14).20Although the N–O bond is often considered to be weak it was found that a combination of Lewis acid and copper(i) species was essential for activity. The Lewis acid plays two roles, first activating the N–O bond in36, thus allowing the copper(i) to reduce it to an aminyl radical37. The radical can then undergo intramolecular addition to the alkene efficiently when it is activated by the Lewis acid. The resulting alkyl radical38is rapidly oxidised by a copper(ii) complex to give the product39and regenerate the catalyst.Zard has continued to investigate extensively tin-free radical synthesis utilising dithiocarbonyl derivatives and lauroyl peroxide (DLP) as radical initiator.21Analogously to Göttlich, pyrrolidinones40could be synthesised by a group transfer radical cyclisation (Scheme 15).22In an elegant extension of this work, use of stoichiometric DLP allowed a radical cascade onto an aromatic ring to be achieved, generating the tetracycle41in good yield (Scheme 15).Tin hydrides still hold a privileged position in radical chemistry and as a result methods to improve their utility in synthesis continue to be developed. Clive has developed stannane42(Fig. 1).23This reagent behaves analogously to tributyltin hydride but has the advantage that it can be readily removed by either mild acid or base hydrolysis followed by an aqueous NaHCO3wash, thus alleviating one of the disadvantages of conventional tin reagents. The polyaromatic hydrocarbon-supported tin hydride reagent43also allows for facile purification.24Again, the reagent mediates radical reactions well and can be removed simply by adsorption on to activated carbon. The greatest drawback of such reagents is their lengthy synthesis.Radical reactions continue to play a key role in organic synthesis due to their good functional group compatibility and ability to perform multi-step processes. Renaud has developed a three-component, one-pot coupling reaction that formally results in the carboazidation of alkenes (Scheme 16).25Hexabutyldistannane and di-tert-butyl hyponitrite (TBHN) are used to form an electrophilic enolate radical in the presence of an alkene and phenylsulfonyl azide. The radical adds exclusively to the alkene and not to the sulfonyl azide as this reagent is also electrophilic. The resulting alkyl radical then undergoes azidation, either directly or through an atom transfer process, to give44. The reaction can be coupled with a reduction step to give an amine that spontaneously cyclises allowing rapid entry to the bicyclic lactam45framework. A diastereoselective variant of this reaction has also been achieved.26An alternative means of forming C–N bonds has been reported with the first examples of radical-mediated vinyl amination.27The cyclisation of a vinyl radical onto an azomethine nitrogen allows the direct synthesis of enamines by a non-dehydrative method. Normally the resulting enamines were trapped as their benzoylated adduct in reasonable yields for the two steps. The vinyl radicals could either be formed directly from vinyl halides or by addition of heteroatom-centred radicals to an alkyne (Scheme 17). In all cases just one alkene geometry was observed.Bowman has developed an impressive cascade reaction for the formation of tetracyclic alkaloids46by radical addition to an aromatic ring (Scheme 18).28Good yields could be achieved if the vinyl iodide47was used as opposed to the bromide. The reaction had to be carried out with hexamethylditin to avoid reduction of the reactive intermediates48or49. It is believed that the reaction proceeds through a 5-exocyclisation of a vinylic radical48onto the nitrile followed by 6-endocyclisation. The driving force for this second cyclisation is thought to be delocalisation of the unpaired electron over nearly the entire compound. Finally hydrogen abstractionviaan unknown species gives the product46in an impressive 73%. It is possible that the reaction proceedsviaa spirocyclic intermediate, but the use of substituted aryl rings suggest this is not the case.Azadirachtin (Fig. 2) is a challenging synthetic target that has yet to succumb to total synthesis. Two groups have reported the use of radicals in model studies towards this demanding target. The main obstacle is the formation of the C8–C14 bond bridging the two halves of the molecule. Nicolaou has investigated a radical cyclisation approach to the formation of this bond (Scheme 19).29Linking the appropriate bromide to the decalin portionviaa temporary acetal tether allowed the C-7 hydroxyl group to control the stereochemistry of the new bond. The pentacycle50was found to undergo spontaneous hydrolysis to the desired product51. Although the route shows great potential, it is currently limited by the non-stereoselective formation of the radical precursor.In an alternative strategy, Ley forms the C8–C14 bond by a Claisen rearrangement and then utilises a radical cyclisation of the xanathate52on to an allene to generate analogue53(Scheme 20).30Intriguingly, the desiredendoalkene53and not the anticipatedexoalkene was formed exclusively. The authors suggested that the highly congested nature of the tertiary radical centre (at C-14) prevents protonation occurring at this point and only allows it to occur at the more accessible primary radical centre (C-18). The high yield demonstrates the utility of radicals and their high functional group tolerance.The [3+2]-cycloaddition of homoallylic methine radicals to simple alkenes is a well-known means of producing the cyclopentane skeleton. Surprisingly, prior to 2002 there had been only one example of the use of dienes in this reaction. Such systems would allow the formation of bicyclic systems through a radical cascade. Problems associated with the reaction include the limited reactivity of the homoallylic radicals and the necessity forcisstereoselectivity in the initial cyclisation. Taguchi has overcome these with the use of54as the homoallylic radical precursor in an iodine atom transfer reaction in the presence of Et3B and Yb(OTf)3.31The success is thought to arise due to the increased reactivity of the methine radical due to coordination of the malonate to the Lewis acid. A variety of dienes and enynes can be employed in good yields (Scheme 21).Stereoselectivity in radical chemistry remains an important area of study. In a fascinating study Curran has investigated stereocontrol at the steady state in radical cyclisations of acyclic dihalides55(Scheme 22).32In this reaction two radical precursors compete for one acceptor. Under these conditions, stereoselectivity is not due to two competing stereoisomeric transition states, as observed in the majority of stereoselective processes, but is instead the result of the two stereoisomeric intermediates56and57undergoing different chemical reactions. For brevity only the two pathways leading to the major diastereoisomers are illustrated (Scheme 22). For stereoselection to occur, the initially-formed radicals56and57must undergo either reduction or cyclisation at different rates. As long as56undergoes reduction faster and57undergoes cyclisation then the desired diastereoisomers58should be the major product. The results show that it is possible to achieve reasonable, predictable selectivities by extending the principles of the Beckwith–Houk model.Sulfoxides are attractive chiral auxiliaries but their use in diastereoselective radical reactions can be problematic. Toru has investigated the radical allylation of α-(arylsulfinyl)alkyl radicals generated by the addition oftert-butyl radicals to vinyl sulfoxides59to give products60and61(Scheme 23).33Interestingly, only the phenyl sulfoxide provided sufficient activation to allow radical addition to the alkene59. Unfortunately subsequent allylation occurred with no selectivity even in the presence of a Lewis acid. Use of electron-rich aromatic rings (Ar = Py) deactivated the alkene. When a Lewis acid was able to coordinate to both the sulfoxide and the heterocycle then not only was the alkene activated for the initial addition, but also good diastereoselectivity could be achieved. The best example used a 1-methylimidazol-2-yl ring with Zn(OTf)2.Guindon has utilised a diastereoselective radical hydrogen atom transfer process to access the challenging 2,3-anti-3,4-antipropionate motif.34The initial 3,4-antirelationship was set up by the Mukaiyama aldol reaction of a tetrasubstituted selenosilylketene acetal62(Scheme 24). Treatment of the resulting product63with tributyltin hydride in the presence of triethylborane, Hünig's base and a boron Lewis acid resulted in the formation of the desired 2,3-antiproduct64in excellent yield and selectivity (75%; ≫ 20 : 1). Remarkably, the reaction could be carried out in a one-pot procedure with excellent yields and selectivities.Sibi has continued to test the limits of diastereoselective radical additions to electron deficient alkenes. Having previously investigated stereocontrol at both the α- and β-centres, attention has turned to the γ-centre. This can be achieved by adding prochiral radicals to substituted alkenes.35Interestingly, the best diastereoselectivity between the β- and γ-centres was achieved with halogenated radicals, indicating that a subtle stereoelectronic effect could be involved. The use of lanthanide Lewis acids in the presence of achiral additives was also found to improve the selectivity. Combining all the information garnered, an elegant example utilising a chiral auxiliary was reported (Scheme 25). This promising result bodes well for the future.Garner has developed an effective chiral auxiliary for hydroxylalkyl radicals (Scheme 26).36A number of tetrahydropyran (THP) and sugar derivatives were investigated. The results indicated that the C-6 substituent was vital for good selectivity. The simple C-6-tert-butyl THP gave excellent diastereoselectivity but unfortunately resulted in only moderate isolated yields. This was overcome by forming a more robust sugar-derived auxiliary. Utilising this auxiliary allowed formation of the protected aldol product65with excellent diastereoselectivity (Scheme 26). The complementary nature of this reaction to more classical means of forming the aldol product suggests that it has great potential.Ultimately the development of enantioselective radical reactions is more attractive than that of the analogous diastereoselective processes. Sibi utilised a variety of Lewis acid-based systems to control the absolute stereochemistry in radical conjugate additions to enoates.37The best control of β-stereocentre was achieved utilising samarium triflate in the presence of the proline-derived ligand66(Scheme 27). The optimum conditions were found to be 30 mol% of the Lewis acid catalyst in the presence of the achiral additive67(95%, 84% ee). It is thought that this additive prevents the product from coordinating to the samarium and so producing a less selective complex.It is possible to control the absolute stereochemistry at the α-position by the addition of alkyl radicals to a α-methacrylate followed by enantioselective hydrogen atom transfer. In a comprehensive survey of conditions, Sibi varied the nature of the Lewis acid, the ligand and the achiral template on the methacrylate.38The optimum conditions utilised magnesium and bisoxazoline68as the Lewis acid. More interesting is the effect of the achiral template on the selectivity. The best results were obtained with 1,8-naphthosultam69(Scheme 28). It appears that the tetrahedral nature of the sulfone moiety is the key to the success of this template.Considering that one of the advantages of radical transformations is their ability to undergo tandem and cascade reactions, it is somewhat surprising that 2002 saw the first report of an enantioselective atom-transfer tandem radical cyclisation.39Although the best enantioselectivity was 84% ee, this was at the expense of chemical yield. The most promising result was the formation of 6,5-cis-70from the diene71in the presence of a stoichiometric amount of Yb(OTf)3and tridentate bisoxazoline72in 60% yield and 66% ee (Scheme 29). Impressively, two rings and four contiguous stereocentres are set up in one step. Such a reaction shows great potential for the future.Roberts has employed carbohydrate-derived thiols as catalysts for enantioselective radical-chain reactions.40Lactone73undergoes enantioselective hydrosilylation in the presence of triphenylsilane, an initiator and the appropriate thiol (Scheme 30). The thiol acts as a chiral source of hydrogen atoms and the chain-carrier. The enantiocontrol appears to be controlled by two factors: the orientation of the thiol in relation to the pyranose ring (β-glucose thiols are active whilst α-glucose thiols give no selectivity) and the orientation of the C-2 substituent (β-mannose is far more effective than β-glucose).