Tributyltin mediated radical reaction

Radical reactions are now a well-established and commonly used methodology for the synthesis of heterocycles and indoles in particular. Tributyltin hydride mediated radical reactions including additions, substitutions, and cyclizations continue to he... 

Radical addition to carbon-carbon unsaturated bonds has also been carried out in microflow reactors. Tributyltin hydride-mediated radical reactions of organic halides have been successfully carried out in a continuous microflow system [20]. Rapidly decomposing radical initiators such as V-65 and V-70 are fairly effective and the reactions proceed within a very short period of time. The continuous flow reaction system can be applied to gram-scale synthesis (7.6 g, 185 min) of a key intermediate for furofuran lignans (Figure 5.2). 

Tributyltin hydride-mediated radical reaction proceeded smoothly with the use of a PI film reactor. For example, the radical cyclization product was obtained in 59% yield using the standard tin hydride/AIBN conditions (Scheme 5.16). 

Crich and Rumthao reported a new synthesis of carbazomycin B using a benzeneselenol-catalyzed, stannane-mediated addition of an aryl radical to the functionalized iodocarbamate 835, followed by cyclization and dehydrogenative aromatization (622). The iodocarbamate 835 required for the key radical reaction was obtained from the nitrophenol 784 (609) (see Scheme 5.85). lodination of 784, followed by acetylation, afforded 3,4-dimethyl-6-iodo-2-methoxy-5-nitrophenyl acetate 834. Reduction of 834 with iron and ferric chloride in acetic acid, followed by reaction with methyl chloroformate, led to the iodocarbamate 835. Reaction of 835 and diphenyl diselenide in refluxing benzene with tributyltin hydride and azobisisobutyronitrile (AIBN) gave the adduct 836 in 40% yield, along with 8% of the recovered substrate and 12% of the deiodinated carbamate 837. Treatment of 836 with phenylselenenyl bromide in dichloromethane afforded the phenylselenenyltetrahydrocarbazole 838. Oxidative... 

A detailed mechanistic analysis of the factors affecting the success of these tin hydride mediated addition reactions has been provided by Giese.3 This analysis, which is especially illustrative of how experimental conditions for free radical reactions are planned, is summarized in Scheme 27. Three intermediate radicals, (8), (9) and (10), are involved. As is characteristic of all radical reactions, these radicals are simultaneously exposed to the same reagent pool and each can potentially undergo an addition reaction or an atom transfer reaction. The required reaction of the tributyltin radical (8) is atom ab-... 

Tributyltin enolates are useful radical mediators [47], although they generally exist in equilibrium with a-tributyltin ketones [48], Three-component coupling reactions proceed readily to give functionalized ketones in good to excellent yields, where an equilibrium shift to provide tin enolates operates efficiently (Scheme 6.28) [49]. Unlike the aforementioned case of allyltin-mediated reactions, acrolein is difficult to use in this reaction, since the Aldol reaction of the tin enolate with acrolein precedes the radical reaction. 

The exocyclic C(2)-S bond of a 2-thiopenem 50 can undergo radical reactions. As depicted in Scheme 28, its desulfurative stannylation reaction with azobis(isobutyronitrile) (AIBN) and tributyltin hydride leads to a penem stannane 51 <1995TL775>. The latter allows subsequent palladium(0)-mediated cross-coupling reactions with... 

Early examples of intramolecular aryl radical addition reactions to heteroatom containing multiple bonds included cyclizations on N=N and C=S moieties [52, 53]. Recently, cyclizations to imines have been used as part of a new enantio-selective approach to indolines (Scheme 8). In the first step of the sequence, the required ketimines 19 were obtained by phase-transfer catalyzed alkylation of 2-bromobenzyl bromides 20 with glycinyl imines 21 in the presence of a cincho-nidinium salt [54], Due to the favorable substitution pattern on the imine moiety of 19, the tributyltin hydride mediated radical cyclization to 22 occurred exclusively in the 5-exo mode. The indoline synthesis can therefore also be classified as a radical amination. 

Allenylidene-THFs can be prepared by the tributyltin hydride-mediated radical cyclization of bromoalkynyl-oxiranes, where the epoxide ring serves as an efficient radical terminator (Equation 42). The reaction proceeds through the normal 5-exo-n oAe <1995CC897>. 

Radical chemistry has relied on the use of tributyltin hydride (TBTH) as a mediator.2 Although extremely useful and robust, this compound is very toxic and its by-products are difficult to remove from reaction mixtures. For this reason and because radical reactivities are complementary to other reactivities, the quest for alternative mediators/hydrogen donors is extremely active. Thus, recent years, hypophosphorus acid and its derivatives have been used as mediators in several radical reactions in aqueous media. The mechanism of action of the P-H-containing phosphorus compounds is shown in Scheme 5.1.2... 

The alkylating-cyclization method may be extended to the enantioselective introduction of an alkyl chain, if a chiral alcohol is used as starting material. The tributyltin hydride mediated radical cyclization of the bromoacetal of 18,19-bisnor-9/i-podocarp-l 3-en-12-one gives a tetracyclic d-lactone, the characteristic structural feature of quassinoids, a complex family of degraded triterpenes82. The hydrogen abstraction in the last step of the reaction has to occur stereoselectively, because only two C-16 diastereomers are formed during the reaction. 

Routledge et al. [7] investigated the formation of dihydrobenzofuran 1 from an aryl halide precursor (Scheme 1). With polystyrene, more than 1 equivalent of AIBN was required, while the reaction was complete within 20 h using 6 mol% of AIBN on TentaGel resin (which has a polyethylene spacer between the polystyrene and the site of compound attachment). Addition of t-butanol helped prevent an alternative y -elimination pathway. An attempt to force the latter was made with thiyl linker 2, but only trace amounts of the )9-elimination product 3 were formed. Also investigated were the cyclizations of iodides 4, in which the cyclization of an alkyl radical to an acetylene is approximately 10 times slower than the aryl radical cyclization to a double bond. A direct comparison of the same reaction on solution phase was attempted, but yields could not be determined for the latter because of contamination by tin residues. This illustrates one advantage of solid-phase radical reactions mediated by tributyltin hydride, namely the ease of product purification. 

For transformations based on stannane-mediated radical chain sequences, selenol esters are the precursors of choice owing to their ease of preparation, stabilities, and ability to accomplish Sh2 reactions (see Sect. 3.2.1). However, replacing the selenol esters by thiol esters in these tributyltin hydride- or allyl-tributylstannane-mediated chain reactions would be attractive from a synthetic viewpoint. 

Many reports on tributyltin hydride-mediated intramolecular aryl-aryl coupling reactions have appeared in the literature in the 1990s [27, 121], One of the latest articles, in which many references on previous work have been included, focuses on the preparation of aporphines (Scheme 23) [122], Due to steric repulsion, an undesired 5-endo cyclization of the aryl radical on the imine nitrogen atom occurs only when more bulky substituents R are present in the benzyldihydroisoquinoline 64. With R = H, the cyclization to 65 proceeds in high yields. 

Fig. 8. ESI(+)-MS of the Stille reaction of 3,4-dichloroiodobenzene and vinyl-tributyltin in acetonitrile mediated by Pd(PPh3)4. A radical cation intermediate undergoing transmetallation is observed at m/z 958.

Recently, Sit et al. extended the reaction to isoquinolines in an elegant synthesis of the dopamine agonist, (+)-dinapsoline 210 <02JMC3660>. The key step of the synthesis was a tributyltin hydride mediated cyclisation of aryl bromide 208 to pentacycle 209, a procedure that could be scaled up to 100 g of starting material at a time. The authors commented that the tributyltin hydride and AIBN combination was by far the most efficient reductive system for generating the free radical species for cyclisation. Acetic acid (or trifluoroacetic acid) was added to the reaction medium to aid removal of the tin by-products. No comment was made as to whether the acid played any further role, such as protonation of the heteroaromatic base. 

More recently, a radical-mediated variation of this addition-fragmentation has been explored. The reaction, summarized in Scheme 77 for a one-carbon expansion, involves the generation of a radical at the terminus of a chain by homolytic cleavage of a carbon-heteroatom bond. Addition of the radical to the carbonyl produces a bicyclic intermediate, which on cleavage of the alternate bond regenerates the ketone carbonyl group with formation of a new radical. The sequence is terminated by the reduction of the radical with the tributyltin hydride reagent. The near neutral conditions of the reaction avoid the reclo-... 

Radical cyclizations of nucleophilic N-alkyl radicals 96 onto the benzimidazole 2-position, mediated by tributyltin hydride and activated by quater-nizing the pyridine-like N-3 of imidazole with camphorsulfonic acid, have recently been reported (Scheme 20) [67]. These new five-, six- and seven-membered homolytic aromatic substitutions of nucleophilic N-alkyl radicals onto the benzimidazole-2-position occurred upon the use of large excesses of the azo-initiator, l,T-azobis(cyclohexanecarbonitrile), to supplement the non-chain reaction. The intermediate 97 aromatizes in high yields to the cy-clized benzimidazoles 98. 

The free radical chain reaction between PhCOCHjHgCl and 1-morpholinocyclohex-cne has been reported to involve addition of the acceptor radical PhCOCHj- to the jS-position of the enamine followed by electron transfer to regenerate the attacking radical (Scheme 19). Photostimulated reactions of simple alkylmercury halides failed since an electrophilic radical is required. Photolysis of p-nitrobenzyl chloride in the presence of enamines gave the -/>-nitrobenzyl ketone on hydrolysis . Radical mediated reductive alkylation of acyclic-enamines has also been reported with radical precursors such as PhSCH2CN, PhS02CH2Cl and Me3CS02CH2SePh . Reductive alkylation also occurred with chloromethyl p-tolyl sulphone in the presence of tributyltin hydride and azobis(isobutyronitrile) (AIBN) (Scheme 20). 

---