Tandem radical additions

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

A tandem radical addition/cyclization process has been described for the formation of benzindolizidine systems from l-(2-iodoethyl)indoles and methyl acrylate <00TL10181>. In this process, sun-lamp irradiation of a solution of the l-(2-iodoethyl)ethylindoles 149 in refluxing benzene containing hexamethylditin and methyl acrylate effects intermolecular radical addition to the activated double bond leading to the stabilized radical 150. Intramolecular cyclization to the C-2 position of the indole nucleus then affords the benzindolzidine derivatives 151 after rearomatization of the tricyclic radical. 

Scheme 52 Tandem radical addition aldol reaction...

The combination of Baylis-Hillman reaction and tandem radical addition/ cyclization sequences [259], has been reported as a useful synthetic tool for the asymmetric synthesis of functionalized monocyclic and bicyclic (3-lactams (III and IV, Fig. 7). 

Tandem radical additions have also been utilized for the synthesis of nitrogen containing heterocycles. These reactions have the same requirements as those discussed for the oxygen heterocycles. The reductive addition of phenylsulfanyl radicals to the unsaturated amide 153 has been investigated [95JCS(P1)19], The nucleophilic radical adds selectively to the enamide followed by 5-exo-cyclization to give 154 in excellent yield with high trans selectivity. 

Tandem radical additions have been used in the preparation of piperidines. Substituted nitrogen containing heterocycles with ring sizes ranging from 5-8 have been synthesized by radical methods [95JCS(P1)19]. Addition of sulfur radicals to 225 occurs selectively at the enamide portion followed by an intramolecular 6-exo cyclization to produce a diastereomeric mixture of 226 in good yield. 

Tandem radical addition/cydization reactions have been performed using unsaturated tertiary amines (Scheme 9.11) [14,15]. Radical attack is highly stereoselective anti with respect to the 5-alkoxy substituent of 2-(5f-J)-furanones, which act as the electron-deficient alkenes. However, the configuration of the a position of the nitrogen cannot be controlled. Likewise, tandem addition cyclization reactions occur with aromatic tertiary amines (Scheme 9.12) in this case, acetone (mild oxidant) must be added to prevent the partial reduction of the unsaturated ketone [14]. 

Fiirstner reported the first McMurry-type reactions working with 5-10 mol% of titanium trichloride and stoichiometric amounts of zinc powder in the presence of chlorotrimethylsilane. The amount of TiCl3 could be reduced to 2 mol% when (ClMe2SiCH2)2 was used as a reagent [125, 131]. At the same time, Burton and coworkers reported atom transfer radical additions of perfluoroalkyl iodides 39 to alkenes 40 catalyzed by 20 mol% of a low-valent titanium compound generated from TiCLt and zinc powder affording 41 in 10-85% yield (Fig. 13). A tandem radical addition/5-exo cyclization/iodine transfer reaction with diallyl ether proceeded in 66% yield [132]. 

Ishii and coworkers developed a Mn(OAc)2-catalyzed hydrophosphonation of alkenes 40 (Fig. 47) [271]. The active Mn(III) catalyst is generated by reaction of Mn(OAc)2 with oxygen. Hydrogen abstraction from diethyl phosphite 169 forms a phosphonyl radical, which adds to 40. The resulting alkyl radical is reduced by 169 to continue the chain reaction. Alkylphosphonates 170 were isolated in 51-84% yield. With (3-pinene a cyclobutylcarbinyl radical ring opening was observed in 32% yield, while 1,5-cyclooctadiene underwent a tandem radical addition/ transannular 5-exo cyclization (cf. Fig. 38). 

Diethyl malonate or ethyl cyanoacetate 187 afforded bicyclo[3.3.0]octane derivatives 188 in a tandem radical addition/transannular 5-exo cyclization sequence with cyclooctadiene 131 in 76 and 78% yield, respectively [275]. (4-Pentenyl)arenes were employed in a similar tandem radical addition/radical... 

The Re(III) complex Re(PPh3)2(MeCN)Cl3 (2 mol%) catalyzes the ATRA of tetrachloromethane or bromotrichloromethane to terminal alkenes in 39-76% yield [303]. p-Pinene suffered a cyclobutylcarbinyl radical ring opening, thus supporting the free radical mechanism. With l, -dienes double addition was found, while 1,3-dienes gave the 1,4-addition product. Internal alkenes were almost inert under the reaction conditions. 1,6-Dienes 158 underwent a tandem radical addition/ cyclization reaction to cycles 159 in 64—87% yield with 3-6 1 c/s-diastereos-electivity (cf. Fig 43). This compares well to the results obtained with the most frequently used catalyst Ru(PPh3)3Cl2 (see Part 2, Sects. 3.3.1 and 3.3.2). 

Grigg reported tandem radical addition/5-exo cyclization reactions of bromotri-chloromethane and 1,6-dienes 169 catalyzed by 5 mol% Ru(PPh3)3Cl2 (Fig. 42). 

Fig. 56 Cobalt-catalyzed tandem radical addition/cross-coupling reactions...

Reductive radical cyclization and tandem radical addition/cyclization reactions catalyzed by Ni(II) complexes, such as Ni(cyclam)(C104)2 98a, were studied starting in the 1990s by Ozaki s group [128]. The reaction conditions are applicable to alkyl and aryl halides bearing suitable positioned olefin units. Iodides and bromides can be used in some cases even aryl chlorides were successfully applied. The field was reviewed recently, and thus only more recent results are summarized here [19, 20]. 

Benzindolizidine systems 963 are generated in moderate yields by a hexabutylditin-mediated consecutive radical addition, cyclization, and oxidation process from easily accessible l-(2-iodoethyl)indoles 962 and methyl acrylate, in one step (Scheme 186) <2000TL10181>. l-(2-Iodoethyl)-l//-pyrrole-2-carbaldehyde was also subjected to the tandem radical addition-cyclization process, and the indolizidine derivative 964 was isolated in modest yield as the major product together with a small amount of starting material (Equation 229). 

Tandem radical addition-aldol-type reaction of a,/3-unsaturated oxime ethers bearing an Oppolzer sultam auxiliary leads to stereoselective incorporation of alkyl groups in the 5- and 3-positions in tetrahydrofurans (Scheme 77) <2005AGE6190>. The observed /ra r,/ra r-stereoselectivity was explained by invoking a cyclic six-membered ring transition state. 

Sibi et al. reported an elegant new tandem radical addition-cyclization process for the synthesis of oxacycles [122]. The method relies on the inter-molecular addition of alkyl radical to a doubly activated Michael acceptor moiety, followed by a cyclization step (Scheme 39). The outcome of the re-... 

Ueda et al. reported a tandem radical addition-cycUzation reaction in aqueous media [184]. This reaction was initiated by single-electron transfer from indium to an alkyl iodide. Fragmentation of the iso-propyl iodide radical anion generated the iso-propyl radical, which triggered the addition/cyclization tandem. Final SET and in situ hydrolysis delivered cyclic sulfonamides in good yield but low stereoselectivity. 

Naito has also described analogous tandem radical addition-cyclization processes under iodine atom-transfer reaction conditions [16,32], Treatment of 186 with z-PrI (30 eq.) and triethylborane (3x3 eq.) in toluene at 100 °C gave, after cleavage from the resin, the desired lactam product 190 in 69% yield (Scheme 46). Similar reactions involving cyclohexyl iodide, cyclopentyl iodide, and butyl iodide were also reported as well as the reaction with ethyl radical from triethylborane [16,32], The relative stereochemistry of the products was not discussed. 

Acyl radicals are very useful synthetic intermediates. Their preparation is not simple since the corresponding halides are highly electrophilic and cannot be used as radical precursors. Organocobalt compounds were proposed as suitable source of acyl radicals [44]. However, the use of acyl selenides proved to be more general [45, 46]. These radical precursors can be efficiently prepared from the corresponding carboxylic acids and esters [47]. Acyl phenyl selenides should be preferred, when possible, relative to acyl methyl selenides due to the consumption of two equivalents of tin hydride with this last system (Scheme 1) [4]. Acyl selenides have found many applications in tandem radical additions to alkenes. Examples of intermole-cular [Eq. (18)] [48,49] and intramolecular reactions [Eq. (19)] [50a] are reported. The enoyl selenide 68 give the unsaturated acyl radicals 69. This intermediate... 

Sensitizers such as benzophenone, anthrone and xanthene were also observed to catalyze these reactions [327]. Anthraquinone sensitized photoreactions of N-allylamines with a,jff-unsaturated esters also yield lactams as the main product. Minor amounts of tandem radical addition products were also formed [328]. 

Xanthate 446 undergoes cyclization in the presence of camphorsulfonic acid via a radical chain reaction initiated by a small amount of lauroyl peroxide to give pyrroloimidazoles 449 in 56% yield. The use of an acid and anhydrous medium inhibits nucleophilic attack of the basic heterocycles at the xanthate moiety and allows radical reactions to occur. Fused heteroaromatic compounds can also be prepared directly from benzimidazole carrying an N-alkenyl substituent and xanthates by a tandem radical addition/cyclization to provide, for example, pyrrolobenzimidazole 453 in 57% yield (Scheme 106) <2002OL4345>. 

Scheme 7.10 Indium-mediated tandem radical addition-cyclisation-trapping reactions in aqueous media.

The addition of dimedone to limonene mediated with CAN was expected to proceed by tandem radical additions to the two double bonds but the only isolated product was dihydrofuran 111 (96SC4531). The oxidative addition of 1 can also occur similarly to exocyclic alkenes to afford spiroannulated dihydrofurans 112-114 in moderate to good yields, whereas Mn(OAc)3 mediated addition gave low yields (95SC3981, 06S609, 06S2335) (Scheme 18). 

Compound 74 was obtained when A,A-dimethylaniline and furanone 72 were irradiated in the presence of the Michler s ketone 73. These compounds are formed by tandem radical addition-cyclization. The a-amino alkyl radical 71, produced by... 

Sato determined that the use of Lewis acid was advantageous for tandem radical addition/reduction reactions in terms of both yield and selectivity [25]. As shown in Scheme 8, Lewis acid promoted the addition of the butyl radical to the a,fi-unsaturated ester, which in turn led to the formation of chelated transition state N. The improved selectivity was likely the result of a tighter complexation between the hydroxyl and carbonyl functions of the substrate and the aluminum atom. Nagano and collaborators used the same strategy with y-methoxy-a-methylenecarboxylic esters [26]. The use of La(fod)3 delivered a very good ratio of anti isomer in that reaction involving 1,3-asymmetric induction and a 7-membered cyclic transition state, illustrated by O in Scheme 8. 

To support the intermediacy of free radicals in chelation-controlled reactions, our group compared the level of diastereoselectivity in tandem radical addition/ reduction reactions with that of reactions involving the homolytic cleavage of a halide (Scheme 8) ]3j. The stereochemical outcome in this series was the same regardless of the manner in which the radical was generated. Other examples involving tandem intra- or intermolecular addition/reduction reactions will be presented and discussed later in this chapter. 

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