Tandem Addition-Cyclization

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. 

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... 

Tandem addition-cyclization reactions can be used for a simultaneous construction of the central and terminal rings. This is illustrated in Equation (10) by the synthesis of 121 from 120 <2002BMC1275>. 

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. 

Ma et al. described the palladium(0)-eatalyzed three-component tandem double-addition-cyclization reaction of 2-(2,3-allenyl)malonate 218, Phi, and A-Ts-imine 219 for the stereoselective synthesis of 2,5-m-pyrrolidine 220... 

Examples of tandem intermolecular addition-cyclization under iodine atom-transfer conditions are depicted in Scheme 16 [38,41],... 

Cascade Addition-Cyclization Reactions Given the importance of cascade reactions in modem chemical synthesis, the MacMillan group has proposed expansion of the realm of iminium catalysis to include the activation of tandem bond-forming processes, with a view toward the rapid constraction of natural products. In this context, the addition-cyclization of tryptamines with a,p-unsaturated aldehydes in the presence of imidazolidinone catalysts 11 or 15 has been accomplished to provide pyrroloindoline adducts in high yields and with excellent enantioselectivities (Scheme 11.3a). This transformation is successful... 

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). 

Similarly, cyclizative tandem double-carbonylation reactions of 4-pentenyl iodide under irradiation conditions, is boosted by the addition of a catalytic amount of palladium complexes [72]. When performed in the presence of diethylamine, the carbonylation provided a triply carbonylated a,<5-diketo amide as the major product along with the doubly carbonylated y-keto amide (Scheme 6.48). Experimental evidence supports the interplay of two reactive species, radicals and organopalladium... 

Scheme 16 Tandem intermolecular addition-cyclization reactions...

Wu et al.91 published a tandem addition-cyclization reaction using 2-alkynyl-benzenamines 89 (Scheme 5.40). The reaction proceeded under AgOTf catalysis... 

Cyclizations onto triple bonds have also been employed commonly in the constructions of cyclic organic molecules. For example, Rainier and Kennedy utilised a tandem Bu3SnH addition/cyclization strategy in their construction of some substituted indoles (101), an example of which is depicted in equation 76659. 

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]. 

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). 

Ruthenium(II)-Catalyzed Tandem Reactions Involving Kharasch Additions/Cyclizations... 

Fig. 42 Tandem addition/cyclization sequences of 1,6-dienes and CCI4...

Yang and Burton studied reductive radical additions of iododifluoroacetate 37 to olefins 38 and dienes catalyzed by 6-17 mol% of a catalyst generated from NiCl2 and stoichiometric amounts of zinc in the presence of water (Fig. 8) [90, 91]. Olefins gave the reductive addition products 40a in 60-83% yield, while 1,5-hexadiene or 1,8-nonadiene provided double addition products exclusively in 55% and 73% yield. 1,7-Hexadiene gave an inseparable mixture of the expected acyclic double addition product and a tandem addition/cyclization product, in which the former dominated. The radical nature of the addition is supported by inhibition of the reaction by para-dinitrobenzene. The reaction proceeds probably via initially formed atom transfer product 39, which is subsequently reduced by nickel(0) and zinc. This is supported by deuterium incorporation, when D20 was used instead of water. No deuterium incorporation was observed with THF-dg, thus ruling out hydrogen transfer from the solvent. 

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]. 

A novel radical anion (LDMAN) methodology developed by Cohen and coworkers (see Section IILA.2) was then applied efficiently for the two-pot synthesis of the sesquiterpene ( )-cuparene, 184, starting from the allyl reagent 180118. The tandem addition/cyclization... 

Notwithstanding, one disadvantage of this method is the necessity of using THF as the solvent, owing to the ability of organolithiums to remove a proton from the 2-position of THF. As an example, in the tandem addition-cyclization on a-methylstyrene, the yields are compromised by the presence of THF, which promotes an undesired side reaction102. 

A tandem Michael addition/cyclization was also the key step in the synthesis of fura-none lignan derivatives recently described (Scheme 90). 

The tandem sequence occurs between o-benzoylbenzyllithiums and furan-2-(5/7)-one168. The o-benzoyl-a-methoxybenzyllithium intermediate was generated by deprotonation of 2-methoxymethylphenyl phenyl ketone, 292, with LDA. Treatment of the a-lithiated product with furan-2-(5//)-one afforded the Michael addition/cyclization product, 293. The 9-aryl-9-hydroxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-l-(3//)-one 293 thus obtained was converted into the corresponding 9-aryl-4-methoxy-3a,4-dihydronaphtho[2,3-c]furan-] -(3//(-one 294 in good yield the subsequent dehydrogenation gave the desired product 4-methoxy-9-phenylnaphtho[2,3-c]furan-l(3/7)-one 295. 

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