Tandem radical addition/cyclization reactions

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... 

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). 

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]. 

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 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]. 

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. 

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>. 

The same group reported indium-mediated tandem radical addition-cyclization-trap reactions in aqueous media [52c], The use of water-soluble radical initiator 2,2 -azobis[2-(2-imidazolin-2-yl)propane], water-soluble chain carrier 1-ethyl-piperidinium hypophosphite (EPHP) and surfactant cetylammonium bromide (CTAB) allowed the C-C bond-forming radical reactions of highly hydrophobic substrates in water [53], Similarly, the use of CTAB and EPHP in presence of 4,4 -azobis(4-cyanovaleric acid) promoted the indium-mediated radical addition to P-substituted conjugated alkenes in water [54]. 

H. Miyabe, M. Ueda, K. Fujii, A. Nishimura, T. Naito, Tandem carbon-carbon bond-forming radical addition-cyclization reaction of oxime ether and hydrazone, J. Org. Chem. 68 (2003) 5618-5626. 

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. 

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). 

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). 

The Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes gave homoallylic alcohols, which have been used for the diastereoselective preparation of fused bicyclic, tricyclic and tetracyclic p-lactams of non-conventional structure 49 and 50, using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences <03JOC3106>. 

A photochemically sensitized radical tandem addition cyclization reaction was carried out with aniline derivatives such as 122 (Scheme 29.20) [81]. Thus, tetrahydroquinoline derivatives such as 123a,b are obtained in with diastereoselectivities around 90%. The reaction is highly efficient... 

SCHEME 29.20 Photochemically sensitized radical tandem addition cyclization reaction. 

The Kolbe electrolysis has also been used to initiate tandem radical cyclization reactions [21]. Recently, Matzeit and Schafer reported that these reactions could be used to construct angularly fused tricyclic ring skeletons (Scheme 8) [22]. The reaction led to the formation of three new C-C bonds. In addition to the desired tricyclic product, the reaction formed a pair of products having the... 

Enynes are also excellent substrates for tandem addition reactions. Pandey and co-workers have reported a photoinduced electron transfer (PET) promoted reaction of a selenium radical addition to an enyne [95T1483]. The high stereoselectivity observed in this cyclization is noteworthy. 

As an extension of the known radical additions to isonitriles [87], aryl radical cyclizations to /V-acyl cyanamides provide new access to pyrrolo-quinazolines (Scheme 16) [88]. In a tandem process, the iminyl radical 41 resulting from the 5-exo cyclization onto the nitrile was used for a second cyclization step. In this way, the alkaloid luotonin A (42) was synthesized from cyanamide 43 in a single reaction. 

Fig. 52 Tandem oxidative radical addition/transannular radical cyclization reactions...

A tandem radical 5-exo cyclization/radical addition/allylic substitution reaction was subsequently described [292]. Allylic ot-bromo acetal 242b cyclized cobalt-catalyzed. Addition to diene 245 and subsequent coupling with coformed organocobalt(I) species generates an allylcobalt complex, which undergoes reductive elimination to cyclic product 246 in 93% yield (cf. Fig. 56). 

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