Alkyl radical addition-cyclization

Scheme 46 Alkyl radical addition-cyclization by Naito [16,32]...

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... 

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]. 

Kinetic data for the 5-exo cyclization of alkyl radical additions to the yV-aziridinylimino groups were obtained by competitive 5-exo cyclization to the A-aziridinylimino group versus an alkenyl group (Eq. 15). Reaction of compound 59 with BujSnH in benzene at 20 °C at 350 nm yielded only 61. Apparently, the primary alkyl radical... 

Furthermore, we also performed kinetic studies for alkyl radical additions onto different types of C=N bonds such as imines and oxime ethers. The kinetic data are summarized in Figure S. Kinetic analysis of the intramolecular addition of alkyl radicals to C=N bonds provides several experimentally important results. First, alkyl radical additions to C=N bonds are much faster than the corresponding additions to C=C bonds, indicating that C=N bonds are much better radical acceptors than C=C bonds. Furthermore, 5-exo cyclization is faster than 6-exo cyclization. Second, the intramolecular additions of alkyl radicals to C=N bonds are essentially irreversible. Third, alkyl radical additions to oxime ethers and hydrazones are faster than alkyl radical additions to imines, suggesting the possibility of a dependence of the cyclization rate on the electron density at the carbon atom of the radical acceptor. 

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-... 

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... 

Radical reactions ofallenes are largely unknown [57]. Recently, Ma and coworkers [58] developed the first example of a radical addition/cyclization reaction of allene-enes in an alkene-to-allene manner (Scheme 5.32). The reaction of the allene 146 and polyfluoro alkyl iodide 147 with zinc powder as a cheap, readily available, efficient, and mild initiator led to 148 in moderate to good yields (53-86%), which on treatment with TBAF (tetra-n-butylammonium fluoride) gave the allene 149. 

A5-hexenyl substituent, extensive cyclization occurs to yield the cyclopentylcarbinyl product from the yields of uncyclized and cyclized products for A5-hexenylmercury chloride, the rate constants for equation 50 have been estimated (vide supra). The SH2 reaction 49 has also been invoked to be the key step in the alkylation of -substituted styrenes by a free-radical addition-elimination sequence, namely96... 

In addition to the radical ipso-substitution of indolyl sulfones producing stannanes described earlier <96T11329>, Caddick has also reported an approach to fused [l,2-a]indoles based on the intramolecular cyclization of alkyl radicals. Thus, treatment of 112 with BuaSnH leads to the fused ring derivatives 113 (n = 1-4) <96JCS(P1)675>. 

From a synthetic point of view, the regioselectivity and stereoselectivity of the cyclization are of paramount importance. As discussed in Section 11.2.3.3 of Part A, the order of preference for cyclization of alkyl radicals is 5-exo > 6-endo 6-exo > 7-endo S-endo > 1-exo because of stereoelectronic preferences. For relatively rigid cyclic structures, proximity and alignment factors determined by the specific geometry of the ring system are of major importance. Theoretical analysis of radical addition indicates that the major interaction of the attacking radical is with the alkene LUMO.321 The preferred direction of attack is not perpendicular to the it system, but rather at an angle of about 110°. 

Unsaturated carboxylic acids can be de-carboxylated to alkyl radicals that undergo an intramolecular addition. The S-exo-trig-cyclization of fi-allyloxy radicals, generated from an appropriate carboxylic acid, combined with a final heterocoupling has been applied to synthesize a precursor of prostaglandine PGF2q (Fig. 47) [246] and a branched carbohydrate (ratio of diastereo-mers 1.8 1) (Fig. 48) [247]. A radical tandem cyclization of a doubly unsaturated monocyclic carbocyclic acid provides a... 

The absolute rate constants for a variety of cyclizafions have been measured. In particular, the rates of decarbonylafion of a variety of alkoxycarbonyl radicals have been obtained by LFP studies on PTOC oxalates." From these data, rate constants for the reduction of alkoxycarbonyl radicals with BusSnH and their 5-exo cyclizafions were determined. Whereas cyclizations were slightly faster than the analogous alkyl radical 5-exo cyclizations, their reactions with BusSnH were 10 times slower, indicating that cyclization processes should be synthetically useful. The rate constants for the cyclization of a number of variously substituted a-amide radicals have been determined together with their relative reactivities towards reduction using BusSnH (Scheme 16). Cyclizations of secondary-based radicals were found to be similar to the corresponding alkyl-substituted radicals. In addition, the rate constants were subject to minor electronic... 

The endo-mode of cyclization is found to be the preferred path also in the lower homologues. Reaction (6.2) shows the reactions of two silanes (8) with thermally generated t-BuO radicals to afford the five-membered ring in low yields via a 5-endo-trig cyclization [1], EPR spectra recorded from these two silanes with photogenerated t-BuO radicals are assigned to secondary alkyl radical intermediates formed by an intermolecular addition involving the expected silyl radical and the parent silane [2],... 

The a-silyloxy alkyl radical generated by the addition of (TMS)3Si radical to the aldehyde moiety of 45 has been employed in radical cyclization of (3-aminoacrylates (Reaction 7.53) the trans-hydroxy ester and the lactone in a 2.4 1 ratio were the two products [62]. 

Fhe electrochemical generation of alkyl radicals catalysed by square planar nickel complexes has been used to achieve radical-alkene addition reactions. Complex 64 was the catalyst of choice. Intramolecular cyclizations to give five raem-... 

The use of vinyl radicals in cyclizations of this type is particularly promising. Addition of a vinyl radical to a double bond is usually thermodynamically favorable because a more stable alkyl radical results. The vinyl radical can be generated by dehalogenation of vinyl bromides or iodides. An early study provided examples of both five- and six-membered rings being formed.243... 

It is the opinion of the present authors that isomerization of a tertiary alkyl radical to a primary radical as in the formation of II from I is improbable. The formation of IV is similarly unlikely. The cycliza-tion of V by intramolecular alkylation seems quite plausible however, equation 9 does not explain either the formation of V or its subsequent cyclization. The following mechanism has the advantages that, like the generally accepted free radical-initiated mechanisms, it postulates a chain reaction and that the intramolecular alkylation step is directly analogous to that proposed for thermal alkylation, namely addition of an alkyl radical to the double bond of the alkene (Frey and Hepp, 12). The method of formation of the chain initiator, R —, again is not critical since R —, merely starts the first cycle of the chain reaction it may be formed by decomposition of the isobutylene. 

A novel tandem carbonyiation/cyclization radical process has been developed for the intramolecular acylation of l-(2-iodoethyl)indoles and pyrroles <99TL7153>. In this process, an acyl radical is formed when CO is trapped by an alkyl radical formed from the AIBN-induced radical reaction of l-(2-iodoethyl)indoles 104 with BusSnH. Intramolecular addition of the acyl radical to the C-2 position of the heteroaromatic system presumably affords a benzylic radical which undergoes in situ oxidative rearomatization to the bicycloketones 105. 

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