Cyclization atom transfer method

The hydrogen atom transfer method is most useful for electrophilic radicals (for example, malonate, acetoacetate, etc.). Because radicals are generated from C—H bonds, the preparation of cyclization precursors by alkylation is routine. The hydrogen atom transfer method is very good for conducting slow cyclizations. In addition reactions, the hydrogen donor is typically used in large excess relative to the acceptor to facilitate H-transfer however, cyclizations must use different conditions because the H-donor and the alkene acceptor are in the same molecule. 

Several recent examples of metal-promoted cyclizations of perchlorocarbonyl compounds are presented in Scheme 28, and a full paper by Weinreb is recommended as an excellent source of references to prior work in this area (including mechanistic studies on the role of the metal).127 The first two examples illustrate that the choice of substrates can dictate the types of products that are formed the initially formed y-chloro esters are stable to subsequent ionic reactions, but the ris-y-chloro acids form lactones. Interestingly, Weinreb has shown that the metal can equilibrate the cis- and /rans-y-chloro esters by reversible chlorine atom transfer. The third example128 illustrates a general feature of the atom transfer method yields at high concentration are comparable to (and sometimes better than) those provided by using tin hydride at low concentrations. Indeed, in the third example, the three chlorines on the ester provided three opportunities for cyclization during the tin hydride reduction, but 40% of the product still failed to cyclize. (Unfortunately, the tin hydride concentration was not specified.)... 

Cyclizations of aromatic diazonium salts138 (intramolecular Meerwein arylations) are pieparatively related to atom transfer reactions because a radical cyclization is terminated by the transfer of an atom or group other than hydrogen. However, the two methods are not mechanistically related. In the atom transfer method, the atom that is transferred to the cyclic product always derives from the radical precursor, but in the cyclizations of aryldiazonium salts, die atom or group transferred derives from an added reagent. This means that many different products can be prepared from a single diazonium precursor, but it... 

Following the pioneer work of Kharasch [60], methods involving radical transfer of halides have been developed. The atom transfer method has emerged in the 1980s as one of the best method for conducting intra- and intermolecular radical additions to olefins [61]. This approach is particularly appealing from an atom economy point of view since all atoms remains in the final product. The non-reductive nature of these reactions is also particularly important for the preparation of functionalized molecules. Halides transfers and more particularly iodine atom transfers have found nice applications for cyclizations, annula-tions and cascade reactions [62]. These reactions are based on exothermic radical steps, such as the addition of an alkyl radical to an olefin, followed by an... 

It is important to emphasize that the hydroxy dithioketal cyclization can be conducted under mild reaction conditions and can be successfully applied to a variety of substrates.15 However, the utility of this method for the synthesis of didehydrooxocane-contain-ing natural products requires the diastereoselective, reductive removal of the ethylthio group. Gratifyingly, treatment of 13 with triphenyltin hydride and a catalytic amount of the radical initiator, azobisisobutyronitrile (AIBN), accomplishes a homolytic cleavage of the C-S bond and furnishes didehydrooxocane 14 in diastereo-merically pure form (95 % yield), after hydrogen atom transfer. 

Iodine atom transfer reactions between alkyl radicals and iodocarbonyls are very rapid (107 M-1 s-1 to 109 M-1 s-1).130 This means that, even when these iodides are cyclized by the tin hydride method, iodine atom transfer may supersede hydrogen transfer, and the reductively cyclized product will ultimately be derived from the reduction of a cyclic iodide. Tin hydride cyclizations of halocarbonyls also often require very low concentration to avoid reduction of the initial radical prior to cyclization. For these reasons, reductively cyclized products are best formed by atom transfer cyclization at high concentration, followed by reduction of the product in situ. In a recent full paper, we have described in detail the preparative and mechanistic features of these cyclizations,19 and Jolly and Livinghouse have reported a modification of our reaction conditions that appears to be especially useful for substrates that cyclize very slowly.131 Cyclizations of a-iodocarbonyls can also be promoted by palladium.132... 

Alkoxyl radicals can be generated by a variety of methods including peroxide reduction, nitrite ester photolysis, hypohalite thermolysis, and fragmentation of epoxyalkyl radicals (for additional examples of alkoxyl radical generation, see Section 4.2.S.2). Hypohalites are excellent halogen atom donors to carbon-centered radicals, and a recent example of this type of cyclization from the work of Kraus is illustrated in Scheme 43.182 Oxidation of the hemiketal (57) presumably forms an intermediate hypoiodite, which spontaneously cyclizes to (58) by an atom transfer mechanism. Unfortunately, the direct application of the Barton method for the generation of alkoxyl radicals fails because the intermediate pyridine-thione carbonates are sensitive to hydrolytic reactions. However, in a very important recent development, Beckwith and Hay have shown that alkoxyl radicals are formed from N-alkoxypyridinethiones.183 Al-... 

Atom transfer cyctization (14, 173-174). This method of cyclization can be more useful than reductive tin hydride cyclization in the case of 6-substituted 5-hexynyl iodides such as 1 and has the further advantage of resulting in a vinyl iodide, which can be used for further functionalization.1 The reaction is best conducted by photolysis in benzene at 80° with catalytic amounts of hexabutylditin. 

In 1989 Curran and co-workers reported on a photocatalytically induced free-radical cyclization leading to various cyclic, bi-, or polycyclic carbocycles (fused and spiro) via isomerization of unsaturated iodides (alkenes, alkynes) [63]. This corresponds to the nonreductive variant of the tin hydride method. Under sunlight irradiation and in the presence of 10 mol% hexabutylditin, a-iodo esters, ketones, and malonates are efficiently transformed via an iodide atom transfer chain mechanism (eq. (4)). 

In a similar process, the a-chloro-a-thioacetamide 37 leads to the pyrrolizidines 38 and 39 upon chlorine atom-transfer cyclization initiated by catalytic ruthenium chloride (Eq. 2). The high efficiency of this method, which was applied to alkaloid synthesis, was attributed to the captodative effect [30],... 

A complex intramolecular reaction occurs with 5-iodoalkynes (Fig. 40).229 Some amounts of iodovinylidenecyclopentane are formed, which formally relates this reaction to the atom transfer cyclization methods developed by Curran.230 The relative amounts of the acyclic reduction product and the cyclic compounds depend on the substituents R and R, the stoichiometry, and the reaction conditions. 

Atom-transfer radical cyclization (ATRC) is an atom-economical method for the formation of cyclic compounds, which proceeds under mild conditions and exhibits broad functional group tolerance. Okamura and Onitsuka described a planar-chiral Cp-Ru complex 124-catalyzed asymmetric auto-tandem allylic amidation/ATRC reaction in 2013. This protocol proceeds highly regio, diastereo, and enantioselec-tively to construct optically active y-lactams from readily available substrates in a one-pot manner (Scheme 2.32). In this process, a characteristic redox property of ruthenium complexes would work expediently in different types of catalyzes involving mechanistically distinct allylic substitutions (Ru /Ru ) and atom-transfer radical cyclizations (Ru /Ru ), thus leading to the present asymmetric auto-tandem reaction [48]. 

Many of the methods discussed in this section can also be treated as combinations of more than two fragments. For instance, in the cyclization of C,A-diaryl hydrazones (425) with ammonia described in Section 6.11.9.2.2 the a-acylamino-hydrazones are treated as a five-atom fragment, but since these compounds were prepared from methylene ketones (424) via diazo group transfer and acylation of the a-hydrazono-ketones, the entire reaction sequence may be described as a [2 -I- 2 -I-1 -I-1] combination. 

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