Atom transfer radical addition alkenes

The addition of halocarbons (RX) across alkene double bonds in a radical chain process, the Kharasch reaction (Scheme 9.29),261 has been known to organic chemistry since 1932. The overall process can be catalyzed by transition metal complexes (Mt"-X) it is then called Atom Transfer Radical Addition (ATRA) (Scheme 9.30).262... 

Carbon-carbon bond formation is a fundamental reaction in organic synthesis [1, 2,3,4], One way to form such a bond and, thus, extend a carbon chain is by the addition of a polyhalogenated alkane to an alkene to form a 1 1 adduct, as shown in Scheme 1. This reaction was first reported in the 1940s and today is known as the Kharasch addition or atom transfer radical addition (ATRA) [5,6], Historically, Kharasch addition reactions were conducted in the presence of radical initiators or... 

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]. 

Nedelec and coworkers reported a manganese(III)-initiated cyanoacetate-catalyzed atom-transfer radical addition of polyhalomethanes or dibromomalonate 172 to alkenes 126 (Fig. 48) [272]. Since neither Mn(II) nor Mn(III) is useful to initiate Kharasch-type additions, an organocatalyst served this purpose. Thus, a short electrolysis of a mixture of 126,172,10 mol% of Mn(OAc)2, and 10 mol% of methyl cyanoacetate 171 led to initial oxidation of Mn(II) to Mn(III), which served to form the cyanoacetate radical 171A oxidatively. The latter is able to abstract a halogen atom from 172. The generated radical 172A adds to 126. The secondary... 

Electron transfer from copper or copper salts to alkyl halides has been used to initiate atom transfer radical additions. One modification of this process involves catalytic amounts of copper powder and fluorinated alkyl iodides the radicals so generated may react in either inter- or intramolecular fashion with alkenes (equation 13)19. Alternatively, a-chloroesters with remote alkene functions undergo cyclization in the presence of cat-... 

Metal-catalyzed living radical polymerization can be traced back to metal-catalyzed radical addition reactions to alkenes, sometimes collectively called Kharasch or atom-transfer radical addition (ATRA) reactions in organic chemistry (Scheme 2).33 Thus, a... 

Atom transfer radical additions and cyclisations have been used successfully in organic chemistry for the preparation of 1 1 adducts from alkyl halides, RX, and alkenes, CH2=CHY (Scheme 9.2) Under such conditions, the required catalytic amount of transition metal, Mt (e.g. CuCl, FeBr2, RuC12 in the presence of corresponding ligand) is used to provide a low stationary concentration of radicals, R (and of oxidised transition metal Mtw+1X, e.g. CuCl2), which subsequently react with an alkene by abstraction of a halogen atom from the oxidised form of the catalyst to produce the final product, R-CH2-CHY-X. 

A soluble dendritic Ni catalyst for the atom-transfer radical addition (ATRA, i.e., polyhalogenated alkane addition to olefins, the Kharasch addition) was described by van Leeuwen and van Koten et al. in 1994 [17]. GO and G1 carbosilane den-drimers, fimctionalized with NGN pincer-nickel(II) groups, were synthesized and applied as homogeneous catalysts for the addihon of organic halides to alkenes [Eq. (7)]. 

The complex, Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 acted as a good photoredox catalyst for atom transfer radical addition of haloalkanes to alkenes. ... 

Atom radical transfer polymerisation (ATRP) has its roots in atom transfer radical addition (ATRA), which involves the formation of 1 1 adducts of alkyl halides and alkenes, and is also catalysed by transition metal complexes. ATRP is a modification of the Kharasch addition reaction (Kharasch et al. 1945) although there may be some differences (Minisci 1975). A general mechanism for ATRP is shown in Scheme 10.5. In ATRP the radicals or the active species are generated through a reversible redox process catalysed by a transition metal complex (Mtn-L/... 

Radical addition to alkenes has been used in cyclizations in aqueous media. Oshima and co-worker studied triethylborane-induced atom-transfer radical cyclization of iodoacetals and iodoacetates in water.121 Radical cyclization of the iodoacetal proceeded smoothly both in aqueous methanol and in water. Atom-transfer radical cyclization of allyl iodoacetate is much more efficient in water than in benzene or hexane. For instance, treatment of allyl iodoacetate with triethylborane in benzene or hexane at room temperature did not yield the desired lactone. In contrast, the compound cyclized much more smoothly in water and yielded the corresponding y-lactone in high yield (Eq. 3.31). 

There are extensive relative rate measurements at temperatures close to ambient for hydrogen transfer reactions of methyl radicals. Their data have been compiled and evaluated by Kerr and Parsonage [49]. The same authors have also evaluated the data on addition reactions of atoms and radicals with alkenes, alkynes and aromatic compounds [69]. 

Et3B is an effective tool for halogen atom transfer radical reactions (see also Chap. 1.5). Perfluoroalkyl iodide [29], a-halo nitrile and a-halo ester [30] added to alkenes and alkynes at low temperature. Not only terminal alkenes but also internal alkenes can be employed to furnish iodine atom transfer adducts (Scheme 23). Furthermore, addition of perfluoroalkyl iodide to silyl and germyl enolate provided a-perfluoroalkyl ketones [31]. The reaction would involve the elimination of a tri-... 

AA sec acrylic acid abstraction sec hydrogen atom transfer abstraction v,v addition and micleophilicity 35 by aikoxy radicals 34-5, 124-5, 392 by alkoxycarbonyloxy radicals 103,127-8 by alkyl radicals 34 5, 113, 116 by f-amyloxy radicals 124 by arenethiyl radicals 132 by aryl radicals 35, 118 by benzovloxy radicals 35, 53, 120, 126 wilh MM a" 53, 120 by /-butovy radicals 35, 53, 55, 124 solvent effects 54, 55. 123 with alkenes 122 3 with ally I acrylates 122 wilh AMS 120, 123 wilh BMA 53, 123 with isopropenvl acetate 121 with MA 120 with MAN 121 with MMA 53, 55, 120.419 with VAc 121 with vinyl ethers 123... 

The carbon-centered radical R, resulting from the initial atom (or group) removal by a silyl radical or by addition of a silyl radical to an unsaturated bond, can be designed to undergo a number of consecutive reactions prior to H-atom transfer. The key step in these consecutive reactions generally involves the intra-or inter-molecular addition of R to a multiple-bonded carbon acceptor. As an example, the propagation steps for the reductive alkylation of alkenes by (TMSfsSiH are shown in Scheme 6. 

Radicals for addition reactions can be generated by halogen atom abstraction by stannyl radicals. The chain mechanism for alkylation of alkyl halides by reaction with a substituted alkene is outlined below. There are three reactions in the propagation cycle of this chain mechanism addition, hydrogen atom abstraction, and halogen atom transfer. 

The simple addition reaction in Scheme 19 illustrates how the notation is used. Ester (1) can be dissected into synthons (2), (3) and (4). Synthons for radical precursors (pro-radicals) possess radical sites ( ) A reagent that is an appropriate radical precursor for the cyclohexyl radical, such as cyclohexyl iodide, is the actual equivalent of synthon (2). By nature, alkene acceptors have one site that reacts with a radical ( ) and one adjacent radical site ( ) that is created upon addition of a radical. Ethyl acrylate is a reagent that is equivalent to synthon (3). Atom or group donors are represented as sites that react with radicals ( ) Tributyltin hydride is a reagent equivalent of (4). In practice, such analysis will usually focus on carbon-carbon bond forming reactions and the atom transfer step may be omitted in the notation for simplicity. 

The addition of a single-bonded reagent across a multiple bond is one of the fundamental reactions of organic radicals. The basic principles of this reaction were first advanced by Kharasch in pioneering studies on the mechanism of the peroxide-initiated anti-Maikovnikov addition of hydrogen bromide to alkenes.1 In the atom transfer method, the generation and removal of radicals are coupled and occur in the key atom transfer step. Compared to other methods, the atom transfer method provides unique options for synthetic reactions. But there are also important limitations. Recently, there has been a renewed interest in the application of the characteristics of atom transfer reactions in synthesis and new developments have been reviewed.5,161... 

It is more difficult to conduct the addition reactions of nucleophilic radicals to electron poor alkenes because the resulting atom transfer steps are often endothermic and are too slow to propagate chains, even with iodides. An exception is illustrated in Scheme 57 resonance-stabilized vinyl radicals (especially if they are secondary or tertiary) are reactive enough to abstract iodine from alkyl iodides.178... 

The Meerwein arylation is at least formally related to the atom transfer method because a net introduction of an aromatic ring and a chlorine across a double bond is accomplished (Scheme 62). Facile elimination of HC1 provides an efficient route to the kinds of substituted styrenes that are frequently prepared by Heck arylations. Standard protocol calls for the generation of an arene diazonium chloride in situ, followed by addition of an alkene (often electron deficient because aryl radicals are nucleophilic) and a catalytic quantity of copper(II) chloride. It is usually suggested that the copper salt operates in a catalytic redox cycle, reducing the diazonium salt to the aryl radical as Cu1 and trapping the adduct radical as Cu11. 

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. 

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