Atom transfer radical cyclization reactions

It was reported that Pd(0)-catalyzed coupling reactions of allenic alcohols, amines and acids with hypervalent iodonium salts afforded cyclized heterocyclic tetrahydrofurans, tetrahydropyrans, pyrrolidines, piperidines, or lactones under mild conditions <99SL324>. Intramolecular 1,5-hydrogen atom transfer radical cyclization reaction of pyrrolidine derivatives was examined. Reaction of 3,4-dialiyloxy-JV-(0-bromobenzyl)pyrtolidine gave hexahydro-... 

Fig. 38 Molybdenum-catalyzed atom transfer radical cyclization reactions...

Cu(I)-Catalyzed Atom Transfer Radical Cyclization Reactions. 387... 

A-(4-Pentenyl)iodoacetamides (i.e., 142 and 145) underwent atom transfer radical cyclization reactions in the presence of trifluoroborate etherate at room temperature, usually with an excellent 8-endo regioselectivity (Schemes 59 and 60 <2005JOC1539>). It was thus shown that 8-endo cyclization of iV-alkenyl a-carbamoyl radicals is an intrinsically favored process easily promoted by a Lewis acid, such as BF3-OEt2. 

Atom transfer radical cyclization reactions mediated by copper complexes to form furan and pyrrole rings, lactones and /f-lactams 02CSR1. 

The EtsB-induced halogen atom transfer radical cyclization reaction is a successful application. Cyclization of iodo acetal 44 afforded the tetrahydrofuran derivative 45 in almost quantitative yield (Scheme 26) [32]. Et3B also induced radical cyclization of A -allylic a-iodoacetamide to give y9-iodomethyl-y-lactam via an atom transfer process [34]. The reaction of 46 prepared from 2-prolinol proceeded smoothly within 10 min in boiling benzene in the presence of Et3B to yield IR, 8S)-... 

Following Yang s report, the atom-transfer radical cyclization reaction of 58 provided chiral cyclopentane ring 59. The bromide of 59 was removed by radical dehalogenation reaction to produce 60. Wittig olefination followed by reduction of the ester group gave chiral alcohol 62 that could be easily converted into the allylic alcohol 57 (Scheme 17). 

Though the stereochemical control of the isopropyl and methyl groups on the cyclopentane ring using the atom-transfer radical cyclization reaction, as well as further functional group modifications, were successful, this strategy revealed critical problems for our synthesis. First of all, the radical cyclization reaction produced small amounts of undesired diastereomeric side product... 

Yang D, Yan Y, Zheng B, Gao Q, Zhu N. Copper(I)-catalyzed chlorine atom transfer radical cyclization reactions of unsaturated a-chloro p-keto esters. Org. Lett. 2006 8 (25) 5757-5760. 

TMC ATRA reactions can also be conducted intramolecularly when alkyl halide and alkene functionalities are part of the same molecule. Intramolecular TMC ATRA or atom transfer radical cyclization (ATRC) is a very attractive synthetic tool because it enables the synthesis of functionalized ring systems that can be used as starting materials for the preparation of complex organic molecules [10,11], Furthermore, halide functionality in the resulting product can be very beneficial because it can be easily reduced, eliminated, displaced, converted to a Grignard reagent, or if desired serve as a further radical precursor. The use of copper-mediated ATRC in organic synthesis has been reviewed recently and some illustrative examples are shown in Scheme 3 [10,11,31,32,33],... 

Highly enantioselective atom transfer radical cydization reactions catalyzed by chiral Lewis acids have been reported by Yang et al. [80]. Two main advantages of these enantioselective cyclizations include installing multiple chiral centers and retaining a halogen atom in the product, which allows for further functionalization. 

Intramolecular cyclization of the chiral oxime ether 993 in the presence of isopropyl iodide and triethylborane affords the 3,4,5-trisubstituted tetrahydropyran-2-one 994 in poor yield but with good diastereoselectivity (Equation 388) <2003JOG5618>. Similarly, a triethylborane-induced atom transfer radical cyclization of 3-butenyl 2-iodoacetate leads to 4-(iodomethyl)tetrahydropyran-2-one. Higher yields are achieved when conducting the reaction at lower concentrations (Equation 389) <2000JA11041 >. 

Chiral Lewis acid-catalyzed atom-transfer cyclization is performed by the reaction of a-bromo-a-methyl-(3-keto esters (46) in the presence of Mg(C104)2 and a chiral ligand such as Z fsoxazoline, initiated by Et3B, as shown in eq. 10.22. The Lewis acid promotes not only the atom-transfer radical cyclization, but also high stereoselectivity through the chelation onto Mg2+. Intermediate [X] is a plausible chelated radical intermediate. 

Nagashima and colleagues showed subsequently that 5-10 mol% of Pd(PPh3)4 catalyzed atom transfer radical cyclizations (ATRC) of /V-allyl-difluoroiodo-acetamides 158b in fluorescent lab light at ambient temperature [194], Under these conditions, 34—98% yield of cyclized compounds 159b were obtained. No reaction occurred in the dark, while it was considerably slower in the absence of the catalyst. The low yield of 34% in one example (R=Bn) is due to the unfavorable rotational barrier in the substrate, which cannot be influenced by the presence of the catalyst. 

Evidence based on product mixtures now suggests, at least in the cases of a-halocarbonyl and perhaloalkyl starting marterials, that these reactions are in fact atom transfer radical cyclizations (equation 166)324,325. In them, the palladium catalyst is proposed to have roles both as the radical initiator and as a trap for iodine, similar to the more commonly used hexabutylditin. Intramolecular allyl halide-alkyne cyclizations proceed with trans-addition to the triple bond this is evidence that a still different mechanism may be operating in these cases (equation 167)1,326. 

The radical intermediates from Cr(II) reduction of alkyl halides can in principle be used synthetically, but have only seen limited attention to this point. co-Haloalkynes (bromides, iodides), in the presence of excess Cr(C104)2, undergo cyclization reactions to form exo-alkylidene cycloalkanes (equation 176)347. These reactions proceed by the radical cyclization of intermediate 42 onto the alkyne unit, which undergoes subsequent reduction by Cr(II) to give a hydrolytically unstable vinylchromium(III). Rings of four, five and six members can be formed. Alternatively, a-iodo esters undergo intramolecular atom transfer radical cyclizations onto alkynes or alkenes with catalytic or stoichiometric amounts of... 

This catalytic sequence is known as Kharasch addition or atom transfer radical addition (ATRA) [4]. Various polyhalogenated compounds such as CCI4 and CCI3CO2R are used as the organic halides, and transition metal salts or complexes are used as the catalyst [3]. Intramolecular version of the Kharasch addition reaction (atom transfer radical cyclization, ATRC) has opened novel synthetic protocols to the synthesis of carbocyde or heterocyles catalyzed by transition metals [5-7], and this has become a very important field in free radical cydization in organic synthesis. Transition metal-catalyzed Kharasch reactions sometimes afford telomers or poly-... 

The atom transfer radical cyclization of allyl iodoacetate is also more efficient in water than in benzene or hexane. For instance, treatment of the iodoacetate with triethylborane in benzene or hexane did not give any desired lactone while in water the reaction proceeds with high yield.It is suggested that the large... 

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]. 

Finally, isolated reports on the ability of NHC-Cu complexes to catalyze diverse organic transformations can be found throughout the literature and notably include heterocycles synthesis, atom-transfer radical cyclization leading to chloronaphthalenes, and allylation reactions using [(IPr)CuFj and an allylsiloxane. An increasing number of studies involving the use of CO2 with NHC-Cu catalysts has also been reported lately, they encompass... 

Yorimitsu H, Nakamura T, Shinokuho H, Oshima K, Omoto K, Fujimoto H. Powerful solvent effect of water in radical reaction triethylborane-induced atom-transfer radical cyclization in water. J. Am. Chem. Soc. 2000 122(45) 11041-11047. 

Reaction conditions have been developed in which the cyclized radical can react in some manner other than hydrogen atom abstraction. One such reaction is an iodine atom transfer. The cyclization of 2-iodo-2-methyl-6-heptyne is a structurally simple example. 

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]. 

Indium-mediated radical cyclization reactions of aliphatic iodoalkynes proceeds with a catalytic amount of In and I2. Iodoalkyne 94 undergoes an atom-transfer 5-exo cyclization to give five-membered iodoalkene. In contrast, the reaction with In (200mol%) and I2 (100mol%) yields the reductive 5-m -cyclization product via the same 5-exo-cyclization (Scheme 116).387-389 The existence of a vinylindium intermediate formed via the radical 95 has been confirmed by a Pd-catalyzed cross-coupling reaction (Scheme 117).390... 

Some free-radical cyclization reactions require only a catalytic amount of BusSnH or Bu3SnSnBu3. Such a reaction, instead of replacing a C-X bond with a OH bond, simply relocates the X atom. These atom transfer cyclizations differ from more conventional free-radical cyclizations in that the last step in the propagation involves abstraction of X- from a C-X bond not by -SnBu3 but by the cyclized starting material. The last step is kinetically viable only when a stronger bond is made from a weaker one. In the following example, a Si-1 bond is made at the expense of a OI bond. 

Phenyl selenide transfer radical addition reactions can be limited by the lack of reactivity observed in some precursors. Simple alkyl phenyl selenides do not undergo inter- or intramolecular radical additions to olefins. Phenylselenotrichloromethane will add to olefins upon photolysis, and the products formed can be elaborated into a, ff-unsaturated carboxylic acids (Scheme 20) [57], Benzyl phenylselenides have been observed to undergo atom transfer cyclization (Scheme 20) [58]. 

Atom transfer radical methodology was also explored in the 1-endo cyclizations. Curran and Chang [71] have investigated the cyclization of a-iodoesters. Photolysis of the a-iodo ester and a-iodo malonates 280 in the presence of hexabutyldistannane generated a mixture of the 6-exo and 1-endo trig radical cyclized iodides 281 and 282. Quite expectedly, the presence of a methyl group on the internal carbon of the olefin (283) shifted the reaction to 1-endo mode exclusively. The product underwent spontaneous cyclization to furnish the lactone 284. 

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