Barton reaction radical cyclizations

Carbon-centered radicals generated by Barton s thiohydroxamate method can also participate in ring-forming reactions (see Scheme 26).52b,s3 For example, irradiation of 129 results in the formation of compound 130 (82% yield). The outcome of this transformation is reminiscent of Stork s elegant radical cyclization/trapping processes (see Schemes 7 and 8), in that/botn alkene carbon atoms have become functionalized. / I... 

Since this is a source of radicals, the reagent can find use in Barton-McCombie Reaction and Dowd-Beckwith Bine Expansion, as well as radical cyclization reactions. 

Hexenyl radicals cyclize to cyclopentylmethyl radicals (see Volume 4, Chapter 4.2). Thus radical decarboxylation of 6-heptenoic acids, by whatever means, usually results in die formation of five-mem-v beied rings. Although this fact had been appreciated previously it is only recendy, widi the advent of the 0-acyl thiohydroxamates, that it has been exploited from a syndietic point of view. An example is provided by the synthesis of bicyclo[4.3.0]proline derivatives from aspartic acid carried out by the Barton group (equation 51). It will be noted that activation of die C—C double bond acting as a radical trap is not necessary in these intramolecular reactions. 

A further use of Barton esters has been described as a path to enol ether radicals. The reaction involves the photochemical decomposition at 355 nm of the derivative (85). As part of an approach to the synthesis of a series of Kopsia alkaloids, the reductive decarboxylation of the derivative (86) was carried out. This involved irradiation of the Barton ester (86a) in the presence of t-BuSH. This affords the product (86b). The photochemical decomposition of the Barton ester (87) provides a path to the silyl derivatives (88). The nature of the trapping agent X is dependent on the conditions under which the reaction is carried out. Thus a variety of derivatives can be obtained using alcohols to afford ethers, or using ethanesulfonyl azide to give azides. The Barton esters (89) undergo the usual photochemical decarboxylation to afford ethenoyloxy radicals. Cyclization within these, in the presence of tributylstannane yields the lactones (90). ... 

Free-radical cyclization is sometimes followed directly by fragmentation of the new free radical, as in the Barton-McCombie reaction and the free-radical ally-lation reaction. Addition of a radical to a carbonyl group followed by fragmentation can be used to prepare a medium-sized ring from a smaller one. 

Fortunately, Bertrand was able to obtain nitrite esters of ethylenic alcohols as pure, characterized products. She assumed that photolysis of the nitrites would lead to the alkoxyl radical, as in the Barton reaction, with subsequent intramolecular addition. Isolation of tetrahydrofurfural oxime (62 R = H) starting from the nitrite of 4-pentene-l-ol (61 R = H) supported this hypothesis (Scheme 33). This mechanism was later confirmed by esr spin-trapping techniques and, independently by Rieke, who scavenged the cyclized radical with bromotrichloromethane. 

R2 = -Bu) (Scheme 33), where a competitive Barton reaction could be anticipated, gives only the corresponding oxime (62) and no product resulting from the Barton reaction. Gilbert and Norman have recently been able to provide indirect quantitative confirmation that the cyclization of the 4-pentenyl-1-oxy radical in aqueous solution is very selective toward formation of the (Cy 5) radical, and is even faster (>10 liter mol sec ) than the cyclization of the 5-hexenyl radical. 

Barton and coworkers used free radical cyclization in the synthesis of tetracyclines (Scheme 105). Photolysis of 254 (X,Y = SR or OR) gives the corresponding radical, which cyclizes to the (Cy6) compound 255 in 80% yield when X,Y = SCH2CH2O. Quite remarkably, 255 is formed only in the cis form. Another completely stereoselective reaction toward the cis compound involving intramolecular addition to an acetylenic bond has been described by Pradhan and was discussed in Section IX.2 (Scheme 70). An analogous reductive cyclization (K, NH3) of ethynyl ketones has been used by Stork in the construction of a tricyclic intermediate for the synthesis of gibberellic acid. ... 

The photolysis of a tertiary hypohalite (readily prepared from the corresponding alcohol) generates alkoxy radical, which abstracts hydrogen from 5-carbon to produce an alkyl radical. The resulting alkyl radical abstracts halogen atom from a second molecule of the hypohalite to give 5-haloalcohol, which is cyclized in presence of a base to form a tetrahydrofuran derivative [9]. These reactions are very similar to the Barton reaction and proceed through a six-membered cyclic transition... 

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-... 

Sequences in which addition precedes cyclization are not as straightforward to conduct as the reverse however, they are very important because a net annulation results (that is, a new ring is formed by the union of two acyclic precursors in one experimental step). The intermediate radical is differentiated from the other radicals provided that the cyclization reaction is rapid, but it can be difficult to differentiate the initial radical from the final radical. As illustrated in Scheme 57, this is particularly true in the tin hydride method because many different types of radicals react with tin hydride at similar rates. Reaction of (69) under standard radical addition conditions produces (70), which results from a sequence of addition/cy-clization/addition.233 That the last C—C bond is formed actually results from a lack of selectivity the initial and final radicals are not differentiated and they must undergo the same reaction. Of course, this lack of selectivity is of no consequence if the product contains the desired skeleton and the needed functionality for subsequent transformations. Such sequences are very useful for forming three carbon-carbon bonds, and they can also be conducted by Barton s thiohydroxamate method.234 Structural modifications are required to differentiate the initial and final radicals, and, as illustrated by the conversion of (71) to (72), phenyl groups can provide the needed differentiation (probably by retarding the rate of addition more than they retard the rate of hydrogen abstraction). Clive has demonstrated that phenyl-substituted vinyl radicals also provide the needed selectivity, as illustrated by the second example in Scheme 57.233... 

TBS-Protected 7-lactol is obtained through the formation of hypoiodite, followed by the formation of an alkoxyl radical, 1,5-H shift, and then formation of 8-iodoalcohol, and finally polar cyclization. The Fenton system with ROOH and Fe2+ also generates alkoxyl radical, RO. These reactions indicate that the Barton (-type) reactions are remote functionalization of non-activated C-H bonds at the 8- or e-position. 

Tin hydride 2 prepared from hydroxyl acid behaves like the conventional Bu3SnH in standard free-radical reactions, but the tin-containing by-products are easily removed by mild hydrolysis which converts them into base-soluble materials. The performance of these tin hydrides is evaluated for a range of radical reactions involving halides, selenides, Barton-McCombie deoxygenation, and enyne cyclizations.72... 

A related carbocycle is synthesized starting from carbohydrate precursors. The radicals are generated via Barton deoxygenation of the intermediate 5-heptenolsiei. The effect of 1-, 2-, 3-and 4-substituents on the stereoselectivity of the cyclization reaction has also been described 17-18. The formation of the 1,5-m-product is rationalized by the Beckwith modelThe 4,5-configuration of the main product is tram and is explained by the influence of allylic strain. 

The Barton nitrite ester photolysis is undeniably one of the most popular and useful reactions in radical chemistry for the functionalization of remote and inactivated positions within steroids (Scheme 19). Photolysis of nitrite esters gives nitric oxide and an alkoxyl radical that abstracts an ideally positioned hydrogen atom (1,5-hydrogen atom abstraction). The resulting alkyl radical reacts with nitric oxide in a solvent cage to afford the nitroso-alcohol derivative that is finally isolated as an oxime [53]. Related cyclizations of alkoxyl radicals have been reported by Surzur photolysis of y,(5-alkenyl nitrite esters leads to alkoxyl radicals that undergo subsequent tandem 5-exo cyclization followed by NO-trapping [54, 55]. 

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