Intramolecular reactions free radical cyclizations

Intramolecular cyclization of sulfonyl radicals is almost absent from literature. The fact that free radical cyclization has been the subject of a large number of studies and applications in the last decade in organic chemistry48 and that sulfonyl radicals add quickly to multiple bonds (vide infra) makes cyclization of sulfonyl radicals a rather attractive area. Recently, Johnson and Derenne49 studied the reaction of 6-methylhept-5-en-2-ylcobaloxime(III) with sulfur dioxide and, based on the product analysis, they suggested reaction 15 to be an intermediate step. 

X. Zhen, P. Agback, J. Plavec, A. Sandstrom, and J. Chattopadhyaya, New stereocontrolled synthesis of isomeric ( -branched [1 D-nucleosides by intramolecular free-radical cyclization— opening reactions based on temporary silicon connection, Tetrahedron 48 349 (1992). 

T. V. RajanBabu, Stereochemistry of intramolecular free-radical cyclization reactions, Acc. Chem. Res. 24 139 (1991). 

Free-radical cyclization reactions nicely complement the Pd(0)-catalyzed intramolecular Heck reaction, which also provides cyclic products from unsaturated halides. Free radicals can be generated easily at saturated carbons from saturated alkyl bromides, and the products are reduced relative to the reactants. In contrast, intramolecular Heck reactions work best for vinyl and aryl bromides (in fact they do not work for alkyl halides), and the products are at the same oxidation level as the reactants. Moreover, free radicals attack the double bond at the internal position, whereas palladium insertion causes cyclization to occur at the external carbon. 

Cyclizations of the type (156) - (151) include the conversion of (a) carboxylic acids (218 X = O, S) into diones (219) (34% yield) under acidic conditions <74MI 715-01) (b) pyridine derivative (220) into the pyrano[3,2-c]pyridine (221) (72% yield) via an intramolecular Grignard reaction <82JCS(P1)93> and (c) a 1 1 mixture of diastereoisomers (222) into a 1 1 mixture of diastereoisomeric pyranopyrans (223) via a HSnBu3-mediated free radical cyclization <93LA629>. The diethyl ethoxymethylenemalonate (EMME) synthesis of 3-ethoxycarbonyl-4-naphthyridone derivatives has been discussed in CHEC-I <84CHEC-i(2)58i>. 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

Over the past decades, radical chemistry has been developed into an important and integral part of organic chemistry. Radical cyclization becomes a facile and useful strategy for stereo-and regioselective C-C bond formation, affording useful chiral synthons for the synthesis of C-branched sugar derivatives [56,57]. The reactions in this section are divided into intramolecular and intermolecular free radical cyclization. 

Intramolecular free radical cyclization of dicarboxylic esters leads to a-hydroxy ketones (acyloins). Reductive coupling of dicarbonyl compounds provides 1,2-diols ipinacols) and further reaction of these yields cycloalkenes (McMurry reaction). These cyclization reactions are especially valuable for the preparation of medium and large rings that are not readily accessible by other methods. 

Synthesis of carbocyclic systems intramolecular free-radical cyclization, the Diels-Alder reaction, and ring-closing metathesis... 

Free-radical cyclization reactions (i.e., the intramolecular addition of an alkyl radical to a C=C ir bond) have emerged as one of the most interesting and widespread applications of free-radical chemistry to organic synthesis. Free-radical cyclizations are useful because they are so fast. The cyclization of the 5-hexenyl radical to the cyclopentylmethyl radical is very fast, occurring at a rate of about 1.0 X 105 s-1. In fact, the rate of formation of the cyclopentylmethyl radical is much faster than the rate of cyclization to the lower energy cyclohexyl radical. This stereoelectronic effect is derived from the fact that the overlap between the p orbital of the radical and the rr MO of the double bond is much better when Cl attacks C5 than when it attacks C6. The relative rates of 5-exo and 6-endo ring closures are strongly dependent on the nature of the substrate and especially on the amount of substitution on the ir bond. Cyclization of the 6-heptenyl radical in the 6-exo mode is also very favorable. 

Free-radical cyclization reactions (i.e., the intramolecular addition of an alkyl radical to a C=C rrbond) have emerged as one of the most interesting and widespread applications of free-radical chemistry to organic synthesis. Free-radical... 

The mechanisms of intramolecular free-radical cyclization reactions are no different from their intermolecular counterparts. The propagation part of the mechanism usually involves (1) abstraction of -Br, T, or -SeR by Bu3Sn- to give an alkyl radical, (2) one or more additions of an alkyl radical to a tt bond, and... 

In 1988, Boger and co-worker found that the intramolecular free-radical cyclization reactions of acyl radicals generated from selenol esters proceeded efficiently, suppressing competing reduction and decarbonylation (Eq. 47) [98]. 

In further illustrations of the use of free-radical cyclization reactions in terpene synthesis Snider et al. have described the 5-exo-trig cyclization from the imidazolide (29) to produce both B-copaene (30a) and B-ylangene (30b), Stork and Baine have synthesized seychellene (32) [from (31)], and Ladlow and Pattenden have featured a novel, stereoselective intramolecular radical cyclization step onto an enolic double bond, viz. (33) - (34), in their synthesis of ( )-alliacolide (35). 

It also appears that intramolecular thiyl radical addition is a very efficient process compared to other free radical cyclizations. But competitive reactions such as polymerization are sometimes very difficult to suppress. Furthermore, other easy cyclization pathways, such as ionic ones, may complicate the interpretation of the results. Dronov s work exemplifies this possibility. Under all the experimental conditions used, l-pentene-5-thiol led to a Cy5/Cy6 mixture of products, with the (Cy5) compound being favored in sulfuric-acid-promoted cyclization and the (Cy6) compound being favored in photolysis. Thus the claim to have observed a homolytic reaction in cyclizations of ethylenic thiols generated from fatty acids, under conditions which did not avoid acid treatment, must be considered with care. 

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. ... 

Described in this section are a couple of reports on the synthesis of 5-lactones wherein the ring closure has been achieved through a radical cyclization. Bachi and Bosch have reported the synthesis of 5-lactones by free-radical annelation of phenylselenyl carbonates [103] (Scheme 58). An intramolecular addition of an alkoxycarbonyl radical, formed by reaction of phenylselenyl carbonates 275 with tri-n-butyltin hydride in the presence of AIBN, to carbon-carbon multiple bonds provided the highly substituted lactone 276. The salient features of this free-radical cyclization include high regioselectivity favoring exo addition and a high ratio of cyclization to reduction products. 

R = H) undergoes a variety of enzyme-catalyzed free-radical intramolecular cyclization reactions, followed by late-stage oxidations, eliminations, rearrangements, and O- and N-alkylations. Working from this generalization as an organizing principle, the majority of known AmaryUidaceae alkaloids can be divided into eight stmctural classes (47). 

Wawzonek et al. first investigated the mechanism of the cyclization of A-haloamines and correctly proposed the free radical chain reaction pathway that was substantiated by experimental data. "" Subsequently, Corey and Hertler examined the stereochemistry, hydrogen isotope effect, initiation, catalysis, intermediates, and selectivity of hydrogen transfer. Their results pointed conclusively to a free radical chain mechanism involving intramolecular hydrogen transfer as one of the propagation steps. Accordingly, the... 

When free radicals are added to 1,5- or 1,6-dienes, the initially formed radical (9) can add intramolecularly to the other bond, leading to a cyclic product (10). When the radical is generated from an precursor that gives vinyl radical 11, however, cyclization leads to 12, which is in equilibrium with cyclopropylcarbinyl radical 13 via a 5-exo-trig reaction. A 6-endo-trig reaction leads to 14, but unless there are perturbing substituent effects, however, cyclopropanation should be the major process. 

A moderate diastereoselectivity was observed in these reactions where a mixture of diastereomers could be generated.58 The reactivity of the halides followed the order of tertiary > secondary primary and iodide> bromide (chlorides did not react). The preferred solvent system was aqueous ethanol. The process was suggested to proceed by a free radical mechanism occurring on the metal surface under sonochemical conditions. Efforts to trap the intermediate [A] intramolecularly gave only a very low yield of the cyclization product (Scheme 10.4).59... 

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