Intramolecular radical cyclizations

Bromobenzy 1)-1,4-dihydro-3-methoxycarbonyIpyridine (135a) upon treatment with BusSnH undergoes intramolecular radical cyclization to give both... 

A new strategy for the syntheas of oxide-containing fragments of morphine has been developed. Thus, the tricyclic (ANO) morphine fragment 45 was obtained as the sole product via an intramolecular radical cyclization. The tetracyclic (ACNO) fragment 46 was synthesized in a similar fashion starting from 5,6,7,8-tetrahydroisoquinoline <96T10935>. 

An intramolecular radical cyclization gives the cxo-cyclic compounds, which has been extensively used in the synthesis of cyclic compounds. Michael additions of allyl alcohols or propargy 1 alcohols to nitroalkenes and the subsequent treatment with tin radicals provide a useful method for the preparation of substituted furans (Eqs. 7.83 and 7.84).126... 

Intramolecular radical cyclization of methylenecyclopropanes accompanies ring rearrangement [115]. In the case of (methylenecyclopropyl)propyl radicals, 5-exo-cyclization is observed as illustrated in Scheme 83, but 6-exo- and 1-endo-cyclizations occur with (methyleneeyelopropyl)butyl radicals, depending on the substituent. (Scheme 83)... 

Methylenetetrahydrofurans can also be realized by an intramolecular radical cyclization of bromoalkynes utilizing indium(I) iodide as a radical initiator <06TL2859>. 3-Diiodomethylenetetrahydrofurans were also prepared from l,to-diiodo-l-alkynes in the presence of l-hexynyllithium<06CC638>. 

Spiro tricyclic pyrrolizinone 171 was obtained with 65% yield (and almost poor stereoselectivity) by intramolecular radical cyclization of the xanthate 170 upon exposure of the latter to 2equiv of lauroyl peroxide, in a refluxing 3 1 mixture of methanol and 1,2-dichloromethane. The radical generated from the xanthate moiety cyclizes with the... 

Curran2 has reviewed recent applications of the tin hydride method for initiation of radical chain reactions in organic synthesis (191 references). The review covers intermolecular additions of radicals to alkenes (Giese reaction) as well as intramolecular radical cyclizations, including use of vinyl radical cyclization. 

An interesting intramolecular radical cyclization followed by enantioselective hydrogen atom transfer has recently been reported (Scheme 11) [40]. This reaction is carried out in the presence of a chiral complexing agent 38, which... 

The same strategy was also employed in the synthesis of the saturated analogue of protolichesterinic acid ( )-dihydroprotolichesterinic acid (4) can be synthesized using epoxide 32 as a starting material for the intramolecular radical cyclization to yield 33 as the major diastereomer (Scheme 5). Subsequent oxidation gave finally rise to ( )-4, which could be obtained in di-astereomerically pure form by fractional crystallization. 

Other examples include the intramolecular radical cyclization of 3-bromoaIkyl-2(3fl)-oxazolones 192 and 196 with tributyltin hydride/azobisisobutyronitrile to give the pyrrolooxazolidinones 194,198, and 199. The 2,5-disubstituted pyrrolidine derivatives 195 are produced enantioselectively (Fig. 5.49). 

Hudlicky and co-workers reported a stepwise radical cyclization approach for the preparation of the complete morphinan ring skeleton 216 (Fig. 5.52). One of the key steps involves the intramolecular radical cyclization of cyclohexenyl... 

Many methods have been developed for the enantioselective synthesis of unnatural a-amino acids. Jeff Johnston of Indiana University reports (J. Am. Chem. Soc. 125 163,2003) coupling the asymmetric alkylation of O Donnell with intramolecular radical cyclization, leading to what appears to be a general method for the enantioselective construction of indolines. 

A-w-Iodoalkylpyridinium salts (371, R = H, Me, n = 0-2) undergo intramolecular radical cyclization upon treatment with tributyltin hydride and AIBN to give the [6,5], [6,6], and [6,7] fused pyridinium salts (372) in good yields (90TL1625). 

An intramolecular free radical addition was used to prepare the 1,2-thiazepine derivatives 30 and 31 from 29 (Equation 6). A further elegant intramolecular radical cyclization was then used to convert 30 to a new aza-bicyclic system with a bridgehead nitrogen <2001JOC3564>. 

Until now, the chemistry of radicals on solid supports has been investigated mostly in respect to intramolecular radical cyclizations and radical chain reactions. One reason for refraining from free radical transformations is the chemical nature of the polystyrene with its abundance of benzylic positions that are prone to H-radical abstraction and oxidation. 

According to Baldwin s rules [10], the 5-endo-trig mode of cyclization is disfavored stereoelectronically. As a result, most five-membered ring formations employing intramolecular radical cyclization proceed via the 5-exo-trig path. The few exceptions to Baldwin s rule occur when substrates possess structural moieties (e.g. an amide bond) that conformationally bias the substrates in favor of the 5-endo-trig mode. 

In summary, intramolecular radical cyclization reactions onto aromatic rings can provide quick access of otherwise not so easily assembled Ca0. -C.ryi bonds, although the yields are generally low and the process suffers from a lack of regioselectivity. Noticeably, Crich found that a catalytic amount of benzeneselenol, which can also be generated in situ reduction of diphenylselenide with stannane [57]. This method should find synthetic utility in intramolecular radical addition to arenes. 

Intramolecular radical cyclization followed by trapping of the intermediate with an enone has been investigated by Fraser-Reid and co-workers [95JOC3871] as a method for the synthesis of highly functionalized C-glycosyl derivatives. The control of the anomeric stereochemistry as well as the facial selectivity in the addition to the chiral enone is impressive. 

Intramolecular radical cyclization of haloarenes 464 (Rz = CH=CHPh, CH=NCH2Ph, CH=CHC02Me, CMe=CHPh) in the presence of tributyltin hydride gave the fused tricyclic /3-lactams 465 in reasonable yields (Equation 75) <1997M1149, 2005T2767>. 

Intramolecular radical cyclization of an aryl bromide and an alkyne can be used to produce dihydroquinolines (Equation 57) <1998TL2965>. An analogous reaction setup utilizes a Lewis acid-catalyzed novel one-pot domino pathway using silver catalysis in high regioselectivity (Scheme 26) <2005OL2675>. Three mole equivalents of the alkyne are used with the final cyclization step arising from alkynic addition. 

An intramolecular radical cyclization provides the basis for an asymmetric synthesis of 3-aminochromans. The chirality of the cyclization precursor 473 is derived from either L- or D-serine, and the separable regioisomeric chromans, S)-tert-buty 5-acetylchroman-3-ylcarbamate and R)-tert-butyl 7-acetylchroman-3-ylcarbamate arise due to two possible cyclization modes A or B of the radical intermediate 474 (Scheme 105) <2003OL4253>. 

Dienone 475 undergoes an intramolecular radical cyclization to afford the bicyclic enone 476, which is readily aromatized to 8-methoxychroman-6-ol in excellent yield (Scheme 106). Various alkylations and/or halogenations can also be carried out prior to aromatization allowing entry to highly functionalized isochromans <2004JOC3282>. 

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