Radical cyclizations annulation reactions

The simple piperidine alkaloid coniine (for selected asymmetric syntheses of coniine see [22, 81-85]) offered a preliminary test case for hybrid radical-ionic annulation in alkaloid synthesis. From butyraldehyde hydrazone and 4-chloro-iodobutane (Scheme 4), manganese-mediated photolysis afforded the acyclic adduct in 66% yield (dr 95 5) the cyclization did not occur in situ [69, 70]. Nevertheless, Finkelstein conditions afforded the piperidine, and reductive removal of the auxiliary afforded coniine in 34% overall yield for four steps. This reaction sequence enables a direct comparison between radical- and carbanion-based syntheses using the same retrosynthetic disconnection an alternative carbanion approach required nine to ten steps [81, 85]. The potential for improved efficiency through novel radical addition strategies becomes quite evident in such comparisons where multifunctional precursors are employed. 

Last and Hoffmann described 5-exo radical annulation reactions of cyclic p-bromo propargyl ethers or acetals 259 (X=CH2) and their benzo analogs catalyzed by 5 mol% 255 as an approach towards the total synthesis of aflatoxins and analogs (entry 3) [311]. The cyclizations gave the products 260 in 35-95% yield. 

Reverse annulation reactions of bromoacetaldehyde cyclohexenyl acetals 261 catalyzed by 255 using NaBUt as the stoichiometric reducing agent provided bicycles 262 in 40-71% yield (Fig. 64, entry 5) [314, 315]. Cathodic reduction at — 1.8 V was also successfully applied to regenerate 255 or vitamin B12 247 in radical 5-exo cyclizations of 261 under optimized conditions (entry 6) [316, 317]. Less than 10% of the cyclic reduced products 263 were detected. 

Insertion reactions using CO and CH2N,2. Radical cyclization reactions of azaenynes in the presence of butyl stannanes in carbonylation conditions furnished /3-lactams <2003JA5632>. Azocanone 150 (Scheme 62) was prepared in good yield from enyne 149. The reaction occurred via a-stannylmethylene lactam of type 154 (Scheme 63). This free radical-mediated stannyl carbonylation is quite versatile and provides a general [ -pl]-type annulation leading to 4-exo and 8-exo systems. The yield of the isolated stannylene lactam intermediate 154 was reported as 61%, while the destannylation to lactam 150 was quantitative. 

Palladium-catalyzed cyclization of the oxime derivative 47 provided a good yield of the pyrrole 48 (Equation 9) <1999CL45>. Similar reactions have been observed in connection with cyclization studies of related ketone trimethylhydrazonium salts <2005H(65)273>. Photochemical radical cyclization of 7,5-unsaturated ketone oximes has been reported to produce 1-pyrrolines <2005TL2373>. Similar 0-acetyloximes may also be annulated to 1-pyrrolines by treatment with acetic acid in the presence of 1,4-cyclohexadiene and naphthalene-l,5-diol, possibly proceeding via a radical mechanism <2002CL144>. 

Indolines can also be prepared by radical cyclization. For example, the precursor 62 was annulated to the indoline 63 with incorporation of a N-substituent originating from the ketone component (Equation 16). This reaction seems to proceed via aryl radical addition onto an initially formed imine <20010L1009>. 

Scheme 3.31. Intramolecular [4+1] and [4+2] annulation reactions employing domino radical cyclizations.

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). 

Interestingly, the 3 chloro 1 iodopropane addition (Table 2.6, entry 9) led exclusively to pyrrolidine 37 (Scheme 2.4) none ofthe acyclic adducts was found [31]. Presumably, radical addition was followed by in situ Sn2 type cyclization. The same type ofcyclization, giving the epimeric pyrrolidine (epi 37), occurs upon ethyl addition to the 3 chlorobu tyraldehyde hydrazone (Table 2.6, entry 18). These reactions are hybrid radical ionic annulations of the C=N bond, a new class of radical polar crossover reactions [32]. 

Ring annulation by radical cyclization of ene-diynes and (Z)-allene-ene-ynes in a thermal reaction to give aromatics (electrocyclization). 

Annulated ring systems have as /1,7-substituents, when compared to annulated cyclopentyl radical systems, a stronger effect on the stereoselectivity than the corresponding combination of acyclic substituents. In all cases, attack tram to the /J.y-m-annulated ring is preferred. The stereoselectivity depends, furthermore, on additional substituents at the radical and the alkene, but it appears that the reactions of cyclohexyl radicals proceed less selectively than their cyclopentyl analogs. One frequently used route to these systems is sequential cyclization/ addi-tion reactions, in which the primary radical cyclizes to form the bicyclic ring system, followed by intermolecular addition to an alkene45,47 74. 

Similar to the selectivities observed in five-ring annulations of carbocyclic systems (see previous section), cyclic 3-oxa-5-hexenyl radicals exhibit a distinct preference for the formation of l,5-c( s-configurated products. This is illustrated by the reaction of five- and six-membered /i-phenylselenocrotonates with triphenyltin hydride59. The intermediate cyclopentyl or cyclohexyl radicals cyclize exclusively in the 5-exo mode to yield the corresponding c -fused "/-lactones. 

As radical cyclizations often proceed under mild reaction conditions and tolerate most of the common protecting groups, they are useful reactions for the functionalization of carbohydrates. The construction of C-1- or C-2-branchcd carbohydrates serve as illustrative examples. The radical precursors for the C-2-branched sugars, derived in one step from a iriacetyl-D-gly-cal, give the m-annulated bicyclic acetals as mixture of diastereomers65. 

It is worth noting that, unlike the analogous reactions with alkynes, all of these annulations involving the cyano group always led to a unique quinoxaline derivative, since the final iminyl radical cyclizes onto the aromatic ring of the isonitrile in an exclusive 1,6-fashion. 

Annulation reactions are possible when a precursor monocyclic substrate contains an activated alkene in a tether [4a]. As demonstrated in Scheme 5, an ester was employed to activate the olefin appended to cycloalkanone 17. Upon generation of the 0-stannyl ketyl with tributyltin hydride, the carbon-centered radical attacks the electron-poor /(-position on the activated alkene. The corresponding cyclized adduct 18 is a bicyclic skeleton with a bridgehead hydroxyl group. An example of this reaction shows cyclopentanone 19 undergoing cyclization to diquinane 20 and tricycle 21 (76 24) in 69% yield. The presence of reasonable amounts of the minor, yet readily isolable, jn-diastereomers in the reaction indicated that the reaction may not be reversible. 

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