Radical spirocyclization

In the context of the synthesis of naturally occurring product cardamom peroxide (7), radical spirocyclizations of the hydroperoxides 190, 193 and 196 were studied (Scheme 44) . It was found that the DBPO-induced oxidative cyclization of 190 follows the 5-exo-mode to give the spiroendoperoxide 191, which was subsequently converted... 

Spirocyclization was also the reaction pathway under radical conditions if furan was tethered to a radical precursor at the 2-position, as shown below <06CC665>. 

The reaction of [H2C(SiMe3)2C]2Si 180 with cyclopropylmethyl chloride proceeds via ring opening and formation of product 192 containing a spirocyclic Si atom, whose formation can be attributed to a radical-reaction pathway... 

Although cyclic azoalkanes are well known as biradical precursors [159] they have been used as 1,2- and 1,3-radical cation precursors only recently [160-164]. Apart from the rearrangement products bicyclopentane 161 and cyclopentene 163, the PET-oxidation of bicyclic azoalkane 158 yields mostly unsaturated spirocyclic products [165]. Common sensitizers are triphenyl-pyrylium tetrafluoroborate and 9,10-dicyanoanthracene with biphenyl as a cosensitizer. The ethers 164 and 165 represent trapping products of the proposed 1,2-radical cation 162. Comparison of the PET chemistry of the azoalkane 158 and the corresponding bicyclopentane 161 additionally supports the notion that the non-rearranged diazenyl radical cation 159 is involved (Scheme 31). 

Novel bridged spirolactones have been synthesized via tandem radical cycli-zations of enol ether radical. In Reaction (7.85) the first 5-exo spirocyclization is followed by a 6-endo cyclization to give the bridged derivative as a single diastereoisomer [96]. 

Several mechanisms have been proposed for the intriguing interconversions of sulfur (or selenium) rings. These include the formation of (i) radicals by homolytic S-S bond cleavage, (ii) thiosulfoxides of the type S =S via ring contraction (an intramolecular process) or (iii) spirocyclic sulfuranes (or sele-nanes) via an intermolecular process. A fourth alternative (iv) invokes nucleophilic displacement reactions. Generic examples of mechanisms (ii)-(iv) for homoatomic sulfur or selenium rings are depicted in Scheme 12.1. 

The photochemical transformation of the spirocyclic 4//-pyran derivative 622 shown in Eq. (47)333 resembles the reverse of the phototransformation 349->350. Upon reaction with Pb02 622 gave a stable nitroxide radical.454... 

More recently, the radical cyclization onto azide groups pioneered by Kim was applied in the construction of the B/E spirocyclic junction found in the [6.5.6.5] ABCE ring system of indole alkaloids such as strychnine, the clinically used anticancer agents vincristine and vinblastine and, in particular, aspidospermine87. In model system studies, cyclization of the iodoazide 24, prepared in 6 steps, in the presence of (TMS SiH, produced the N—Si (TMS>3 protected alkaloid 25, that after washing with dilute acid afforded the amine 26 in 95% yield from 24 (equation 58). The formation of the liable N—Si(TMS)3 bond was considered to arise from the reaction of the product amine 26 with the byproduct (TMS)3SiI. 

Notwithstanding this safety aspect, mCPBA continues to be used as an epoxidizing agent. In one such reaction, a diepoxidation (equation 1) was brought about as a key step in the synthesis of the spirocyclic core of aranorosin15, which is a novel antibiotic. A radical inhibitor was added in order to achieve an acceptable yield of 46%. 

According to ESR measurements, the intermediate glycosyl radical exists in the boat-like conformation [20], which was previously observed in some photoproducts of spirocyclization (Sect 2.2). This preferred conformation of the pyranosyl radical results from the stabilizing interaction of the single occupied p orbital with the a -Lumo of the adjacent p-C-OR bond (Scheme 6). 

The use of hypervalent iodine reagents in carbon-carbon bond forming reactions is summarized with particular emphasis on applications in organic synthesis. The most important recent methods involve the radical decarboxylative alkylation of organic substrates with [bis(acyloxy)iodo]arenes, spirocyclization of para- and ortho-substituted phenols, the intramolecular oxidative coupling of phenol ethers, and the reactions of iodonium salts and ylides. A significant recent research activity is centered in the area of the transition metal-mediated coupling reactions of the alkenyl-, aryl-, and alkynyliodonium salts. 

Beckwith and Storey have developed a tandem translocation and homolytic aromatic substitution sequence en route to spiro-oxindoles [95CC977]. Treatment of the bromoaniline derivative 122 with tin hydride at 160 °C generated the aryl radical 123 which underwent a 1,5-hydrogen atom transfer to give intermediate 124. Intramolecular homolytic aromatic substitution and aromatization gave the spiro-oxindole 125. Intramolecular aryl radical cyclization on to a pyrrole nucleus has been used to prepare spirocyclic heterocycles [95TL6743]. 

Spirocyclic pyrrolidin-2-ones (151) are prepared through the initial 1,5-radical translocation by an sp2 carbon-centered radical, followed by cyclization as shown in eq. 3.55 [161]. 

The latter example (reaction 36) already indicates that the Yang cydization can also be used to synthesize four-membered heterocycles. After light absorption, the a,(3-unsaturated carbonyl compound 84 undergoes intramolecular hydrogen abstraction at the a-position of the carbonyl moiety (reaction 37), leading to the 1,4-biradical intermediate XXX [87]. A radical combination then efficiently yields the spirocyclic P-lactam derivative 85, and only one stereoisomer is formed in this case. In this transformation, the a,P-unsaturated carbonyl function can be considered as being vinylogous to a simple ketone. 

An unusual 4-exo-trig cyclization accompanied by a later rearrangement was observed with aryl enolether 13 (Scheme 6) [48], The benzoxetane 14, which is formed in the initial cyclization step, undergoes ring-opening to form the phenoxy radical 15. 5-Endo cyclization of 15 and reduction of the resulting benzylic radical leads to the spirocycle 16. Diverse polycyclic products have also recently been obtained by intramolecular aryl radical cyclizations to tetrahydropyridines [49]. 

In all the following examples, the targeted double bonds were activated by suitable substituents to increase the efficacy of the desired cyclization mode. For the total synthesis of acutumine (26), an activated a,p-unsaturated ketone 27 was chosen as precursor (Scheme 10) [74, 75], Aryl radical additions to this type of alkenes are known to proceed about ten times faster than to comparable allylic alcohols. In a radical-polar crossover reaction, the spirocyclic product 28 was obtained in the presence of triethylaluminum as promoter and an oxaziridine as hydroxylating agent. The fact that even the efficient hydrogen donor tetrahydrofuran could be used as solvent nicely demonstrates the high efficacy of the cyclization step. 

As shown in other sections of this chapter, overall attention has shifted from diazonium salts as aryl radical sources to bromo- or iodobenzenes. One of the few recent attempts to improve the classical Pschorr cyclization using diazonium ions as starting materials led to the discovery of new catalysts [119]. Results from a first samarium-mediated Pschorr type show the variety of products that can be expected from intramolecular biaryl syntheses under reductive conditions (Scheme 22). Depending on the substitution pattern of the target aromatic core and the reaction conditions, either the spirocycle 60, the biphenyl 61, or the dearomatized biphenyl 62 were formed as major product from 63 [120]. 

Spirocycles can be obtained from intramolecular radical biaryl coupling reactions when suitable substituents are present for an alternative stabilization of the cyclohexadienyl intermediate (c.f. 69, Scheme 25). Otherwise, rearomatization can occur by cleavage of one substituent from the quaternary center of the spirocycle, such as the C-P bond in 69. First examples for an alternative reaction course have been reported in studies on the photochemically induced cyclization of iodoarenes [134]. Recently, ferf-butyldimethylsilyl ethers [135] and azides [136] were identified as well-suited substituents to lead the ipso substitution into the pathway towards spirocycles (Scheme 27). 

Mattay et al. used triethylamine as electron donor in tandem fragmentation/cyclization reactions of a-cyclopropylketones (49) [48]. The initial electron transfer to the ketone moiety is followed by subsequent cyclopropylcarbinyl-homoallyl rearrangement yielding a distonic radical anion (50). With an appropriate unsaturated side chain attached to the molecule both annelated and spirocyclic ring systems are accessible in moderate yields. Scheme 26 shows some representative examples. 

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