Intramolecular radical-induced cyclization

An intramolecular 2-alkylation was also observed in a sulfonyl free radical induced addition-cyclization <95SL763>. A key intermediate in a new synthesis of pallescensin A (a biologically active labdane diterpene) was prepared by a cationic cyclization reaction with a furan <95SYN1141>. The sonochemical Barbier reaction was extended to carboxylate salts. 2-Furanylketones 10 can be obtained by sonication of a mixture of furan, lithium carboxylate, an alkylchloride, and lithium in THF <95JOC8>. 

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). 

These cyclizations both involve the reductive intramolecular addition of an electron deficient alkene function to an aldehyde carbonyl function, and both are effected in ca 90 % yields. The mechanism of this latter type of electrochemically induced cyclizations of carbon-carbon double bonds to carbonyl double bonds have been studied rather extensively, with especial attention to the fundamental mechanistic question of whether the cyclization step involves an anion radical, radical, or anionic mechanism [122]. The latter two mechanisms would involve the protonation of the initially formed anion radical intermediate to form a radical, which could then cyclize or, alternatively, be further reduced to an anion, which could then cyclize. Extensive and elegant electrochemical and chemical studies have led to the formulation of these reactions as involving anionic cyclization (Scheme 74). 

Intramolecular pinacol coupling reactions are known, giving cyclic 1,2-diols. Dialdehydes have been cyclized by reaction with TiCls to give cyclic 1,2-diols in good yield. ° A radical-induced coupling of an a,03-dialdehyde led to cw-l,2-cyclo-pentanediol when treated with BuaSnH and AIBN. or induced photochemically. ... 

By Addition o/P—H to Unsaturated Compounds. There has been a marked reduction in the number of papers concerned with this route in the past year, but nevertheless a number of interesting studies have been reported. Thus, for example, the primary phosphine (21) undergoes free-radical-induced intramolecular cyclization to form the bicyclic phosphine l-phosphabicyclo[3,3,l]nonane (22). ... 

Intramolecular carbon carbon bond formation is more efficient as demonstrated by Kim and Rawal, who reported the radical-induced fragmentation of epoxides followed by hydrogen abstraction and cyclization (Scheme 11). Kim s approach... 

Radically induced coupling of two t-systems also provides a synthetically useful route to cyclohexanes. The 6-endo-tng cyclization of the vinyl radical generated by Bu3Sn radical addition to the carbohydrate alkyne 147 provided a novel route to carbasugar 148 [93]. The intramolecular pinacol coupling of 1,6-dicarbonyl compounds such as 149 provides a direct synthesis of the inositol 150 [94] (Scheme 24). 

The Fukuyama indole synthesis involves the intramolecular radical cyclization of 2-alkenylisocyanides, the availability of which often limits the utility of this process. In order to access a wider variety of such substrates, the author prepared the versatile Horner-Wadsworth-Emmons reagent 131 using the Pudovik reaction <01SL1403>. Reaction of 131 with a variety of aldehydes thus provides a convenient and general route to diverse alkenyl precursors 132. Additionally, instead of the standard radical conditions using tri-n-butyltin hydride, Fukuyama now finds that excess thiols arc quite effective for inducing cycliz.ation, whereupon desulfurization of the indoles 133 can be effected with Raney-Ni if desired. 

Regardless of the precise structure of the chosen half southern synthon, the two main problems to be solved are the establishment of the carbon skeleton and the introduction of the necessary chirahty into the molecule. The published approaches have introduced chirality either by resolution, by starting with a chiral precursor, or via use of asymmetric synthesis techniques. The carbon skeleton has been established by use of a wide variety of techniques including the Diels-Alder and other cycloaddition reactions, heteroatom induced cyclizations, intramolecular Michael or Aldol cyclizations, intramolecular ether formation, and radical cyclization. 

The photochemical behavior of o-allylanilines such as 88 has been studied. Such compounds cyclize to give the (Cy5) compounds, indolines (89) (Scheme 45). This result is clearly reminiscent of the photochemical behavior of o-allylphenols (Section VIII.3), and although the selectivity is the one expected from aminyl radical intramolecular addition, it also seems best explained by photochemical excitation of the n double bond. This is an interesting conclusion since metal-salt-induced cyclization of compounds such as 88 generally yields a mixture of (Cy5) and (Cy6) products. 

In conclusion, intramolecular free radical addition may be a useful method of synthesizing bridged cyclic compounds. From the examples of the Cy5/Cy6 case noted in this section, it may be concluded that a large preference for the (Cy 5) radical formation again exists and that, in some cases, a very high stereoselectivity in the last transfer step may be observed. The same stereoselectivity is often observed in cationic-induced cyclizations. 

Intramolecular HAS induced by reducing reagents has been intensively applied to obtain a large number of compounds, where either alkyl, vinyl, aryl, or heteroaryl radicals successfully add onto arenes [31b, 40]. Different synthetic strategies, such as ring expansion [41], ipso substitution [42], 1,5-hydrogen translocation, and tandem cyclization [43], among others, have been applied to afford important cyclic compounds such as phenanthridines [44], polycyclic arenes [45], 6//-benzo[c] chromen-6-ones [13a], and strained helicenes [46]. 

Two unselective approaches to the two alkaloids are illustrated in Scheme 50. A straightforward synthesis by King relied on acid-induced intramolecular Mannich reaction of ammoketone 396, prepared from 5-aminopentanal diethyl acetal and pent-3-en-2-one, to give a mixture of ( )-394 (55%) and ( )-395 (20%) (367). The synthesis by Pilli et at. involved a one-pot trimethylsilyl triflate-catalyzed condensation between pent-3-en-2-one and the acyliminium ion derived fium JV-Boc-2-ethoxypiperidine (397) (368,369). Under the reaction conditions, the intermediate 398 underwent spontaneous V-deprotection and cyclization to give a 5.5 1 mixture of ( )-394 and ( )-395 (67%). In the same Scheme is also shown the much shorter stereoselective synthesis of ( )-394 by Beckwith et al, who used a radical-mediated cyclization on the V-acylated 2,3-dihydropyridin-4-one 399 to give the bicyclic product 400 as the sole diastereomer (91%) (370). Compound 400 was readily converted into the target alkaloid by reduction of both carbonyl groups with lithium aluminum hydride followed by reoxidation of the secondary alcohol at C-2. 

Scheme 13.14 Visible-light-induced intramolecular radical cyclization.

New cyclizations via photochemically generated aminyl radicals have been reported, including further examples of the Hofmann-Loeffler-Freytag reaction.313 Intramolecular addition of an aminyl radical, generated by photochemically induced nitrogen chlorine bond homoysis, is also accompanied by cyclization as illustrated by the conversion of the unsaturated N-chloroamide 378 to the pyrrolidine 379.314 Piperidine formation can also... 

Sonochemically induced cation-radical intramolecular cyclization on action of an iodo-nium salt was also demonstrated (Arizawa et al. 2001). Being oxidized with phenyliodonium bis(trifluoroacetate), l-(3-anisyl)-2-(l,3-cyclohexadien-2-yl) ethane formed the cation-radical and then 5 -methoxyspiro[cycloxehane-l,T-indan]-2,6-dione. The yield of this final product was high enough. 

A novel tandem carbonyiation/cyclization radical process has been developed for the intramolecular acylation of l-(2-iodoethyl)indoles and pyrroles <99TL7153>. In this process, an acyl radical is formed when CO is trapped by an alkyl radical formed from the AIBN-induced radical reaction of l-(2-iodoethyl)indoles 104 with BusSnH. Intramolecular addition of the acyl radical to the C-2 position of the heteroaromatic system presumably affords a benzylic radical which undergoes in situ oxidative rearomatization to the bicycloketones 105. 

The preparation of the catalyst starts with the synthesis of 1-mes-ityl-3-(7-octene)-imidazole bromide. This compound is prepared by condensing mesityl imidazole with 8-bromooctene. The resulting salt is deprotonated with (TMS)2NK, where TMS is the tetrameth-ylsilyl radical. This step is performed in tetrahydrofuran at -30°C for 30 min. To this product a solution of the ruthenium complex (PCy3)2Cl2Ru=CHPh is added at 0°C. Bringing the solution slowly to room temperature, after 1 h the ligand displacement was determined to be complete. Afterwards, the reaction mixture is then diluted with n-pentane and heated to reflux for 2 h to induce intramolecular cyclization. 

The radical intramolecular cyclization of a-anilino-oi-(chloromethylcarbonyl)phenylacetonitriles 150 is induced by tri- -butyltinhydride/azoisobutyronitrile to afford l-aryl-2-cyano-2-phenylazetidin-3-ones 151 (Equation 34) <1997JCM254>. 

Intramolecular cyclization of the chiral oxime ether 993 in the presence of isopropyl iodide and triethylborane affords the 3,4,5-trisubstituted tetrahydropyran-2-one 994 in poor yield but with good diastereoselectivity (Equation 388) <2003JOG5618>. Similarly, a triethylborane-induced atom transfer radical cyclization of 3-butenyl 2-iodoacetate leads to 4-(iodomethyl)tetrahydropyran-2-one. Higher yields are achieved when conducting the reaction at lower concentrations (Equation 389) <2000JA11041 >. 

B. K. Banik, Tributyltin Hydride Induced Intramolecular Aryl Radical Cyclizations Synthesis of Biologically Interesting Organic Compounds, Curr. Org. Chem. 1999, 3, 469 496. 

A tandem carbonylation-cyclization radical process in heteroaromatic systems bearing electron-attracting substituents such as l-(2-iodoethyl)indoles and pyrroles 970 result in the formation of 2,3-dihydto-l//-pyrrolo[l,2- ]indol-1-ones and 2,3-dihydro-l//-pyrrolizin-l-ones 974 (Scheme 188). The AIBN-induced radical reaction of compounds 970 with Bu3SnH under pressure of CO suggests that the acyl radical 972, derived from radical 971 and CO, would undergo intramolecular addition to C-2 of heteroaromatic system, and the benzylic radical 973 so obtained, upon in situ oxidation would produce final product 974 <1999TL7153>. 

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