Radical-based cyclizations

PhI(OAc)2 in trifluoroethanol and in the presence of carbonate base within rather short reaction time and displays a remarkably large substrate scope. Mechanistically, the authors propose an iititial interaction between the hypervalent iodine(lll) reagent and the amidine nitrogen, which upon homolytic cleavage of the N-1 bond initiates the start of a radical-based cyclization onto the arene ring. The reaction can also be conducted as a catalytic transformation using 20 mol% of Phi as catalyst and mCPBA as terminal oxidant. For this transformation HFIP is the preferred solvent [11]. 

Schemes aimed at the construction of elaborate two-dimensional -PAHs with boron at their center represent the cutting edge in synthetic methodology toward well-defined graphene-like materials with atomically precise 5-doping (Section 10.4.2.2). Yamaguchi and coworkers showed that oxidative (Friedel-Crafts/Scholl-type reactions) or radical-based cyclizations of triarylboranes with reactive pendant functionalities could be used to fuse the 5-aryl groups into planar arrays. The seminal synthesis of a planarized dibo-raanthracene (Scheme 10.7) is representative of the oxidative/acid-catalyzed approach [24]. Installation of pendant 2,6-di(2-propenyl)phenyl groups via...

The majority of sequential radical reactions deal with cyclizations as the key steps. The constructions of carbocycles, oxygen, and nitrogen heterocycles using (TMSlsSiH as a mediator are many and represents the expansion and importance of these synthetic approaches. For example, Nicolaou and coworkers found that (TMSlsSiH serves as a superior reagent in the radical-based approach toward the synthesis of azadirachtin, an antifeedant agent currently used as an insecticide, and in other related systems. ° ° Here below we collected a number of reactions mostly from the recent work in the area of intramolecular reactions. 

The field of alkaloid synthesis via tandem cyclizations favors the application of (TMSlsSiH over other radical-based reagents, due to its very low toxicity and high chemoselectivity. For example, cyclization of the iodoarylazide 102, mediated by (TMSlsSiH under standard experimental conditions, produced the N-Si(TMS)3 protected alkaloid 103 that after washing with dilute acid afforded the amine 104 in an overall 83% yield from 102 (Reaction 81). ° The formation of the labile N-Si(TMS)3 bond was thought to arise from the reaction of the product amine 104 with the by-product (TMSlsSil. The skeletons of ( )-horsfiline, ( )-aspidospermidine and (+ )-vindoline have been achieved by this route. - ... 

A radical tandem cyclization, consisting of two radical carbocyclizations and a heterocoupling reaction, has been achieved by electrolysis of unsaturated carboxylic acids with different coacids. This provides a short synthetic sequence to tricyclic products, for example, triquinanes, starting from carboxylic acids which are accessible in few steps (Scheme 6) [123]. The selectivity for the formation of the tricyclic, bi-cyclic, and monocyclic product depending on the current density could be predicted by applying a mathematical simulation based on the proposed mechanism. 

The radical-based strategy has invaded the field of A-containing heterocycles. Cyclizations mediated by silyl radicals have been introduced as the key step in the synthesis of alkaloids and pharmacologically active compounds, with many advantages both in terms of selectivity and bio-compatibility. Some of the most significant and innovative examples are described in this section. 

Since the introduction of the titanocene chloride dimer 67a to radical chemistry, much attention has been paid to render these reactions catalytic. This field was reviewed especially thoroughly for epoxides as substrates [123, 124, 142-145] so only catalyzed reactions using non-epoxide precursors and a few very recent examples of titanium-catalyzed epoxide-based cyclization reactions, which illustrate the principle, will be discussed here. A very useful feature of these reactions is that their rate constants were determined very recently [146], The reductive catalytic radical generation using 67a is not limited to epoxides. Oxetanes can also act as suitable precursors as demonstrated by pinacol couplings and reductive dimerizations [147]. Moreover, 5 mol% of 67a can serve as a catalyst for the 1,4-reduction of a, p-un saturated carbonyl compounds to ketones using zinc in the presence of triethylamine hydrochloride to regenerate the catalyst [148]. 

In a more recent study Co(dppe)I2 was used as a catalyst for reductive additions of primary, secondary, and tertiary alkyl bromides or iodides 249 to alkyl acrylates, acrylonitrile, methyl vinyl ketone, or vinylsulfone 248 in an acetonitrile/water mixture using zinc as a stoichiometric reducing agent [305]. The yields of the resulting esters 252 were mostly good. The authors tested radical probes, such as cyclopropylmethyl bromide or 6-bromo-1-hexene (cf. Part 1, Fig. 8). However, the latter did not cyclize, but isomerized during addition, while the former afforded complicated mixtures. On this basis the authors proposed a traditional two-electron mechanism to be operative the results do not, however, exclude a radical-based Co(I) catalytic cycle convincingly (Fig. 61). 

Beckwith has observed moderate diastereoselectivity in this reaction involving cyclic systems. The cyclizations of allyl and homoallyloxycarbonyloxy radicals are potentially useful as radical based alternatives for an overall oxidation or hydrolysis of a double bond, and also various further transformations of the cyclic carbonates can lead to synthetically useful products.62b In contrast, simple alkoxycarbonyloxy radicals 91a add intermolecularly to ethyl vinyl ether to give, ultimately, carbonates of glycoaldehyde derivatives 91b, Scheme 37.62a... 

In the total synthesis of (-)-conocarpan, the chiral 2,3-dihydrobenzo[b furan core was constructed by radical based intramolecular cyclization as shown below <07CC2151>. In addition, chiral 2-isopropeny 1-2,3-dihydrobenzo[6J furans and 2-amido-bcnzo b furans were be made by palladium-catalyzed reaction in the presence of Trost ligand, and the rhodium(I)-catalyzed cyclization, respectively <07JOC2857 07OL2361>. 

Reactions of oxime 186, containing an electron-deficient carbon-carbon double bond, were also investigated (Scheme 45) [31]. In the case of stannyl radical addition-cyclization using triethylborane as the radical initiator, the reaction proceeded as efficiently as in previous cases giving the cyclized product 188 in 64% yield, after base-induced cleavage from the resin and hnker. 

Abstract This review provides an overview of some of the more recent work directed to exploit radical-based chemistry for the modification of some of Natures most important biomolecules, such as amino acids, peptides, and carbohydrates. Radical reactions are particularly advantageous for carrying out a variety of structural modifications on biomolecules as the reaction conditions are typically compatible with a wide variety of functional groups and solvents. An array of effective synthetic transformations will he discussed including selective side chain and backbone modifications of amino acids and peptides, along with methods for the transformation of carbohydrate substituents, as well as fragmentation and cyclizations reactions for the preparation of either structurally modified carbohydrates or chiral building blocks. 

The base-catalyzed or radical-initiated cyclizations of primary arsines to dialkynes, for example (43) - (44) (Equation (6)) (Sections 6.26.4.1.4 and 6.26.4.4.2), are closely related to the corresponding reactions of primary phosphines (see Chapter 6.25). 

Since S-endo ring closure is a disfavored process, the formation of five-membered ring radicals by radical cyclizations is not generally possible. To solve this problem, radical cyclization of (V-aziridinylimines was studied and these have been found to be the most ideal radical trap to provide ready access to five- and six-membered ring radicals. Based on the Eschenmoser reaction [29], the present approach comprises three steps cyclization, the opening of a cyclopropane ring, and consecutive -fragmentations (Scheme 8). 

During the last decade the application of radical addition reactions for solving problems in organic synthesis has grown, as documented by numerous review articles . In this survey we will deal mainly with the synthetical aspects of the radical-based addition of a molecule to alkynes, with Section IV dedicated to radical cyclizations and to the preparation of biologically active compounds. In Section II, in order to familiarize the reader with the properties of the vinyl radical, we will briefly examine the structural characteristics of vinyl radicals and make some considerations about the stereochemical outcome of their reactions. 

In continuance of studies on the radical ip.so-substitution of indolyl sulfones, Caddick has developed an alternative approach to fused [l,2-a]indoles based on the intramolecular cyclization of alkyl radicals <97TL6249>. Thus, treatment of 120 with sub-stoichiometric amounts of tosyl radical generates an alkyl radical which cyclizes to the indole ring leading to the fused ring derivatives 121 (n = 1,2) with regeneration of the catalyst. 

An aza-variant of the cycloaromatization of propargyl azaeneynes, such as 50, via azaenyne-allenes 51, has been reported by Kerwin et al. The aza-Myers-Saito cyclization provides a,5-didehydro-3-picoline diradical 52, which affords either polar or radical-based trapping products 53 and 54, depending on the reaction solvent. The facility of the aza-Myers-Saito cyclization relative to the parent Myers-Saito cyclization was predicted based on DFT calculations these results also indicate that the corresponding C2-C6 (aza-Schmittel) cyclization, although disfavored in the case of 51, is... 

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