Oxidative cyclization, nucleophilic addition

The initial step of olefin formation is a nucleophilic addition of the negatively polarized ylide carbon center (see the resonance structure 1 above) to the carbonyl carbon center of an aldehyde or ketone. A betain 8 is thus formed, which can cyclize to give the oxaphosphetane 9 as an intermediate. The latter decomposes to yield a trisubstituted phosphine oxide 4—e.g. triphenylphosphine oxide (with R = Ph) and an alkene 3. The driving force for that reaction is the formation of the strong double bond between phosphorus and oxygen ... 

Interestingly, the nucleophilic addition of water in the sequence of events giving rise to 41 represents a relevant model system for investigating the mechanism of the generation of DNA-protein cross-links under radical-mediated oxidative conditions [80, 81]. Thus, it was shown that lysine tethered to dGuo via the 5 -hydroxyl group is able to participate in an intramolecular cyclization reaction with the purine base at C-8, subsequent to one electron oxidation [81]. 

The formation of derivatives of 2,3,6,8-tetraazabicyclo-[3.2.1]3-octene (425) arises from an intramolecular nucleophilic addition to the nitrone group of hydra-zone (424). Compound (424) was prepared by reaction of 2-acyl-3-imidazoline-3-oxides (423) with hydrazine. From the cis- and frans-derivatives (424), exo- and enr/o-isomers (425) were obtained (Scheme 2.197). The reaction of intramolecular cyclization does not occur in cases with monosubstituted hydrazones (316). 

Most syntheses of naturally occurring phenazines, though, are based on a two-step elaboration of the central heterocycle of the phenazine [78]. The first key step involves the generation of orf/zo-monosubstituted 88 or orf/zo, ortho -disubstituted diphenylamines 89-91 via nucleophilic aromatic substitution. Ring formation is then achieved by means of reductive or oxidative cyclization, for which a number of efficient methods are available. The main flaw of this approach is the synthesis of the substituted diphenylamines via nucleophilic aromatic substitution, as this reaction often can only be performed under strongly basic reaction conditions and at high temperatures. In addition, the diphenylamines required may only be achieved with certain substitution patterns with high yields. 

Intermolecular anodic cyclizations often involve initial coupling of radical-cations followed by a chemical cyclization reaction. An alternative is cyclization by internal nucleophilic addition of some reactant to an intermediate derived by anodic oxidation. 

The versatility of 5-nitrosopyrimidines in pteridine syntheses was noticed by Pachter (64MI21603) during modification of the Timmis condensation between (262) and benzyl methyl ketone simple condensation leads to 4-amino-7-methyl-2,6-diphenylpteridine (264) but in the presence of cyanide ion 4,7-diamino-2,6-diphenylpteridine (265) is formed (equation 90). The mechanism of this reaction is still uncertain (63JOC1187) it may involve an oxidation of an intermediate hydroxylamine derivative, nitrone formation similar to the Krohnke reaction, or nucleophilic addition of the cyanide ion to the Schiff s base function (266) followed by cyclization to a 7-amino-5,6-dihydropteridine derivative (267), oxidation to a quinonoid-type product (268) and loss of the acyl group (equation 91). Extension of these principles to a-aryl- and a-alkyl-acetoacetonitriles omits the oxidation step and gives higher yields, and forms 6-alkyl-7-aminopteridines, which cannot be obtained directly from simple aliphatic ketones. 

A critical step in a synthesis of the benzoquinone antibiotic sarubicin A (5) is addition of a methyl nucleophile to the aldehyde group of 2. Reaction with CH3MgBr is very slow at low temperatures and the yield and stereoselectivity are low. In contrast, methyltriisopropoxytitanium reacts with 2 to give the desired triol 3 in 80% yield. Oxidative cyclization of 3 to 4 was carried out in two steps benzylic bromination followed by silver-catalyzed ring closure.5... 

As mentioned earlier, direct hydride abstraction from 5-exo-substituted cyclohexadiene complexes is in general difficult, except for the 2-trimethylsilyl-substituted derivatives such as (48) and (50). Oxidative cyclization techniques have been developed to overcome this problem, exemplified by the conversion of (52) to (53) and thence to (54 Scheme 7). Stereocontrolled addition of a second nucleophile has already been illustrated by the conversion of (54) to (126) or (127), and the limitations imposed by a sterically demanding 6-exo substituent have been mentioned. 

Intramolecular oxidative cyclizations in the appropriately substituted phenols and phenol ethers provide a powerful tool for the construction of various practically important polycyclic systems. Especially interesting and synthetically useful is the oxidation of the p-substituted phenols 12 with [bis(acyloxy)iodo]-arenes in the presence of an appropriate external or internal nucleophile (Nu) leading to the respective spiro dienones 15 according to Scheme 6. It is assumed that this reaction proceeds via concerted addition-elimination in the intermediate product 13, or via phenoxenium ions 14 [18 - 21]. The recently reported lack of chirality induction in the phenolic oxidation in the presence of dibenzoyltar-taric acid supports the hypothesis that of mechanism proceeding via phenoxenium ions 14 [18]. The o-substituted phenols can be oxidized similarly with the formation of the respective 2,4-cyclohexadienone derivatives. 

The oxidation of phenols with hypervalent iodine compounds has been used frequently and nucleophilic additions can be performed as well as cyclization reactions using this technique. The resulting quinone derivatives show high reactivity and they have been used in a various subsequent reactions. Substituted phenols like 32 [78] or 34 [79] have been oxidized by hypervalent iodine reagents and, depending on the substitution pattern, cyclizations have taken place as shown in Scheme 16. Product 33 is unstable and undergoes subsequent... 

The authors used silver salts since gold salts catalyzed the reaction with R=H (giving oxazole 34, Scheme 5.16) but not with R=Me. Moreover, only traces of the desired furopyrrolidinone were formed with the use of a cationic gold species activated with silver additives. Therefore, silver traces were thought to be the active reagent. Indeed, on activation of compound 33 mediated by AgN03 in the presence of sodium acetate (Scheme 5.16), the enol moiety V can then accomplish a nucleophilic attack to produce the pyrrolidinone W and after protonolysis give compound X. Pyrrolidinone Y (the enol version of X) can, in turn, be subject to an oxidative cyclization to yield the furopyrrolidinone 35. Two equivalents of silver salts are needed for the activation step and the oxidative cyclization. 

Bauld and coworkers studied the [2+2] cycloaddition of A-vinyl carbazoles 86a and electron-rich styrenes 86b catalyzed by iron(III) catalysts A or B in the presence of 2,2 -bipyridine as a ligand, which was reported originally by Ledwith and coworkers (Fig. 21) [142, 143]. Deuterium-labeling studies provided support for the stepwise nature of the process, consisting of reversible SET oxidation of the electron-rich olefin to a radical cation 86 A. Nucleophilic addition of excess 86 leads to distonic radical cation 86B, which cyclizes to cyclobutane radical cation 86C. Back electron transfer affords cyclobutanes 87 and regenerates the catalyst. Photoelectron transfer catalysis gave essentially the same result, thus supporting the pathway. 

Allylphenyl sulfamate cyclizes under oxidizing conditions to furnish bicyclic aziridine. Subsequent nucleophilic addition of alcohols or H2O occurs selectively to afford 1,2,3-oxathiazocine stmctures 47a and 47b (Scheme 49 <2005OL4685>). Similarly, Rh-catalyzed oxidative transformation of hex-5-enyl sulfamate leads to 1,2,3-oxathio-azocane with annulated aziridine ring <2004AGE4349>. 

Cyclization of amidines 1 to the corresponding quinoxalin-3-amine 1-oxides 2 can be readily achieved by reaction with bases. This ring closure occurs via deprotonation of the benzyl group and intramolecular nucleophilic addition to the nitro group giving structurally definite compounds, in contrast to the mono-A -oxidation reaction of the parent hcterocycles (sec Section6.3.2.1.4.1.). ... 

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