General reactions oxidative cyclization

The number of methods available for the synthesis of bicyclic systems containing two fused five-membered rings with one bridgehead nitrogen can be summarized in a few general reactions dehydrative ring closure, oxidative Schiff base cyclization, and base-induced closure (Scheme 3). One-pot reactions involving precursor synthesis followed by cyclization are also known. 

Application of the reaction sequence periodate oxidation - cyclization with nitromethane hydrogenation to rt6o-nucleosides provides a general synthetic entry to 3-aminohexosyl p5nimidines i7-20) and purines 21-as) which otherwise are not readily accessible. That this sequence can be extended to nitroethane to give 3 -C-methyl branched aminosugar nucleosides, has been demonstrated, starting from uridine 4.10,26)... 

The use of N-trifluoroacetyl in place of the piotonated N-methyl function in these oxidative cyclization reactions has been explored. Generally these substrates lead to products of the O-methylflavinanthine type. In one instance, the delocalised carbonium ion intermediate 34 was found to undergo a competitive rearrangement when lack of a nucleophile in solution led to a slow demethylation step [137],... 

Open chain ketone phenylhydrazones take part in a number of cyclization reactions to form heterocyclic rings. Many of the electrochemical reactions describe can also be achieved using chemical oxidising agents. In general, electrochemical oxidation proceeds to the two-electron level to generate an electrophilic species... 

Judging from literature precedents including the two representative syntheses of pyridine alkaloids shown here, not only ate the yields for oxidative cyclizations generally low, but also the reaction consumes at least stoichiometric amounts of expensive Pd(OAc)2. Therefore, this method has limited utility in synthesis. Nonetheless, great progress has been made recently towards catalytic palladium oxidative addition <99SL596>, making the method mote attractive for preparative purposes. 

Tetrahydrofuranes. Cekovic, BoSnjak, and Mihailovic have reviewed their work on the oxidative cyclization of aliphatic alcohols to tetrahydrofuranes by oxidation with lead tetraacetate. The reagent should be free of acetic acid. Anhydrous calcium carbonate can be added to neutralize the acetic acid in the oxidant and that formed during the reaction. The reaction involves selective oxygenation of a 8-carbon the actual mechanism is uncertain, but is probably a radical reaction. Direct oxidation of the alcohol is generally of minor importance, but P-fragmentation can be a problem, particularly when a stable benzyl or allyl radical is formed. 

Metallacycles have been claimed to play pivotal roles in many transition metal-mediated multi-component coupling reactions [1]. For example, [2 -i- 2 -i- 2] alkyne cyclo-trimerization leading to benzenes - the Reppe reaction - has been considered to proceed via metallacyclopentadiene and elusive metallacycloheptatriene intermediates ("common mechanism ), while metallacyclopentenes have been proposed as intermediates for the [2 -i- 2 -i- 1] cyclo-coupling reactions of an alkyne, an alkene, and CO leading to a cyclopentenone (the Pauson-Khand reaction). A metallacyclic compound - which is defined here as a carbocyclic system with one atom replaced by a transition metal element - can be generally formed by oxidative cyclization of two unsaturated molecules with a low-valent transition metal fragment [2-4]. Alter-... 

As noted above, the styryl unit does not photocyclize, but groups substituted in the (3-position may react with the arene and lead to cyclization products. Pete and co-workers have, this year, described three examples of a reaction which may prove to be very general. Irradiation of the 3-arylcyclo-hexen-2-ones (200) induces useful and convenient oxidative cyclization to give (201), (202), and (203). Yields are very variable (15—70%) but the reaction has been successful with variously substituted derivatives. 

Intramolecular cyclization is a general reaction in the anodic oxidation of substituted amino alkenes. Thus, the already mentioned A-methyl-A-phenyl-1,2,2-triphe-nylvinylamine leads to a new 3/7-indole by anodic oxidation in the presence of 2,6-lutidine [149,150]. The corresponding enediamine undergoes an electrolytic double cyclization to form an indolooxazolidine [149]. The formation of isoquinolines, benzaze-pines, and tetrahydrocarbazoles may also be obtained by anodically initiated intramolecular cyclization of A-benzyl, A- S-phenethyl, and anilino enaminones [Eq. (30)] [158]. 

Abdrakhmanov and co-workers observed the cycloaddition of iV-(l-methyl-2-butenyl)aniline or 2-( l-methyl-2-butenyl)anilme with PdClj/DMSO to give a 69% yield of a mixture of 2-ethyl-3-methylmdole and 2,4-dimethylquinoline [87]. The authors propose that a Claisen rearrangement is initially involved. A similar oxidative cyclization of a 5-amino-indoleacrylate was the starting point for syntheses of CC-1065 and related compounds [88]. In an elegant mechanistic analysis, Sarnes has developed a general Pd-catalyzed arylation of indoles, at C-2 or C-3 depending on the reaction conditions [89]. 

The oxidation of certain dihydro-1,3,5-triazines can be effected with either potassium permanganate or tetrachlorobenzoquinone (chloranil). The dihydro-1,3,5-triazines 1, which can be prepared by cyclization reactions, are treated with the oxidizing reagents in dichloromethane or acetone to provide the corresponding 1,3,5-triazines 2 in 24 to 85%.5-8 In general, these oxidations are used to prove the structure of the dihydrotriazines. 

Treatment of Br(CH2) Br with NaaS under heterogeneous conditions yields the appropriate thiacycloalkane. Similarly, the oxidative cyclization of the dithiol HS(CH2) X(CH2) SH (X = O, CH2, or S) with iodine yields the corresponding medium-ring disulphide. A general synthesis of mediumring and macrocyclic disulphides and a variety of dithia-crown ethers has been devised, using caesium dithiolates as starting materials [reaction (1)]. ... 

A more general and effective modification of the reagent is the system (RC00)Re03/(RC0)20, particularly the (dichloroacetyl)perrhenate with excess dichloroacetic anhydride, which is suitable for iyn-oxidative cyclization of acid-sensitive substrates (in the same reaction as described above). 

Oxidative cyclization. The earlier observation of conversion of (-)-citro-nellol to ( —)-pulegone (7, 308) has been shown to be a general reaction for anne-lation of cyclic unsaturated alcohols or aldehydes. Several intermediates have been detected as shown for the oxidative cyclization of I to 2. 

We have been interested in developing oxidative free-radical cyclizations using Mn(OAc)3 (26-49). These reactions have the potential to prepare complex, highly functiondized, polycyclic molecules from simple precursors. They also pose a more stringent challenge for the method than oxidative additions of simple substrates, like acetic acid or acetone, to alkenes. Acetic acid and acetone are used in excess as solvent and the yield is based on the oxidant consumed. Further oxidation of the product is not generally a problem since the starting material is present in vast excess. In oxidative cyclizations, the substrate is too complex and expensive to use in excess. Further oxidation of the product is a major concern and common side reaction. 

Oxidative cyclizations are generally facilitated by the use of Pd(OAc)2 in acetic acid under reflux. The initial step in these oxidative cyclization reactions is believed to be the electrophilic palladation of the aromatic ring. An example is presented in the preparation of anti-malarial agent quindoline, isolated from a West African plant Cryptolepis sanguinolenta, which was synthesized through an oxidative cyclization of the appropriately 3-substituted quinoline in the presence of two equivalents of Pd(OAc)2 in trifluoroacetic acid. ... 

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