Cyclization extension

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). 

Olier, C., Kaafarani, M., Gastaldi, S., Bertrand, M. P. (2010). Synthesis of tetrahydropyrans and related heterocycles via prins cyclization extension to aza-prins cyclization. Tetrahedron 66,413 45. 

The intramolecular allylation of soft carbon nucleophiles with allylic acetates as a good cyclization method has been extensively applied to syntheses of various three, four, five and six-membered rings, and medium and macrocyclic compounds[44]. Only a few typical examples of the cyclizations are treated among numerous applications. 

The Fischer cyclization has proved to be a very versatile reaction which can tolerate a variety of substituents at the 2- and 3-positions and on the aromatic ring. An extensive review and compilation of examples was published several years ago[3]. From a practical point of view, the crucial reaction parameter is often the choice of the appropriate reaction medium. For hydrazones of unsymmetrical ketones, which can lead to two regioisomeric products, the choice of reaction conditions may determine the product composition. 

Another issue of regioselectivity arises with meta-substituted arylhydrazones from which either 4- or 6-substitutcd indoles can be formed. Robinson has tabulated extensive data on this point[9]. A study comparing regioselectivity of cyclization as catalysed by HCl/EtOH and ZnClj was carried out for several m-substituted arylhydrazones of diethyl ketone[10]. The results given in Table 7.1 show some dependence on catalyst but mixtures are obtained under all conditions studied. 

Tertiary 3- and 4-phenylaIkanols undergo cyclo alkylation readily with H2SO4. Primary and most secondary 3-phenylaIkanols, however, do not, even at higher temperatures with H PO (64). Cyclization of phenyl alkyl alcohols to tetrahydronaphthalenes and iadanes has been extensively iavestigated (65). 

The Pictet-Gams method involves the cyclization of P-hydroxy- or P-methoxy- P-phenethylamides, and produces the isoquinoline derivative rather than the reduced form. A further extension of method is based on a metboxyetbyl amine. 

Another successhil strategy for derivatization of erythromycin employed modification of functional groups involved in intramolecular cyclizations. The C-9 ketone, C-6 hydroxyl group, C-8 proton, and/or C-ll,12-diol of erythromycin were converted into functional groups which participate poorly, if at all, in intramolecular cyclizations. Some derivatives which have been extensively evaluated in preclinical and clinical trials exhibit such desirable properties as better stabiUty under acidic conditions, greater oral bioavadabihty, and higher and more prolonged concentrations of antibiotic in semm and tissues. 

Coum rinic Acid Compounds. These synthetic phyUoquinone derivatives and congeners have been employed as anticoagulants since the isolation of 3,3 -methylenebis(4-hydroxy-2H-l-benzopyran-2-one) [66-76-2] (bis-4-hydroxycoumarin or dicoumarol) (1) from spoiled sweet clover in 1939. The ingestion of the latter was responsible for widespread and extensive death of bovine animals at that time. The parent compound for the synthesis of many congeners is 4-hydrocoumarin, which is synthesized from methyl salicylate by acetylation and internal cyclization. The basic stmctures of these compounds are shown in Figure 2, and their properties Hsted in Table 6 (see Coumarin). 

Many methods for the oxidative cyclization of 2-aminophenones to 2,1-benzisoxazoles have been reported and these were extensively discussed by Wiinsch and Boulton (67AHC(8)277). An illustrative reaction is the treatment of an aminophenone with hydrogen peroxide or potassium persulfate to produce 2,1-benzisoxazoles (Scheme 181) (64USP3261870). 

The most important oxirane, from an anthropocentric viewpoint, is probably squalene oxide (72), a precursor of lanosterol (73) and thus of the maligned but essential cholesterol (74 Scheme 87) 78MI50501). The cyclization of (72) to (73) represents nucleophilic tr-attack on oxirane carbon cf. Section 5.05.3.4.3(t)()), and the process has also been extensively investigated in vitro (68ACR1). Oxiranes are even more ubiquitous in steroid biosynthesis than had been thought, for a cholesterol epoxide has been shown to be a product of mammalian steroid biosynthesis <81JA6974). 

In 1909, Robinson demonstrated the utility of acylamidoketones as intermediates to aryl-and benzyl-substituted 1,3-oxazoles through cyclization with sulfuric acid. Extension of sulfuric acid cyclization conditions to alkyl-substituted oxazoles can give low yields, for example 10-15% for 2,5-dimethyl-l,3-oxazole. Wiegand and Rathbum found that polyphosphoric acid can provide alkyl-substituted oxazoles 4 in yields equal to or greater than those obtained with sulfuric acid. Significantly better yields are seen in the preparation of aryl- and heteroaryl-substituted oxazoles. For example, reaction of ketoamides 5 with 98% phosphoric acid in acetic anhydride gives oxazoles 6 in 90-95% yield. ... 

Other zinc reductions have been used extensively. Zinc dust in aqueous ammonium chloride is a standard reagent for the reductive cyclization of nitro esters to hydroxamic acids. These reactions are usually carried out at low temperatures (0°-10°) to avoid further reduction. Despite the fact that good yields can often be obtained, these reductions are highly capricious, depending on the quality of the zinc (impurities seem to improve the reaction) and other unknown factors. 

In an extension of this work, the Shibasaki group developed the novel transformation 48—>51 shown in Scheme 10.25c To rationalize this interesting structural change, it was proposed that oxidative addition of the vinyl triflate moiety in 48 to an asymmetric palladium ) catalyst generated under the indicated conditions affords the 16-electron Pd+ complex 49. Since the weakly bound triflate ligand can easily dissociate from the metal center, a silver salt is not needed. Insertion of the coordinated alkene into the vinyl C-Pd bond then affords a transitory 7t-allylpalladium complex 50 which is captured in a regio- and stereocontrolled fashion by acetate ion to give the optically active bicyclic diene 51 in 80% ee (89% yield). This catalytic asymmetric synthesis by a Heck cyclization/ anion capture process is the first of its kind. 

A5-hexenyl substituent, extensive cyclization occurs to yield the cyclopentylcarbinyl product from the yields of uncyclized and cyclized products for A5-hexenylmercury chloride, the rate constants for equation 50 have been estimated (vide supra). The SH2 reaction 49 has also been invoked to be the key step in the alkylation of -substituted styrenes by a free-radical addition-elimination sequence, namely96... 

Chemistry, reaction mechanisms, and properties have been extensively reviewed.4,5,10-20 Hie present chapter deals witii only one type of fully cyclized aromatic heterocyclic polymers die high-molecular-weight linear polymer witii a special emphasis on die synthesis and structure—property relationships for specific applications. 

---