Intramolecular Oxidative Heterocyclization Reactions

Palladium(II)-promoted oxidative cyclization of alkenes bearing tethered nucleophiles represents an intramolecular variant of the Wacker reaction. These reactions, which typically generate five- and six-membered heterocycles, have been the subject of considerable interest in organic chemistry [89-96]. Contemporary interest centers on the development of enantioselective examples [95,97] and reactions that employ dioxygen as the sole oxidant for the Pd catalyst [92-96]. 

Both oxygen and nitrogen heterocycles have been prepared with mono-NHC-coordinated Pd11 complexes of the general structure 44. o-Allylphenol 

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The intramolecular addition of carbon nucleophiles to alkenes has received comparatively little attention relative to heterocyclization reactions. The first examples of Pd-catalyzed oxidative carbocyclization reactions were described by Backvall and coworkers [164-166]. Conjugaled dienes with appended al-lyl silane and stabilized carbanion nucleophiles undergo 1,4-carbochlorination (Eq. 36) and carboacetoxylation (Eq. 37), respectively. The former reaction employs BQ as the stoichiometric oxidant, whereas the latter uses O2. The authors do not describe efforts to use molecular oxygen in the reaction with allyl silanes however, BQ was cited as being imsuccessful in the reaction with stabihzed car-banions. Benzoquinone is known to activate Ti-allyl-Pd intermediates toward nucleophilic attack (see below. Sect. 4.4). In the absence of BQ, -hydride eUm-ination occurs to form diene 43 in competition with attack of acetate on the intermediate jr-allyl-Pd" species to form the 1,4-addition product 44. 

A very large number of these systems with ring junction heteroatoms exists, and this number is constantly increasing. Only illustrative examples of the preparation of such systems can be given here. The synthetic methods for the formation of this type of heterocycle can be usefully classified as follows (i) various cyclocondensations between the corresponding heterocyclic derivatives and bifunctional units, (ii) intramolecular cyclizations of electrophilic, nucleophilic or (still rare) radical type, (iii) cycloadditions, (iv) intramolecular oxidative coupling, (v) intramolecular insertions, (vi) cyclization of open-chained predecessors, (vii) various reactions (quite often unusual) which are specific for each type of system. Examples given below illustrate all these cases. 

The platinum-catalysed intramolecular domino annulation reaction of o-alkynylben-zaldehydes has been described as a versatile approach to naphthalenes with annulated carbocycles or heterocycles of various sizes (Scheme 32).94 A plausible mechanism for the platinum(II)-catalysed annulation reaction shows that the double annulation process most probably proceeds through the benzopyrylium cation (117), which results from the nucleophilic attack of the carbonyl oxygen at the alkyne, activated by the Lewis-acidic platinum salt. A subsequent intramolecular Huisgen-type 3 + 2-cycloaddition of the second alkyne is assumed to generate intermediate (118). Rearrangement to (119) and the formal 4 + 2-cycloaddition product (118) leads to the aromatized final (116), liberating the active catalyst. In the case of FeCl3 as the Lewis acid, we assume that intermediate (118) is oxidatively transformed to (121). 

Oxidative coupling has been observed for benzene (52), methyl substituted benzenes (53), triphenylethylene (54), triphenyl-amines (55-59), anilines (57), carbazoles (60,61), iminobibenzyls (62), and heterocyclic phenols (71,72). Intramolecular anodic coupling reactions are used for synthesizing specific ring structures (63-68). Both dimer and octamer of dibenzothiophene have been detected (69,70)... 

Intramolecular oxidative-addition processes give metal atom heterocyclic compounds. When the ortho hydrogen atom of an aryl ring is transferred to the metal atom and a metal atom is inserted into a C-H bond, the reaction is also called orthometalla-tion. The more general term cyclometallation includes aryl and alkyl ring formation and is schematically described as follows " ... 

Dehaen WH, Hassnta- A (1991) Cycloadditions. 45. Annulation of heterocycles via intramolecular nitrile oxide-heterocycle cycloadditirai reaction. J Org Chem 56 896-900... 

C-H Amination. A number of amine-based starting materials will react with PhI(OAc)2 and a transition metal catalyst to promote selective C-H bond amination. Intramolecular oxidation of substrates such as carbamates, ureas, sulfamates, sulfonamides, and sulfamides affords the corresponding heterocycles in high yields and, in many cases, with excellent diastereocontrol (eqs 60 and 61). Insertion into optically active 3° C-H centers is reported to be stereospecific (eq 62). Chiral Ru, Mn, and Rh catalysts have all been utilized for asymmetric C-H amination, though product enantiomeric induction is variable. Many of the heterocyclic structures furnished from these reactions function as versatile precursors to 1,2- and 1,3-amine derivatives. 

A starting material that is suitable for the direct construction of a heterocycle by an intramolecular Heck-type reaction has to fulfil some simple but fundamental requiranents there has to be the halide function or a triflate for the oxidative addition onto the Pd catalyst, a side chain with an unsaturated functionality such as an alkene or an alkyne in an appropriate distance, and of course the heteroatom in this side chain. Figure 1 presents a substrnctnre typical for very many starting materials, which were transformed to heterocycles by intramolecnlar Heck-type reactions (X = halide, Het = heteroatom). This type of substrnctnre with an allylic side chain is easily accessible by derivatization of 2-bromo- and 2-iodo anilines, phenols, and thiophenols and leads to interesting heterocycles such as indoles and benzofurans, which are related to many natural products and other biological active componnds. 

Hypervalent iodine(III) mediated/catalyzed intramolecular oxidative C-H bond functionalization of (hetero)arenes and alkenes has been widely applied in the synthesis of several biologically active heterocyclic scaffolds. This intramolecular oxidative C-H bond functionalization reaction leads to the formation of carbon-carbon and carbon-heteroatom bonds in an efficient manner. Of all bond formation reactions, C-N bond annulations have been exploited most and are of immense... 

Aminoalkyl acids and their derivatives. Montchamp and coworkers have synthesized new / ,A -heterocyclic frameworks [3-hydroxy-1,3-azaphospholane (121) and 3-hydroxy-l,3-azaphosphorinane-3-oxides (122)] from readily available oo-amino-Zf-phosphinates (123)-(124) and aldehydes or ketones via the intramolecular Kabachnik-Fields reaction under thermal or microwave heating. The heterocycles constitute novel analogues of a-amino acids, which might be useful in preparation of peptidomimetics. The Kabachnik-Fields reaction has been also employed in the one-pot and solvent-free synthesis of a-aminophosphonates using commercially available titanium oxide (Ti02) as an extremely efficient catalyst. " ... 

The oxidative addition reactions to alkenes promoted or catalyzed by PdCl2(CH3CN)2 have been classified based on the nature of the attacking species. Oxygen nucleophiles such as water, alcohols and carboxylic acids undergo oxypalladation, while ammonia, amines and their derivatives are typical nucleophiles for aminopalladation. Carbopalladation with active methylene compounds is also discussed The palladium-catalyzed intramolecular hetero- and carbopalladation of olefins is extensively used as the ring-forming step in the synthesis of a variety of heterocyclic and carbocyclic systems, and representative examples are provided. 

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