Annulation tandem process

Scheme 13.12 Iron-catalysed nthesis of polysubstituted benzofuran via an oxidative coupling/annulation tandem process.

The carbonylative cyclization of 2-iodophenols with norbornadiene or norbornene was also carried out. In 1989, Catellani s group studied the annulation of 2-iodophenol with norbornadiene to coumarin (Scheme 3.11a). ° In this method, the elimination of cyclopentadiene via retro-Diels-Alder reaction was involved in the formation of the terminal product. Fiaud and co-workers reported the palladium-catalyzed carbonylative cyclization of 2-iodophenol with norbornene in 1997 (Scheme 3.11b). They reported that the selectivity for the production of the two regioisomers can be controlled. Catellani and co-workers studied the intramolecular cyclization of ort/zo-iodophenyl 3-butenoate to 4-methylcoumarin with a palladium catalyst. 85% of 4-methylcoumarin was produced in the presence of benzonitrile and carbon monoxide, which is compulsory (Scheme 3.12a). Silva, Costa and their co-workers reported a tandem process for the synthesis of coumarins from 2-iodophenols and enoates with the assistance of a palladium catalyst (Scheme 3.12b). The general scope of this Heck-lactonization involves E- and Z-enoates as substrates. It was shown that this reaction is sensitive to steric hindrance around the double bound in... 

A novel method of pyrrole ring annulation onto a pyridazinc based on a tandem Sn -Sn amination process using enamines as difunctional nucleophiles, was reported <01TL5981>. Thus, enamine 144 reacted with 145 in the presence of AgPy2Mn04 to afford 146 in one pot in modest yields. A mechanism was also presented. 

The Bode group documented a remarkable annulation reaction of 3-alkyl or 3-aryl enals with chalcone-derived imines which allows direct access to cyclopentyl-fused p-lactams with four contiguous stereocenters in an operationally simple process/ A pronounced effect of the catalytic base on the diastereoselectivity was discovered. Using 3-alkyl enals as the substrates, DBU performed as the most optimized base to afford products in up to 94% yield, >10 1 dr, and 99% ee. When cinnamaldehyde derivatives were used, it was necessary to choose DMAP as the catalytic base in order to ensure the formation of desired products in a diastereoselective manner (up to 80% yield, >20 1 dr, >99% ee). Supported by the stereochemical outcome, a tandem, or possibly concerted, crossed-benzoin/oxy-Cope reaction as the key bond-forming step was rationalized (Scheme 7.57). 

A diastereoselective [4+l]-annulation of phthalaldehyde and an M-Boc-imine gives a c -2-amino-3-hydroxyindanone (28). Catalysed by simple thiazolium NHCs, the process may involve a tandem aza-benzoin/aldol. " (S>... 

The formal NHC-catalysed 4 + 1-annulation reaction of phthalaldehyde with imines has been developed, thus furnishing c -2-amino-3-hydroxyindanone scaffolds (123) with an excellent level of diastereoselectivity. The annulation process is suggested (g) to involve a tandem aza-benzoin/aldol reactions. 

Desmaele and co-workers reported an interesting annulation process based on a tandem i7 -allylpalladium complex alkylation-Michael addition for the approach of erythramineJ It was well known that arylnitronate anions react with 7r-allylpalladium derivatives to give C-aUcylated products. The unsaturated ester 260 was prepared as described in Scheme 59. Treatment of a mixture of diester 260 and arylnitronate 261 with DBU and LiCl in the presence of a catalytic amount of Pd(PPh3)4 and PPhs gave, in a one-pot reaction, nitro esters 262 in 57% yield. Such nitro esters could be suitable intermediates for the synthesis of Erythria alkaloids, exemplified by erythramine. 

Usually, carbodiimides obtained by an aza-Wittig reaction of A-vinyUc phosphazenes with isocyanates cannot be isolated. Therefore, the very reactive carbodiimides can be used as synthetic intermediates of polyheterocyclic natural products by domino processes involving aza-Wittig/intramolecuIar cycUzation (AW-IC). In the synthesis of variolin B (58), the formation of the annulated 2-aminopyrimidine ring 57 is achieved from phosphazene 56 by a tandem aza-Wittig/carbodiimide-mediated intramolecular cyclization process (Scheme 15.12). 

The following discussion focuses on the synthesis of aromatic heterocycles where a key palladium- or copper-catalyzed aryl halide (or equivalent) amination, etherification or thioetherification process is employed. Annulative routes utilizing anilines and related compounds with alkynes (Larock type) are also considered. Routes that do not lead to aromatic products or that rely on the functionalization of preexisting heterocycles have been discounted. Similarly, the synthesis of heterocycles via TT-allylpalladium chemistry or intramolecular cyclization of palladium Tr-olefin and TT-alkyne complexes is not featured. The discussion is structured predominantly around the type of bond being formed (C—N, C—O, or C—S) and is classified further by heterocycle type. Intramolecular and intermolecular C—X bond formations as well as tandem catalytic processes leading to aromatic heterocycle products are all discussed. 

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