Heterocycles Through Cycloaddition Reactions

The diastereoselectivity achieved in these conversations is moderate (4-10 1). However, all products 43 can be obtained in diastereomerically pure form either through recrystallization or flash chromatography. The absolute configuration of the products has not yet been confirmed, but it can be assumed that the major dia-stereomers have (S) configuration according to a controlled approach of the diene to zinc complex A from the less shielded side. Some examples of these Aza-Diels -Alder reactions, are shown in Table 4.6. 

R Temperature x CO Yield (%) Diastereome-ric ratio Isolated pure diastereomer (%) 

The isolation of an intermediate revealed that the reaction proceeds via a tandem Mannich-Michael addition pathway. The zinc (II) chloride-promoted cascade reaction starts with a Mannich reaction. For a number of reactions, the Mannich-type intermediate can be isolated if the reaction is stopped by addition of diluted ammonium chloride solution [52,53]. 

The confusion about the configuration of natural coniine in the literature [54] was clarified by a X-ray analysis of crystals of 46a, which proved the -configuration of the synthesized compound, and also of the naturally occuring coniine [53]. 

The cis 2,6 disubstituted piperidinones 49 are formed preferentially in this Michael-type addition reaction (Table 4.7). 

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Five-tnembered heterocycles through a cycloaddition reaction... 

Closure of the oxadiazole ring is still achieved through cycloaddition between pyridine iV-oxides and isocyanates, affording adducts such as 142 (Scheme 38) <1995T6451>. Nonaromatic imine fV-oxides exhibited similar reactivities, since azasugar-derived fV-oxides as a mixture of 143 and 144 underwent cycloaddition reactions in the presence of phenyl isocyanate or trichloroacetonitrile. Compounds 145 and 146 (Scheme 39) were obtained from the aldoxime W-oxide 143 two other regioisomeric heterocycles arose from the ketoxime derivative 144 <1996T4467>. 

In 1981 we published the first paper [22] on the synthesis of s-triazolo[4,3-a]pyridinium salts, 4, by the anodic oxidation of hydrazones 3 in the presence of pyridine (Scheme 5). In our working mechanistic scheme we proposed nitrilimine as the possible intermediate and pointed out that this reaction opens the door to a wide range of heterocyclic systems via anodic oxidation of aldehyde hydrazones through 1,3-dipolar cycloaddition reactions of the nitrilimine involved. 

The ability to produce 1,3-dipoles, through the rhodium-catalyzed decomposition of diazo carbonyl compounds, provides unique opportunities for the accomplishment of a variety of cycloaddition reactions, in both an intra- and intermolecular sense. These transformations are often highly regio- and diastereoselective, making them extremely powerful tools for synthetic chemistry. This is exemplified in the number of applications of this chemistry to the construction of heterocyclic and natural-product ring systems. Future developments are likely to focus on the enantioselective and combinatorial variants of these reactions. 

Dipolar cycloaddition reactions between nitrile oxides and aUcenes produce 2-isoxazolines. Through reductive cleavage of the N—O bond of the 2-isoxazohnes, the resulting heterocycles can be readily transformed into a variety of important synthetic intermediates such as p-hydroxy ketones (aldols), p-hydroxy esters, a,p-unsaturated carbonyl compounds, y-amino alcohols, imino ketones and so forth (7-12). 

The catalytic [2 + 2 + 1]-cycloaddition reaction of two carbon—carbon multiple bonds with carbon monoxide has become a general synthetic method for five-membered cyclic carbonyl compounds. In particular, the Pauson-Khand reaction has been widely investigated and established as a powerful tool to synthesize cyclopentenone derivatives.110 Various kinds of transition metals, such as cobalt, titanium, ruthenium, rhodium, and iridium, are used as a catalyst for the Pauson-Khand reaction. The intramolecular Pauson-Khand reaction of the allyl propargyl ether and amine 91 produces the bicyclic ketones 93, which bear a heterocyclic ring as shown in Scheme 31. The reaction proceeds through formation of the bicyclic metallacyclopentene intermediate 92, which subsequently undergoes insertion of CO to give 93. 

Catalytic [3 + 2]-cycloaddition of the carbonyl and azomethine ylides 129 with olefins gives the five-membered heterocycles 130 (Scheme 45). Longmire et al. reported that the catalytic asymmetric [3 + 2]-cycloaddition of the azomethine ylides 131 with dimethyl maleate in the presence of AgOAc and a bis-ferrocenyl amide ligand 133 gave the pyrrolidine triesters 132 in excellent yields with very high enantiomeric excesses (Scheme 46).122 As described in section 8, the [3 + 2]-cycloaddition reaction of diazo compounds with olefins proceeds similarly through the formation of carbonyl ylides. 

The hetero-cycloaddition of C—C unsaturated bonds with C=0 and C=N bonds constructs heterocycles through concerted formation of both a carbon—carbon and a carbon—heteroatom bond.177 The hetero-Pau-son—Khand reaction using CO, alkyne, carbonyl group is a typical hetero-[2 + 2 + 1]-cycloaddition, giving five-membered heterocycles. Hetero-Diels— Alder reaction, that is, hetero-[4 + 2]-addition, produces six-membered heterocycles. 

An example of cycloaddition reactions that involve transformation of five-membered heterocycles with one heteroatom into benzo[c]-fused heterocycles through a sequence of Diels-Alder reactions is presented in Scheme 1. 

The same thiazolium ylide (172) was utilized for the synthesis of other compounds (15) (Table 2) through 1,3-dipolar cycloaddition reactions exploiting assorted dipolarophiles (e.g., MeCOCHCHMe, MeCOCHCHPh, CH2CHC02Et) followed by silica gel-assisted cyclization <85T3537>. Other thiazolium ylides (172b) were also used for the preparation of this type of heterocycle. 

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