Five-membered ring heterocycles formation

The formation of a diverse array of five-membered ring heterocycles via the cycloaddition of isocyanides with furan- or pyrrole-based enones was reported. The reaction mechanism is discussed and an example is shown below <06OL3975>. 

Electrochemical oxidation of alkyl substituted butadienes in the presence of di-methylurea as a 1,3-bidentate nucleophile, leads to formation of a five membered ring heterocycle [46]. Unsyrametrically substituted butadienes show no regiospeci-... 

HeterocycUzation. Captodative radicals are generated from a-heterosubstituted a-chloroacetic esters by treatment with CuCl bipy. Such a radical can be trapped in-tramolecularly by an alkene (e.g., a 3-butenyl group) attached to the a-heteroatom. Formation of five-membered ring heterocycles is a favorable process. Thus methyl 3-chloromethyltetrahydrofuran-2-carboxylate has been obtained in 75% yield as a mixture of cis and trans isomers (ratio 64 36). The glycine analog gives both pyrrolidine and piperidine derivatives. ... 

As the third component in the reaction of isocyanates with isonitriles enamines can also be used In this three-component reaction the isonitrile can be replaced by sulfur. Five-membered ring heterocycles are also formed from two equivalents of isocyanates and 2,2-bis(dialkylamino)-acetonitrile. This reaction proceeds via initial dissociation of the nitrile with formation of an isonitrile . 

Formation of five-membered ring systems (1,2-addition) can compete with formation of the seven-membered heterocycles (1,4-addition). If the first step of the reaction sequence, namely the nucleophilic attack of the terminal heteroatoin of the diene, is hindered by steric or electronic effects, the five-membered ring product is formed exclusively. 

This tendency is especially significant in compounds containing functional groups capable of addition with the formation of both five- and six-membered rings. It has been shown that for amides and hydrazides of azolecarboxylic acids, selectively, and for the acids with any arrangement of a function and triple bond, heterocyclization always leads to the closure of the six-membered ring. Similar reactions in the benzoic series mainly lead to the formation of five-membered rings. 

Scheme 21 Formation of five- and six-membered ring heterocycles by lanthanocene complexes...

Many versatile approaches to the construction of fused heterocyclic systems (6 5 6) with ring junction heteroatoms have been reported. More general reactions which can be used for synthesis of derivatives of several tricyclic systems, and transformations which have potential for use in the preparation of a series of substituted compounds, are discussed in this section. Formation of the five-membered ring is presented first because it is a conceptually simple approach. It should be noted, however, that the addition of a fused six-membered ring to a bicyclic component offers much more versatility in the construction of a (6 5 6) system. Each subsection below starts with intramolecular cyclization of an isolated intermediate product. Reactions which follow are one-pot intermolecular cyclizations. 

As with five-membered ring formation, the reactions of ADC compounds which lead to six-membered ring heterocycles can be classified according to how the ADC compound reacts in the initial step. Most common is the Diels-Alder reaction, with the ADC compound acting as dienophile. Six-membered rings also result from the reaction of monoenes with ADC compounds acting as the 4n component, and by cyclization or other transformation of an initial adduct. 

A lot of methods are available for the synthesis of this heterocycle, and most of them rely on the formation of the five-membered ring. In this section, only the methodologies of reasonable scope will be reported. The most classical method involves the cyclocondensation of 2-aminopyridine with an a-halo carbonyl compound. Due to the broad availability of the required substrates and the efficiency of this cyclocondensation, it continues to be the method of choice to prepare this heterocycle. New examples highlighting the generality of this reaction are collected in Table 14. 

Vacuum thermolysis (160°C) of the hemiaminal 11 generates the azaphos-phetane 65 in 85% yield.32 This product clearly results from the intramolecular insertion of the transient (amino) (phosphino)carbene 2h into the C-H bond of a diisopropylamino group bonded to phosphorus. Note that the four-membered heterocycle 65 is formed exclusively in spite of the ratio of six methyl-CH bonds to one methine-CH bond, and that only one of the two possible diastereomers is detected. The same regio- and diastereo-selectivity have already been observed with the di(phosphino)carbene 2g,74 but is in marked contrast to the exclusive formation of five-membered rings... 

The coordination abilities of A-heterocyclic thiols such as 2-thiopyridine, HSpy (66a), 2-mercapto-pyrimidine, Hspym (66b), or 2-mercaptothiazoline (67) with rhenium centers has already been described for oxorhenium(V) complexes is Section 5.3.2.3.L It has been outlined that ligands with five-membered rings preferably coordinate as monodentate neutral thiones whereas chelate formation is possible for mercaptopyridine or mercaptopyrimidine. Similar complex formation... 

The Sjv -cyclization is also suitable for the construction of enantioenriched heterocycles as demonstrated by the synthesis of the divinylpyrrolidine 333 (90% ee) from the dialkenylamine 331 (equation 88) ". The absolute configuration (3R,4R) (elucidated by anomalous X-ray diffraction) again results from stereoinversion at the metal-bearing C(l) atom in (S)-332 during the formation of the five-membered ring by S -substitution. 

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

From this point of view, both the pyranoses and the furanoses may participate in the mutarotation reaction, and both a- and /3-d 1uco-pyranose will have similar mutarotation constants. We may expect a heterocyclic five-membered ring with two adjacent cis hydroxyl groups to have a A of about 1000 units for 0.5 M solutions. In the case of D-glucose it is between 93 and 80 hence, the concentration of a-D-glucofuranose is probably less than 10 per cent. This quantity is sufficient, however, to explain the formation of derivatives of the furanoses. 

Chiral carbo- and heterocycles are widespread structural motifs in biologically active compounds. The cycloisomerization of 1,6-dienes (A) offers an elegant and atom-economic [56] approach to five- or six-membered carbo- or heterocycles [57]. Metal complexes based on Pd [58], Ni [59], Rh [60], Ru[61], and Ti[62] have been identified as promising lead structures for catalyst development. Some of the reported systems are highly chemo- and regioselective toward the formation of the individual five-membered ring compounds B-D (Scheme 2.1.5.2). Enantioselec-tive cycloisomerization, however, has been assessed only sparsely so far, and remains a challenging task [46, 63]. 

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