Five-membered heterocycles insertion reactions

Insertion of a C=0, C=S or S=0 group between an amino and a hydroxy function of a 1,2-aminoalcohol produces a five-membered heterocycle with O and N as ring heteroatoms linked by -CO-, -CS- and -SO-groups. Although the reaction proceeds in two steps, it can often be carried out as a one-pot process. 

The reaction of alkoxy(alkyl)carbene chromium complexes with alkynes has been reported to give modest yields of cyclopentenones [368] and a few examples of intramolecular carbene C-H insertions of Fischer-type carbene complexes, leading to five-membered heterocycles, have been reported [369,370] (Table 2.22). 

Pd and Pt atoms derived from (Ph3P)2PdCl2 and (Ph3P)2 Pt(CH2=CH2) are smoothly inserted into 1,2-disilacyclobutane (261) to give the corresponding five-membered heterocycles (262 M = Pd, Pt) <84JOM(27l)337>. Reaction of the heterocycle (263) with aldehydes in the presence of PhsP leads ultimately to the 1,2,5-oxadisilacyclopentane (264) <830M1846>. 

Transition metal catalyzed insertion reactions offer a convenient route for the preparation of five membered heterocyclic rings. Besides intramolecular Heck-couplings and CO insertion, examples of the intramolecular insertion of an acetylene derivative constitute the majority of this chapter. Although some of these processes involve the formation of a carbon-heteroatom bond, they are discussed here. 

The transition metal catalysed formation of five membered heterocycles through the insertion of a triple bond has also been explored. o-Halophenyl-alkynylamines, propargylamines and propargyl-ethers have been subjected to ring closure reactions. These processes, however also require the presence of a second, anionic reagent, which converts the palladium complex formed in the insertion step to the product. 

A Ni°-based system related to those already described in connection with syntheses of both cyclobut-enediones and several five-membered heterocycles (Sections 9.4.2.1, 9.4.3.3 and 9.4.3.5) is also capable of catalyzing pyridone synthesis from isocyanates and alkynes. However, the structures found for the isolable metallacyclic intennediates in this system imply a completely different insertion sequence isocyanate first, followed by the two alkynes (Scheme 35). As a consequence, the regiochemistry found in the products of reaction of unsymmetrical alkynes is the reverse of that typical of Co larger substituents end up at positions 4 and 6. Thus, starting wiA the carbonyl carbon of the isocyanate, each carbon-caib-on bond forming event is strongly regioselective for the less-hindered alkyne caibon (equation 46). The... 

TMS = SiMc3) [127-130]. The reaction starts with cleavage of the Ln-Alk bond by the phosphine resulting in formation of the phosphide derivative of the metal (Scheme 8.47). After insertion of the multiple carbon-carbon bond into the Ln-P bond five-membered heterocycle with two chiral centers was formed. On the next step phosphoms heterocycle is released as a final product and catalytically active Ln species were regenerated. Multiple carbon-carbon insertion into the Ln-P bond was found as rate Umiting step of the reaction [129]. 

The transition metal catalyzed synthesis of seven membered and larger heterocycles attracted considerably less attention than the preparation of their five and six membered analogues. Typical examples in this chapter include the formation of heterocycles in insertion reactions, or through carbon-heteroatom bond formation. Although the formation of some macrocyclic natural products was also achieved in cross-coupling reactions they will not be discussed in detail. 

Unlike common five and six membered heterocycles, purines rarely undergo coupling reactions including the insertion of an olefin or carbon monoxide. This behaviour is not well understood since Heck and CO insertion reactions are known to proceed on similar systems. 

The predominant formation of five-membered carbocydes or heterocycles 122 (Scheme 50) via a sequential conjugate addition-carbene insertion pathway is generally observed in the reactions of the appropriate alkynyliodonium salts 119 (R = long alkyl chain or other group with C-H bond available at C5) with various relatively hard nucleophiles. Typical nucleophiles used to initiate these selective cyclizations are enolate, azide, sulfinate, tosylamide, thioamide and some other anions. 

The formation of five- and six-membered heterocycles by radical cyclization is discussed in a comprehensive review <2004H(63)1903>. Representative examples of ring syntheses involving carbenoid (Table 6) or nitrenoid (Table 7) intermediates are given. In many cases, the free carbene or nitrene is probably not involved, and the distinction between insertion and addition reactions given in the tables is not always clear cut. Such reactions are particularly useful for the preparation of tricyclic compounds. The application of carbenes and carbenoids in the synthesis of heterocyles is summarized in a review <1996AHC(65)93>. 

Similar to the benzynezirconocene, cyclohexyne, cyclopen-tyne, alkyne, alkene, cycloaUcene zirconocenes, and related species insert various substrates such as alkynes, alkenes, aldehydes, ketones, nitriles or phosphaalkynes. They lead in general five-membered zirconacycles, which can be converted by transmetalation or exchange reactions into fused-ring aromatic or heterocyclic compounds. The extension of this chemistry to heterobenzyne complexes can be realized, for instance, in phosphinine compounds. Consequently, under mild conditions, ) -phosphabenzyne-zirconocene complexes are formed and can be isolated either as PMes adducts or as dimers when the elimination reaction is carried out without added phosphane (Scheme 28). 

Key to method (A) exchange reaction with tin heterocycle (B) hydride addition to diyne (C) oxidation of saturated ketone (D) bromination-dehydrobromination by pyrolysis (E) reaction of RLi or ArLi with exocyclic M-Cl of preformed diene (F) ring expansion reaction from cyclopentadiene derivative (G) LiAlHi reduction of exocyclic M-Cl (H) carbene insertion into five-membered cyclo-pentadiene derivative. Doering-Hoffman method (I) 1,6-cycloaddition of GeCU. 

Dihalocarbenes, like CCI2 or CBr2, generated in situ by phase transfer catalysis are inserted into a / C—H bond of the five- and six-membered heterocycles 40b,c to give the functionalized metallacycles 63 and 64 (Scheme 23). A precondition for this reaction is a trans-M—C—C—H... 

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. 

Carbonylation with aUcenylation is one of the most important reactions in the application of intramolecular five-membered ring compounds. Heterocyclic ketones are synthesized by the insertion of carbon monoxide into a metal-carbon bond followed by demetalation reactions. Because metal-carbon or metal-nitrogen a-bonds are... 

Rapoport and co-workers have reported a general synthesis of nitrogen, oxygen, and sulphur heterocycles (218) by rhodium-catalysed intramolecular N-H, 0-H, or S-H insertion reactions.of keto-ester precursors (217)- This reaction is well documented as an efficient route to B-lactams but this group has now shown that the reaction works well for the synthesis of five-and six-membered nitrogen heterocycles (Scheme 22). The reaction fails for seven-membered nitrogen heterocycles in this case C-H insertion to give a eyelopentanone is the preferred reaction mode. 

The insertion of CO into Pd-carbon bonds has also been employed in several tandem/cascade reactions that afford five-membered nitrogen heterocycles [97]. A representative example of this approach to the construction of heterocydes involves synthesis of isoindolinones via the Pd-catalyzed coupling of 2-bromobenzaldehyde with two equivalents of a primary amine under an atmosphere of CO [97bj. As shown below (Eq. (1.57)), this method was used for the preparation of 144 in 64% yield. The mechanism of this reaction is likely via initial, reversible condensation of 2-bromobenzaldehyde with 2 equiv of the amine to form an aminal 145. Oxidative addition of the aryl bromide to Pd° followed by CO insertion provides the acylpalladium spedes 146, which is then captured by the pendant aminal to afford the observed product. An alternative mechanism involving intramolecular imine insertion into the Pd—C bond of a related acylpalladium species, followed by formation of a paUadium-amido complex and C—N bond-forming reductive elimination has also been proposed [97b],... 

Since Alper and coworkers have shown that the dipolar insertion reactions of carbodiimides into three-membered ring aziridines can be extended to four- and five-membered ring nitrogen heterocycles, one wonders if these reactions may also occur with the corresponding oxygen heterocycles. 

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