Five-membered heterocycles reactions with carbenes

The 1,3-dipolar cycloadditions are a powerful kind of reaction for the preparation of functionalised five-membered heterocycles [42]. In the field of Fischer carbene complexes, the a,/ -unsaturated derivatives have been scarcely used in cyclo additions with 1,3-dipoles in contrast with other types of cyclo additions [43]. These complexes have low energy LUMOs, due to the electron-acceptor character of the pentacarbonyl metal fragment, and hence, they react with electron-rich dipoles with high energy HOMOs. 

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). 

The two most common methods for the synthesis of complexes with NHC ligands are the reaction of a free carbene (a) or its enetetramine dimer (b) with a suitable metal precursor or the in situ deprotonation of an azolium salt (c) depicted in Fig. 8 using diaminocarbenes with five-membered heterocycles as examples. 

Dipolar cycloaddition reactions are most commonly applied for the synthesis of five-membered heterocyclic compounds.86 87 [3+2] cycloaddition reactions of transition-metal propargyl complexes have been reviewed.88 Addition of diazomethane to carbene complexes (CO)5Cr= C(OEt)R results in cleavage of the M = C bond with formation of enol ethers H2C = C(OEt)R,3 89 but (l-alkynyl)carbene complexes undergo 1,3-dipolar cycloaddition reactions at the M = C as well as at the C=C bond. Compound lb (M = W, R = Ph) affords a mixture of pyrazole derivatives 61 and 62 with 1 eq diazomethane,90 but compound 62 is obtained as sole... 

The theme of this chapter is that transition metals let you do things to organic molecules which are unthinkable without them. Nowhere is this more true than in metathesis reactions, and we finish the chapter with a reminder of the power of the ruthenium catalysts we introduced in Chapter 38. There we discussed the carbene-based mechanism of the reaction, and we showed you some simple examples such as this cyclization of a symmetrical amine to give a five-membered heterocycle using a catalytic amount of the ruthenium complex known as Grubbs 1 catalyst. 

Five-membered carbo- or heterocycles can be prepared with the aid of heteroatom-substituted carbene complexes in several different ways. In the following sections the focus will be on cyclization reactions in which the carbon-metal double bond plays a decisive role. 

Particularly interesting is the reaction of enynes with catalytic amounts of carbene complexes (Figure 3.50). If the chain-length between olefin and alkyne enables the formation of a five-membered or larger ring, then RCM can lead to the formation of vinyl-substituted cycloalkenes [866] or heterocycles. Examples of such reactions are given in Tables 3.18-3.20. It should, though, be taken into account that this reaction can also proceed by non-carbene-mediated pathways. Also Fischer-type carbene complexes and other complexes [867] can catalyze enyne cyclizations [267]. Trost [868] proposed that palladium-catalyzed enyne cyclizations proceed via metallacyclopentenes, which upon reductive elimination yield an intermediate cyclobutene. Also a Lewis acid-catalyzed, intramolecular [2 + 2] cycloaddition of, e.g., acceptor-substituted alkynes to an alkene to yield a cyclobutene can be considered as a possible mechanism of enyne cyclization. 

Ring-closing metathesis is well suited for the preparation of five- or six-membered heterocycles, and has also been successfully used to prepare tetrahydropyridines on insoluble supports (Entries 1 and 2, Table 15.23). Because metathesis catalysts (ruthenium or molybdenum carbene complexes) are electrophilic, reactions should be conducted with acylated amines to avoid poisoning of the catalyst. 

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. 

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. 

Hydrolysis of imidazolylidenes has been studied by DFT calculations and NMR experiments. The outcome of the reaction has been shown to be highly dependent on the amount of water involved in the reaction, and an equilibrium between the carbene and hydroxide ion has been identified. Related to this study, the pAT s of a range of NHCs have been determined via deuterium exchange experiments monitored by H NMR and found to increase markedly with electron donation from nitrogen substituents. Saturation was found to have only minor influence on the acidity of the flve-membered heterocycles. In contrast, the ring size has a major influence (moving from five- to six-membered heterocycles raised the pAT by up to 5 units). 

Reactions of carbenes other than cyclopropanation can also be performed, and recent examples include the ring expansion of five-ring heterocycles, such as the indoles (18), to their six-membered counterparts (19), and the production of formamides from secondary amines (Scheme 7), both with dichlorocarbene. The latter method is of interest because of its relation to the catalysis of dichlorocarbene generation by tertiary amines in two-phase systems. Recent work indicates that such catalysis is possible because the carbene, after generation at the phase boundary, is transferred into the organic phase (to undergo reaction) in the form of the N-ylid adduct (20). 

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