Cyclisation 4 + 2 cycloaddition

Pericyclic reactions (cyclisation, cycloaddition) Intermolecular hydrogen transfers Electron transfer... 

Tandem cyclisation-cycloaddition reaction of a-diazoacetopheno-nes yield polycyclic molecules in one single step. The synthetic interest of these reactions is further enhanced by the fact that the cycloadducts are easily rearranged to different products according to reaction conditions. 

Scheme 1.4 Schreiber s approach to pre-encoding skeletal information via a rhodium-catalysed tandem cyclisation-cycloaddition strategy. Reagents and conditions. (1) Rh2(02CC7His)4, benzene, 50 °C 13a 74% 13b 73% 13c 57%.

Covalent bond Cyclisation Cycloaddition Deactivating group... 

Stabilised sulphur ylides react with alkenylcarbene complexes to form a mixture of different products depending on the reaction conditions. However, at -40 °C the reaction results in the formation of almost equimolecular amounts of vinyl ethers and diastereomeric cyclopropane derivatives. These cyclopropane products are derived from a formal [2C+1S] cycloaddition reaction and the mechanism that explains its formation implies an initial 1,4-addition to form a zwitterionic intermediate followed by cyclisation. Oxidation of the formed complex renders the final products [30] (Scheme 8). 

The reaction of JV,iV-dimethylhydrazones (1-amino-1-azadienes) and alkenylcarbene complexes mainly produces [3C+2S] cyclopentene derivatives (see Sect. 2.6.4.5). However, a minor product in this reaction is a pyrrole derivative which can be considered as derived from a [4S+1C] cycloaddition process [75]. In this case, the reaction is initiated by the nucleophilic 1,2-addition of the nitrogen lone pair to the metal-carbon double bond followed by cyclisation and... 

All around this chapter, we have seen that a,/J-unsaturated Fischer carbene complexes may act as efficient C3-synthons. As has been previously mentioned, these complexes contain two electrophilic positions, the carbene carbon and the /J-carbon (Fig. 3), so they can react via these two positions with molecules which include two nucleophilic positions in their structure. On the other hand, alkenyl- and alkynylcarbene complexes are capable of undergoing [1,2]-migration of the metalpentacarbonyl allowing an electrophilic-to-nucleophilic polarity change of the carbene ligand /J-carbon (Fig. 3). These two modes of reaction along with other processes initiated by [2+2] cycloaddition reactions have been applied to [3+3] cyclisation processes and will be briefly discussed in the next few sections. 

The reaction of ethyl 2,2-diethoxyacrylate with alkynylalkoxycarbene complexes affords 6-ethoxy-2H-2-pyranylidene metal complexes [92] (Scheme 48). The mechanism that explains this process is initiated by a [2+2] cycloaddition reaction (see Sect. 2.3), followed by a cyclobutene ring opening to generate a tetracarbonylcarbene complex. This complex can be isolated and on standing for one day at room temperature renders the final 6-ethoxy-2Ff-pyranylidene pentacarbonyl complex. This last transformation requires the formal transfer of one carbonyl group and one proton from the diethoxy methylene moiety to the metal and to the C3 2H-pyranylidene ring, respectively, with concomitant cyclisation. Further studies on this unusual transformation have been extensively performed by Moreto et al. [93]. 

In a similar process, tertiary enaminones react with alkynylcarbene complexes to give the corresponding pyranylidene complexes following a reaction pathway analogous to that described above. First, a [2+2] cycloaddition reaction between the alkynyl moiety of the carbene complex and the C=C double bond of the enamine generates a cyclobutene intermediate, which evolves by a conrotatory cyclobutene ring opening followed by a cyclisation process [94] (Scheme 49). 

S+3C] Heterocyclisations have been successfully effected starting from 4-amino-l-azadiene derivatives. The cycloaddition of reactive 4-amino-1-aza-1,3-butadienes towards alkenylcarbene complexes goes to completion in THF at a temperature as low as -40 °C to produce substituted 4,5-dihydro-3H-azepines in 52-91% yield [115] (Scheme 66). Monitoring the reaction by NMR allowed various intermediates to be determined and the reaction course outlined in Scheme 66 to be established. This mechanism features the following points in the chemistry of Fischer carbene complexes (i) the reaction is initiated at -78 °C by nucleophilic 1,2-addition and (ii) the key step cyclisation is triggered by a [l,2]-W(CO)5 shift. 

The unconventional structure of fulvenes with a unique C=C bond conjugation leads to unusual cycloaddition reactions with other unsaturated systems. For example, alkenylcarbene complexes react with fulvenes leading to indanone or indene derivatives which can be considered as derived from a [6S+3C] cycloaddition process [118] (Scheme 72). The reaction pathway is well explained by an initial 1,2-addition of the fulvene to the carbene carbon followed by [1,2]-Cr(CO)5-promoted cyclisation. 

Oxazole formation can be envisaged as proceeding by three possible pathways 1,3-dipolar cycloaddition of a free ketocarbene to the nitiile (Path A), the formation and subsequent 1,5-cyclisation of a nitrile ylide (Path B) or the formation and subsequent rearrangement of a 2-acyl-2//-azirine (Path C) (Scheme 9). 

The pyrimidines 62 undergo cyclisation on refluxing in dioxane to yield not only the pyrazolopyrimidines 63, but the novel pyrazolo[3, 4 4,5]pyrido[2,3-rflpyrimidines 64 by an intramolecular 1,3-dipolar cycloaddition reaction (Scheme 9)<96JCS(P1)1999>. 

The formation of the c -annulated hexahydrothioxanthene (34) from thiophenol and hept-6-enals may also result from a [ +2] cycloaddition, although the minor stereoisomers probably arise from a cationic non-concerted cyclisation <96SL396>. 

An unusual [4+1] cycloaddition gold-catalysed reaction between propargyl tosylates 102 and imines 103 led to the formation of eyclopent-2-enimines 104 (Scheme 5.27) [27], A possible mechanism for this reaction involves a 1,2-migration of the tosylate that generates the 1,3-diene 105 followed by a Nazarov-hke cyclisation. 

The product 46 from the Rh(I)-catalysed [2+2+2] cycloaddition of the diynyl ether 44 to the substituted iodobenzene 45 undergoes a Pd-catalysed cyclisation to the fused chromans 47 <00TL3003>. 

Somewhat unusual examples, which illustrate the usefulness of cycloadditions in the synthesis of polycyclic compounds, are the controlled synthesis of an unsymmetrically substituted aromatic compound (131 from very simple commercially available compounds (Scheme 6.9), and the one-step thermal cyclisation of compound J6 to the aromatic steroid 14 (Scheme 6.10). 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

The furo[3,4-ri]oxazoie 54, constracted by cyclisation of a rhodium carbenoid, is a useful compound for the production of unusual benzoxazoles for example, cycloaddition of Al-phenylmaleimide gave the benzoxazole 55 <98JOC7680>. Simpler benzoxazole syntheses include the base catalysed cyclizsation (with loss of the trifluoromethyl anion) of the imines 56 <99TL4119> and the acid catalysed cyclisation of diacylated aminophenols 57 <99H(51)979>. ... 

Dienes, 11 addition to, 194-198 cisoid conformation, 197, 350 conjugated, 11 Cope rearrangement, 354 cyclisation, 346 cycloaddition to, 348 Diels-Alder reaction, 197, 349 excited state, 13 heat of hydrogenation, 16,194 isolated, 11 m.o.s of, 12 polymerisation, 323 Dienone intermediates, 356 Dienone/phenol rearrangement, 115 Dienophiles, 198, 350 Digonal hybridisation, 5 Dimedone, 202 Dimroth s Ej- parameter, 391 solvatochromic shifts, 391 solvent polarity, 391 Y and,392 Dinitrofluorobenzene proteins and, 172... 

Wittig reactions with pyrrole-2-aldehyde led to the esters (79) which were cyclisized to 3a-azaazulen-4-ones (80).104,105 4-Methylene-3a-aza-azulenes (81) have been obtained from 80 with stabilized phos-phoranes.36 Reaction of dimethyl acetylenedicarboxylate with 81 could not be achieved. A similar cycloaddition was successful in the synthesis of cycl[3,3,3]azines (2) (Section V). 

Polar Cycloadditions R. R. Schmidt, Angew. Chem., Int. Ed. Engl., 1973, 12, 212-224. Addition Reactions with Intramolecular Cyclisation V. I. Staninets and E. A. Shilov, Russ. Chem. Rev. (Engl. Transl.), 1971, 40, 272-283. 

The numerous methods which are available for the synthesis of substituted fi-lactams involve a variety of ring-forming strategies. Two categories only are selected and exemplified below to illustrate some of the interesting chemistry involved Cyclisation reactions and Cycloaddition reactions. 

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