Formation of Five-Membered Rings

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. 

Depending on the types of substituents and the precise reaction conditions (l,3-butadien-l-yl)carbene complexes can undergo direct cyclization to yield cyclo-pentadienes [337,350]. As mentioned in Section 2.2.5.1, cyclopentadiene formation occurs particularly easily with aminocarbene complexes [351]. Alternatively, in particular at higher reaction temperatures, CO-insertion can lead to the formation of a vinylketene complex, which, again depending on the electronic properties of the substituents and the reaction conditions, can cyclize to yield cyclobutenones, furans [91,352], cyclopentenones, furanones [91], or phenols (Dotz benzannulation) [207,251,353]. 

One possible mechanism is electrophilic attack of the complexed carbene carbon atom at the terminal carbon of the diene. The resulting zwitterionic intermediate can now eliminate the metallic group (CO)5M directly, or, alternatively, the metallic group can migrate to yield a new, more stable zwitterion (stabilization of the allyl cation by the heteroatom X). 

A further possible mechanism is the concerted electrocyclization of the metalla-1,3,5-triene to yield an intermediate metallacyclohexadiene [333]. Reductive elimination of (C0)5M would also lead to the formation of cyclopentadienes. 

instead of electrocyclization, electrophilic attack of the closer upper edge of the phenyl group by the carbene carbon atom occurs, a zwitterionic intermediate might result, which upon 1,4-elimination of (COljW would yield a 1-methoxy-1,3-cyclopentadiene. Suprafacial hydrogen migration would finally lead to the formation of the observed diastereomer. 

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This polymerization is carried out in the two stages indicated above precisely because of the insolubility and infusibility of the final product. The first-stage polyamide, structure [IX], is prepared in polar solvents and at relatively low temperatures, say, 70°C or less. The intermediate is then introduced to the intended application-for example, a coating or lamination-then the second-stage cyclization is carried out at temperatures in the range 150-300°C. Note the formation of five-membered rings in the formation of the polyimide, structure [X], and also that the proportion of acid to amine groups is 2 1 for reaction (5.II). 

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. 

Treatment of hexafluoroacetone with a P(lll) species results either in formation of five membered ring systems via reductive CC coupling of two molecules of hexafluoroacetone [275, 276 277, 278, 279 280, 281] (equation 60) or in reductive fluoride elimination [282] (equation 61)... 

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. 

With certain substituents, such as methoxy150 or (substituted) phenyl53 functions, in the allylie position the reaction outcome completely changes, giving rise to predominant or exclusive formation of five-membered ring products via a preceding 2-aza-Cope rearrangement of the initially formed A -acyliminium ion. These substituents clearly stabilize the intermediary carbo-cation 3. 

In the same way as arylcarbene complexes, alkenylcarbene complexes typically react with alkynes to provide [3C+2S+1C0] Dotz cycloadducts (see Chap. ccChromium-Templated Benzannulation Reactions , p. 123 in this book). However, some isolated examples involving the formation of five-membered rings through [3C+2S] cycloaddition processes have been reported [71]. In this context, de Meijere et al. found that /J-donor-substituted alkenylcarbene complexes react with alkynes to give cyclopentene derivatives [71a]. This topic is also discussed in detail in Chap.ccThe Multifaceted Chemistry of Variously Substituted a,/J-Unsaturated Fischer Metalcarbenes , p. 21 of this book. 

The most useful of the insertion processes is the intramolecular reactions that occur with high selectivity for the formation of five-membered ring products. The electrophilic nature of the process is suggested by C-H bond reactivity in competitive experiments (3°>20 >1°) [76, 77]. Asymmetric catalysis with Rh2(MPPIM)4 has been used to prepare a wide variety of lignans that include (-)-enterolactone (3) [8], as well as (R)-(-)-baclofen (2) [7],2-deoxyxylolactone (31) [80,81],and (S)-(+)-imperanane (32) [82].Enantioselectivities are 91-96%... 

Dipolar [3 + 2] cycloadditions are one of the most important reactions for the formation of five-membered rings [68]. The 1,3-dipolar cycloaddition reaction is frequently utihzed to obtain highly substituted pyrroHdines starting from imines and alkenes. Imines 98, obtained from a-amino esters and nitroalkenes 99, are mixed together in an open vessel microwave reactor to undergo 1,3-dipolar cycloaddition to produce highly substituted nitroprolines esters 101 (Scheme 35) [69]. Imines derived from a-aminoesters are thermally isomerized by microwave irradiation to azomethine yhdes 100,... 

The aldol reaction can be applied to dicarbonyl compounds in which the two groups are favorably disposed for intramolecular reaction. Kinetic studies on cyclization of 5-oxohexanal, 2,5-hexanedione, and 2,6-heptanedione indicate that formation of five-membered rings is thermodynamically somewhat more favorable than formation of six-membered rings, but that the latter is several thousand times faster.170 A catalytic amount of acid or base is frequently satisfactory for formation of five- and six-membered rings, but with more complex structures, the techniques required for directed aldol condensations are used. 

Scheme 2.10 illustrates intramolecular aldol condensations. Entries 1 and 2 are cases of formation of five-membered rings, with aldehyde groups serving as the electrophilic center. The regioselectivity in Entry 1 is due to the potential for dehydration of only one of the cyclic aldol adducts. 

Intramolecular insertion reactions show a strong preference for formation of five-membered rings.219 This was seen in a series of a-diazomethyl ketones of increasing chain length. With only one exception, all of the products were five-membered lactones.220 In the case of n = 3, the cyclization occurs in the side chain, again forming a five-membered ring. 

In a reaction similar to the (>-alkoxide elimination reactions seen with zir-conocenes, catalytic Rh(OH)(cod)2 and 2 eq. of arylboronic acids gave cyclic products 165 from enynes 166 (Scheme 35) [100]. In this reaction, transmet-allation of Rh - OR with B - Ph gave Rh - Ph species 167, which inserted into the alkyne, cyclized to 168, and finally underwent [>-alkoxidc elimination to provide Rh-OCH3. This reaction is limited to the formation of five-membered rings, but it can also undergo cascade type reactions of enediynes to give multicyclic products [100]. 

Formation of five-membered rings onto central pyridine core... 

Not only the formation of these insertion by-products but also the ring-formation described in Section Hf (see also Table 6) proved that the activation of the a C-H bond by a vicinal negative charge for the carbene insertion is more effective than the non-ionic as well as entropy-controlled formation of five-membered rings. 

Addition of excess /-butyl isocyanide, CO2, or CyNCO resulted in the formation of five-membered ring chelate compounds 107, the metal-bound imino acid 108, and the metal-bound imino amide 109, respectively, as shown in Scheme 47.170... 

Another possible termination step that has been utilized for the cycloetherification of alkynols involves CO insertion and esterification of the resulting acyl metal with an exogenous alcohol. This process has typically employed MeOH as solvent and a stoichiometric oxidant since the catalyst is turned over in a reduced form. Following this mechanistic motif, a variety of alkynols have been cyclized under Pd(n) catalysis to five- and six-membered oxacycles with incorporation of methyl esters into the products.294,327-329 For the formation of five-membered ring products, this reaction has been carried out in both exo- and endo-mode to provide 1- and 2-substituted... 

Vinyllithium cyclizations. The vinyl lithiums formed from trisylhydrazones (9, 486) can participate in intramolecular cyclizations. This anionic cyclization is presently limited to formation of five-membered rings. It has the advantage of greater stereoselectivity than a corresponding radical cyclization. 

All three cases involve the formation of six-membered rings, as would be expected, since the formation of five-membered rings is generally much more efficient in conformationally flexible systems. The imidazole reactions present no real problem since the reference reaction used in each case was the attack of... 

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... 

In fact, the formation of five-membered rings during the radical cyclisation has been used extensively in the past few years for the synthesis of several polyquinanes. 

Intramolecular carbene C-H insertion frequently leads to the formation of five-membered rings [967,990,1021,1113-1128], In particular l-diazo-2-alkanones tend to yield cyclopentanones exclusively when treated with rhodium(ll) carboxylates. The use of enantiomerically pure catalysts for diazodecomposition enables the preparation of non-racemic cyclopentane derivatives [1005,1052,1074,1092,1129]. Intramolecular 1,5-C-H insertion can efficiently compete with 1,2-C-H insertion... 

In addition to the [3-1-2] and [2-I-2-I-1] carbocycHzations that facilitate the formation of five-membered rings, the [4-t-l] carbocycHzation also has merit. Several transition metals have been engaged in this transformation [37], wherein it was found that vinylallene 63 a reacts with 1 equiv of WiUdnson catalyst to afford the planar (T2-bonded (vinylallene)rhodium complex 64a upon simple ligand displacement (Scheme 11.16). The stmcture of 64a was confirmed unambiguously by X-ray crystallography, and represents the first structural characterization of a metallacycle intermediate [38 a]. 

Iodine is a very good electrophile for effecting intramolecular nucleophilic addition to alkenes, as exemplified by the iodolactonization reaction.49 Reaction of iodine with carboxylic acids having carbon-carbon double bonds placed to permit intramolecular reaction results in formation of iodolactones.50 The reaction shows a preference for formation of five-membered rings over six-membered ones51 and is a strictly anti stereospecific addition when carried out under basic conditions. 

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