Formation of Carbocycles

Other methods that rely on the use of the carbohydrate template to construct fused carbocycles have been successfully investigated as strategies for the formation of carbocycles from sugars. Chirality transfer from the sugar to the new carbocycle is observed for these reactions. These annulation reactions are the subject of the second part of this section. 

Organisch-Chemisches Institut, Westfdlische Wilhelms-Universitdt Munster, Corrensstrafie 40, D-48149 Munster, Germany 

In a narrower sense, this review covers intramolecular Mizoroki-Heck [1] reactions forming carbocycles [2] that is, the palladium-catalyzed intramolecular coupling of vinyl/aryl (pseudo-)halides with an alkene tethered by a hydrocarbon chain. Ring closures furnishing heterocycles are covered in Chapter 6 also beyond the scope of this chapter are the domino/cascade or tandem (Chapter 8) and asymmetric processes (Chapters 12 and 16) dealing with formation of a carbocycle. 

Cyclopropanes and cyclobutanes were only accessible via xo-type cyclizations, the former only within domino/cascade reactions (see Chapter 8) and the latter being realized by Erase [5a] in desymmetrizing Mizoroki-Heck cyclizations (see Chapter 13) and by Mulzer et al. [5b] five-membered and larger rings are formed in both modes. 

For the common ring sizes (n = 5-7), the selected representative examples are subdivided into sections according to the specific (formal) cyclization mode those leading to larger cycles are summarized in a single paragraph. 

The Mizoroki-Heck Reaction Edited by Martin Oestreich 2009 John Wiley Sons, Ltd. ISBN 978-0-470-03394-4 

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It was also of interest to apply such lOOC reactions to formation of carbocyclic rings. Oxime olefins 230 a-e, formed in good yield via reaction of 229 with 0-silyl-a-bromoaldoximes 228 in the presence of F ions, cyclized in a sealed tube at 190 °C to provide 231 a-e (Eq. 24, Table 22) [63]. Reduction of 231a provided amino alcohol 232 a in 68% yield. Amino alcohol 232 e was converted stereo-specifically to the fused -lactam 233. 

As demonstrated by Hoffmann and coworkers, hydroformylation can also be combined with an allylboration and a second hydroformylation, which allows the formation of carbocycles and also heterocycles [213]. A good regioselectivity in favor of the linear aldehyde was obtained by use of the biphephos ligand [214]. Reaction of the allylboronate 6/2-76 having an B-configuration with CO/H2 in the presence of catalytic amounts of Rh(CO)2(acac) and biphephos led to the lactol 6/2-80 via 6/2-77-79 (Scheme 6/2.17). In a separate operation, 6/2-80 was oxidized to give the lactone 6/2-81 using tetrabutyl ammonium perruthenate/N-methylmorpholine N-oxide. 

In a similar way as described for the hydroformylation, the rhodium-catalyzed silaformylation can also be used in a domino process. The elementary step is the formation of an alkenyl-rhodium species by insertion of an alkyne into a Rh-Si bond (silylrhodation), which provides the trigger for a carbocyclization, followed by an insertion of CO. Thus, when Matsuda and coworkers [216] treated a solution of the 1,6-enyne 6/2-87 in benzene with the dimethylphenylsilane under CO pressure (36 kg cm"2) in the presence of catalytic amounts of Rh4(CO)12, the cyclopentane derivative 6/2-88 was obtained in 85 % yield. The procedure is not restricted to the formation of carbocycles rather, heterocycles can also be synthesized using 1,6-enynes as 6/2-89 and 6/2-90 with a heteroatom in the tether (Scheme 6/2.19). Interestingly, 6/2-91 did not lead to the domino product neither could 1,7-enynes be used as substrates, while the Thorpe-Ingold effect (geminal substitution) seems important in achieving good yields. 

Yu and co-workers have expanded upon Ojima s work through development of an effective Rh-catalyzed protocol for the cyclization/hydrosilylation of allenyl carbonyl compounds to form silylated vinylcycloalkanols and heterocyclic alcohols.For example, reaction of tosylamide 44 (X = NTs, R = H, n= ) and triethylsilane catalyzed by Rh(acac)(GO)2 (1 mol%) under GO (10 atm) at 70 °G for 8h gave the silylated vinyl pyrrolidinol 45 (X = NTs, R = H, n= ) in 74% yield with exclusive formation of the m-diastereomer (Equation (29)). The rhodium-catalyzed reaction was also effective for the cyclization of alleneones and for the formation of carbocycles, oxygen heterocycles, and six-membered cyclic alcohols (Equation (29)). However, Rh-catalyzed cyclization/hydrosilylation of allenyl carbonyl compounds that possessed substitution on an allenyl carbon atom was not established (Equation (29)). The efficiency of the Rh-catalyzed reaction of allenyl carbonyl compounds depended strongly on GO pressure. Reactions run under 10 atm GO were more efficient than were... 

In the majority of dehydration reactions, heterocyclic compounds are formed, rather than carbocyclic compounds. Many possibilities for formation of carbocyclic compounds exist, but these are important only if (a) the heterocyclic or acyclic tautomers cannot undergo further elimination reactions, or (b) the conditions of reaction greatly favor the formation of an acyclic tautomer capable of affording only the carbocyclic compound. Both five- and six-membered carbocyclic compounds have been isolated, with reductic acid being the compound most frequently reported. Ring closure occurs by an inter-molecular, aldol reaction that involves the carbonyl group and an enolic structure. Many examples of these aldol reactions that lead to formation of carbocyclic rings have been studied.47 As both elimination and addition of a proton are involved, the reaction occurs in both acidic and basic solutions. As examples of the facility of this reaction, pyruvic acid condenses spontaneously to a dibasic acid at room temperature in dilute solution, and such 8-diketones as 29 readily cyclize to form cyclohexenones, presumably by way of 30, either in acid or base. 

The absence of a hydroxyl group from C-2 makes elimination of the 4-hydroxyl group impossible, but two other reactions are possible for 57. The more important is, apparently, the formation, between C-l and C-4, of a 2,5-dihydrofuran ring that is readily dehydrated to the furan. A competitive reaction, namely, the elimination of the 5-hydroxyl group by an extended enolization, would lead to formation of carbocyclic compounds. 

Obviously, a similar mechanism can be presented for the formation of carbocyclic compounds from the hexoses, but less is known about the products and the variation in their distribution within the group. Most of the work with the hexoses has been conducted with D-glucose and D-fructose. It is known that D-mannose and D-galactose give significantly lower yields of 5-(hydroxymethyl)-2-furaldehyde than either D-glucose or D-fructose when treated in concentrated sulfuric acid,52 but no homolog of 75 has been reported. 

In alloys with 0-23% Cu the activation energy of the total conversion of n-hexane is only marginally influenced and the observed effects are consequently connected with the preexponential factors. Since the selectivity of nickel diluted with copper is near the value found by Anderson et al. (113) for highly dispersed films, considering a common cause is suggested (60). Anderson assumes that with a large fraction of surface atoms in very small crystals the isolated corner atoms favor the formation of carbocyclic intermediates of isomerization, whereas hydrogenolysis requires two or more adjacent platinum atoms in a crystal plane. 

Further examples of the formation of carbocyclic and carbopolycyclic compounds from (Z)-vinyl iodides with triethylamine as base have been reported and as noted in the related bromide reactions, double-bond isomerization is commonly observed.92... 

Steric protection by the bulky 2,4,6-tri-f-butylphenyl (TTBP) group of the selenium atom in the episelenonium ion intermediate (17), generated in situ from (16), has been utilized in the selective formation of carbocyclic compounds (17)—>(19)—>(20) and (21)—>(22). The selenophilic attack (17)—>(18), leading to isomerization, can thus be avoided (Scheme 8).33... 

The reaction products of the treatment of a, 3-unsaturated ketones with malononitrile in most cases are the expected derivatives of 2-amino-3-cyanopyridine. But an alternate direction with the formation of carbocyclic compounds 120 was described [128]. It is clear from structure 120 that two molecules of unsaturated ketone 5 and 1 equiv of malononitrile 107 are involved in the reaction (Scheme 3.37). 

Stereoselective formation of carbocycles has been carried out through [RhCl(cod)]2 (cod = cyclooctadiene) catalyzed reaction of alkenylzirconocene chloride to co-carbonyl carboxymide <07TL6471>. When the camphor sultam auxiliary is incorporated into amide 206, the Rh(I)-catalyzed reaction of alkenylzirconocene chloride 207 forms the cyclization product 211 with high diastereoselectivity. The tt-facial differentiation of the double bond in 206 for the initial attack of vinyl group can be explained by taking into consideration either of the reactive conformers A or B. No matter which reactive conformer is involved, the attack of the vinyl group to the less crowded C p si-face would account for the observed chirality. 

Selenium reagents can be used to fonn carbocycles. A good example of the formation of carbocycles is the elegant synthesis of hirsutene (equation 31). The key step involves the attack of an enol on a selenitanium ion. This type of carbocyclization proceeds very nicely and in high yield."... 

Of special interest is the use of protected cyanohydrins in the formation of carbocyclic rings. Ring closure of an acyclic intermediate to form a five-membered ring (75-85%) has been Ascribed in the synthesis of prostaglandins (equation 17). In addition this method is applicable to the formation of cyclopropyl, cyclobutyl and cyclohexyl rings (60-70%). ... 

Retrosynthetic analysis of six-membered ringformation almost always boils down to a Diels-Alder reaction176) or a Robinson annelation 177) (or variations thereof) as the crucial C—C bond forming step. Both methods have in common that more than one carbon—carbon bond is formed in a one pot reaction which allows a rapid and efficient construction of complex organic molecules from rather simple building blocks. No such general tool exists for the formation of carbocyclic five-membered rings. 

Copper complexes of the bisoxazoline ligands have been shown to be excellent asymmetric catalysts not only for the formation of carbocyclic systems, but also for the hetero-Diels-Alder reaction. Chelation of the two carbonyl groups of a 1,2-dicarbonyl compound to the metal atom of the catalyst sets up the substrate for cycloaddition with a diene. Thus, the activated diene 20 reacts with methyl pyruvate in the presence of only 0.05 mol% of the catalyst 66 to give the adduct 138 with very high enantiomeric excess (3.99). 

Azulenes are basic compounds (see Section 4.1.1). The formation of carbocyclic azulenium cations in the presence of strong adds is a transformation to tropylium salts that is accompanied by a large hypsochromic shift and the color changes to yellow (55FCF(3)334, p. 380 66CZ691). Azulenes fused to heterocyclic nitrogen bases, which are primarily N-protonated, do not behave uniformly. 

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