Carbocycles six-membered

Intramolecular condensation reactions to generate six-membered carbocycles are mentioned in section 1.12, the polyene cyclization in section 1.15. 

Since an annulated six-membered carbocycle is a common structural element of natural products, the Robinson annulation is an important reaction in organic synthesis. 

Generally, oxepins have a tendency to contract to a six-membered carbocycle when treated with acid. The driving force is the aromaticity of the phenol formed. However, when the less stable cyclohexa-2,5-diene-1,4-diol with an appropriate substitution pattern is treated with acid, the oxepin system is obtained. The treatment of cyclohexadienediols that are substituted with tert-butyl groups in the 2- and 6-positions and aryl at Cl and C4 with trifluoroacetic acid produces oxepins 1 with elimination of water.186 187 This reaction, however, is restricted to certain aryl substituents with at least some electron-donating effect. Generally, cyclohexa-2,4-dienone derivatives 2 are formed.187,188... 

Michael addition has been shown to lead to useful building blocks. According to a publication by Johnson and coworkers, highly functionalized unsymmetrical malonic acid derivatives are accessible in this way [268]. Moreover, as described by Takeda and coworkers, substituted four- to six-membered carbocycles 2-507 can be prepared starting from 2-504 by reaction with PhLi via the intermediates 2-505 and 2-506 (Scheme 2.115) [269]. 

The tandem-Knoevenagel-ene reaction is a powerful tool to synthesize five-and six-membered carbocycles.2 5 The process is exemplified by the diastereoselective synthesis of 4a. Compound 4a has been obtained In both enantiomeric forms and as a racemate according to the procedure described here. The sequence includes the Knoevenagel reaction of citronellal, 1, and dimethyl malonate, 2, followed by the intramolecular ene cyclization of the chiral 1,7-diene 3 to yield the trans 1,2-disubstituted products 4a and 4b. Whereas the thermal cyclization of 3 at 160°C provides 4a and 4 b in a ratio of only 89.7 10.3, the Lewis acid... 

The Diels-Alder reaction is a useful way of synthesizing six-membered carbocyclic rings. Since ADC compounds are usually better dienophiles than the corresponding C=C compounds, the Diels-Alder reaction provides a good general route to pyridazines, and their reduced derivatives. Although vast numbers of examples of Diels-Alder reaction involving ADC compounds have been reported, not many of these have been aimed specifically at heterocyclic synthesis. 

This alkylation reaction can be applied to intramolecular alkylation affording cyclic products, as shown in Equations (19)-(21). The reaction of 2-vinylpyridines with 1,5- or 1,6-dienes results in the formation of five- or six-membered carbocycles with good efficiency.20,20a,20b In addition to pyridine functionality, oxozole and imidazole rings can be applied to this intramolecular cyclization. When the reaction is conducted in the presence of a monodentate chiral ferrocenylphosphine and [RhCl(coe)2]2, enantiomerically enriched carbocycles are obtained. A similar type of intramolecular cyclization is applied to TV-heterocycles. The microwave irradiation strongly... 

Intramolecular arylation of G-H bonds gives cyclic aromatic compounds. In this intramolecular arylation, the carbon-palladium cr-bond is first formed by the oxidative addition of Pd(0) species and then the resulting electrophilic Pd(n) species undergoes the intramolecular G-H bond activation leading to the formation of the palladacycle, which finally affords the cyclic aromatic compounds via reductive elimination.87 For example, the fluoroanthene derivative is formed by the palladium-catalyzed reaction of the binaphthyl triflate, as shown in Scheme 8.88 This type of intramolecular arylation is applied to the construction of five- and six-membered carbocyclic and heterocyclic systems.89 89 89 ... 

A variety of six-membered carbocycles and heterocycles were synthesized by Shibata et al.81 using Wilkinson s catalyst (Equation (79)). The proposed catalytic cycle (Scheme 24) rationalizes the exclusive formation of the (Z)-isomer. Additionally, the mechanism is supported by the results of a isotope-labeling study reported by Brummond... 

Five-membered carbocycles are the most easily formed [45, 107, 196, 200, 202,203]. Five-membered carbocyclic rings can be formed (with 2% MoF6 as the catalyst) even when the double bond is tetrasubstituted (Eq. 24) [200]. The stability of the catalyst toward the free OH group in this case is noteworthy. Evidently this particular t-butoxide-like alcohol does not react with this particular catalyst for steric reasons. Six-membered carbocyclic rings are also formed readily (Eq. 25) [200], as are seven-membered rings, especially if one takes advantage of a Thorpe-Ingold effect (e.g., Eq. 26) [20] or a similar conformational predisposition for the double bonds to remain near one another. 

Another interesting example of a photochemi-cally induced domino process is the combination of the photocyclization of aryl vinyl sulfides with an intramolecular addition as described by Dittami et al. [901 as intermediate a thiocarbonyl ylide can be assumed. The domino-Norrish I-Knoevenagel-allyl-silane cyclization developed by us allows the efficient stereoselective formation of 1,2-trans-subsituted five- and six-membered carbocycles.1911 A photochemical cycloaddition of enamino-aldehydes and enamino-ketones with the intermediate formation of an iminium salt followed by addition to allylsilanes gives access to novel bicyclic heterocy-des. New examples of photochemically induced... 

The reaction of allenylsilanes with a,/8-unsaturated acylsilanes presents a new [3 + 3]-cycloaddition approach to a six-membered carbocycle [189]. Lewis acid-promoted ring expansion of the [3 + 2]-annulation product 260 is followed by a second cationic 1,2-silyl migration to produce the cyclohexenone 261 after desilylation. 

C NMR spectroscopy of 1,7-dioxa- (314), l-oxa-7-thia- (315), and 1,7-dithiaspiro[5.5]undecane (316) and many of their derivatives, with special emphasis on stereoelectronic and steric effects governing the configurational and conformational properties of these compounds (484-486). This work showed that chemical-shift parameters developed for six-membered carbocyclic compounds in chair conformations (149) could be applied successfully only to sulfur and not to oxygen heterocycles (486). 

Another isomerization reaction of arene oxides is equilibrium with oxe-pins [5], Here, the fused six-membered carbocycle and three-membered oxirane merge to form a seven-membered heterocycle, as shown in Fig. 10.2. An extensive computational and experimental study involving 75 epoxides of monocyclic, bicyclic, and polycyclic aromatic hydrocarbons has revealed much information on the structural factors that influence the reaction rate and position of equilibrium [11], Thus, some compounds were stable as oxepins (e.g., naphthalene 2,3-oxide), while others exhibited a balanced equilibrium... 

An important exception to this regularity is the cyclization of aromatic alkoxides containing aromatic radical moieties. In these cases, C-0 bond formation is not observed, but C-C bond formation is achieved instead. As Galli and Gentili (1998) pointed out, this is primarily due to the unfavorable thermodynamic driving force for C-0 bond formation compared to C-C bond formation. Thus, the photostimulated reaction depicted in Scheme 7.39 results in the formation of a six-membered carbocycle rather than an octa-membered oxa-heterocycle. The carbocycle is formed in 75% yield (Barolo et al. 2006). This product is a precursor to the thalicmidine biomolecule of the alkaloid group. 

The intramolecular version of the described radical reaction provides an easy approach to the synthesis of six-membered carbocycles. ... 

The preparation of compounds with a six-membered heterocycle fused to a six-membered carbocyclic ring is one of the most researched areas in organic chemistry. However, there are few examples for the construction of the carbocyclic ring. There are several review articles in this area <1984CHEC(2)395, 1984CHEC(3)599, 1996CHEC-II(7)921>. 

In Delfourne and co-workers study toward the total synthesis of meridine, the Meldrum s acid derivative 91 was prepared. After several unsuccessful attempts to cyclize this material to the desired tricyclic compound 92, it was found that conversion into the quinone 93 was necessary for cyclization to occur (Scheme 4) <1997T1743>. Another approach to compounds with a central six-membered carbocyclic ring using Meldrum s acid derivatives has been... 

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. 

However, if a tetrasubstituted pyrylium ion possessed one or two condensed six-membered carbocyclic rings, then only 4//-pyrans 191, 192, 27, and 193 are isolable (35 to 92%) after reaction with PhCH2MgCl236 or with other Grignard reagents RMgX.210... 

The next two chapters demonstrate the power of anionic, free-radical and electron-transfer processes in the systematic construction of highly functionalized five- and six-membered carbocycles. 

SYNTHESIS OF BENZOTHIOPHENES BY FUSION OF SIX-MEMBERED CARBOCYCLIC RINGS TO THIOPHENES... 

The formation of 5-hexenal (reaction 18) is believed to be an intramolecular rearrangement since the addition of oxygen does not cause its suppression. At least in a methyl substituted cyclohexanone the analogous process has been shown to occur by the transfer of a hydrogen atom from the beta position to the carbonyl group before the fission of the six-membered carbocyclic ring (29) as only one of the two possible isomeric heptenals is formed. 

The Baeyer-Villiger oxidation remains the main route to oxepines from six-membered carbocycles. After publication of CHEC-II(1996), some new oxidative procedures are published. 

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