Cycloheptene 1-substituted

An early example of the use of a subcatalytic amoimt of sparteine for the activation of an organolithium nucleophile was reported by Lautens et al. in the carbometallation of a meso-unsaturated oxabicycle 25, with ring opening leading to the substituted cycloheptene derivative 26 (Scheme 4) [4]. Both yield and enantiomeric excess remained virtually unchanged when the ratio n-BuLi sparteine was lowered to 1 0.15. However, when a 3 mol% amount of the ligand 1 was used, a 20% decrease in enantioselectivity was observed. 

Using substituted a-methylene-(3-acetoxy ketones 2-494 with R = Me, Et, iPr, Ph and LiOtBu as base, the yields of the cycloheptene oxide 2-498 could be greatly enhanced to up to 77 %, as in the case of2-498b. In addition, cyclooctene oxides can be prepared (though in lower yield and stereoselectivity) starting from a six-membered oxosulfonium ylide. 

Brown s result was supported by later experiments in which bromonium ions were generated by bubbling gaseous hydrobromic acid through a solution of bromohydrins in halogenated solvents. Under these conditions, bromine is eliminated as it is formed, so that the resulting alkene is observed directly (Scheme 15). This method has been applied to the bromohydrins derived from cis- and trans-stilbenes (Scheme 16) and from 5//-dibenzo[a,d]-cycloheptene and -azepine systems ([29a] and [29b] respectively Scheme 17), in which steric constraints should favour elimination (path a) as against substitution (path b). 

Trost and Toste51 isolated unexpected cycloheptene 69 upon exposing enyne 68 to their optimized ruthenium-based Alder-ene conditions (Equation (42)). Further exploration into the effects of quaternary substitution at the propargylic carbon revealed the ability of ruthenium to catalyze a non-Alder-ene cycloisomerization to form seven-membered rings, presumably via allylic C-H activation (Scheme 15). 

With this revision in our original plans, both alkenes and allenes were found to undergo efficient cycloadditions to produce cyclooctenone products in a new [6+2] cycloaddition process. This novel cycloaddition has been shown to proceed efficiently with alkenes tethered with sulfonamide, ether, or geminal diester Hnkers (Tab. 13.15, see page 294). Isomerization of the olefin, a potential competing reaction in this process, is not observed. Methyl substitution of either alkene in the substrate is well tolerated, resulting in the facile construction of quaternary centers. Of mechanistic importance, in some cases cycloheptene byproducts were isolated from [6+2] cycloaddition reactions in addition to the expected cyclooctenone products (that is, entries 3 and 4). 

Since reactivity of alkenes increases with increasing alkyl substitution, hydration is best applied in the synthesis of tertiary alcohols. Of the isomeric alkenes, cis compounds are usually more reactive than the corresponding trans isomers, but strained cyclic isomeric olefins may exhibit opposite behavior. Thus, for example, frans-cyclooctene is hydrated 2500 times faster than cw-cyclooctene.6 Similar large reactivity differences were observed in the addition of alcohols to strained trans cycloalkenes compared with the cis isomers. frans-Cycloheptene, an extremely unstable compound, for instance, reacts with methanol 109 faster at —78°C than does the cis compound.7... 

The nature of the oxidation products is traceable to the nature of the rhodium-alkene interaction. Terminal alkenes and internal ones (e.g. cycloheptene), which form 77-complexes of rhodium(I), e.g. [RhCl(alkene)2]2, are selectively converted into methyl ketones, whereas alkenes which form 7r-allylic complexes of rhodium(III) (e.g. cyclopen-tene) give alkenyl ethers via oxidative substitution of the alkene by the solvent alcohol.204... 

We know of no experimental measurements for the enthalpy-of-formation difference of (Z)- and ( )-cycloheptene or cyclohexene. Admitting for now the 1-phenyl derivative, the (Z)-/(E)-differences are 56, 121 and 197 kJ mol-1 for the substituted cyclooctene, cycloheptene and cyclohexene. [These results derived from photoacoustic calorimetric measurements were reported... 

The complex 8W (R = Me) can also be used in a stoichiometric metathesis sequence to effect the ring closure of unsaturated ketones so as to form 1-substituted cyclopentenes, cyclohexenes and cycloheptenes in good yield, e.g. equation 24. The C=C bond reacts first to give [W]=CH(CH2)3C0(CH2)0(CH2)3Ph, which then undergoes an internal carbonyl-olefination reaction13. 

C-H activation pathway cannot be ruled out for this transformation, however. They subsequently observed C-H insertion of a cis substituent by means of isotope studies [32], The cycloheptene product was observed as the major product when cis- or tri-substituted enyne and acetylenic ester termini were present. Ruthenium hydride catalysts reported by Mori and Dixneuf can also initiate the cycloisomerization of 1,5- and 1,6-enynes and dienes [33, 34], The vinylruthenium hydride can be obtained from RuClH(CO)(PPh3)3 or in the presence of acetic acid or ethanol. 

The chemically and radiochemically pure NCA 5-[18F]fluoromethyl- and 5-/ -[18F]fluo-roethyl-10,ll-dihydro-5/7-dibenzo[tf, d]cyclohepten-5, 10-imines 151 and 152 have been prepared for i.v. injection from [18F]fluoride by nucleophilic substitution at the cyclic sulphamates 153 and 154 (equation 96). The labelled products 151 and 152 have been evaluated for receptor binding in animals and in man189. MK801, 155, readily crosses the BBB in mammals and binds to a high affinity site on the TV-methyl-D-aspartate receptor190. 

Blechert and co-workers have also explored the use of cycloheptenes in RRM in processes where the thermodynamic driving force is the final RCM (Scheme 6). In one example of this novel process, ROM-RCM-RCM of 7 leads to an excellent yield of the substituted tetrahydrooxepin 8 <02T7503>. This strategy also featured significantly in the preparation of (+)-dihydrocuscohygrine 9 <02JOC6456>. The more common sequential reactions of strained cyclic alkenes have been reviewed <03EJO611>. 

These results can be explained in terms of an interplay of stereoelectronic and steric factors. Steric factors are evidently more important in the reaction of bulky cuprate clusters than in the Sakurai reaction. Thus stereoelectronic factors predominate in the allylsilane reaction. Similar effects are observed in conjugate additions to substituted cyclohepten-ones. 

The rate of alkene oxidation depends on the substitution pattern of the alkene. For a series of alkenes oxidized in aqueous solution, with benzoquinone as oxidant for the PdCl2, the relative rates are ethene (850) > propene(450) > 1-butene (380) > tra i-2-pentene (90) > cfr-2-pentene (80) > cyclohexene (8) > cycloheptene (1). Thus, selective oxidation of terminal alkenes to methyl ketones can occur in the presence of internal alkenes (equation 84). 

While this methodology could be extended to more-substituted cyclooctene oxides (Scheme 56, Equation 12), examination of cycloheptene oxide (Scheme 56, Equation 13) revealed the need for considerably longer reaction times, leading to reduced yields due to competing carbenoid-insertion pathways (cycloheptanone formation and reductive alkylation) <2002AGE2376, 2003OBC4293>. 

The equilibrium constants for a series of cycloalkenes decrease in the order norbomene > c -cyclooc-tene > cyclopentene > cycloheptene > cyclohexene, which correlates with the calculated strain energies as well as the kinetically determined relative adsorption constants on Pt (Table 2). Tolman states that electron donation from a filled metal rf-orbital to an empty alkene Tr -orbital is extremely important in determining the stability of these complexes. Steric effects of substituents are relatively unimportant compared to electronic effects, and resonance is more important than inductive interactions. The ability of the metal to back bond is lowered progressively in the series Ni° > Pt° > Rh > Pt" > Ag which reduces the importance of resonance and decreases the selectivity of the metal for different substituted alkenes. 

A dramatic reverse in selectivity was observed for 2-substituted cyclohexene oxide by simply changing the t-butyl group to a TMS or trimethylgermyl group,as depicted in equation (8). Regiocontrol by the TMS group is further demonstrated in the corresponding cyclopentene and cycloheptene oxides. ... 

The conformation of cycloheptene oxide has been examined via the C nmr spectra of deuterated compounds on the basis of the temperature-dependence of the chemical shifts of the individual signals. In phenyl-substituted oxiranes, the C shifts have revealed the inductive and hyperconjugative effects of the oxirane ring, and thus the ring behaves as an electron-acceptor. " ... 

A similar reaction carried out with cyclohexene led to the formation of 3-methoxycyclohexene When this reaction sequence is carried out with internal olefins, the methoxyalkyl phenyl tellurium oxides are not stable and decompose to methoxyalkenes in the basic medium required for the hydrolysis of the methoxyalkyl phenyl tellurium dibromides(see p. 583). Aqueous solutions of sodium hydrogen carbonate cause the same transformations at a slower rate". Thus, 5-hydroxy and 5-methoxy-4-hexyl phenyl tellurium dibromide were converted to the corresponding 5-substituted 3-hexenes. 3-Hydroxy- and 3-methoxy-l-cycloheptene were similarly obtained. ... 

As you now know (p. 1134) aU esters and lartones prefer to be in the conformation shown for the first compound so that they can enjoy stabilization by the anomeric effect. The second ester would also prefer o be like this too (first diagram below) but in this conformation it cannot cyclize at all. Even in the less favourable conformation it uses for reaction, it prefers conjugate to dirert substitution as the latter would give a strained truns-cycloheptene. The first compound can enjoy both the anomeric effert and conjugate addition as a frans-alkene in a ten-membered ring is fine. It is better than fine in the heterocyclic product as the lactone also enjoys the anomeric effect... 

The scope of the lanthanide-mediated, intramolecular amination/cyclization reaction has been determined for the formation of substituted quinolizidines, indolizidines, and pyrrolizidines,1046 as well as tricyclic and tetracyclic aromatic nitrogen heterocycles.1047 The amide derivative OT ro-[ethylene-bis(indenyl)]ytterbium(m) bis(trimethyl-silyl)amide catalyzes the hydroamination of primary olefins in excellent yields.701 A facile intramolecular hydroamination process catalyzed by [(C5H4SiMe3)2Nd(/r-Me)]2 has also been reported. The lanthanide-catalyzed hydroamination enables a rapid access to 10,1 l-dihydro-5//-dibenzo[tf,rf]cyclohepten-5,10-imines (Scheme 283).1048... 

Treatment of bicyclo[4.1.0]heptan-2-ols with perchloric acid in acetic acid caused very clean rearrangement with formation of cyclohept-3-enyl acetates (Table 1). Only in the case of cxo-7-methylbicyclo[4.1.0]heptan-2-ol was the cyclohex-2-enyl acetate the major product probably because the 7-methyl group conferred additional stabilization on the carbocation formed by j0-scission of the outer cyclopropane bond. The same type of reactant could be oxidatively rearranged using pyridinium chlorochromate to afford cyclohepten-4-ones, together with (chloromethyl)cyclohexenes. However, if the chloride in the reagent was replaced with tetrafluoroborate, or if pyridinium chlorochromate was used with silver(I) nitrate, formation of the substituted cyclohexenes was completely suppressed, e.g. formation of 7 from 6, although the reported yields were low. ... 

Use of the chiral pool typically requires a series of subsequent transformations to achieve the substitution pattern desired and sometimes may be limited by the availability of only one enantiomer. Microbial oxidations of benzene derivatives have provided an excellent route to cyclohexadienediols in enantiomerically pure form. Although this provides only one enantiomer, synthetic methods have been devised to circumvent this problem [36]. Far fewer methods exist for the enantioselective synthesis of cycloheptenes for which there exists no reaction analagous to the Diels-Alder process [37,38,39,40,41,42]. The enantioselective hydroalumination route to dihydronapthalenols may prove to be particularly important. Only one other method has been reported for the enantioselective synthesis of these compounds microbial oxidation of dihydronaphthalene by P. putida generates the dihydronaphthalenol in >95% ee and 60% yield... 

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