Cyclohexyl systems

Nucleophilic substitution in cyclohexyl systems is quite slow and is often accompanied by extensive elimination. The stereochemistry of substitution has been determined with the use of a deuterium-labeled substrate (entry 6). In the example shown, the substitution process occurs with complete inversion of configuration. By NMR amdysis, it can be determined that there is about 15% of rearrangement by hydride shift accon any-ing solvolysis in acetic acid. This increases to 35% in formic acid and 75% in trifiuoroacetic acid. The extent of rearrangement increases with decreasing solvent... 

Cyclohexyl systems have a very strong preference for anti elimination via conforma-... 

The amino functional group is not commonly encountered in steroid synthesis except perhaps in steroidal alkaloids. However, certain elimination reactions have been shown to have theoretical and limited preparative importance, largely due to the efforts of McKenna and co-workers. The Hofmann rule for 2 elimination predicts that alkaline elimination of quaternary ammonium salts will occur towards the carbon carrying the most hydrogen atoms cf. the converse Saytzeff orientation, above). In cyclohexyl systems, the requirement for diaxial elimination appears to be important, as in other 2 eliminations, and the Hofmann rule frequently is not obeyed [e.g., (116) (117)]. 

However, the E2C mechanism has been criticized, and it has been contended that all the experimental results can be explained by the normal E2 mechanism. McLennan suggested that the transition state is that shown as 18. An ion-pair mechanism has also been proposed. Although the actual mechanisms involved may be a matter of controversy, there is no doubt that a class of elimination reactions exists that is characterized by second-order attack by weak bases. " These reactions also have the following general characteristics (1) they are favored by good leaving groups (2) they are favored by polar aprotic solvents (3) the reactivity order is tertiary > secondary > primary, the opposite of the normal E2 order (p. 1319) (4) the elimination is always anti (syn elimination is not found), but in cyclohexyl systems, a diequatorial anti elimination is about as favorable as a diaxial anti elimination (unlike the normal E2 reaction, p. 1302) (5) they follow Zaitsev s rule (see below), where this does not conflict with the requirement for anti elimination. 

The marked ANTI stereoselectivity observed with cyclohexyl systems (see above) reflects the ability to achieve, and the very marked preference to eliminate from, the so-called trans-diaxial conformation (34) ... 

The reaction fails if the proton to be removed is sterically hindered - either tertiary as in 21 or neopentyl-like as in 2263). In six membered rings, the ds, syn hydrogen must be axial for elimination. In the parent cyclohexyl system 23, a mixture of 24 and 25 results29) whereas, in a eonformationally rigid cyclohexane... 

This result has been explained72 390 by the particular instability of the alkene complex resulting from exocyclic addition (14) relative to endocyclic addition (15) in the cyclohexyl system. This rationale is supported by the results obtained by the use of the considerably more sterically bulky tri-o-tolylphos-phine instead of triphenylphosphine. A 13 83 exocyclic endocyclic ratio is obtained with the bulky phosphine. This result is nicely explained by the ability of the bulky phosphine to magnify the instability of the endocyclic alkene-palladium complex (14) relative to the exocyclic alkene complex (15) and favor endocyclic addition. 

Lambert and coworkers41 studied the solvolysis reactions of the two cyclohexyl systems 10 and 11. 

Kresge and Tobin48 also studied the hydrolysis of vinyl ethers and found a rate ratio of 130 between methyl vinyl ether and ethyl cA-trimethylsilylvinyl ether, corresponding to a stabilization of the /J-silyl carbocation of 2.9 kcal mol-1. In this case the small rate acceleration (compared to the cyclohexyl systems studied by Lambert) can be attributed to the unfavourable dihedral angle. The dihedral angle in the vinyl ether is 90° (24), and on protonation it drops to 60° (25), whereas maximum hyperconjugative interaction requires a dihedral angle of 0°. 

However, the -effects in the aliphatic systems are still much smaller than the 1012 rate acceleration observed in the cyclohexyl system. As mentioned earlier, this is due to the unfavourable dihedral angle 9 in the alkene protonations and the angle

[Pg.370]

In germanium chemistry the importance of free radical pathways in substitution reactions of secondary bromides with R3GeLi (R = CH3, CgHs) reagents is strongly indicated by product stereochemistry in cyclohexyl systems and by cyclization of the cA-heptene-2-yl moiety to yield [(2-methylcyclopentenyl)methyl]germanes, with the appropriate cis/trans ratio, as shown in equation 180, Table 9 and equations 181 and 182189. 

A moderately stereoselective vinyllithium cyclisation has been used to make laurene 349 from a vinyl bromide 347.165 The transition state 348 leading to the major isomer has a pseudo-axial tolyl group and a pseudo-equatorial methyl - in accordance with precedent for similar cyclohexyl systems. 

On the other hand, in penta- and hexa(spirotetrahydrofuranyl)cyclohexyl systems the chair conformation of the central cyclohexane ring is still preserved (96JA4504). The boat conformation of the cyclohexane ring can be stabilized also by careful substitution. A series of hopanoid hydrocarbons, the D cyclohexane ring prefers the boat conformation by 1.3-2.5 kcal/mol (95JA6532). 

Systematic investigations of the stereochemical outcomes of reductions of cyclic oximes and their derivatives have been sparse the available information suggests that results sometimes parallel those obtained in other imine reductions (Sections 1.2.2.2.3, 1.2.2.3.3 and 1.2.2.4.2), but differences are also noted. A collection of examples in which the stereochemistry was determined is presented in Table 15. Thus, with cyclohexyl systems enhanced equatorial attack (compared to ketones) leading to axial amines... 

Most E2 elimination reactions of cyclohexyl systems proceed through an anti conformation except when the synperiplanar arrangement is readily attainable. For example, with cyclopentane derivatives and the rigid bicyclo[2.2.1]heptanes and bicyclo[2.2.2]octanes, where the H and X can adopt a synperiplanar arrangement, syn eliminations are observed. 

In cyclic systems, the extent of anti and syn elimination depends on ring size. Cyclohexyl systems have a very strong preference for anti elimination. See [62, 63]. 

Intramolecular imino ene reaction of an allenylsilane has recently been found to generate cyclohexyl systems with adjacent cis-amino and -alkynyl moieties. This enantioselective ene cyclization was developed for the enantio-selective total syntheses of (—)-montanine (338), (-)-coccinine (351), (-)-pancracine (339), and (-)-brunsvigine (356) (a formal total synthesis) by the same research group (181) (Schemes 40 and 41). A precursor allenylsilane-aldehyde 370 for the enantioselective ene cyclization was synthesized from scalemic epoxy alcohol 369 in nine steps. The allenylsilane-aldehyde 370 thus obtained reacted with A -triphenylphosphinyl-(2-bromo-4,5-methy-lenedioxy)phenylmethylimine in boiling mesitylene to lead to a cyclized product 371 in 63% yield after protodesilylation. Hydrogenation of 371... 

The A values for imidazole and imidazolium in cyclohexyl systems, measured directly, are both 9.2 0.4 kJmol but measurement of the difference in Aia directly indicates that the imidazolium A... 

Three-center SN2 displacement and anti-eliminations from unsaturates are obvious examples of the coplanarity principle. DePuy et al. (1965) noted that when anti eliminations cannot have coplanar reacting centers the syn coplanar-transition state may become more favorable. Syn bimolecular eliminations had been noted in various systems previously, e.g. haloethenes (Miller, 1961), but these were generally slower than anti eliminations. There were, however, syn bimolecular eliminations whose rates approached that of the anti form or exceeded it. The relative rates of elimination of 2-phenylcyclopentyl and cyclohexyl tosylates with t-butoxide in t-butyl alcohol at 50° are as follows syn-cyclopentyl, 3 awii-cyclopentyl, 26 syw-cyclohexyl, 0 and anii -cyclohexyl, 2. In the cyclopentyl system in which the torsional angle (r) between the leaving groups approaches zero the syn rate is close to the anti rate. In the cyclohexyl system in which t of the stable form is ca. 60° the syn rate is 0. LeBel et al. (1964), report that in the reactions of t-butoxide with the 2,3-dihalobornanes, 92-95,... 

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