Alkylation axial

Interestingly, Allingham et al. (66) have analyzed a series of N-alkyl 5-nitrotetrahydro 1,3-oxazines and concluded that there is a preference for the N-alkyl axial conformer U)l when the alkyl substituent is methyl, ethyl or propyl and a preference for the N-alkyl equatorial conformer 102 when the substituent is isopropyl, cyclohexyl or t-butyl. Thus, J01 is still preferred despite the 1,3-diaxial steric interaction between the nitro group and a primary N-alkyl group. Finally, Katritzky et al (70) have proposed the conformation 103 as the major one for compounds 104 and 105,... 

The stereoselective reactions in Scheme 2.10 include one example that is completely stereoselective (entry 3), one that is highly stereoselective (entry 6), and others in which the stereoselectivity is modest to low (entries 1,2,4, 5, and 7). The addition of formic acid to norbomene (entry 3) produces only the exo ester. Reduction of 4-r-butylcyclohexanone (entry 6) is typical of the reduction of unhindered cyclohexanones in that the major diastereomer produced has an equatorial hydroxyl group. Certain other reducing agents, particularly sterically bulky ones, exhibit the opposite stereoselectivity and favor the formation of the diastereomer having an axial hydroxyl groi. The alkylation of 4-t-butylpiperidine with benzyl chloride (entry 7) provides only a slight excess of one diastereomer over the other. 

Because of the same preference for coplanarity in the enamine system, a alkyl substituents adopt an axial conformation to minimize steric interaction with the amino groi. ... 

The presence of 1,3-diaxial interaction between the C-2 alkyl group and the C-4 axial hydrogen atom is reflected in the rate of enamine formation of 2-substituted cyclohexanone. It has been shown by Hunig and Salzwedel (20) that even under forcing conditions, the yield of pyrrolidine and morpholine enamines of 2-methylcyclohexanone does not exceed 58%, whereas the C-2 unsubstituted ketones underwent enamine formation under rather milder conditions in better than 80 % yield. 

The reactions of pyrrolidinocyelohexenes with acid have also been Considered from a stereochemical point of view. Deuteration of the 2-methylcyclohexanone enamine gave di-2-deuterio-6-methylcyclohexanone under conditions where ds-4-/-butyI-6-methyIpyrrolidinocycIohexene was not deuterated (2J4). This experiment supported the postulate of Williamson (2JS), which called for the axial attack of an electrophile and axial orientation of the 6 substituent on an aminocyclohexene in the transition state of such enamine reactions. These geometric requirements explain the more difficult alkylation of a cyclohexanone enamine on carbon 2, when it is substituted at the 6 position, as compared with the unsubstituted case. 

Conversely, when A-alkyl tryptophan methyl esters were condensed with aldehydes, the trans diastereomers were observed as the major products." X-ray-crystal structures of 1,2,3-trisubstituted tetrahydro-P-carbolines revealed that the Cl substituent preferentially adopted a pseudo-axial position, forcing the C3 substituent into a pseudo-equatorial orientation to give the kinetically and thermodynamically preferred trans isomer." As the steric size of the Cl and N2 substituents increased, the selectivity for the trans isomer became greater. A-alkyl-L-tryptophan methyl ester 42 was condensed with various aliphatic aldehydes in the presence of trifluoroacetic acid to give predominantly the trans isomers. ... 

The methodology of precomplexing a cyclic ketone with MAD, followed by addition of a nucleophile, has also been successfully used for the mcthylation of 5a-cholestan-3-one (7). Thus, addition of methyllithium4 or methylmagnesium iodide57 to the steroidal ketone affords predominantly 3/ -methyl-5a-cholestan-3a-ol, whereas alkylation with melhyllithium/MAD almost exclusively affords 3a-methyl-5a-cholestan-3/J-ol via predominant axial attack of the nucleophile4. 

Alkylations of 6-methoxycarbonyl six-membered cyclic (V-acyliminium ions show a strong preference for the formation of m-products. This is explained by the A0-3 strain between the substituent and the (V-mcthoxycarbonyl group of the iminium ion, forcing the substituent into an axial position. Stereoelectronically preferred axial attack by the nucleophile then leads to the 2,6-d.v-disubstituted piperidine derivatives. 

Addition of the anion occurs anti to the bulky acctonide moiety of the 1,3-benzodioxole while alkylation of the intermediate sulfonyl anion occurs from the axial direction which ensures that the phenylsulfonyl group remains equatorial. 

Bei der elektrochemischen Reduktion von Cycloalkanonen steht i. a. der stereochemi-sche Aspekt (cis/trans axial/aquatorial) im Vordergrund, so z. B. bei der Reduktion der Methyl- und anderer Alkyl-cyclohexanone, substituierter 2-Oxo-bicyclo[2.2.1]heptane und bei Oxo-dekalinen. Mit zumeist Alkoholen als Solvens fallen die entsprechenden cy-clischen sekundaren Alkohole zu 47-60% d.Th. an7-11. 

Hall et al.1 s estimated the conformational equilibrium for the structural units in the polymer of 2 using the numerical parameters determined for carbohydrates16. For a frans-l,3-tetrahydropyranoside, conformer 8 is calculated to be more stable than 7 by 9.2 kJmol-1 and would therefore occur almost exclusively (ca. 98%) at equilibrium. For a m-1,3-tetrahydropyranoside unit, the anomeric effect favors con-former 9, but its severe syn-axial interaction between alkoxy and alkyl groups would highly favor 10 (ca. 99%). 

An interesting anomaly is a//-rra j-l,2,3,4,5,6-hexaisopropylcyclohexane, in which the six isopropyl groups prefer the axial position, although the six ethyl groups of the corresponding hexaethyl compound prefer the equatorial position. The alkyl groups of these compounds can of course only be all axial or all equatorial, and it is likely that the molecule prefers the all-axial conformation because of unavoidable strain in the other conformation. 

An alkyl group located on a carbon a to a heteroatom prefers the equatorial position, which is of course the normally expected behavior, but a polar group in such a location prefers the axial position, An example of this phenomenon, known as the anomeric is the greater stability of a-... 

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