Regioselectivity methyl groups

Unique chemistry is associated with the cyclopentenone all five carbon atoms can be functionalized, and the endo-methyl groups of the acetonide assure clean stereoselective addition of the alkenylcopper reagent from the convex side. The use of the acetonide group to control enolate regioselectivity and to mask alcohols should be generally applicable. 

The allyl-substituted cyclopentadiene 122 was prepared by the reaction of cyclopentadiene anion with allylic acetates[83], Allyl chloride reacts with carbon nucleophiles without Pd catalyst, but sometimes Pd catalyst accelerates the reaction of allylic chlorides and gives higher selectivity. As an example, allylation of the anion of 6,6-dimethylfulvene 123 with allyl chloride proceeded regioselectively at the methyl group, yielding 124[84]. The uncatalyzed reaction was not selective. 

The regioselectivity of addition is consistent with the electron distribution in the complex Hydrogen is transferred with a pair of electrons to the carbon atom that can best support a positive charge namely the one that bears the methyl group... 

The least sterically hindered p hydrogen is removed by the base m Hofmann elim matron reactions Methyl groups are deprotonated m preference to methylene groups and methylene groups are deprotonated m preference to methmes The regioselectivity of Hofmann elimination is opposite to that predicted by the Zaitsev rule (Section 5 10) Elimination reactions of alkyltrimethylammonmm hydroxides are said to obey the Hofmann rule, they yield the less substituted alkene... 

Radical cyclization of perhydro-l,3-benzoxazines 64, promoted by Bu4SuH in the presence of AIBN gave a mixture of perhydropyrido[2,l-6][1,3]benzoxazin-9-ones 65 and 66 and seven membered tricyclic derivatives 67 and 68, formed in a 6-exo and 7-endo cyclization process, respectively (99TL2421). Cyclization of parent acrylamide 64 (R = R = H) occured with moderate regioselectivity (6-exo/7-endo ratio 65 35) and poor stereoselectivity (65/66 ratio 42 43). The presence of a /3-methyl group in... 

The corphins 2 and 3 formed can be tautomerized back to pyrrocorphins,6 but less complicated model compounds bearing methyl groups can also be similarly tautomerized.yab When magnesium nonamethylpyrrocorphin is first methylated and then tautomerized, the D pyrrole ring is regioselectively attacked by iodomethane followed by tautomerization to establish a pyrrole ring in the C position of the macrocyclic system 4. 

Similarly a marked increase of regioselectivity has been shown in the catalyzed Diels-Alder reactions of the chiral bicyclic lactame 24 (Scheme 3.9) with a variety of dienes [27] (isoprene, mircene, (E,E)-L4-dimethylbutadiene, 2,3-di-methylbutadiene, 2-siloxybutadiene). The catalyzed reactions were more regio-selective and totally enJo-antz-diastereoselective anti with respect to the bridgehead methyl group). The results of the cycloadditions with isoprene and mircene are reported in Scheme 3.9. The cycloadducts have then been used to provide interesting fused carbocycles [28] with high enantiomeric purity as shown in Scheme 3.10. 

Cycloaddition reactions of (E)-l-acetoxybutadiene (18a) and (E)-l-methoxy-butadiene (18b) with the acrylic and crotonic dienophiles 19 were studied under high pressure conditions [9] (Table 5.1). Whereas the reactions of 18a with acrylic dienophiles regioselectively and stereoselectively afforded only ortho-enJo-adducts 20 in fair to good yields, those with crotonic dienophiles did not work. Similar results were obtained in the reactions with diene 18b. The loss of reactivity of the crotonic dienophiles has been ascribed to the combination of steric and electronic effects due to the methyl group at the )S-carbon of the olefinic double bond. 

A method for regioselective introduction of a bis(methoxycarbonyl)-methyl group into the 4-position of the piperidine skeleton was explored, and this method was applied to the preparation of cis- and rra j-2,4-disubstituted piperidines (e.g., 114) starting from 2-piperidinecarboxylic acid <96TL(37)5715>. 

Hydrazones can also be deprotonated to give lithium salts that are reactive toward alkylation at the (3-carbon. Hydrazones are more stable than alkylimines and therefore have some advantages in synthesis.119 The A N-dimcthyl hydrazones of methyl ketones are kinetically deprotonated at the methyl group. This regioselectivity is independent... 

Entry 7 features a quinone dienophile. The reaction exhibits the expected selectivity for the more electrophilic quinone double bond (see p. 506). The reaction is also regioselective with respect to the diene, with the methyl group acting as a donor substituent. The enantioselectivity is 80%. 

The oxidation chemistry of a-tocopherol and the regioselectivity of the o-QM formation are well investigated (Section 6.3.2). This is in complete contrast to [3-tocopherol. At a first glance, the [3-tocopherol case would appear much simpler as the free aromatic position at C-7 offers no alternative methyl group to be involved in o-QM formation. However, preliminary results show that the oxidation chemistry of [3-tocopherol is rather complex, the free position undergoing alkylation by the o-QM... 

Radical cyclization of perhydro-l,3-benzoxazines 518, promoted by Bu vSnI I in the presence of 2,2 -azobis(2-methylpro-pionitrile) (AIBN) gave a mixture of perhydropyrido[2,T ][l,3]benzoxazin-9-ones 519 and 520 and the seven-membered tricyclic derivatives 521 and 522, formed by a 6-exo- and a 7-rwr/o-cyclization process, respectively (Scheme 54) < 1999TL2421 >. Cyclization of parent acrylamide 518 (R = R1 = H) occurred with moderate regioselectivity (()-exo/7-endo ratio = 65 35) and poor stereoselectivity (519/520 ratio = 42 43). The presence of a [1-methyl group in crotylamide 518 (R = Me, R1 = H) disfavored the 7-/w/ -cyclization process, but did not influence the stereoselectivity of the cyclization (519/520 ratio = 66 34). The presence of an a-methyl group in methylacrylamide 518 (R=H, R1 Me) caused a retardation of the 6-oeo-attack, favoring the 7-/w/ -cyclization with a higher stereoselectivity (521/522 ratio = 75 12). 

Regioselectivity, the production of a linear ester rather then one with a branching methyl group... 

This process is likely to proceed via a palladacycle intermediate followed by a Pd(ll) to Pd(iv) oxidation. Reductive elimination occurs with C-O bond formation and regeneration of the Pd(ll) catalyst. Evidence for a palladacycle intermediate is supported by the high regioselectivity (8-Me group oxidized) observed for the oxidative functionalization of 5,8-dimethylquinoline, which, in the absence of a possibility of coordination, would otherwise contain two identical methyl groups (Equation (57)). 

The reaction presumably involves a cis, syn elimination. As Eq. 34 illustrates, regioselectivity can be controlled by choice of base 49). The higher kinetic acidity of the benzylic position of 20 determines the regioselectivity with a- non-hindered base whereas, steric hindrance directs the base to the methyl group. 

Alkoxycarbonylation of 2,3-dichloro-5-(methoxymethyl)pyridine (78) took place regioselectively at C(2) to give ester 79 [79], Aminocarbonylation of 2,5-dibromo-3-methylpyridine also proceeded preferentially at C(2) to give amide 80 despite the steric hindrance of the 3-methyl group [80]. 

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