Selectivity in alkylation

J. A. Hartley, Selectivity in alkylating agent-DNA interactions, in Molecular Aspects of Anticancer Drug-DNA Interactions Vol. 1 (Eds. S. Neidle, M. Waring), CRC Press, Boca Raton, FL, 1993, 1. 

The electroreduction of CHT in DMF in the presence of n-butyl chloride gives, for example, 6-butyl-l,3-cycloheptadiene as the main product (equation 26). This selectivity in alkylation is interesting, since it is also known that the reductive butylation of CHT using Li/NH3 as the reducing agent gives a mixture of 5-butyl-l,3-cycloheptadiene and 3-butyl-l,4-cycloheptadiene in which the latter is the main product22,23. 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

The behavior of 2,3,4-trlmethylpentane reinforces the conclusions of the study of the t-butylchloride reaction with methyl-cyclopentane In suggesting that a means of Increasing the hydride transfer rate in H2S0 could lead to improved selectivity in alkylation. The next reaction was chosen to Investigate this possibility. 

Yadav, G. D., Bisht, P. M. Novelties of microwave assisted liquid-liquid phase transfer catalysis in enhancement of rates and selectivities in alkylation of phenols under mild conditions. Catat. Common. 2004, 5, 259-263. 

Scheme 5.1.19 High selectivity in alkylation of a dibutylstannylene acetaH°...

Siloxyallylbarium reagents (from allyl silyl ethers by consecutive treatment with sec-BuLi and Bah) also show a high y-selectivity in alkylation reactions. ... 

The preference for the lowest energy conformation of the enolate anion is seen in larger ring systems as well (sec. 1.5.B,C), leading to good selectivity in alkylation and condensation reactions. The methyl group provides only small steric encumbrance to approach of the electrophile in enolate 505 (derived from lactone 504 and LDA). The preferred mode of attack for this relatively stable conformation was from the top face (path a, pseudoequatorial attack) and gave the syn diastereomer (506) with >99 1 selectivity.- ... 

Figure 8.9 Shape selectivity in zeolite pores. From top to bottom reactant selectivity in alkanol dehydration diffusion selectivity in alkylation of aromatics diffusion selectivity in xylene isomerisation transition state selectivity in xylene isomerisation.

The synthesis of both R)- and (5)-enantiomers of 4,4,4-trifluoro-3-methyl-1-butanol (19,20) by Jacobs et al. [54] as building blocks for leuko-triene antagonists Scheme 5.12), demonstrates how oxazolidinone auxiliaries (21) and (22), derived from L-valine and (lS,2/ )-norephedrine, respectively, impart complementary selectivity in alkylation of chelated (Z)-enolates. Similarly, Trova et al. [55] have utilized the iV-acyl oxazolidinone (23), from L-phenylalanine and 3-phenylpropanoyl chloride, for the construction of diastereomeric lactones (24) and (25) as synthons for HIV-1 protease inhibitors Scheme 5.12). Following allylation and hydrolytic removal of the auxiliary, stereocomplementary iodolactonization reactions of... 

High iS-selectivity in alkylation of naphthalene and methylnaphthalene with methanol over H - ZSM-5 was reported by Fraenkel et al Thus, 76% selectivity for 2-methylnaphtalene and 2,6/2,7-dimethylnaphthalene was achieved with 15% naphthalene conversion at 623... 

Because the nature of the halogen atom can be varied, these salts show useful selectivity in their alkylation reaetions. We also prepared other halonium ions and studied their alkylating ability. 

Sulfonic acids are prone to reduction with iodine [7553-56-2] in the presence of triphenylphosphine [603-35-0] to produce the corresponding iodides. This type of reduction is also facile with alkyl sulfonates (16). Aromatic sulfonic acids may also be reduced electrochemicaHy to give the parent arene. However, sulfonic acids, when reduced with iodine and phosphoms [7723-14-0] produce thiols (qv). Amination of sulfonates has also been reported, in which the carbon—sulfur bond is cleaved (17). Ortho-Hthiation of sulfonic acid lithium salts has proven to be a useful technique for organic syntheses, but has Httie commercial importance. Optically active sulfonates have been used in asymmetric syntheses to selectively O-alkylate alcohols and phenols, typically on a laboratory scale. Aromatic sulfonates are cleaved, ie, desulfonated, by uv radiation to give the parent aromatic compound and a coupling product of the aromatic compound, as shown, where Ar represents an aryl group (18). 

Monochlorophenols. Chlorination of phenol [108-95-2] between 50 and 120°C gives a ortho ratio of 1.65. To improve the selectivity in the paia position, it is possible to use dialkyl sulfides, diaiyl sulfides (12), oi alkyl and aiyl sulfides combined. Sulfides are active only at low tempeiatuies (<50 C), because at high tempeiatuies the active species decomposes into sulfui and chlorine. 

Table 10.9. Substrate and Position Selectivity in Friedel-Crafts Alkylation Reactions...

The results shown for compounds (26)-(29) and (36) suggest that a rather subtle balance of various factors has to be considered for a prediction of relative yields and structures of products. Although fission of the more highly alkyl substituted bond by a-cleavage proceeds with a high degree of selectivity in the primary photochemical step, the subsequent disproportiona-... 

As mentioned before, in the alkylation of thiophene the proportion of 2- to 3-isomer varies from 1 1 to 3 1, depending on the reagent and catalyst The poor selectivity in the Friedel-... 

Stable enolates such as diethyl malonate anions react with allyl sulfones (or acetates) in the presence of nickel complexes to give a mixture of the a- and /-product83. The regioselectivity is generally poor in the nickel-catalyzed reaction, but the molybdenum-catalyzed reaction is selective for alkylation at the more substituted allylic site, thereby creating a quaternary carbon center84. 

Apart from information on stereochemistry, bromine bridging does not provide a priori any rule regarding regio- and chemoselectivity. Therefore, we systematically investigated (ref. 3) these two selectivities in the bromination of ethylenic compounds substituted by a variety of more or less branched alkyl groups (Scheme 4). 

For a review of selectivity in this reaction, that is, which group preferentially attacks when the reagent contains two or more, see Olah, G.A. in Olah, Ref. 240, vol. 1, p. 881. This review also covers the case of alkylation vs. acylation. 

See Davister, M. Laszlo, P. Tetrahedron Lett., 1993, 34, 533 for examples of paradoxical selectivity in Friedel-Crafts alkylation. 

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