Of alkylation reactions

Quaternization of the enamine has been the more frequent result of alkylation reactions with cyclic enamines 114,277-279), but some successful carbon alkylations have been reported 280-282). 

The first examples of alkylation reactions in molten salts were reported in the 1950 s. Baddeley and Williamson performed a number of intramolecular cycliza-tion reactions [76] (Scheme 5.1-46), carried out in mixtures of sodium chloride and aluminium chloride. The reactions were run at below the melting point of the pure salt, and it is presumed that the mixture of reagents acts to lower the melting point. 

Ketones, esters, and nitriles can all be alkylated using LDA or related dialkyl-amide bases in THE. Aldehydes, however, rarely give high yields of pure products because their enolate ions undergo carbonyl condensation reactions instead of alkylation. (We ll study this condensation reaction in the next chapter.) Some specific examples of alkylation reactions are shown. 

Brown and Grayson reported that the rate of alkylation reactions with benzyl chloride was third order overall first order in aromatic component, first order in AICI3, and first order in benzyl chloride. This indicates that a rate determining nucleophilic attack by the aromatic component on a polar alkyl chloride-aluminum... 

Amine (1) was needed to study the stereochemistry of alkylation reactions. The primary alkyl group had best come from an amide or an Imine while the secondary alkyl group must come from an imine. The disconnections may be carried out in any order. 

Some examples of alkylation reactions involving relatively acidic carbon acids are shown in Scheme 1.3. Entries 1 to 4 are typical examples using sodium ethoxide as the base. Entry 5 is similar, but employs sodium hydride as the base. The synthesis of diethyl cyclobutanedicarboxylate in Entry 6 illustrates ring formation by intramolecular alkylation reactions. Additional examples of intramolecular alkylation are considered in Section 1.2.5. Note also the stereoselectivity in Entry 7, where the existing branched substituent leads to a trans orientation of the methyl group. 

There are also many examples of alkylation reactions involving the norbornyl ring system in which the enolate can be either endo- or c.vo-cyclic. Both the endo-cyclic (6, 7) and evo-cyclic (8) enolates exhibit high levels of asymmetric induction due to the rigid ring system. Scheme 2-8 presents some examples for alkylation involving the norbornyl ring system.15... 

The preparation of macrocyclic diimines and endocyclic enamines are represented by the procedures for the formation of 1,10-DIAZA-CYCLOOCTADECANE and N-METHYL-2-PHENYL-A2-TETRA-HYDROPYRIDINE. Other procedures representative of alkylation reactions and aromaticity (TRI-i-BUTYLCYCLOPROPENYL FLUOROBORATE) round out a volume of tested experimental procedures of general value. 

TABLE 6.1. The 1-butene conversion and product distribution after 1 h of alkylation reaction of isobutane on as-prepared JML-I50 and zeobte Beta catalysts. 

The 1-butene conversion and product distribution obtained at 25°C after 1 h of alkylation reaction of isobutane on JML-I50 and Beta catalysts are summarized in Table 6.1. The conversion (97%) with JML-I50 catalyst is higher than that (86%) with zeolite Beta. The primary products with the above catalysts are Cs compounds (59.9% with JML-I50 and 62% with Beta). The Cg products mainly consist of trimethylpentanes (TMPs), 58.7% for JML-I50 and 73% for zeolite Beta. The TMP/DMH (dimethylhexane) ratios are 13.5 for JLM-I50 and 4.1 for Beta, demonstrating that the selectivity of JML-I50 is higher than that of zeolite Beta. The yields of alkylate are 6.6 mL and 5.2 mL for JML-I50 and Beta zeolite, respectively. The weights of alkylate produced per weight of butene fed to the reactor are 1.13 and 0.95 for JML-I50 and zeolite Beta, respectively. 

A range of examples of alkylation reactions via radicals generated through electron transfer sensitization is available in the literature, and a few of them are reported in Figure 3.12. Alkyl tin derivatives can be used as precursors, but in many cases these highly toxic reagents can be advantageously substituted by... 

Figure 3.12 Examples of alkylation reactions via radicals generated through electron transfer sensitization.

The general feature of alkylation reactions at a carbon atom is that they can be achieved under sonication using solid bases even in apolar solvents. The advantage is that side reactions are generally minimised. Deprotonation occurs readily on a benzylic position in the presence of aqueous sodium hydroxide, as shown with indene (Eq. 3.21) [117]. A quantitative yield of the alkylated product can be obtained using sonication in the presence of a PTC. It was suggested that alkylation of cyclopentadiene or indene by secondary or tertiary alkyl halides in the presence of potassium hydroxide and Ali-quat occurred via a SET process [118]. 

Alkylation of enolate is an important synthetic method.27 The alkylation of relatively acidic compounds such as /i-dikctoncs, /i-ketoesters, and esters of malonic acid can be carried out in alcohols as solvents using metal alkoxides as bases. The presence of two electron-withdrawing substituents facilitates formation of the enolate resulting from removal of a proton from the carbon situated between them. Alkylation then occurs by an Sn2 process. Some examples of alkylation reactions involving relatively acidic carbon acids are shown in Scheme 1.5. These reactions are all mechanistically similar in that a... 

The importance of fluconazole as an antifungal agent has led to a renewed interest in triazole derivatives and a further exploration of methods of alkylation. Reaction of 4-amino triazole (27) with chloroacetophenones (28) gave the corresponding triazolium cations (29) which could be deaminated to (30) with nitrous acid (Scheme 4) <93JHC1405>. 

The investigations discussed above show a clear progression from the discovery of a mutagenic action of H in Drosophila, through the studies of alkylation reactions of H with DNA, to the experimental production of tumors in maianals, including humans. 

The regio- and stereoselectivity of enolate formation are essential for the control of alkylation reactions. The regioselectivity of ketone deprotonation has been extensively investigated and this important step in alkylation reactions has been discussed in many reviews (e.g., refs 1-4, 71) and textbooks (e.g., refs 5, 6). Therefore, this topic will be discussed here only in general terms. 

Enolate geometry is of fundamental interest in order to be able to control the steric course of alkylation reactions of enolates. Determination of the configuration of an enolate is not trivial and has been carried out by first coupling it to the preferential transition state of the Claisen rearrangement2 5. 

Most of the work in this area has concerned complexes racemic at iron. Section D.1.3.4.2.5.1.1. details methods for the preparation and resolution of enantiomerically pure iron acyl complexes. The details of alkylation reactions (see Section 1.1.1.3.4.1.3.) and aldol reactions (see Section 1.3.4.2.5.1.2.) of these and other iron acyl enolates are presented later with examples utilizing enantiomerically pure complexes indicated therein. Table 1 illustrates the scope of iron-acyl enolates prepared by deprotonation of complex 10 and its analogs. 

Functionalization of organic substituents adjacent to the sulfoxide moiety constitutes an important method of synthesis of a variety of sulfoxides which are required for special synthetic purposes or serve as a source of many sulfur-free organic compounds. This section will be mainly devoted to the use of alkylation reactions of sulfinvl anions in stereoselective synthesis and will not review the tremendous amount of work described in the chemical literature without any stereochemical implication. 

There are several factors that limit the usefulness of alkylation reactions. First, it may be difficult to limit reaction to monosubstitution because introduction of one alkyl substituent tends to activate the ring towards a second substitution (see Section 22-5). Therefore, to obtain reasonable yields of a monoalkyl-benzene, it usually is necessary to use a large excess of benzene relative to the alkylating agent ... 

These results are by no means unrelated to the synthetic motivation of the earlier studies of alkylation reactions in CH2C12 as solvent. Comparisons of N and 5 values of alkenes and aromatics with those of hydroxylic solvents offer a guide to the conduct of Friedel-Crafts and other electrophilic carbon-carbon bond-making reactions in hydroxylic solvents. Not surprisingly, TFE is a particularly favorable solvent for such reactions and if allowance is made for a minor solvent dependence of N values for arenes and alkenes a good estimate of the likely feasibility of such reactions can be made.290 293... 

Although alkylation with these anions is usually a high-yielding reaction, there are several possible side-reactions that must be eliminated by careful choice of reaction conditions494 98. These side-reactions include O-alkylation and multiple C-alkylations. The yields of alkylation reactions with anions is often significantly reduced if the halide is unable to react via a S -type process. This may be alleviated to some extent by the use of trimethylsilyl enol ethers using Lewis acid catalysis499 503. 

You may have noticed that aldehydes were conspicuously absent from the examples of alkylation reactions presented in Sections 20.3 and 20.4. This is due to the high reactivity of the carbonyl carbon of an aldehyde as an electrophile. When an enolate anion nucleophile is generated from an aldehyde, under most circumstances it rapidly reacts with the electrophilic carbonyl carbon of an un-ionized aldehyde molecule. Although this reaction, known as the aldol condensation, interferes with the alkylation of aldehydes, it is a very useful synthetic reaction in its own right. The aldol condensation of ethanal is shown in the following equation ... 

Schmerling (9,10) had originally postulated that a hydride Ion transfer from Isobutane was both the most Important method of hydride transfer and also part of the chain set of reactions (see Reaction C of Table I and Reaction M-2 of Table IV). Other hydride transfer steps that have now been suggested Include transfer with the acid-soluble hydrocarbons (RH), see Reaction M-1 of Table IV (8,11), and with Isobutylene, see Reaction M-3 (8). Reaction M-3 Is however considered to be of minor Importance since only trace amounts of free Isobutylene are likely ever present at the acid-hydrocarbon Interface (the probable location of alkylation reactions) Isobutylene quickly protonates to form t-CaHg . Reaction M-1 Is considered to be more Important than Reaction H-2 especially when sulfuric acid Is used as the catalyst for the reasons listed as follows ... 

A number of alkylation reactions, Michael-type additions, and base-catalyzed rearrangements have been previously reported for Reissert compounds. These reactions appear to proceed through the conjugate... 

The acute toxic effects of mustard vesicants are usually attributed to the consequences of alkylation reactions with organic compounds including nucleoproteins such as DNA. Alkylation reactions can result in physiological and metabolic disturbances as well as genotoxic effects. Several hypotheses have been advanced concerning the primary cause of cell death following acute exposures. As reviewed by Papirmeister et al. (1991), the three major hypotheses are ... 

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