Alkylation reactions acid synthesis

The Arbuzov reaction,also called the Michaelis-Arbuzov reaction, allows for the synthesis of pentavalent alkyl phosphoric acid esters 4 from trivalent phosphoric acid esters 1 (Z,Z = R,OR) by treatment with alkyl halides 2. 

The fundamental aspects of the structure and stability of carbanions were discussed in Chapter 6 of Part A. In the present chapter we relate the properties and reactivity of carbanions stabilized by carbonyl and other EWG substituents to their application as nucleophiles in synthesis. As discussed in Section 6.3 of Part A, there is a fundamental relationship between the stabilizing functional group and the acidity of the C-H groups, as illustrated by the pK data summarized in Table 6.7 in Part A. These pK data provide a basis for assessing the stability and reactivity of carbanions. The acidity of the reactant determines which bases can be used for generation of the anion. Another crucial factor is the distinction between kinetic or thermodynamic control of enolate formation by deprotonation (Part A, Section 6.3), which determines the enolate composition. Fundamental mechanisms of Sw2 alkylation reactions of carbanions are discussed in Section 6.5 of Part A. A review of this material may prove helpful. 

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. 

A recent formal synthesis of the alkaloid (—)-mitralactonine relied on a reaction that allowed the simultaneous creation of three new bonds, two of them a and one ft with respect to the quinolizine nitrogen. As shown in Scheme 112, treatment of triptamine with chiral aldehyde 480 in the presence of acid directly gave a mixture of diastereo-meric indoloquinolizidines 481 and 482 through a mechanism involving a Pictet-Spengler cyclization and a N-alkylation reaction <2007SL79>. 

In a separate study, Ohberg and Westman applied the same PS-DMAP in a one-pot microwave-induced base-catalyzed reaction of N-aryl and N-alkyl amino acids (or esters) and thioisocyanates for the library synthesis of thiohydantoins (Scheme 7.115) [136]. Thiohydantoins are of interest due to their ease of preparation and the range of biological properties associated with this heterocyclic ring system. The use of PS-DMAP as the base in this reaction gave slightly lower yields compared to when triethylamine (TEA) was used, but it resulted in a cleaner reaction mixture and an easier purification procedure. Cyclizations of a number of N-substituted... 

SYNTHESIS and CHARACTERIZATION of O-ALKYLATED EXTRACTS. Alkylation occurs when tetrabutylanunonium hydroxide is used to promote the reaction of the alkyl iodide with the coal in tetrahydrofuran.(14) The alkylation reaction occurs primarily on acidic oxygen functionalities such as phenolic hydroxyl and carboxylic acid groups, as shown below. 

Since the formation of optically active, dioxolanone-based di-enolates was not successful, a consecutive alkylation strategy was developed for a short synthesis of (-)-wikstromol (ent-3) from (-)-malic acid (99) (Scheme 25). The first alkylation reaction was analogous to that reported for the enantioselective total synthesis of (-)-meridinol (97). In order to avoid a reduction/re-oxidation sequence and an almost unselective second alkylation, two disadvantages of the synthesis of meridinol (97) [55], we planned to use a different strategy for the second alkylation. Therefore, we have focused our strategy on two stereoselective alkylation reactions, one of dialkyl malates and one of a dioxolanone prepared thereof. Both alkylation reactions were previously described by Seebach and coworker [56, 63, 64]. The... 

A reaction in which an electrophile participates in het-erolytic substitution of another molecular entity that supplies both of the bonding electrons. In the case of aromatic electrophilic substitution (AES), one electrophile (typically a proton) is substituted by another electron-deficient species. AES reactions include halogenation (which is often catalyzed by the presence of a Lewis acid salt such as ferric chloride or aluminum chloride), nitration, and so-called Friedel-Crafts acylation and alkylation reactions. On the basis of the extensive literature on AES reactions, one can readily rationalize how this process leads to the synthesis of many substituted aromatic compounds. This is accomplished by considering how the transition states structurally resemble the carbonium ion intermediates in an AES reaction. 

Deprotonation at an activated 4-position has been employed extensively in asymmetric synthesis, which is the key step in the Seebach protocol for the preparation of a-alkyl amino acids.The existing alkyl group at the 5-position acts as a directing group for the alkylation and is oriented trans to the new alkyl group (Scheme 8.118). This reaction provides an efficient methodology for normally difficult stereoselective construction of a quaternary chiral center. 

Replacement of the pyridine ring by a more strongly basic ethylpiperidine moiety leads to the antiarrhythmic dmg disobutamide (55-5). The synthesis of this compound also involves successive carbanion alkylation reactions. Thus, reaction of the anion from ortho-chloroacetonitrile (55-1) with A-(2-chloroethyl) piperidine gives the intermediate (55-3) alkylation of the anion from this leads to (55-4). Hydrolysis with sulfuric acid completes the preparation of disobutamide (55-5) [56]. 

Xu, W. Mohan, R. Morrissey, M. M. Polymer Supported Bases in Solution-Phase Synthesis. 2. A Convenient Method for /V-Alkylation Reactions of Weakly Acidic Heterocycles, Bioorg. Med. Chem. Lett. 1998, 8, 1089. 

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