Esters alkylation with

NaOCHjCHa. White solid (Na in EtOH). Decomposed by water, gives ethers with alkyl halides reacts with esters. Used in organic syntheses particularly as a base to remove protons adjacent to carbonyl or sulphonyl groups to give resonance-stabilized anions. 

The carbopalladation is extended to homoallylic amines and sulfides[466. Treatment of 4-dimethylamino-l-butene (518) with diethyl malonate and Li2PdCl4 in THF at room temperature leads to the oily carbopalladated complex 519, hydrogenation of which affords diethyl 4-(dimethylamino) butylmalonate (520) in an overall yield of 91%. Similarly, isopropyl 3-butenyl sulfide (521) is carbopalladated with methyl cyclopentanonecarboxylate and Li2PdCl4. Reduction of the complex affords the alkylated keto ester 522 in 96% yield. Thus functionalization of alkenes is possible by this method. 

Alkylation with other alkylating agents such as ethyl iodide (43. 180, 181j, chloracetic acid and its esters (182). and dialkylaminoalkylhalides (40.43) occurs also on the ring nitrogen. 

Direct alkylation of esters can be carried out by forming the enolate with LDA fol lowed by addition of an alkyl halide Tetrahydrofuran (THF) is the solvent most often used m these reactions... 

Section 21 6 The acetoacetic ester synthesis is a procedure in which ethyl acetoac etate is alkylated with an alkyl halide as the first step in the preparation... 

Acylated Corticoids. The corticoid side-chain of (30) was converted iato the cycHc ortho ester (96) by reaction with a lower alkyl ortho ester RC(OR )2 iu benzene solution ia the presence of i ra-toluenesulfonic acid (88). Acid hydrolysis of the product at room temperature led to the formation of the 17-monoesters (97) ia nearly quantitative yield. The 17-monoesters (97) underwent acyl migration to the 21-monoesters (98) on careful heating with. In this way, prednisolone 17a,21-methylorthovalerate was converted quantitatively iato prednisolone 17-valerate, which is a very active antiinflammatory agent (89). The iatermediate ortho esters also are active. Thus, 17a,21-(l -methoxy)-pentyhdenedioxy-l,4-pregnadiene-liP-ol-3,20-dione [(96), R = CH3, R = C Hg] is at least 70 times more potent than prednisolone (89). The above conversions... 

Hydrazine as Nucleophile. Reaction of hydrazine and carbon dioxide or carbon disulfide gives, respectively, hydrazinecarboxyhc acid [471-31-8], NH2NHCOOH, and hydrazinecarbodithioic acid [471-32-9], NH2NHCSSH, in the form of the hydrazinium salts. These compounds are useful starting materials for further synthesis. For example, if carbon disulfide reacts with hydrazine in basic medium with an alkyl haUde, an alkyl dithiocarbazate ester is obtained in a one-step reaction ... 

In place of a proton source, ie, a Briimsted acid, a cation source such as an alkyl haUde, ester, or ether can be used in conjunction with a Friedel-Crafts acid. Initiation with the ether-based initiating systems in most cases involves the haUde derivative which arises upon fast haUdation by the Friedel-Crafts acid, MX (2). 

Dehydiation with POCl, followed by N-alkylation with isobutylene, gives the cyano ester intermediate, which on treatment with methylamine yields (64), a compound having good herbicidal activity (eq. 15). 

The antibacterial agent nalidixic acid [389-08-2] (37) is formed by reaction of 2-ainino-6-methylpyridine [1824-81 -3] with an alkoxymethylenemalonic ester to form the 1,8-naphthyridine carboxyUc ester followed by alkylation and ester hydrolysis (37). 

Reaction with Water. The alkyl carbonate esters, especially the lower ones, hydroly2e very slowly in water when compared to the carbonochloridic esters (chloroformates). Under alkaline conditions, the rates of hydrolysis are similar to those of the corresponding acetic acid esters. 

Alkyl hypochlorites, esters of hypochlorous acid, are nonpolar, volatile Hquids with irritating odors and are extremely lachrimatory. The known alkyl hypochlorites (ROCl) are methyl (CH ) [593-78-2] ethyl (C2H ) [624-85-1] /-butyl (/-C H ) [307 0 ], and /-amyl [24251 -12-5], Primary and... 

Cl Disperse Blue 87 (107) and related dyestuffs are also prepared from l-oxo-3-imino-4,7-diamino-5,6-phthaloyhsoiQdoline [13418-50-3] (111) by alkylation with corresponding alkyl haUdes (122), sulfonic esters (123), or alkyl amines (124), ie, X of RX = halogen, -toluenesulfonyloxy, or NH2. 

Methylpyrazine reacts with sodamide in liquid ammonia to generate the anion, which may be alkylated to give higher alkylpyrazines (Scheme 10) (61JOC3379). The alkylpyrazines have found extensive use as fiavouring and aroma agents (see Section 2.14.4). Condensation reactions with esters, aldehydes and ketones are common, e.g. methyl benzoate yields phenacylpyrazine in 95% yield, and reactions of this type are summarized in Scheme 11. 

Mel, CH3CN morpholine or diethylamine, methanol, 76-95% yield. These conditions also cleave tlie 4 -pyridyl derivative. The Pet ester is stable to the acidic conditions required to remove the BOC and r-butyl ester groups, to the basic conditions required to remove the Fmoc and Fm groups, and to hydrogenolysis. It is not recommended for use in peptides that contain methionine or histidine since these are susceptible to alkylation with methyl iodide. 

Methylsuccinic acid has been prepared by the pyrolysis of tartaric acid from 1,2-dibromopropane or allyl halides by the action of potassium cyanide followed by hydrolysis by reduction of itaconic, citraconic, and mesaconic acids by hydrolysis of ketovalerolactonecarboxylic acid by decarboxylation of 1,1,2-propane tricarboxylic acid by oxidation of /3-methylcyclo-hexanone by fusion of gamboge with alkali by hydrog. nation and condensation of sodium lactate over nickel oxide from acetoacetic ester by successive alkylation with a methyl halide and a monohaloacetic ester by hydrolysis of oi-methyl-o -oxalosuccinic ester or a-methyl-a -acetosuccinic ester by action of hot, concentrated potassium hydroxide upon methyl-succinaldehyde dioxime from the ammonium salt of a-methyl-butyric acid by oxidation with. hydrogen peroxide from /9-methyllevulinic acid by oxidation with dilute nitric acid or hypobromite from /J-methyladipic acid and from the decomposition products of glyceric acid and pyruvic acid. The method described above is a modification of that of Higginbotham and Lapworth. ... 

Because they are acrylic monomers, alkyl cyanoacrylate esters still require the addition of radical polymerization inhibitors, such as hydroquinone or hindered phenols, to prevent radically induced polymerization over time [3j. Since basic initiation of alkyl cyanoacrylate monomers is the predominant polymerization mechanism, large quantities of free radical inhibitors can be added, with little or no effect on adhesive performance. 

Hydrolysis of alkyl perfluoroalkylacetylenic esters with aqueous sodium hydroxide gives (Z)-P-alkoxy-P-perfluoroalkylacrylic acids [3] (equation 4)... 

Stereochemical positioning of a functional group, relative to a separate enamine moiety in the same molecule, can be done in such a manner that a simple intramolecular alkylation or acylation will cause cyclization. Such intramolecular cycloalkylations with alkyl halides have been reported 107,108). Inftamolecular cycloacylations of enamines with esters 109, 110,110a) and with nitriles 110a,l 11,111a) have also been observed. 

Another improvement was reported by Leonard et al. in their preparation of a promising antimalarial, Endochin. The improvement was the alkylation of intermediate enamino-ester 28 by reaction with NaOEt followed by alkylation with an alkyl bromide, rather than forming 29 by reaction of 27 and a suitable P-keto-ester. This provided the important intermediate 29 required for cyclization to Endochin (30). Endochin was first reported by German scientists but was not publicly disclosed until the Department of Commerce made this information available after World War II.Leonard was able to improve upon the chemistry reported by Andersag and Salzer in 1940 and isolated Endochin in 40% overall yield from m-anisidine (27). 

The rate of the alkylation reaction depends on the enolate concentration, since it proceeds by a SN2-mechanism. If the concentration of the enolate is low, various competitive side-reactions may take place. As expected, among those are E2-eliminations by reaction of the alkyl halide 2 with base. A second alkylation may take place with mono-alkylated product already formed, to yield a -alkylated malonic ester however such a reaction is generally slower than the alkylation of unsubstituted starting material by a factor of about 10. The monoalkylation is in most cases easy to control. Dialkylated malonic esters with different alkyl substituents—e.g. ethyl and isopropyl—can be prepared by a step by step reaction sequence ... 

Phenylacetonitrile is alkylated with secondary butyl bromide and the resultant nitrile is hydrolyzed to 3-methyl-2-phenylvaleric acid. The acid is converted to the acid chioride with thionyl chloride and the acid chloride is in turn reacted with 1-methyl-4-piperidinol. Finally dimethyl sulfate is reacted with the ester. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

Certain of the monoalkylated ethyl phenylacetates have been further alkylated with alkyl and aralkyl halides to produce the corresponding disuhstituted phenylacetic esters.4 Ethyl 2-phenyl-propanoate has been alkylated by methyl iodide to give pure ethyl 2-methyl-2-pheny]propanoate in 81% yield. Similarly, the alkylations of ethyl 2-phenylhexanoate with methyl iodide, M-butyl bromide, and benzyl chloride gave the corresponding pure dialkylated products in 73%, 92%, and 72% yields, respectively. 

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