Ethyl iodide alkylation

Methyl iodide ethyl bromide ethyl iodide, higher alkyl halides, chloroform, iodoform, carbon tetrachloride, chlorobenzene, bromobenzene, iodobenzene, benzyl chloride (and nuclear substituted derivatives)... 

It is of interest to note that by substituting alkyl bromides for cyciohexyl bromide the corresponding a-phenyl-a-alkyl-acetonitriles are obtained, which may be hydrolysed to the a-phenylaliphatic acids thus with ethyl iodide a-phenyl-lwt3Tonitrile is produced, hydrolysed by ethanoUo potassium hydroxide to a-phenylbutyric acid. 

Note 1. Prepared by adding CS2 to CH MgBr in THE at 0°C, preferably in the presence of a small amount of CuBr (2 mol %), and subsequently alkylating with ethyl iodide . 

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. 

Substitutions. The cyanamide anion is strongly nucleophilic and reacts with most alkylating or acylating reagents (4) addition to a variety of unsaturated systems occurs readily (4). In some cases, a cyanamide salt is used in others, base catalysis suffices. Ethyl iodide reacts with sodium hydrogen cyanamide [17292-62-5] to form a trisubstituted isomelamine. 

Alkylations of cinnolin-4(lf/)-one (8) with methyl iodide, ethyl iodide, dimethyl and diethyl sulfates, isopropyl bromide, benzyl chloride, etc. take place predominantly at position 2 to give 2-alkyl-4-hydroxycinnolinium anhydro salts (83), together with small amounts of l-methylcinnolin-4-one (84). 

Various alkylating agents are used for the preparation of pyridazinyl alkyl sulfides. Methyl and ethyl iodides, dimethyl and diethyl sulfate, a-halo acids and esters, /3-halo acids and their derivatives, a-halo ketones, benzyl halides and substituted benzyl halides and other alkyl and heteroarylmethyl halides are most commonly used for this purpose. Another method is the addition of pyridazinethiones and pyridazinethiols to unsaturated compounds, such as 2,3(4//)-dihydropyran or 2,3(4//)-dihydrothiopyran, and to compounds with activated double bonds, such as acrylonitrile, acrylates and quinones. 

Deghenghi et al studied the reductive alkylation of 16-dehydropregneno-lone acetate in ammonia-tetrahydrofuran using excess lithium and alkyl iodides. Alkylation with methyl iodide followed by reacetylation of the 3-hydroxyl group affords 17a-methylpregnenolone acetate in 20% yield after purification by column chromatography. Ethyl iodide affords the 17a-ethyl analog in 40% yield, but n-propyl iodide affords the 17a-propyl compound in only a 12 % yield. 

I hc alkyl halides are utilised in a taiiety of leactioiis, examples of w hich arc gi en, ethyl iodide being taken as the type. 

Ethylmalonic Acid.—Like acetoacetic ester (see p. 83), diethylmalonate contains the gioup CO.CHj.CO. By the action of sodium or sodium alroholate, the hydrogen atoms of the methylene group are successively replaceable by sodium. The sodium atoms are in turn replaceable by alkyl or acyl groups. Thus, in the present preparation, ethyl malonic ester is obtained by the action of ethyl iodide on the monosodium compound. If this substance be treated with a second molecule of sodium alcoholate and a second molecule of alkyl iodide, a second radical would be in roduced, and a compound formed of the general formula... 

With enamines of cyclic ketones direct C alkylation occurs with allyl and propargyl as well as alkyl halides. The reaction is again sensitive to the polarity of the solvent (29). The pyrrolidine enamine of cyclohexanone on reaction with ethyl iodide in dioxane gave 25% of 2-ethylcyclohexanone on hydrolysis, while in chloroform the yield was increased to 32%. 

Alkylation of enamino ketones occurs on oxygen, as would be expected from the site of protonation. Thus 4-N-pyrrolidino-3-penten-2-one (47) gave N-(2-ethoxy-2-penten-4-ylidene)-pyrrolidinium iodide (48) on alkylation with ethyl iodide (22), and the enamino ketones derived from 5,5-... 

In a similar manner it was shown (47) that the enamino ketone (54) on treatment with ethyl iodide gave an intermediate hydroiodide from which 7-ethoxy-2,3,4,5,6,10-hexahydroquinoline (55) was obtained on treatment with base. The corresponding N-alkylated product was obtained by alkylation of (54) in the presence of sodium hydride. 

Electrostatic interactions can guide alkylation under certain conditions. Examine the electrostatic potential map of the potassium enolate of ethyl acetoacetate. Is carbon or oxygen more electron rich Are electrostatic interactions likely to favor addition of oxygen or carbon Examine atomic charges and electrostatic potential maps for diethylsulfate, ethyl chloride, ethyl bromide and ethyl iodide, pay attention to the backside of the electrophilic carbon. Order the systems from most to least electron poor. Which reaction is most likely to be guided by electrostatics Least likely Can the experimental results be fully explained on this basis ... 

Angier and Marsico followed the course of alkylation first. The 7-dimethylamino-5-methylmercapto derivative reacted with dimethyl sulfate in an alkaline medium to yield a mixture of the 2- and 3-methyl derivatives. The reaction of the 7-diraethylamino derivative with ethyl iodide in an alkaline medium led to a mixture of all three possible monoethyl derivatives. The position of the alkyl group in all these substances was defined by comparing the UV spectra with derivatives prepared by a straightforward synthesis. After reacting the mercuric salts with tri-0-benzoylribofuranosyl chloride, they demonstrated the ribose residue to be bound in position 2. The same structure was shown to be valid for the derivative prepared by Andrews and Barber. ... 

Ethyl iodide and 5-amino-2-methyl-l,3,4-thiadiazole react at 110° to give the N-3 salt (78 R = Me, R = NH2, R" = Et), as shown by the presence of the very reactive methyl group this salt is also used to prepare cyanine dyes. The slow quatemization at the ring-nitrogen atom furthest from the amino group is consistent with the reactions observed in other ring systems. As would be e pected, 5-alkylthio-2-methyl-l,3,4-thiadiazoles form salts at the N-3 (78 R = Me, R - S-alkyl).i ... 

That alkylation of the anhydro-bases takes place at the indole nitrogen atom in the jS-carboline series was established conclusively by the identity of the product (429), prepared by treatment of pyr-N-ethyl-jS-carboline anhydro-base (428) with ethyl iodide, with 2,9-diethyl-jS-carbolinium iodide (429) obtained from the reaction of imi-A-ethyl-jS-carboline (430) with ethyl iodide (see Section IV, A, 2). 

Because of the basic nitrogen atom, alkyl-selenazoles form quaternary salts. 2,4-Dimethyl-3-ethylselenazolium iodide (mp 157-158 0) was prepared by Brooker et al in 87% yield as colorless crystals by heating of 2,4-dimethylselenazole in excess ethyl iodide for 2 days. By reaction with the corresponding quaternary salts, the following cyanine dyes (8) were prepared" l 3-diethyl-4-methylselenazolo-2 -... 

One of the earliest preparations of this ring system starts with displacement of the hydroxyl of benzaldehyde cyanohydrin (125) by urea. Treatment of the product (126) with hydrochloric acid leads to addition of the remaining urea nitrogen to the nitrile. There is thus obtained, after hydrolysis of the imine (127), the hydantoin (128). Alkylation by means of ethyl iodide affords ethotoin (129)... 

An imidazole derivative which is also a hypotensive agent by virtue of adrenergic a-2-receptor blockade is imiloxan (75). Its synthe.sis begins by conversion of 2-cyanomethyl-1,4-benzodioxane (72) to its iminosMhylether with anhydrous HC in clhanol (73). Reaction of the latter with aminoacetaldehyde diethylacetal and subsequent acid treatment produces the imidazole ring (74). Alkylation of 74 with ethyl iodide mediated by sodium hydride completes the synthesis [251. 

Benzaldehyde cyanohydrin is reacted with urea to displace the hydroxyl group of the cyanohydrin. That intermediate is treated with HCI to convert the urea nitrogen to a nitrile. The resultant imine is hydrolyzed to the phenylhydantoin. Alkylation with ethyl iodide gives ethotoin, as described by A. Pinner in Chem. Ber. 21, 2325 (1888). 

Between sulfur dioxide radical anions, dithionite, and sulfoxylate/sulfite there exists a pH-dependent equilibrium465 (equation 86). Therefore, dithionite has been used as a source of sulfoxylate in order to prepare sulfinate and hence sulfones. Alkylation with triethyl oxonium fluoroborate leads to ethyl ethanesulfinate, alkyl iodides lead to symmetrical sulfones466 (equation 87). 

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