Methyl iodide, reaction with enamines

Anotheranalogy between the enolate anions derived from a,)3-unsatura ted ketones and the corresponding enamines is encountered in their alkylation reactions (57), which proceed by the kinetically controlled attack at the a-carbon atom. For instance, Stork and Birnbaum (51) found that the alkylation of the morpholine enamine of /J -octalone-2 (117) with methyl iodide gave the C-1 methylated derivative (118). 

The pyrrolidine enamines of /l -3.]cetosteroids (111), on alkylation with methyl iodide, gave mainly the N-alkylated product (5,55) in nonpolar solvents such as benzene. The reaction in more polar solvents gave the 4-methylated product (5.S). The reaction of (111) with perchloryl fluoride involves attack at the C-4 atom to give, after acid hydrolysis, either 4-fluoro-zJ -3-ketone (119) or 4,4-difluoro-zJ -3-ketone 120), depending on the reaction conditions (59). 

The scheme used to produce a somewhat more complex 5-a-reductase inhibitor relies on a chiral auxiliary to yield the final product as a single enantiomer. The first step in a sequence similar to that above starts with the reaction of bromotetralone (23-1) with R-a-phenethyl amine (23-2) to afford the enamine (23-3). Reaction with methyl iodide adds the methyl group at what will be a steroid-like AB ring junction... 

Pyrrolizidine itself can be oxidized by H20-Fe3+ to an enamine (38) which gives (28) with methyl iodide (79CPB1981). The alkaloid derivative, ( )-isoretrorecanol, has been synthesized via (39) (69JOC1066) by the use of transannular reactions of the type described above. 

C- Methylation takes place in preference to /V-methylation in the reaction of (99) with methyl iodide. This is in contrast to the corresponding quinolizidine enamine, presumably because of the greater steric strain of a tetrahedral nitrogen atom in a five-membered ring. 

There is, however, a major problem with enamines reaction at nitrogen. Less reactive alkylating agents—simple alkyl halides such as methyl iodide, for example—react to a significant degree at N rather than at C. The product is a quaternary ammonium salt, which hydrolyses back to the starting material and leads to low yields. 

A significant improvement in the alkylation of ketone and aldehyde enamines involves the use of sterically hindered amines63. N-Alkylation is prevented with consequent increase in C-alkylation. For example, reaction of the w-butylisobutylamine enamine of cyclohexanone (29) with methyl iodide in boiling acetonitrile (Scheme 16), or trimethy-loxonium tetrafluoroborate at room temperature gave 2-methylcyclohexanone in increased yields of 56% and 74%, respectively63 (compare Scheme 10). 

A valuable feature of the enamine reaction is that it is regioselective. Thus, in the alkylation of an unsymmetrical ketone, e.g. 3.4, the substitution takes place at the less substituted a-carbon atom. However, direct base-catalyzed alkylation of unsymmetrical ketones usually gives a mixture of products. Also in the enamine reactions, since no alkali is used, there is no possibility of side products, which are normally obtained from carbonyl compounds. For example, the reaction of enamine 3.42 with methyl iodide followed by hydrolysis gives almost exclusively 2,6-dimethylcyclohexanone (3.43) (Scheme 3.20). 

The monomethylation of the pyrrolidine enamine of -tetralone shown in Scheme 41 provides a highly successful example of the reaction. Attempted alkylation of the ketone with 1 equiv. of methyl iodide in the presence of a strong base gave almost exclusively the recovered ketone and its dimethylated derivative. 

Imidazoles.—Formation. Several new syntheses of imidazoles from isocyanides have been reported these include the formation of 1-alkyl-imidazoles (396) by the action of primary amines on 2-isocyano-2-tosylstyrene, PhCH=C-(NOTos, the cyclization of the enamine Me2NCH=C(NC)C02Me to compound (397) in the presence of methyl iodide,and the preparation of the ethers or thioethers (398) from isocyano-cyanides R CH(NC)CN by their reaction with alcohols or thiols R XH, respectively.Aromatic aldehydes are converted into 2-aryl-4,5-dichloroimidazoles (399) by the combined action of cyanogen and hydrochloric acid. 5-Acetyl-4-methylimidazole (400) results when form-amido-acetylacetone, AC2CHNHCHO, is heated with formamide and formic acid. Exhaustive chlorination of tetramethyldithio-oxamide leads to the tri-chloro-imidazolium cation (401). ... 

Having precursor 407 in hand. Brooks et al. were able to synthesize anguidine (376) in a further 17 steps. Thus, precursor 407 was converted into enamine 409, which was hydrolyzed to hydroxymethylene derivative 410. Michael reaction with butanone afforded the exo product 411. Followed by an intramolecular Michael aldol condensation, enone 412 was obtained, which was methylated to the allyl alcohol 413 using methyl iodide. Subsequent reduction with Ufliium aluminum hydride led to tetraol 414. This was converted to the triacetate and selectively deprotected to diol 415. Acid-catalyzed cycUzation and protection of the free OH group afforded the trichothecene skeleton 416. Afterwards, the acetal 416 was deprotected and the ketone was reacted in a Wittig reaction to the olefin, which was treated with TBAF to afford compound 417. Epoxidation with /n-CPBA, followed by acetylatiOTi and final mono-deprotection, afforded the trichothecene, anguidine (376) (Scheme 8.4). 

Condensations of amines with 1-chlorocycloheptene in the presence of the complex base , sodamide and sodium t-butoxide, gave mixtures of enamines and cyclo-hepta-1,2-diene dimer. Excess n-butyl-lithium has been used to convert vinyl and aryl bromides into organolithium compounds which undergo useful reactions with, for example, benzophenone, dimethyl disulphide, diphenyl disulphide, trimethylsilyl chloride, and methyl iodide. Hence 1-bromo-cis-cyclononene was converted into 1-methylthio-cis-cyclononene via 1-lithio-cis-cyclononene the 1-methylthio... 

The reactions of enamines with electrophiles follow a similar course and are also of OE t type. Enamines are isoconjugate with enolate ions and can likewise react with electrophiles in two different ways, either on nitrogen to form an enammonium ion or on carbon to form a methyleneammonium ion. As in the case of enolate ions, protonation takes place more rapidly on the heteroatom (here nitrogen) rather than carbon while allyl halides, e.g., methyl iodide, give C-alkylated products e.g.. 

Both of these reactions result in the alkylation of 4-t-butylcyclohexanone, but the selectivity obtained is very different. The lithium enolate produced on reaction with LDA is sterically undemanding, and hence approach of the methyl iodide is possible either axially or equatorially there is a marginal preference for the more stable equatorial product. However, the pyrrolidine ring of the enamine is much bulkier and inhibits approach to the equatorial position more than it does to the axial position. 

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