Chloromethyl with sodium iodide

A) PivaloyloxymethylD(—j-Oi-azidobenzylpenicillinate Toa suspension ofpotassiumD(—)-a-azidobenzylpenicillinate (4.14g) and potassium dicarbonate (1.5 g) in acetone (100 ml) and 10% aqueous sodium iodide (2 ml), chloromethyl pivalate (2.7 ml) was added and the mixture refluxed for 2 hours. After cooling, the suspension was filtered and the filtrate evaporated to dryness in vacuo. The remaining residue was washed repeatedly by decantation with petroleum ether to remove unreacted chloromethyl pivalate. The oily residue was taken up in ethyl acetate (100 ml), and the resulting solution washed with aqueous sodium bicarbonate and water, dried and evaporated in vacuo to yield the desired compound as a yellowish gum, which crystallized from ether, melting point 114°C to 115°C. 

Another way to synthesize ibuprofen consists of the chloromethylation of Ao-butylben-zene, giving 4-Ao-butylbenzylchloride (3.2.24). This product is reacted with sodium cyanide, making 4-Ao-butylbenzyl cyanide (3.2.25), which is alkylated in the presence of sodium amide by methyl iodide into 2-(4-iAo-butylbenzyl)propionitrile (3.2.26). Hydrolysis of the resulting product in the presence of a base produces ibuprofen (3.2.23). 

Methylthiomethyl has been used as the protecting group in the total synthesis of neoechinulin A (80TL2817). Cyclo(L-Ala-Gly) was treated with sodium hydride in DMF and N-alkylated with chloromethyl methyl thioether at room temperature, to give the bis(methylthiomethyl) derivative. After further chemical transformations, deprotection was achieved by treatment with methyl iodide in the presence of NaHC03 at 40°C for 3 days, followed by heating in dioxane at 100°C for 1 h. 

A simple variant of this strategy has been applied to the successful synthesis of ( )-hippeastrine (180) (Scheme 20) (140). In the event, vigorous hydrolysis of the urethane ester 61 followed by the carbodiimide-induced cyclization of the resulting amino acid and N-methylation with sodium hydride in methyl iodide furnished the lactam 207. Conversion of 207 to 208 was achieved by chloromethylation followed by reaction of the intermediate chloromethyl compound... 

Methylthiomethyl esters have been prepared by reaction of trie thy lammonium salts of carboxylic acids with chlorodimethylsulfonium chloride191 or by reaction of the potassium salts of carboxylic acids with chloromethyl methyl sulfide in the presence of sodium iodide and 18-crown-6.192... 

Protection of hydroxyl groups. Hydroxyl groups can be protected as the methylthiomethyl ether, prepared by reaction of a sodium alkoxide with chloromethyl methyl sulfide and sodium iodide (1 eq. of each) at 0° for 1 hr. and... 

The mobile chlorine atoms in the CICH2 groups can easily be substituted with iodine by boihng the chloromethylated polymer with twofold molar excess of sodium iodide in a mixture of acetone and dioxane (3 1, v/v) [378]. A polymer with an 83% degree of iodomethylation was thus obtained on the base of a macronet isoporous matrix prepared by post-crosshnking of a styrene-0.8% DVB copolymer with 11% additional bridges formed by 4,4 -bis (chloromethyl) diphenyl. 

Weakly acidic phenols that do not react with diazomethane can be methylated with sodium hydride and methyl iodide in THF at room temperature. The methoxymethyl ether moiety can be used to protect phenols. It is stable to alkali, Grignard reagents, lithium aluminum hydride, and catalytic hydrogenation, and is readily removed by mineral acid. Dimethoxymethane can be used in lieu of the carcinogenic chloromethyl methyl ether for this purpose. Alternatively, phenols may be protected as methyl thiomethyl ethers.The (9-acetylation of phenols in the presence of primary and secondary amines can be carried out with acetyl bromide and TFA. ... 

Although phase transfer catalysis is certainly an important and extremely versatile tool for the chemical modification of chloromethyl polystyrene, it is not necessarily always the best method as excellent results can also be obtained for some nucleophilic displacements when DMF or even DMSO (at low temperature to avoid oxidation to the carboxaldehyde polymer) are used as solvent for the nucleophile. For example, we prefer to use a solution of sodium cyanide in DMF to prepare cyanomethyl polystyrene from I rather than using a different solvent and phase transfer conditions, and we routinely prepare iodomethyl polystyrene from I by reaction with sodium or potassium iodide in acetone rather than under the conditions of Gozdz (Ref. 25). Recent work by Bied-Charreton et al. (Ref. 32) has also shown that excellent results could be obtained even under classical conditions in the transformation of I into its malononitrile derivative if the chloromethylated polymer is first transformed into the more reactive iodomethyl derivative this is in sharp contrast with earlier data from the same laboratory (Ref. 33). 

A mixture of norcodeine hydrochloride (11.48 g, 27.8 mmol), (chloromethyl)cyclopropane (5.14 g, 55.6 mmol), sodium carbonate (14.73 g, 139.0 mmol), and potassium iodide (4.61 g, 27.8 mmol) in ethanol (250 ml) was heated at reflux for 20 hr, cooled, and evaporated in vacuo to dryness. The residue was basified with NH4OH, and extracted with methylene chloride. The extract was washed with water and evaporated in vacuo to dryness. The residue (11.7 g) was chromatographed on silica gel with a eluting solvent system of methanol/ethyl acetate (10/90) to give 17-cyclopropylmethylnorcodeine (10.68 g, 91% yield). 

Deuterolysis of 3-chloro-2-chloromethyl-5-methoxypyrazine over 5% palladium on alumina in the presence of sodium isopropoxide in 2-propanol afforded 3-deutero-2-monodeuteromethyl-5-methoxypyrazine (687) and methylation of the bromomagnesium derivative from 2-bromomethyl-3,5,6-trimethylpyrazine with methyl sulfate or methyl iodide gave 2-ethyl-3,5,6-trimethylpyrazine (330). 

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