Iodomethane

MeI

[74-88-4]  · CH3I  · Iodomethane  · (MW 141.94)

(methylating agent for carbon, oxygen, nitrogen, sulfur, and trivalent phosphorus)

Alternate Name: methyl iodide.

Physical Data: bp 41-43 °C; d 2.28 g cm-3.

Solubility: sol ether, alcohol, benzene, acetone; moderately sol H2O.

Form Supplied in: colorless liquid; stabilized by addition of silver wire or copper beads; widely available.

Purification: percolate through silica gel or activated alumina then distill; wash with dilute aqueous Na2S2O3, then wash with water, dilute aqueous Na2CO3, and water, dry with CaCl2 then distill.

Handling, Storage, and Precautions: toxic, corrosive and a possible carcinogen. Liquid should be stored in brown bottles to prevent liberation of I2 upon exposure to light. Keep in a cool, dark place. Use only in well ventilated areas.

C-Methylation.

Methyl iodide is an active alkylating agent employed in the C-methylation of carbanions derived from ketones, esters, carboxylic acids, amides, nitriles, nitroalkanes, sulfones, sulfoxides, imines, and hydrazones.1 The quantity of methyl iodide utilized in methylations varies from a slight (1.1 equiv) to a large excess (used as solvent).

The monomethylation of carbanions derived from 1,3-cyclohexanedione and acetylacetone has been described (eqs 1 and 2).2 Selective monomethylation of b-diketones is dependent upon the base employed; variable amounts of O-methylation, dimethylation, and carbon-carbon bond cleavage may occur. The tetraethylammonium enolate of b-diketones reportedly provides higher yields of C-methylation without competing side reactions (eq 3).3 Dimethylation is sometimes a desired reaction pathway. In this case, a large excess of both methyl iodide and base favors the dimethylated product (eq 4).4 Recently, the combination of a potassium base and a catalytic amount of 18-Crown-6 (eq 5) has been described to provide a higher yield of dimethylation.5,6

Methylation of kinetically derived enolates is most readily accomplished via the corresponding silyl enol ether.7 Lithium enolates, generated by treatment of the silyl enol ether with Methyllithium, may then be alkylated with methyl iodide (eq 6).8 Alternatively, quarternary ammonium enolates are produced by treatment of the silyl enol ether with the corresponding fluoride salt. For example, monomethylation of a ketone is cleanly effected by treatment of an anhydrous mixture of the trimethylsilyl enol ether of the ketone in methyl iodide with benzyltrimethylammonium fluoride (eq 7).9 Kinetic enolates produced from the conjugate addition of an organocuprate to an unsaturated ketone or a dissolving metal reduction of an enone may be methylated directly.7c However, the choice of solvent is crucial for the success of these reactions. Ether, the solvent typically used in organocopper conjugate additions, is a poor solvent for alkylation reactions.10 N,N,N,N-Tetramethylethylenediamine (TMEDA), Hexamethylphosphoric Triamide (HMPA) and liquid Ammonia have been used as additives to increase the efficiency of alkylation. Alternatively, the solvent used in the conjugate addition can be removed in vacuo and replaced with a more effective medium for alkylation. For example the rate of methylation of the enolate produced in the conjugate addition of Lithium Dimethylcuprate to an enone is approximately 105 times faster in DME than in ether (eq 8).11

The stereoselectivity of the methylation of ketone enolates is determined by the structure of the substrate.12 Stereoselective methylation of cyclic ketone enolates has been examined in detail and current models reliably predict the stereochemical outcome (eqs 9-11).13-15 Diastereoselective methylation of acyclic ketone and ester enolates has been accomplished employing a variety of chiral auxiliaries (eq 12).12,16 Efficient catalytic enantioselective methylation of 6,7-dichloro-5-methoxy-1-indanone has been accomplished via a chiral phase-transfer catalyst (eq 13).17 An enantiomeric excess of 92% was observed when employing Chloromethane as the methylating agent, whereas methyl iodide provided a product of only 36% enantiomeric excess.

O-Methylation.

Carboxylic acids can be converted to the corresponding methyl ester by stirring a mixture of the carboxylic acid in methanol with an excess of methyl iodide and Potassium Carbonate.18 A recent report describes the esterification of carboxylic acids using Cesium Fluoride and methyl iodide in DMF (eq 14).19 Dimethyl Sulfate has also been advantageously utilized to effect O-methylation of carboxylic acids as well as alcohols (eq 15).18c,20 These methods often serve as useful alternatives to Diazomethane for preparative scale esterification of carboxylic acids.

Phenolic hydroxyls are readily methylated by methyl iodide under basic conditions. The most common conditions are methyl iodide and potassium carbonate in acetone (eq 16).18a,21 The use of Lithium Carbonate as the base allows for the selective protection of phenols with a pKa < 8 (eq 17).18c The peri-hydroxy group of an anthraquinone is methylated using methyl iodide and Silver(I) Oxide in chloroform (eq 18).18a,22

Aliphatic alcohols are also methylated by methyl iodide under basic conditions in dipolar aprotic solvents (eqs 19 and 20).23 Typical conditions employ Sodium Hydride as a base, DMF as the solvent and an excess of methyl iodide.24 Alternatively, dimethyl sulfate or Methyl Trifluoromethanesulfonate may be used as the methylating agent. Under acidic conditions, diazomethane will also methylate aliphatic hydroxy groups. Finally, methylation of a hydroxy group may be achieved under essentially neutral conditions using silver(1) oxide (eq 21).23,25

S-Alkylation.

Methyl iodide alkylates thioalkoxides and sulfides to produce sulfides and sulfonium ions, respectively. For example, thioalkoxides produced from thiocarbonyl compounds are methylated with methyl iodide to generate the corresponding methyl thioether (eq 22).26 Sulfonium halides, derived from the reaction of methyl iodide with an alkyl sulfide, are sometimes labile in solution and may undergo further reaction (eq 23).27,28 Dimethyl Sulfoxide when refluxed with an excess of methyl iodide produces trimethyloxosulfonium iodide, which is collected as a white solid and recrystallized from water. Similarly, methylation of Dimethyl Sulfide produces trimethylsulfonium iodide.29 Treatment of trimethyloxosulfonium and trimethylsulfonium salts with a base yields the corresponding ylides, which serve as useful methylene transfer reagents. Silver(I) Perchlorate promotes the methylation of less reactive sulfides (eq 24).30

Hydrolysis of sulfonium salts serves as a useful protocol for removal of a protecting group or hydrolysis of a carboxylic acid derivative. For example, thioamides are converted into the corresponding methyl esters by methylation with methanolic methyl iodide followed by treatment with aqueous potassium carbonate (eq 25).31 Methyl thiomethyl ethers are readily hydrolyzed using an excess of methyl iodide in aqueous acetone (eq 26).32 Under similar reaction conditions, thioacetals are hydrolyzed to the corresponding carbonyl compounds (eq 27).33

N-Methylation.

The direct monomethylation of ammonia or a primary amine with methyl iodide is usually not a feasible method for the preparation of primary or secondary amines since further methylation occurs. However, methylation of secondary and tertiary amines leading to the production of tertiary amines and quaternary ammonium salts, respectively, is a useful method. Secondary N-methylalkylamines can be prepared from primary amines by a multi-step sequence involving first methylation of the benzylidene of the primary amine followed by hydrolytic removal of the benzylidene group (eq 28).34 An alternative to the methylation procedure using methyl iodide is the employment of Eschweiler-Clarke conditions.35 Exhaustive N-methylation of amines results in the production of a quaternized amine. The use of 2,6-Lutidine as base is beneficial to carry out quaternization of amines due to the slow rate of methylation of 2,6-lutidine (eq 29).36 Quaternized ammonium salts are employed in the Hofmann elimination (eqs 30 and 31).37,38 As in the case of alcohol methylation, silver(I) salts may be used to facilitate the methylation process (eq 32).39 Finally, conditions for the methylation of indole have been reported (eq 33).40

P-Methylation.

Phosphonium salts are prepared by the quaternization of phosphines with methyl iodide.41 The displacement reaction is usually conducted in polar solvents such as acetonitrile or DMF. Dialkyl phosphonates are prepared from the reaction of trialkyl phosphites with alkyl halides, commonly known as the Arbuzov reaction.42 For example, diisopropyl methylphosphonate is prepared by heating a mixture of methyl iodide and Triisopropyl Phosphite (eq 34).43


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Gary A. Sulikowski & Michelle M. Sulikowski

Texas A&M University, College Station, TX, USA



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