Ethers, alkylating agent

MAJOR USES Lab reagent chloromethylation monitoring indicator for chloromethyl ether alkylating agent in manufacture of polymers research chemical intermediate in the synthesis of anionic exchange strong base resins of the quartemary ammonium type. 

The hydroxyl groups can be alkylated with the usual alkylating agents. To obtain aryl ethers a reverse treatment is used, such as treatment of butynediol toluenesulfonate or dibromobutyne with a phenol (44). Alkylene oxides give ether alcohols (46). 

The most frequentiy used halo alkylating agents are aldehydes and hydrogen haUdes, haloalkyl ethers, haloalkyl sulfides, acetals and hydrogen haUdes, di- and polyhaloalkanes, haloalkenes, haloalcohols, haloalkyl sulfates, haloalkyl -tosylates, and miscellaneous further haloalkyl esters. Haloalkylations include halomethylation, haloethylation, and miscellaneous higher haloalkylations. Under specific conditions, bis- and polyhaloalkylation can also be achieved. 

Reaction conditions depend on the reactants and usually involve acid or base catalysis. Examples of X include sulfate, acid sulfate, alkane- or arenesulfonate, chloride, bromide, hydroxyl, alkoxide, perchlorate, etc. RX can also be an alkyl orthoformate or alkyl carboxylate. The reaction of cycHc alkylating agents, eg, epoxides and a2iridines, with sodium or potassium salts of alkyl hydroperoxides also promotes formation of dialkyl peroxides (44,66). Olefinic alkylating agents include acycHc and cycHc olefinic hydrocarbons, vinyl and isopropenyl ethers, enamines, A[-vinylamides, vinyl sulfonates, divinyl sulfone, and a, P-unsaturated compounds, eg, methyl acrylate, mesityl oxide, acrylamide, and acrylonitrile (44,66). 

As alkylating agent an alkyl halide, alkyl tosylate or dialkyl sulfate is used in most cases the latter type of reagent is often used in the preparation of methyl and ethyl ethers by employing dimethyl sulfate and diethyl sulfate respectively. Dimethyl sulfate is an excellent methylating agent, but is acutely toxic as well as carcinogenic." ... 

Meerwein s reagent, triethvloxonium tetrafluoroborate, is a powerful ethylating agent that converts alcohols into ethyl ethers at neutral pH. Show the reaction of Meerwein s Teagent with cyclohexanol, and account for the fact that trialkyloxonium salts are much more reactive alkylating agents than alkyl iodides. 

The monoacetate 9a (R1 = Ac) and the diacetate 10a (R1 = R2 = Ac) are obtained by treatment of 8 with acetic anhydride in anhydrous pyridine at room temperature 4 the oxo group in position 5 of 8 is more reactive towards acetylation. Similarly, the S,S-dioxidc of 8 can be converted to the bisacetylated S,5-dioxide of 10a in 78 % yield.74 Methylation of 8 with diazomethane gives 9c (65 % yield), along with 14 % of the 3-methoxy compound 11. Other alkylation agents, such as dimethyl sulfate in the presence of potassium carbonate, selectively give 9c, albeit in lower (30 %) yield.90 The dimethyl enol ether 10c (R1 = R2 = Me) is obtained by a subsequent methylation of 9c (R1 = Me) with dimethyl sulfate and potassium teri-butoxide.90... 

Oxonium ions are excellent alkylating agents, and ethers can be conveniently prepared by treating them with alcohols or phenols. Quaternary ammonium salts can sometimes also be used. ... 

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allyl and benzyl halides, a-halo esters, a-halo ethers, and a-halo ketones are the most successful alkylating agents. The use of enamines for selective alkylation has largely been supplanted by the methods for kinetic enolate formation described in Section 1.2. 

However, pMBCl 42 has a thermal stability issue and is expensive (Aldrich price 25 g for 69.90 the largest bottle). On the other hand, pMBOH 43 is stable and economically viable (Aldrich price 500 g for 84.90 the largest bottle). It was found that mono-N-alkylation of 36 proceeded well by slow addition (over 3 h) of 43 to a solution of 36 in acetonitrile in the presence of a catalytic amount of acid (p-TsOH) at 70 °C, as shown in Scheme 1.16. Slow addition of alcohol 43 minimized the self-condensation of 43 to form symmetrical ether 44, which was an equally effective alkylating agent. The product 41 was then directly crystallized from the reaction mixture by addition of water and was isolated in 90% yield and in >99% purity. A toluene solution of 41 can be used for the next reaction without isolation but the yield and optical purity of the asymmetric addition product were more robust if isolated 41 was used. In general, the more complex the reaction, the purer the starting materials the better. 

To [Co(en)2((S)-GluOBzl)]I2 (5.0 g, 7.3 X 10 3 mol) in dry trimethyl-phosphate (18 ml, 4A sieves) contained in a conical flask equipped with a drying tube was added methyl trifluoromethane sulfonate (8.0 g, 4.9 x 10 2 mol) and the mixture was stirred at room temperature for 30 min (Caution The alkylating agent is believed to be extremely toxic. Use a hood and avoid skin and vapor contact). The deep orange solution was then slowly poured into rapidly stirred dry ether (600 ml) and the precipitated semisolid recovered by decantation. The residue was dissolved in the minimum volume of dry methanol (10-20 ml), the product reprecipitated using further dry ether (400 ml), and the solid recovered as before. A further precipitation using methanol (10-20 ml) and dry ether (800 ml) produced the complex as a finely divided solid. This was recovered by filtration (porosity 4 sin-... 

Method A An excess of the alkylating agent (15 mmol) is added to the glycoside (5 mmol) and TBA-Br (0.16 g, 0.5 mmol) in PhH (20 ml). Aqueous NaOH (50%, 20 ml) is added and the mixture is stirred at ca. 20 °C until the reaction is complete, as shown by TLC analysis. The organic phase is separated, washed with H20 (2 x 25 ml), dried (MgS04), and evaporated to yield the glycosidyl ether. 

The alkylating agent (50 mmol) is added to a stirred solution of potassium O-alkyl dithio-carbonate (50 mmol) and Aliquat (1.68 g, 4 mmol) in H20 (50 ml). The mixture is stirred until the aqueous phase is completely colourless (Table 4.8) and petroleum ether (b.p. 40-60 °C, 150 ml) is then added. The organic layer is separated, dried (MgS04), filtered through silica, and evaporated under reduced pressure to yield the 0,5-dialkyl ester. 

Method A The azole (10 mmol) is added to powdered KOH (1.6 g, 28 mmol) and TBA-Br, 0rTBA-HSO4, (0.25 mmol) and the mixture is stirred at room temperature for 10 min. The alkylating agent (11 mmol) is then added and the mixture is stirred at room temperature for 10-15 min (for the more reactive haloalkanes) or at 50°C for 2 h (for the less reactive haloalkanes). Et20 (30 ml) is added and the mixture is fdtered. Evaporation of the ethereal solution under reduced pressure yields the A-alkylazole. 

Method A Aqueous NaOH (50%, 100 ml) is added to TEBA-Cl (23 mg, 0.1 mol) and the methylene compound (0.1 mol) and the mixture is stirred at room temperature for 15 min. The alkylating agent (0.2 mol) in CH2C12 or PhH (100 ml) is then added dropwise and the two-phase system is stirred for 10-30 min at ca. 50 °C. The organic phase is then separated, dried (MgS04), and evaporated. Et20 (50 ml) is added to the residue and the ethereal solution is filtered and evaporated to yield the alkylated product. 

Method F The phosphoric diamide (30 mmol) and alkylating agent (72 mmol) in CH2C12 (30 ml) are added rapidly with stirring to TBA-OH (9.3 g, 36 mmol) in aqueous NaOH (60%, 65 ml). The mixture is stirred for 30 min and then extracted with CH2C12 (2 x 50 ml). The dried (MgS04) extracts are evaporated and the residue is triturated with EtzO (100 ml). Evaporation of the ethereal solution gives the alkylated product. 

Method H (with microwave irradiation) An intimate mixture of the p-keto ester. (5 mmol), the alkylating agent (5 mmol), KOH K2CO, (1 4, 4 g), and TBA-C1 (0.15 g, 0.5 mmol) is irradiated in a 650 W microwave oven. When the reaction is complete, Et20 (50 ml) is added to the cooled solid, the suspension is filtered, and the ethereal filtrate is evaporated to yield the alkylated product. 

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