Dimethyl sulfate, methylation with

All lation. In alkylation, the dialkyl sulfates react much faster than do the alkyl haHdes, because the monoalkyl sulfate anion (ROSO ) is more effective as a leaving group than a haHde ion. The high rate is most apparent with small primary alkyl groups, eg, methyl and ethyl. Some leaving groups, such as the fluorinated sulfonate anion, eg, the triflate anion, CF SO, react even faster in ester form (4). Against phenoxide anion, the reaction rate is methyl triflate [333-27-7] dimethyl sulfate methyl toluenesulfonate [23373-38-8] (5). Dialkyl sulfates, as compared to alkyl chlorides, lack chloride ions in their products chloride corrodes and requires the use of a gas instead of a Hquid. The lower sulfates are much less expensive than lower bromides or iodides, and they also alkylate quickly. 

Sulfates having alkyl groups from methyl to pentyl have been examined. With methyl as an example, the hydrolysis rate of dimethyl sulfate iacreases with the concentration of the sulfate. Typical rates ia neutral water are first order and are 1.66 x lO " at 25°C and 6.14 x lO " at 35°C (46,47). Rates with alkaH or acid depend on conditions (42,48). Rates for the monomethyl sulfate [512-42-5] are much slower, and are nearly second order ia base. Values of the rate constant ia dilute solution are 6.5 X 10 L/(mol-s) at 100°C and 4.64 X 10 L/(mol-s) at 138°C (44). At 138°C, first-order solvolysis is ca 2% of the total. Hydrolysis of the monoester is markedly promoted by increasing acid strength and it is first order. The rate at 80°C is 3.65 x lO " ... 

SuIfona.tlon, Sulfonation is a common reaction with dialkyl sulfates, either by slow decomposition on heating with the release of SO or by attack at the sulfur end of the O—S bond (63). Reaction products are usually the dimethyl ether, methanol, sulfonic acid, and methyl sulfonates, corresponding to both routes. Reactive aromatics are commonly those with higher reactivity to electrophilic substitution at temperatures > 100° C. Tn phenylamine, diphenylmethylamine, anisole, and diphenyl ether exhibit ring sulfonation at 150—160°C, 140°C, 155—160°C, and 180—190°C, respectively, but diphenyl ketone and benzyl methyl ether do not react up to 190°C. Diphenyl amine methylates and then sulfonates. Catalysis of sulfonation of anthraquinone by dimethyl sulfate occurs with thaHium(III) oxide or mercury(II) oxide at 170°C. Alkyl interchange also gives sulfation. 

Cleavage at A or G If the DNA is first treated with acid, dimethyl sulfate methylates adenine at the 3-position as well as guanine at the 7-position (not shown). Subsequent reaction with OH and piperidine triggers degradation and displacement of the methylated A or G purine base and strand scission, essentially as indicated here for reaction of dimethyl sulfate with guanine. 

Transmetalation of the a-stannylated ethers to the lithium compound and methylation using dimethyl sulfate occurs with high stereoselectivity (80-90% ee)35,36. 

Alkylation of chlorothiazide 154 (R = Cl) with dimethyl sulfate or with allyl bromide in aqueous or alcoholic alkali yields the 4-methyl and 4-allyl derivatives, respectively (60JOC970). Chlorothiazide-type compounds and their 3-oxo compounds, but not their 3,4-dihydro compounds, can be... 

Substrates 1-3 are readily prepared with a few steps as illustrated in Scheme 4. After methylation of pyridine with dimethyl sulfate, oxidation with potassium ferricyanide in the presence of sodium hydroxide leads... 

In the method of Bredereck for permethylation of carbohydrates, partially methylated material is dissolved in ether, sodium wire is added followed by dimethyl sulfate diluted with ether. The reaction is complete in about one hour. 

Veratric aldehyde has been prepared from vanillin by methyl-ation with dimethyl sulfate or with methyl iodide, and from veratrole by reaction with hydrogen cyanide in the presence of aluminum chloride. ... 

A key intermediate for the synthesis of several derivatives is 2-lithiotellurophene, obtained by metallation of tellurophene with 2-butyllithium in ethereal solution. Treatment of 2-lithiotellurophene with dimethyl sulfate, -methyl form anilide, acetaldehyde, carbon dioxide, hexachloroethane, hexabromoethane, and dimethyl sulfide gives, respectively, 2-methyltellurophene (10), tellurophene-2-carboxaldehyde (9), l(2-tellurienyl)ethanol (11), 2-tellurophenecarboxylic acid (12), 2-chloro-(13), 2-bromo- (14), and 2-methylthiotellurophene (15). 

R or X = H, 4-substituted derivatives of (1) are formed preferentially. N-Methyl-ation of (1) is accomplished readily with dimethyl sulfate buffered with sodium bicarbonate to give (2). 

Alkyl Sulfates. The alkyl sulfates used most frequently are dimethyl sulfate, methyl hydrogen sulfate, and diethyl sulfate. Sulfates with longer... 

Simple hydrolysis of natural DNA does not lead anywhere in analysis. If the acid hydrolysis is, however, preceded by base-modification reactions, one obtains Nobel prize-winning differentiations. This is documented in the simplified protocol developed by Maxam and Gilbert (Scheme 8.3.2). Dimethyl sulfate methylates guanine at N7 five times faster than N3 at adenine. None of the other bases reacts with dimethylsulfate if reaction times are kept short and the temperature low. Reaction conditions are selected in a way that only 1-2 % of the nu-cleobases react in a ratio of guanine adenine of 5 1. These bases are now... 

Based on the analysis and comparison of the mentioned chemical reactions, it can be known that 0 In the main reaction, it is easy to produce methyl nitrite, which makes it difficult to increase the total yield the product is not stable under acidic conditions 0 dimethyl sulfate is very easy to decompose into methanol under acidic and basic conditions 0 dimethyl sulfate reacts with sodium nitrite through two steps, in which the first step is the conversion of dimethyl sulfate into the intermediate methyl sulfonate followed by the higher energy-required reaction between methyl sulfonate and sodium nitrite, thus, in this step, the formation of byproduct methanol should be minimized through the hydrolysis of acid and base. 

Bipyridyls are converted by quatemization with dimethyl sulfate, methyl chloride or 1,2-dichloroethane into the herbicides paraquat and diquat, developed by William Boon (/C/). Paraquat is by far the more important of the two quat herbicides. 

The easiest organic azide and smallest member of azidomethanes, CH3N3, was first prepared by O. Dimroth in 1905 by simple methylation of sodium azide with dimethyl sulfate. Methyl azide has been proven to be more explosive than originally reported (same accounts for ethyl azide). The much more hazardous diazidomethane, CH2(N3)2 and triazidomethane, CH(N3)3, are accessible by rather time-consuming slow reactions of dichloro/dibromomethane and tribromomethane with a polymeric ammonium azide reagent. Several reports on the potential risk when working with azides in dichlorometh-ane exist, and are attributed to the potential formation of diazidomethane (please see appropriate references cited in ref. °). 

Also obtained by partial methylation of 2,4,6-trihydroxy-3-methylphenyl benzyl ketone with dimethyl sulfate or with an excess methyl iodide in the presence of potassinm carbonate in refluxing acetone for 3 h [5353],... 

As illustrated by the example in Section 24-8, dimethyl sulfate methylates aU free -OH groups in a molecule, converting them into -OCH3 groups by 8 2 processes. Carrying out this reaction with sucrose gives as the product... 

Chloroterranaphthoic acid monomethyl ether (prepn. s. 921) dissolved under N2 in methanolic 10%-KOH, methanol removed, finally by distillation with benzene, the resulting dry K-salt suspended in acetone, and refluxed 3 hrs. with dimethyl sulfate methyl chloroterranaphthoate dimethyl ether. Y 94%. —No methylation of the phenol group occurs in aq. alkaline soln. H. Muxfeldt, B.92, 3122 (1959). 

The most stable protected alcohol derivatives are the methyl ethers. These are often employed in carbohydrate chemistry and can be made with dimethyl sulfate in the presence of aqueous sodium or barium hydroxides in DMF or DMSO. Simple ethers may be cleaved by treatment with BCI3 or BBr, but generally methyl ethers are too stable to be used for routine protection of alcohols. They are more useful as volatile derivatives in gas-chromatographic and mass-spectrometric analyses. So the most labile (trimethylsilyl ether) and the most stable (methyl ether) alcohol derivatives are useful in analysis, but in synthesis they can be used only in exceptional cases. In synthesis, easily accessible intermediates of medium stability are most helpful. 

J. Rebek, Jr., (1987) first developed a new synthesis of Kemp s acid and then extensively explored its application in model studies. The synthesis involves the straightforward hydrogenation (A. Steitz, 1968), esterification and methylation of inexpensive 1,3,5-benzenetricar-boxylic acid (trimesic acid 30/100 g). The methylation of the trimethyl ester with dimethyl sulfate, mediated by lithium diisopropylamide (V. J. Shiner, 1981), produced mainly the desired aff-cis-1,3,5-trimethyl isomer, which was saponified to give Kemp s acid. 

Alkylation of bis(4-methyl-2-thiazolyl)urea (257) with dimethyl sulfate gives product 258 dimethylated on the ring nitrogens (Scheme 154) (488). Alkylation of l-alkyl-3-(2-thiazolyl)urea from its derived anion formed by NaH gives 259 (Scheme 155). 

The reactivity of sulfathiazoles has been reviewed (65). Methylation in alkaline solution with dimethyl sulfate gives only the ring methylated derivative (85). Mixtures of products are obtained with diazomethane as alkylating agent (see p. 37). Other alkyl halides in aqueous alkali lead also to ring-alkylated products (85. 251, 650. 669-671). 

QuaterniZation. Quaternary ammonium compounds are formed by alkylation of alkyl, alkyl dimethyl, dialkyl, and dialkylmethyl fatty amines with methyl chloride, dimethyl sulfate, or benzyl chloride (1,3,7,12,29). 

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