Diazomethane-Boron trifluoride etherate

The value of methylation studies in structural determination of carbohydrates is well known. Methylation of sucrose has generally been achieved by the use of dimethyl sulfate-sodium hydroxide,34,35 methyl iodide-silver oxide-acetone,20 sodium hydride-methyl io-dide-N,N-dimethylformamide,35 or diazomethane-boron trifluoride etherate.36,37 The last method (already applied to monosaccharides38,39) has been found particularly useful for sucrose, because it proceeds without concomitant migration of acyl groups. The reaction of 2,3,6,T,3, 4, 6 -hepta-0-acetylsucrose (21) and 2,3,4,6,1, 3, 4 -hepta-O-acetylsucrose (22) with diazomethane in dichloromethane in the presence of a catalytic proportion of boron trifluoride etherate for 0.5 h at —5° gave the corresponding 4-methyl (23) and 6 -methyl (24)... 

Methyl Ethers. Methylation of sucrose is generally conducted under basic conditions. Etherification occurs initially at the most acidic hydroxyl groups, HO-2, HO-T, and HO-3f, followed by the least hindered groups, HO-6 and HO-6. Several reagents have found use in the methylation of sucrose, including dimethyl sulfate—sodium hydroxide (18,19), methyl iodide—silver oxide—acetone, methyl iodide—sodium hydride in N, N- dimethyl form amide (DMF), and diazomethane—boron trifluoride etherate (20). The last reagent is particularly useful for compounds where mild conditions are necessary to prevent acyl migration (20). 

The structures of partially benzoylated derivatives of 1,6-anhydro-4, 6 -0-benzylidene-/3-maltose were established by methylation studies.51 During the course of this investigation, 2,3- and 3,3 -di- and 2,3,3 -tri-methyl ethers of l,6-anhydro-4, 6 -0-benzylidene-/3-maltose were prepared by using diazomethane-boron trifluoride etherate reagent. Methyl [methyl 2,3-di-0-methyl-4-0-(2,3,4,6-tetra-0-methyl-a -D-glucopyranosyl)-/3-D-glucopyranosid]uronate (15) has been synthe-... 

Selective acetylation of l,6-anhydro-j8-D-galactopyranose and its 2-acetate with acetic anhydride in pyridine yielded principally the 2,4-diacetate, which isomerized on passage through a column of silica gel to give a 1 1-mixture of the 2,3- and 2,4-diacetates. ° Selective acetylation of D-galactose using 6.2 molar equivalents of acetic anhydride in the presence of sodium acetate gave the jS-penta-acetate (7.5%), a tetra-acetate fraction (16%), a triacetate fraction (3%), and a diacetate fraction (3%) methylation with diazomethane-boron trifluoride etherate was then used to determine the composition of the various fractions. ... 

B-Homosteroids have also been prepared by acid-catalyzed reaction of diazomethane with a,/5-unsaturated ketones. 3/ -Hydroxycholest-5-en-7-one acetate (57) reacts with diazomethane in the presence of concentrated fluoroboric acid, boron trifluoride etherate or aluminum chloride to give 3yS-hydroxy-B-homo-cholest-5-en-7a-one acetate (67). The 7a-keto group is reported to be chemically less reactive than an 11-keto group. 

An alcohol itself is inert towards diazomethane but it can be methylated in presence of boron trifluoride etherate or fluoroboric acid. A mineral acid cannot be used because it will react itself with... 

The first, satisfactory methylation appears to have been effected by Bourne and his colleagues,48 who prepared 6-O-methyl-D-glucose in high yield from the l,2 3,5-bis(phenylboronate), using diazomethane and boron trifluoride etherate in dichloromethane for methylation, and a final separation on a column of cellulose powder. It is this procedure which the same group used for structural analysis of triol phenylboron-ates43 (see Section 111,1) others80 have attempted to use it, but without success. 

Reference should also be made to the use of diazomethane in the presence of a strong acid, such as hydrogen fluoborate or boron trifluoride etherate, for the methylation of alcoholic hydroxyl groups. It has not, however, as yet been used for polysaccharides. 

Methytation of alcohols. Although alcohols alone are inert to diazomethane, they can be methylated efficiently by diazomethane under catalysis by boron trifluoride etherate or fluoroboric acid. A mineral acid cannot be used for catalysis because it itself reacts with the reagent, but a Lewis acid performs the function ascribed above to an organic acid. In investigating the structure of estriol D-glucosiduronic acid,... 

Esterification. An esterifying reagent can be prepared easily by mixing boron trifluoride etherate in an alcohol. This reagent is both thorough and mild. Thus p,//-diphenyldicarboxylic acid, which is inert to diazomethane, is converted into the corresponding dimethyl ester in 40% yield when refluxed in 10% boron trifluoride etherate in methanol for three days. The very sensitive 1,4-dihydro-benzoic acid was successfully esterified by this method. The ethyl ester was obtained in 81% yield when the acid was refluxed for 20 hours in anhydrous ethanol containing boron trifluoride etherate.1... 

ESTERIFICATION Boron trifluoride etherate. Diazomethane. Lithium f-butoxide. Triethyloxonium fluoroborate. Tris(2-hydroxypropyl)amine. 

Cyclisation to the 3-en-2-one could be achieved by pyrolysis of the anhydride obtained by treatment of the diacid (322) with acetic anhydride, but better yields were obtained (especially in the cholestane series) by refluxing the seco-acid in acetic anhydride containing potassium cyanide. Catalytic reduction of the di-nor compound (323) gave the 5j -2-ketone which was ring-expanded to a 1 1 mixture of 5) -B-nor-2- and -3-ketones on treatment with diazomethane and boron trifluoride etherate. Neither AB-dinortestosterone nor its acetate exhibited androgenic or anti-androgenic activity. 

The second approach to (50) was more direct. Acetylation of (51) was followed by sequential treatment with oxalyl chloride and excess diazomethane to afford, after hydrolysis, the diazoketone (53). Boron trifluoride etherate in nitromethane proved to be the best system to catalyse the cyclization of (53) to (50). This route may provide a useful intermediate for syntheses of atisine-type alkaloids. 

However, aliphatic alcohols can be alkylated by diazomethane if boron trifluoride etherate,788 hydrogen tetrafluoroborate,789 or aluminum chloride788 is added to the reaction mixture. Further, aliphatic alcohols can be methylated without further ado by diazomethane if hexane or heptane replaces ether as the solvent.790 Also the hydroxyl groups of hydroxy acids such as tartaric acid and their esters are smoothly methylated by diazomethane in ether 791, 792 and aliphatic alcohols can be methylated by diazomethane in the presence of sulfur dioxide or sublimed selenium dioxide, this reaction proceeding by way of the unstable alkyl methyl sulfite or selenite, respectively.793... 

Boron trifluoride etherate (1 ml) is added to cyclooctanone (18.9 g, 150 mmoles) in anhydrous ether (150 ml), and then a ca. 0.6M-ethereal diazomethane solution (240 mmoles) is dropped in rapidly with stirring and ice-cooling. The reaction is rapid at first but slower later, and it can be accelerated by addition of further boron trifluoride etherate (1 ml). Working up (after combination of three batches of the above size) and distillation through a spinning band column afford cyclooctanone (15 %), cyclononanone (27.7 g, 44%), b.p. 90-93°/ 11 mm, and cyclodecanone (17%). 

Methylation of Heteroatoms. The most widely used feature of the chemistry of diazomethane is the methylation of carboxylic acids. Carboxylic acids are good substrates for reaction with diazomethane because the acid is capable of protonating the dia-zomethane on carbon to form a diazonium carboxylate. The car-boxylate can then attack the diazonium salt in what is most likely an Sn2 reaction to provide the ester. Species which are not acidic enough to protonate diazomethane, such as alcohols, require an additional catalyst, such as Boron Trifluoride Etherate, to increase their acidity and facilitate the reaction. The methylation reaction proceeds under mild conditions and is highly reliable and very selective for carboxylic acids. A typical procedure is to add a yellow solution of diazomethane to the carhoxylic acid in portions. When the yellow color persists and no more gas is evolved, the reaction is deemed complete. Excess reagent can be destroyed by the addition of a few drops of acetic acid and the entire solution concentrated to provide the methyl ester. 

Methylation of Alcohols and Other Less Acidic Functional Groups. As previously mentioned, alcohols require the addition of a catalyst in order to react with diazomethane. The most commonly used is boron trifluoride etherate (eq 11), but Tetrafluo-roboric Acid has been used as well (eq 12). Mineral acids are not effective since they rapidly react with diazomethane to provide the corresponding methyl halides. Acids as mild as silica gel have also been found to be effective (eq 13). Monomethylation of 1,2-diols with diazomethane has been reported using various Lewis acids as promoters, the most effective of which is Tin(II) Chloride (eq 14). ... 

Lewis acids are also effective in activating a-diazo ketones towards intramolecular nucleophilic attack by alkenes and arenes. The reaction has been used effectively for the synthesis of cy-clopentenones (eq 27) starting with 8, /-unsaturated diazo ketones derived from the corresponding acid chloride and diazomethane. It has also been used to initiate polyalkene cyclizations (eq 28). Typically, boron trifluoride etherate is used as the Lewis acid, and electron-rich alkenes are most effective providing the best yields of annulation products. 

Methylation of carbohydrates containing base-labile substituents using a combination of diazomethane, di-chloromethane, and boron trifluoride etherate is knovm to proceed without concomitant migration of acyl groups (17, 18). Consequently, this method was chosen for methylation of various, partially acylated derivatives of sucrose (19) Methylation of 1, 2,3,3, 4, 6 -hexa-0-acetylsucrose (G) with a freshly prepared solution of Jiazomethane in drchloromethane and boron trifluoride etherate for 0.5 hr at -5° after chromatographic separ-... 

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