Amides methylations, diazomethane

The whole concept of direct methylation has recently been critically reviewed and rejected by Gompper as a method to study tautomerism. The difference in the proportions of the two methyl derivatives produced w hen diazomethane is in excess, or the reverse, has now been ascribed to the relative importance of the Sn and Sn reactions of the tautomeric compound with diazomethane. The proportions of N- and 0-methyl derivatives formed by the reaction of cyclic amides with diazomethane has been related to the infrared vC—O frequencies. ... 

A criterion for the position of the extent of the mesomerism of type 9 is given by the bond order of the CO bond, a first approximation to W hich can be obtained from the infrared spectrum (v C=0). Unfortunately, relatively little is known of the infrared spectra of amide anions. How-ever, it can be assumed that the mesomeric relationships in the anions 9 can also be deduced from the infrared spectra of the free amides (4), although, of course, the absolute participation of the canonical forms a and b in structures 4 and 9 is different. If Table I is considered from this point of view, the intimate relationship betw-een the position of the amide band 1 (v C=0) and the orientation (0 or N) of methylation of lactams by diazomethane is unmistakeable. Thus the behavior of a lactam tow ard diazomethane can be deduced from the acidity (velocity of reaction) and the C=0 stretching frequency (orientation of methylation). Three major regions can be differentiated (1) 1620-1680 cm h 0-methylation (2) 1680-1720 cm i, O- and A -methylation, w ith kinetic dependence and (3) 1730-1800 em , A -methylation, The factual material in Table I is... 

Finally the so-called kinetic dependence of methylation by diazomethane must be mentioned. (This phenomenon was first observed by Arndt in 6-methylthiacoumarindioh see later.) Kinetic dependence is found in various amides (or enols) which are methylated principally on nitrogen if they are introduced into excess ethereal diazomethane, but principally on oxygen if the diazomethane is gradually dropped into the ethereal amide solution (or suspension). 

Cyclization to the eight-membered lactams 8 is the key step in the synthesis of other 1,5-diazo-cine derivatives.1 In the first step methylation of amides 6 with diazomethane is nonselective, providing the 0-methylated derivatives 7, which are used for the cyclization, and also the (V-methylated derivatives, which are formed as byproducts. 

The seco amide alkaloids have been subjected to various transformations, mainly for structure elucidation purposes. When treated with lithium aluminium hydride, arnottianamide (206) was converted to the tertiary amine, deoxyarnottianamide (224), which on methylation with the Rodionow reagent gave deoxy-O-methylarnottianamide (225) (172,175). Arnottianamide (206) could be O-acetylated (174) as well as O-methylated with diazomethane in HMPA (172). Isoarnottianamide (208) was O-methylated to trimethoxy derivative 226, which under Bischler-Napieralski conditions recyclized to the benzophenantridine alkaloid, chelilutine (227) (176) (Scheme 33). 

Treatment of D-glucoascorbic acid (XV) with diazomethane gives a 2,3-dimethyl derivative (LXXIX) and this upon repeated treatment with silver oxide and methyl iodide yields 2,3,5,6,7-pentamethyl-D-glucoascorbic acid (LXXX). Ozonization of the latter followed by hydrolysis gives oxalic acid and 3,4,5-trimethyI-D-arabonic acid (LXXXI). This acid was shown to possess a free hydroxyl group at C2 by reason of the fact that the amide of LXXXI gives a positive Weerman reaction for a-hydroxy amides, i.e., when the amide is treated with sodium hypochlorite, sodium isocyanate is produced, the latter being identified by... 

Treatment of the cyclic amide 157 or the dihydro compound 159 with Lawesson s reagent gives the corresponding thioamides 158 and 160 (Equation 20) <1999JME1661>. Methylation of the cyclic amide 161 with diazomethane gives a mixture of 0,0- and TV,O-dimethyl products 162 and 163 in a ratio of 7 6 (Equation 21) <1996EJM651>. 

The elucidation of the hydroxypyrazine-pyrazinone tautomerism has been made using spectral methods. An IR spectral analysis focuses on the carbonyl absorption of the amide group in the keto tautomer. A more useful method is UV spectroscopy, that is, the objective structure in solution is easily estimated by comparison with the UV spectra of bond-fixed compounds related to the two tautomers, namely O-methylated and N-methylated derivatives 9 and 10, which are prepared by methylation of the hydroxypyrazines or pyrazinones with diazomethane (Scheme 1). The above two investigations were achieved by this methodology. 

Another direct approach to chiral polymeric stationary phases is the modification of commercially available polysiloxanes which contain reactive side groups. Thus, the diamide phase was linked to a modified XE-60 polysiloxane phase (Table 2). In one case (XE-60-L-Val-(/ or 5)-a-pea)124 another center of stereogenicity (R or S configuration) has been introduced in the amide group. An XE-60-L-Val-(S)-x-pea column was used for the enantiomer separation of racemic. V-rert-butoxycarbonyl amino acids after their methylation with diazomethane (serine and threonine as the O-trimethylsilyl derivatives) (Figure 12)124. 

Acylation of a / -configurated axially chiral diamine 1 containing a primary amino group with equimolar amounts of monocyclic anhydrides 2 and 4 in toluene or dichloromethane at low temperatures gives the amides 3 or 5 with good diastereoselectivity 10°. Diastereomeric ratios were determined by HPLC analysis after conversion to the methyl esters with diazomethane absolute configurations are based on chemical correlation. 

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). 

Diazomethane has been prepared by the action of base on nitrosomethylurea,2 nitrosomethyluretbane,6 N-nitroso-/3-meth-ylaminoisobutyl methyl ketone,6 / -tolylsulfonylmethylnitros-amide,8 and N-nitroso-N-methyl-N -nitroguanidine.7... 

Thiophene- and benzo[6]thiophene-carboxylic acids undergo all the normal reactions of an aromatic carboxylic acid (63AHC(1)1, 70AHC(11)177). They can be converted to acid chlorides, amides and esters the esters can be used to make hydrazides. Benzo[6]thiophene-2-carboxylic acid chloride has been converted to the methyl ketone with dimethylcadmium and to the diazoketone with diazomethane. Bromodecarboxylation of the silver salts (Hunsdiecker reaction) has been used to prepare the dibromo compounds (340) and (341). 

Hydrolysis of 1-acetoxy- or l-hydroxy-3-cyanoindole (115) by hydrogen peroxide or 1 M sodium hydroxide gave the corresponding amide, while QM sodium hydroxide gave the 3-carboxylic acid which decomposed rapidly at room temperature with diazomethane, the last compound gave the stable methyl l-methoxyindole-3-carboxylate [78JCS(P1)1117]. 1-... 

The 1,3 dipole diazomethane is a mild reagent to furnish methyl esters (see Chapter 13), but it has some disadvantages, too it is volatile, toxic and furthermore explosive. For this reason it has to be prepared by reaction of KOH with 7V-methyl-7V-nitroso-/ ara-toluenesulfon-amide (carcinogenic ) or in situ.11 Another simple method to protect the COOH functionality of the neuraminic acid is the esterification with methanol as solvent and reactand under H+ catalysis e. g. ion exchanger. 

The methyl ester of oxycellulose, produced by alkaline permanganate oxidation of cuprammonium cellulose followed by treatment with diazomethane, has been reacted with protein by the azide method [34]. Acidic oxyce]]uloses are aiso able to react with alcohols and amines, including proteins, to form esters or amide derivatives. 

Methylation of amides- Diazomethane in the presence of silica gel forms methyldiazonium silicate, which can methylate amides. Thus this reagent converts caprolactam (1) into O-methylcaprolactim (2) in 957o yield in 15 minutes. 

E14b, 976 (aus N-NO—amin) Cyclobutan Diazo- X/4, 540 3H-Diazirin 3-Ethenyl-3-methyl-E16c, 722 (R3N-Abspaltung) Diazomethan Cyclopropyl- X/4 535 (aus N-NO —amid) E14b, 976 (aus N-NO —amin)... 

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