C-methylation reaction

To date, only two purely NRPS biosynthetic machineries have been reported from myxobacteria. The first NRPS pathway to be characterized (and the first myxobacterial gene cluster to be identified) directs the biosynthesis of the DNA-binding antibiotic and antitumor agent saframycin Mxl 30 in M. xanthus Its heterocyclic quinone structure originates from a linear peptide intermediate 27 (Ala-Gly-Tyr-Tyr), which is synthesized by a tetramodular assembly line composed of two multifunctional NRPSs, SafA and SafB (Figure 10). It is likely that the tyrosine precursor is modified to 3-hydroxy-5-methyl-0-methyltyrosine through hydroxylation as well as O- and C-methylation reactions, before the monomer is loaded onto the NRPS complex. Once the tetrapeptide structure (27) is constructed, chain release by the last module of the assembly line should occur. However, in SafA, the typical C-terminal TE domain is substituted with a putative... 

Genesis of corydaline (98) along the protoberberine route requires labelling of C-5 and C-13 by [3- C]tyrosine and, in accord with this, one half of the tyrosine label incorporated into (98) was found to be at C-13." Clear support is thus provided by the above results for a pathway (Scheme 12) similar to that for the protoberberine alkaloids. (The illustrated pathway includes a plausible mechanism for the C-methylation reaction but neither the mechanism nor the point after reticuline at which methylation occurs has yet been established.)... 

Figure 1.20. Selected C-methylation reactions that occur when humic materials are treated with methyl iodide-sodium hydride. Reprinted from R. C, Averett et al., Humic Substances in the Suwanee River, Georgia Interactions, Properties, and Proposed Structures, U.S. Geological Survey report 87-557.

C-methylation reaction is the methylation of the C-5 position of cytosine in DNA. In this case, the carbon C-5 of cytosine cannot directly act as a nucleophile. The electron withdrawal by N-3 and the carbonyl, however, makes the C-5—C-6 double bond electron deficient and prone to attack by nucleophiles in a reaction that is similar to a Michael reaction. In DNA methyltransferases (DNMTs), this nucleophile is the thio-late from a Cys residue. The addition product is nucleophilic and reacts with SAM via an Si,j2-like mechanism to capture the methyl group. The resulting intermediate then eliminates the Cys of DNMT to give the methylated cytosine product (Figure 1.9). The methylation of C-5 of cytosine is an example of converting an electron-deficient methyl acceptor to a nucleophile for the methyl-transfer reaction by addition of an active site Cys thiolate. 

A mixture of 0.10 mol of freshly distilled 3-methyl-3-chloro-l-butyne (see Chapter VIII-3, Exp. 5) and 170 ml of dry diethyl ether was cooled to -100°C and 0.10 mol of butyllithium in about 70 ml of hexane was added at this temperature in 10 min. Five minutes later 0.10 mol of dimethyl disulfide was introduced within 1 min with cooling betv/een -100 and -90°C. The cooling bath vjas subsequently removed and the temperature was allowed to rise. Above -25°C the clear light--brown solution became turbid and later a white precipitate was formed. When the temperature had reached lO C, the reaction mixture was hydrolyzed by addition of 200 ml of water. The organic layer and one ethereal extract were dried over potassium carbonate and subsequently concentrated in a water-pump vacuum (bath... 

A solution of l-methylpyrano[4,3-b]indol-3-one (1 mmol) and methyl vinyl ketone (5 ml) in toluene (5 ml) containing 5% Pd/C (40 mg) was heated for 48 h in a sealed tube at 110°C. The reaction mixture was evaporated in vacuo and the residue purified by silica gel chromatography to give the product in 80% yield. 

Lewis Acid Complexes. Sulfolane complexes with Lewis acids, such as boron trifluoride or phosphoms pentafluoride (17). For example, at room temperature, sulfolane and boron trifluoride combine in a 1 1 mole ratio with the evolution of heat to give a white, hygroscopic soHd which melts at 37°C. The reaction of sulfolane with methyl fluoride and antimony pentafluoride inhquid sulfur dioxide gives crystalline tetrahydro-l-methoxythiophenium-l-oxidehexafluoroantimonate, the first example of an alkoxysulfoxonium salt (18). 

Carbon is alkylated ia the form of enolates or as carbanions. The enolates are ambident ia activity and can react at an oxygen or a carbon. For example, refluxing equimolar amounts of dimethyl sulfate and ethyl acetoacetate with potassium carbonate gives a 36% yield of the 0-methylation product, ie, ethyl 3-methoxy-2-butenoate, and 30% of the C-methylation product, ie, ethyl 2-methyl-3-oxobutanoate (26). Generally, only one alkyl group of the sulfate reacts with beta-diketones, beta-ketoesters, or malonates (27). Factors affecting the 0 C alkylation ratio have been extensively studied (28). Reaction ia the presence of soHd Al O results mosdy ia C-alkylation of ethyl acetoacetate (29). 

Studies on covalent hydration of N-heterocycles (67AG(E)919,76AHC(20)117) have revealed the diagnostic value of alkyl substituents in structural assignments due to their steric hindrance effects in addition reactions. C-Methyl substituents are therefore also considered as molecular probes to solve fine-structural problems in the pteridine field. The derivatives... 

The acidic character of the hydrogen atoms of C-methyl groups linked to the pyrazolium ring (Figure 22 Section 4.04.2.1.1(11)) facilitates a number of reactions difficult to carry out with neutral pyrazoles. Since efficient methods of dealkylation have been described (Section 4.04.2.3.lO(ii)), the synthesis via the pyrazolium salt is a useful alternative. The same behaviour is observed for indazolium salts, for example, nucleophilic addition to aromatic aldehydes (78JOC1233). 

Imidazole, 4-acetyl-5-methyl-2-phenyl-synthesis, 5, 475 Imidazole, 1-acyl-reactions, 5, 452 rearrangement, 5, 379 Imidazole, 2-acyl-synthesis, 5, 392, 402, 408 Imidazole, 4-acyl-synthesis, 5, 468 Imidazole, C-acyl-UV spectra, 5, 356 Imidazole, N-acyl-hydrolysis rate constant, 5, 350 reactions, 5, 451-453 synthesis, 5, 54, 390-393 Imidazole, alkenyl-oxidation, 5, 437 polymerization, 5, 437 Imidazole, 1-alkoxycarbonyl-decarboxylation, 5, 453 Imidazole, 2-alkoxy-l-methyl-reactions, 5, 102 thermal rearrangement, 5, 443 Imidazole, 4-alkoxymethyl-synthesis, 5, 480 Imidazole, alkyl-oxidation, 5, 430 synthesis, 5, 484 UV spectra, 5, 355 Imidazole, 1-alkyl-alkylation, 5, 73 bromination, 5, 398, 399 HNMR, 5, 353 synthesis, 5, 383 thermal rearrangement, 5, 363 Imidazole, 2-alkyl-reactions, 5, 88 synthesis, 5, 469... 

Imidazo[4,5-c]pyridine-2(3f7)-thione, 1-methyl-reactions with acrylonitrile, 5, 620 Imidazo[l,2-a]pyridine-2(3H)-thiones synthesis, 5, 632... 

Naphtho[ 1,2-h]thiophene-2-carboxylic acid synthesis, 4, 893 Naphthothiophenes synthesis, 4, 881, 907, 914 Naphthothiophenes, dihydrosynthesis, 4, 113 Naphtho[ 1,2-c]thiophenes synthesis, 4, 891 Naphtho[2, l-h]thiophenes synthesis, 4, 907 Naphtho[2,3-h]thiophenes synthesis, 4, 905, 908-909 Naphtho[ 1,8-de][l,2,3]triazine, 2-methyl-reactions... 

The product described here, 4-(4-chlorophenyl)butan-2-one, was previously prepared in the following ways a) by reduction of the corresponding benzalacetone, b) by catalyzed decarbonylation of 4-chlorophenylacetaldehyde by HFeiCO) in the presence of 2,4-pentanedione, - c) by reaction of 4-chlorobenzyl chloride with 2,4-pentanedione under basic catalysis (K2CO3 in EtOH), d) by reaction of 4-chlorobenzyl chloride with ethyl 3-oxobutanoate under basic catalysis (LiOH), - and e) by reaction of 3-(4-chlorophenyl )-propanoic acid with methyl lithium. - ... 

The following details for the commercial manufacture of poly(vinyl methyl ether) have been made available. Agitated vinyl methyl ether at 5°C is treated over a period of 30 minutes with 0.2% of catalyst solution consisting of 3% BF3 2H20 in dioxane. When the reaction rises to 12°C the reaction is moderated by brine cooling. Over the next 3-4 hours further monomer and catalyst is added. The autoclave is then closed and the temperature allowed to rise slowly to 100°C. 

C-Methylation products, o-nitrotoluene and p-nitrotoluene, were obtained when nitrobenzene was treated with dimethylsulfoxonium methylide (I)." The ratio for the ortho and para-methylation products was about 10-15 1 for the aromatic nucleophilic substitution reaction. The reaction appeared to proceed via the single-electron transfer (SET) mechanism according to ESR studies. 

To a solution of m-ethyl cinnamate (44, 352 mg, 85% pure, 1.70 mmol) and 4-phenylpyridine-A-oxide (85.5 mg, 29 mol%) in 1,2-dichloromethane (4.0 mL) was added catalyst 12 (38.0 mg, 3.5 mol%). The resulting brown solution was cooled to 4°C and then combined with 4.0 mL (8.9 mmol) of pre-cooled bleach solution. The two-phase mixture was stirred for 12 h at 4°C. The reaction mixture was diluted with methyl-t-butyl ether (40 mL) and the organic phase separated, washed with water (2 x 40 mL), brine (40 mL), and then dried over Na2S04. The drying agent was removed by filtration the mother liquors concentrated under reduce pressure. The resulting residue was purified by flash chromatography (silica gel, pet ether/ether = 87 13 v/v) to afford a fraction enriched in cis-epoxide (45, cis/trans . 96 4, 215 mg) and a fraction enriched in trans-epoxide cis/trans 13 87, 54 mg). The combined yield of pure epoxides was 83%. ee of the cis-epoxide was determined to be 92% and the trans-epoxide to be 65%. 

The ratio, at equilibrium, of the hydrated to anhydrous forms (for both neutral species and anions) has been measured for the following 2-hydroxjrpteridine and its 4-, 6-, and 7-methyl and 6,7-dimethyl derivatives 6-hydroxypteridine and its 2-, 4-, and 7-methyl derivatives 2,6-dihydroxypteridine and 2-amino-4,6-dihydroxypteridine. The following showed no evidence of hydration 4- and 7-hydroxy-pteridine 2,4-, 2,7-, 4,7-, and 6,7-dihydroxypteridine and 2-amino-4-hydroxypteridine. The kinetics of the reversible hydration of 2-hydroxypteridine and its C-methyl derivatives (also 2-mercapto-pteridine) have been measured in the pH region 4-12, and all these reactions were found to be acid-base cataljrzed. The amount of the hydrated form in the anions is always smaller than in the neutral species, but it is not always negligible. Thus, the percentages in 2-hydroxy-, 2-hydroxy-6-methyl-, 2-mercapto-, and 2,6-dihydroxypteridine are 12, 9, 19, and 36%, respectively (see also Table VI in ref. 10). 

In the reactions of nucleophilic addition to diacetylene, monoalkylhydrazines behave in two ways (71AKZ743). In an anhydrous medium at 40-50°C, the reaction with methyl- and ethylhydrazines proceeds in such a way that a more nucleophilic disubstituted nitrogen atom attacks the terminal carbon atom of diacetylene to form l-alkyl-3-methylpyrazoles (17), the content of isomeric 1-alkyl-5-methylpyrazoles being 15% according to GLC (71AKZ743 73DIS 77AKZ332). 

Normal reactions are found again for systems containing C=N double bonds. An unstable triazoline is probably an intermediate product in the reaction of pteridin-7-one (117)to give a mixture of the 8-methyl (118) and 6,8-dimethyl derivatives (119). C-Methylation also occurs in the case of quinoxalin-2-one. ... 

A mixture of methyl 3-deoxy-3-C-methyl-3-nitro-ct-D- and fi-L-glucopyranosides d l is formed by the reaction of nitroethane with the sugar thaldehyde obtained from L-glucose The products are separated and converted into branched-chain fluoro nitro l- and L-sugars fEq 361 ... 

A mixture of 274 g of methyl isonicotinate, 367 g of ethyl bromoacetate and 125 cc of ethyl alcohol was stirred without heating for 4 hours in a flask equipped with a reflux condenser. (The reaction was exothermic and precautions were taken to keep the temperature below 70°C.) The reaction mixture was then left for 15 hours at room temperature. 

A mixture of 16.3 g of 4-methyl-6-methoxy-2-pyrimidinyl-hydrazine, 13.7 g of ethyl acetoacetate and 16.3 ml of methanol was refluxed 2 hours on a water bath. After a mixture of 4.7 g of sodium hydroxide, 4.7 ml of water and 27 ml of methanol was added dropwise thereto at about 50°C, the reaction mixture was refluxed for 2 hours more, then methanol was distilled off and the residue was dissolved in 130 ml of water. The solution was adjusted to pH 6 with acetic acid. The precipitate was filtered, washed with water and dried to give 24 g (yield 95.3%) of crystals, MP 97° to 98°C. Recrystallization from ligroin gave 1-(4 -methyl-6 -methoxy-2 -pyrimidinyl)-3-methyl-3-pyrazoline-5-one, MP 102° to 103°C. 

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