Methylation phenol, diazomethane

Diasomethane Method. Diazomethane readily methylates phenolic hydroxy-compounds, primary and secondary amines, and carboxylic acids,... 

Methylation with diazomethane may be carried out as follows (FUME CUPBOARD )-. Dissolve 2-3 g. of the compound (say, a phenol or a carboxylic acid) in a little anhydrous ether or absolute methanol, cool in ice, and add the ethereal solution of diazomethane in small portions until gas evolution ceases and the solution acquires a pale yellow colour. Test the coloured solution for the presence of excess of diazomethane by removing a few drops into a test-tube and introducing a glass rod moistened with glacial acetic acid immediate evolution of gas should... 

Galipoline, C19H19O3N. A process for the extraction and separation of the angostura bark alkaloids was described by Spath and Eberstaller,i and from the phenolic bases obtained Spath and Papaioanou isolated this alkaloid. It crystallises from water, has m.p. 193°, contains two methoxyl groups, and on methylation by diazomethane yields galipine. 

The structure of sanguinine (295) was initially based on spectroscopic comparisons with galanthamine (291) and related alkaloids, but this assignment was subsequently verified by its conversion to 291 by methylation with diazomethane in DMSO (62). Thus, 295 represented the second example of a phenolic base among the galanthamine-type alkaloids. 

GC analysis of underivatized polar fractions did not reveal any volatile sulfur compounds. However, once these fractions were methylated with diazomethane, a number of sulfur compounds were detected. (Presumably, the diazomethane methylated either carboxylic acid, phenolic, thiophenolic, sulfonic acid or even alcohol or thiol groups and thereby increased their parent molecules volatility). These additional sulfur compounds are currently under investigation in our laboratories and the results of these studies will be reported later. 

Lagerstroemine (23), on methylation with diazomethane, afforded 0,0-dimethyldihydroverticillatine (25). Lagerstroemine has two methoxyl and one phenolic hydroxyl group. The methoxylation pattern was established by conversion of the alkaloid to the benzopyran (27) via the methiodide of the diol (28). 

The 1 H-NMR spectrum of laurifinine (6) exhibits signals for an 7V-methyl (2.32) and only two aromatic methoxyl groups (3.82 and 3.80). Its UV spectrum undergoes a bathochromic shift on addition of alkali, suggesting the presence of a phenolic hydroxyl group (IR 3400 cm 1). O-Methylation with diazomethane furnished laurifonine (4), thus establishing the same type of substitution. The... 

Diazomethane will also methylate phenols, because they too are acidic enough to protonate it. Ordinary alcohols, though, are not methylated because they are not strong enough acids to protonate diazomethane. 

Note 4. See Chapter 7.1.2.1 for alternative methods. O-Acetylation modifies both aliphatic and phenolic hydroxyl groups. In the event subsequent O-methylation of carboxylic acid groups by ethereal diazomethane is required, it is essential to carry out the O-acetylation of phenolic hydroxyl groups as completely as possible as unacetylated phenolic hydroxyl groups also undergo O-methylation with diazomethane. 

GC separation of the isolated phenolic compounds occurs prior to identification and quantification using ECD- and MS-coupled detectors (Sect. 4.3). However, phenolic compounds are polar, and derivatization gives better GC peak shapes in the most commonly used types of GC columns. Hitherto the standard method of derivatization of OH-PCBs retained in blood has been methylation by diazomethane to form the corresponding methoxy-PCB (MeO-PCB) [39,43, 135]. OH-PCB methylation by ion-pair alkylation with methyl iodide is an alternative to the diazomethane technique [43,140]. Acetylation has been shown to give comparable recoveries of OH-PCB derivatization as the methyl iodide and diazomethane approaches to OH-PCB methylation [139]. Silylation reactions have also been applied for the derivatization of various OH-PCBs [137]. 

Methylation by diazomethane is a simple method for derivatization of relatively acidic compounds [e.g., phenols (pA = 9-10) or carboxylic acids (pi = 4.4 0.2)]. The application of this reagent for methylation of aliphatic alcohols requires additional acid catalysis. Methyl iodide is the most convenient reagent for synthesis of permethylated derivatives of polyols (including carbohydrates) and phenols. Dimethyl sulfate [(01130)2802] can be used in basic aqueous media for methylation of phenols, but the yields of methyl ethers, in this case, are not enough for quantitative determinations of initial compounds by GC. 

Mecambroline was isolated from Meconopsis carnbrica Vig. (Papaver-aceae), and the elemental data indicated the value C18H17O3N. The alkaloid melts at 145°, and exhibits [aj +76° (in CHCI3). A hydrochloride salt was obtained (inp 264°-266°) as well as a picrate (mp 179°-180°). Color tests showed the presence of a methylenedioxy and a phenolic group. The UV-spectrum had 308 and 275 mp, (log e 4.0 and 4.2), with a shoulder at 269 mp (log e 4.1), typical of a 1,2,10-tri-substituted aporphine. 0-Methylation with diazomethane gave a base (mp 111°-112°) 6). 

These alkaloids were isolated in yields of 0.025 and 0.007%, respectively. Descretinine, C20H23NO4 (mp 212°-214° dec.), [a]j) —371° in pyridine), contains three methoxyl groups and one phenolic hydroxyl. Its methylation with diazomethane to (— )-tetrahydropalmatine (XLI) serves to identify descretinine as a tetrahydroprotoherherine with a 2,3,9,10-oxygenation pattern. The nonidentity of descretinine with (— )-tetrahydrojatrorrhizine [(— )-corypalmine] (XLII) and ( —)-tetra-hydrocolumbamine [(— )-isocorypalmine] (XLIII) means that it is either 9- or 10-0-demethyltetrahydropalmatine. 

Descretamine, C19H21O4N (mp 221°-224° [ ]d —368° in pyridine), eontains two methoxyl groups and two phenolic hydroxyl functions. Methylation with diazomethane gave (— )-tetrahydropalmatine, which implies that descretamine is a bisdemethyl (— )-tetrahydropalmatine (see Section X) isomeric with (— )-scoulerine (XLVI). At the time of writing the location of the hydroxyl groups has not been determined. 

Two phenolic members of this group have been isolated from Haplo-phyllum species. Haplopine (XIV) (mp 203°-204°) occurs, together with the already known evoxine (XV), in the seeds of H. perforatum Kar. et Ker. 103). Skimmianine is obtained on methylation with diazomethane. The phenolic hydroxyl is shown to be at the 7-position since haplopine is... 

In 1935 an alkaloid named oripavine having the composition Ci8H2i03N was isolated from Papaver orientale [124] and subsequently from Papaver bracteatum [125], It was shown to contain one —OMe, one —NMo, and one phenolic —OH group [124], and was eventually converted to thebaine [v] by methylation with diazomethane [126] and is in fact 3-0-desmethylthebaine [xxxvn] it bears the same relationship to morphine as thebaine does to codeine. On boiling with... 

The latter when subjected to a second Ullmann condensation with bromomethoxyphenylacetic acid produces the acid (83). Removal of the /v-butyry1 group and internal amide formation, followed by Bischler-Napieralski cyclisation, A -methy1ation and reduction gives a mixture of diastereoisomeric bases of structure (84), one of which has been reduced to the 4 -benzyl compound and completely 0-demethylated to the tetrahydric phenol (85). This is cyclised to the dioxin by hydrobromic acid at 140°, methylated with diazomethane and reductively debenzy-lated to trilobine (86). The other isomer of the base (84) has been similarly converted into obaberine, the C-1 epimer of trilobine (Y. Inubushi et al.. Tetrahedron Letters, 1976, 2857 Chem.Pharm.Bull., 1977,, 1636). 

The content of free phenolic gronps in lignins has a major biochemical and technological signihcance. When thioacidolysis is performed on diazomethane-methylated samples, additional monomers 8-10 with methylated phenolic groups (Figure 2.6) are recovered [65,66], The total yield of thioacidolysis monomers is similar before... 

I- )-Isoelaeocarpicine, a minor constituent of E. polydactylus, is considered to have the structure (6), and is so named because it corresponds in stereoehemistry with isoelaeocarpine. The molecular formula of isoelaeocarpicine is established by its mass spectrum, and its relationship with the two major alkaloids is demonstrated by the formation of a mixture of elaeocarpine and isoelaeocarpine when isoelaeocarpicine is heated in methanolic alkali. In consonance with the constitution (6), isoelaeocarpicine is phenolic and is readily methylated by diazomethane. Mild acetylation affords a phenolic acetate, but prolonged reaction gives an Af-acetyl compound, formulated as (7), whose formation presumably proceeds via the intermediate (8). 

This substance, CgiHggNOe, m.p. 110-140°, 178-180°, [a] -133° (chloroform), is isomeric with Substance C and very similar to it in chemical properties (296a, 300a, 302). Like Substance C, it is a phenolic material and affords an 0-acetyl derivative on acetylation and colchicine on methylation with diazomethane. Substance Ej is converted... 

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