14C-Methyl iodide

Methyl 3a,6a-dihydroxycholanate, 240 1-Methylestrone 3-methyl ether, 10, 27 4b/3-Methyl-7-ethylenedioxy-1,2,3,4, 4a ,4b/3,5,6,7,8,10,1 Oaa-dodecahydro-phenanthrene-1 /3,4/3-diol, 236 14C-Methyl iodide, 211 ds-Methyl iodide, 210, 214 Methyl lithocholate tosylate, 329 1-Methyl-19-nortestosterone, 27 6a-Methylprednisolone, 410 6a-Methylprednisolone BMD, 410 16/3-Methylprednisone, 87 18-Methylpregn-4-ene-3/3,17a,20f-triol, 243 20-Methylpregn-5-en-3/3-ol, 415 17a-Methylpregnenolone acetate, 48 17a-Methyltestosterone, 438 16/3-Methyl- 11a,17a,21 -trihydroxy- 5 /3-pregnane-3,20-dione 21-acetate, 299, 300 20-Methyl-3/3-trityloxypregn-5-ene, 415 3/3-Methoxycholestane, 136 1-Methoxycyclohexene, 18 3-Methoxyestra-3,5(10)-diene, 18, 27... 

Preparation of 19-14C-testosterone acetate has been achieved by methyla-tion of a 19-nor-seco-androstane derivative (266) with 14C-methyl iodide.144 A sequence of standard transformations of the oxo-steroid intermediate (267) then ultimately led to the desired product (268). In our opinion, this sequence could be applied equally well to the preparation of 19-d3-testosterone acetate in high isotopic purity by methylating (266) with d3-methyl iodide. 

This serendipitous result was advantageously applied to the synthesis of (+)-14C-artemisinin73 using 14C-methyl iodide as well as trideuteroartemisinin from CD3-... 

The 14C-labelled benzoin methyl ether (BEx), utilized by Mochel s group (10), was prepared by methylating benzoin with 14C-methyl iodide. In order to obtain additional information, we also prepared doubly and triply labelled analogs, BE2 and BE3, as outlined on Scheme 1. 

Finally, Persson et al. (1995) measured the UC/14C KIEs for the SN2 reactions between several amine nucleophiles and labelled methyl iodide in dimethoxyethane or acetonitrile at 15°C and 30°C, respectively, to determine how sterically hindered nucleophiles affects the transition state of a Menshut-kin reaction. The results in Table 25 show that all the fc11// 14-values for these reactions are large. In fact, they are all near the theoretical maximum value for these KIEs. Secondly, the KIE for the reaction with the more sterically hindered amine, 2,6-lutidine, is larger than that for the less sterically hindered... 

Unfortunately, the same trend in kll/k14 is not observed in the triethylamine/quinuclidine reactions with methyl iodide. Here, identical UC/14C KIEs are found for both nucleophiles. It is possible that the identical... 

Remote double labelling techniques have been used successfully in the determination of enzyme KIEs (Kiick, 1991). A variant of this technique was applied to a nonenzymatic reaction by Matsson and co-workers (Axelsson et al., 1990). They determined the primary carbon and secondary deuterium KIEs for the SN2 reaction between methyl iodide and hydroxide ion in 50% dioxane-water at 25°C. The a-carbon KIE was determined by the UC method (Axelsson et al. 1987,1991). In this method, a mixture of substrate molecules labelled with UC (tm = 20.4 min) and 14C is used. The reactants and products... 

Fig. 7.3 Kinetic plots for nC and 14C in the reaction of labeled methyl iodide with N,N-dimethyl- -toluidine in methanol at 30°C. (CR is the count rate (cpm) for the reactant fraction and CP the count rate for product fraction) (After Axelsson, B. S. et. al. J. Am. Chem. Soc. 109, 7233 (1987))...

A slightly different example is the separate determination of rates of reaction of nC and 14C labeled methyl iodide with N,N-dimcthyl-/>-toluidine as illustrated in Fig. 7.3. Again the method takes advantage of the convenience of radiochemical analysis. If, as likely, the KIE of interest is ki2/ki4, it can be obtained to sufficiently good approximation by applying a modified Swain-Schaad rule, ln[ki2/ki4]/ln[kn/ki4] = [(12/14)/(11/14)]1/2 obtained from the law of the geometric mean (see Section 10.5). 

Generally, methylation of enolate ions with isotopically tagged methyl iodide is a satisfactory labeling procedure. For example, application of this method has given the C-18 labeled steroids, (244) and (245) (see above), 17/ -acetoxy-4/ -trideuteriomethyI-4a-methyl-19-norandrost-5-en-3-one (264) and 19-14C-testosterone acetate (268). Methylation of the anion derived from 17/ -acetoxy-4-methyl-19-norandrost-4-en-3-one (263) with d3-methyl iodide occurs predominantly at C-4, yielding mainly the 4/S-trideuterio-methyl derivative (264) and about 10% of the corresponding C-4 epimer (265).142... 

The coenzyme evidently functions in a cyclic process. The cobalt alternates between the +1 and +3 oxidation states as shown in Eq. 16-43. The first indication of such a cyclic process was the report by Weissbach that 14C-labeled methylcobalamin could be isolated following treatment of the enzyme with such methyl donors as AdoMet and methyl iodide... 

The above iodides have been used as 1 -labelled building blocks in the preparations of [3-nC]tyrosine, (9-methyl[3-nC]tyrosine, /7-chloro[3-nC]phenylalanine and / -fluoro[3-JlC]phenylalanine by alkylations of glycine derivatives241. The [nC]ethyl ether derivatives (using sodium ethoxide as nucleophile) and 3-nitrophenyl-4-methoxy[(Z-nC]benzyl ether (using sodium 3-nitrophenolate) have been synthesized also, employing 4-methoxy(ar-14C)benzyl iodide 18324. ... 

When l-[14C]methyl-pyridinium aldoxime iodide or radioactive pralidoxime [14C]-labelled in the oxime group was parenterally administrated to rats, 90% of the radioactivity was recovered in urine and 6% in the faeces, irrespective of the position of the label. About 90% of the urinary radioactivity was associated with intact pralidoxime. In addition, some 5% of the dose was excreted as l-methyl-2-pyridone, indicating some cyanogenesis (Enandcret al., 1962). In humans, the l-methyl-2-cyanopyridinium ion was detected in urine of male volunteers without significantly increased urinary thiocyanate. Since 90% of pralidoxime chloride, 5 mg kg 1 IV, was recovered from urine, cyanide formation is probably of no toxicological concern (Garrigue etal., 1990). 

Wittig initially reported that the alkylation of the ylid with methyl iodide gave a low yield of trimethylethylammonium iodide 162>. Subsequently, Weygand and co-workers 158> found that the reaction of completely 14C-labeled ylid with unlabeled methylbromide resulted in the formation of both tetramethylammonium bromide and trimethylethylammonium bromide in a 5 to 1 ratio. These two products contained only about 80% of the original 14C. The remainder of the 14C was found in the polymethylene which had formed during the reaction. To explain these results, it was suggested that most of the ylid decomposes... 

Various approaches for the O-methylation of coals have appeared. These include reaction with diazomethane (7) and, more recently, base-promoted methylation in which coal is first neutralized with an aqueous tetrahydrofuran (THF) base solution followed by reaction with methyl iodide (8-10) or methyl p-toluenesulfonate (II). Instead, we opted to O-methylate PSOC 1197 with 13,14C double-labeled dimethyl sulfate at various pH values. This approach was taken to evaluate the distribution of acidic OH sites and to determine an acceptable set of O-methylation conditions. Briefly, the coal was neu-... 

Because reagent incorporation could effect the results and conclusions of the C-methylation study, further examination of this phenomenon was warranted. Further study was achieved by a 14C analysis of samples subjected to repetitive treatments. In the first set of experiments, a coal sample obtained from the reaction of O-methyl PSOC 1197 with [9-14C]-fluorenyllithium and methyl iodide was treated two additional times with [9-14C]fluorenyllithium having the same isotopic enrichment, and the re-... 

In a second set of experiments, the coal product from the initial [14C]fluorenyllithium and methyl iodide treatment was reacted with unlabeled fluorenyllithium and methyl iodide. Under this set of serial treatment conditions, run at two different isotopic enrichments, as much as 40% (w/ w) of the isotopic label can be removed. The fate of the 14C label was established when the reaction byproducts, fluorene and 9-methylfluorene, were recovered and detected at the expected isotopic enrichment level. This important observation demonstrates that the incorporated reagent can be removed from the coal by chemical exchange and thus suggests a reversible reaction. 

An interesting approach to the generation of l4C-labeled rivastigmine needed for in vivo studies was published by Novartis (Scheme 11).57 The synthesis of 14C-labeled 2 was initiated by l4C-labeled cyanation of iodide 48 to provide 3-methoxybenzo-14C-nitrile (49) in 80% yield. Copper-mediated addition of methyl magnesium bromide to nitrile 49 formed an imine that was hydrolyzed with aqueous HC1 to the corresponding... 

Methyl-,4C D-glucuronate was prepared44 from the D-glucofuran-uronic acid derivative 22 (obtained by benzylidenation of D-glu-curonic acid in the presence of zinc chloride) by treating its sodium salt with methyl-14C iodide, followed by hydrogenolysis of the ester 23 in the presence of palladium-on-carbon the infrared (i.r.) spectrum of the product was identical to that of authentic 2. 

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