Reductive methylations

In contrast to alkylations using [ C]MeI, quartemization cannot occur in reductive [ C]methylations. In reductive [ C]methylations of primary amines the use of a sufficiently large excess of amine can suppress formation of tertiary amine products. 

Reductive [ CJmethylation procedures have found broad application in the rapid labeling of investigational drug substances for in vitro studies where metabolism does not occur, in early exploratory in vivo investigations in drug research and development, and in peptide and protein mapping. However, because A -dealkylation reactions are common metabolic events, compounds labeled by Af-[ C]methylation are usually not suitable for registration studies. 

In the absence of (reactive) nucleophiles, H CHO can undergo polycondensations with amines. Condensation with ammonia forms hexa[ C]methylenetetramine (181), 

4-chlorothiophenol and a tertiary amine, followed by Raney nickel-mediated desulfurization. This Baylis-Hillman type protocol was followed in the synthesis of [4-methyl- C]-epostane (190).  

In general 0-, N-, S- and C-[ C]methylation chemistry does not differ fundamentally from normal organic synthesis, except that for radioprotection reasons reactions are 

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Methylation of Primary and Secondary Fatty Amines. This is done by the Leuckait reaction (1,30) or reductive methylation (1,29,31,32). 

Alkyl dimethyl and dialkylmethyl tertiary amines are commercially available. These amines are prepared by reductive methylation of primary and secondary amines using formaldehyde and nickel catalysts (1,3,47,48). The asymmetrical tertiary amines are used as reactive intermediates for preparing many commercial products. 

ESCHWEILER CLARKE Amine methylation Reductive methylation of amines by a mixture of formaldehyde and formic acid... 

In striking contrast to the above observations is the finding that both reduction and reductive methylation of the tetrahydropyranyl ether of 17a-ace-toxypregnenolone (71) afford the expected products (72a, b) in 85-88 % yields by direct crystallization of the crude reaction products. Clearly, the complications in the reduction of the 16-en-20-one system are attributable primarily to reactions of the carbon-carbon double bond rather than to the a-carbanion (73), which is the final intermediate in both the reduction of the 16-dehydro compounds and the 17-acetoxy ketones. 

As first demonstrated by Stork,the metal enolate formed by metal-ammoni reduction of a conjugated enone or a ketol acetate can be alkylated in liquic ammonia. The reductive alkylation reaction is synthetically useful since ii permits alkylation of a ketone at the a-position other than the one at whicf thermodynamically controlled enolate salt formation occurs. Direct methyl-ation of 5a-androstan-17-ol-3-one occurs at C-2 whereas reductive methyl-... 

Reductive Methylation of the 3-Ethylene Ketal of Pregna-5,16-diene-3,20-dione ... 

Reduction with sodium borohydride without protecting groups, 92 Reductive deacetoxylation of ll-keto-12/3-hydroxytigogenin diacetate, 53 Reductive methylation of the 3-ethylene ketal of pregna-5, 16-diene-3, 20-dione, 54... 

Reductive methylation of the tetrahydropyranyl ether of 17o -acetoxy-3/3-hy-droxypregn-5-en-20-one, 56 Replacement of aromatic amino groups by fluorine, 450... 

That product was then heated under reflux with 50% hydrobromic acid for 1.5 hours. The reaction mixture was evaporated to dryness and reevaporated with three portions of propan-2-ol. The oil obtained was dissolved in propan-2-oi and diluted with ether. 3-Ethyl-3-(m-hydroxyphenyl)hexahydro-1 H-azepine was obtained. That material in turn was reductively methylated by hydrogenation in the presence of formaldehyde in absolute ethanol solution to give 3-ethyl-3-(m-methoxyphenyl)-1 -methylhexahydro-1 H-azepine. 

Palladium catalyst foe partial ee DUCTION OF ACETYLENES, 46, 89 Palladium on charcoal, catalyst for reductive methylation of ethyl p-mtrophenylacetate, 47, 69 in reduction of l butyl azidoacetate to glycine J-butyl ester 4B, 47 Palladium oxide as catalyst for reduction of sodium 2 nitrobenzene sulfinate, 47, S... 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Pr)4, " borohydride-exchange resin,and formic acid. When the last is used, the process is called the Wallach reaction. Conjugated aldehydes are converted to alkenyl-amines with the amine/silica gel followed by reduction with zinc borohydride.In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Esch-weiler-Clarke procedure. It is possible to use ammonium (or amine) salts of formic acid, " or formamides, as a substitute for the Wallach conditions. This method is called the Leuckart reaction,and in this case the products obtained are often the N-formyl derivatives of the amines instead of the free amines. Primary and secondary amines can be iV-ethylated (e.g., ArNHR ArNREt) by treatment with NaBH4 in acetic acid. Aldehydes react with aniline in the presence of Mont-morillonite KIO clay and microwaves to give the amine. Formaldehyde with formic acid converts secondary amines to the N-methyl derivative with microwave irradiation. 

Only a few other cobalt complexes of the type covered in this review (and therefore excluding, for example, the cobalt carbonyls) have been reported to act as catalysts for homogeneous hydrogenation. The complex Co(DMG)2 will catalyze the hydrogenation of benzil (PhCOCOPh) to benzoin (PhCHOHCOPh). When this reaction is carried out in the presence of quinine, the product shows optical activity. The degree of optical purity varies with the nature of the solvent and reaches a maximum of 61.5% in benzene. It was concluded that asymmetric synthesis occurred via the formation of an organocobalt complex in which quinine was coordinated in the trans position (133). Both Co(DMG)2 and cobalamin-cobalt(II) in methanol will catalyze the following reductive methylations ... 

In order to show that the structure of glycophorin A is not greatly perturbed by the reductive methylation reaction, circular dichroism (c.d.)... 

Fig. 2.—C.d. Spectra of Glycophorin A (-) and Reductively Methylated Glycophorin A in H2O at pH 7.0. [Reproduced from Ref. 60, by permission of the publishers, Butterworth Co (Publishers) Ltd. 1984.]...

Fig. 12.—A Portion of the Aliphatic Region of the Proton-decoupled, C-N.m.r. Spectra (at 22.5 MHz) of Fully Reductively Methylated Glycophorin A and Glycophorin in H2O at 30°. [Time-domain data were accumulated in 8192 addresses, with a recycle time of 1 s. A digital broadening of 3.0 Hz was applied (A) 1.5 mM reductively, [ CJmethylated glycophorin A , at pH 7.2, after 12,815 accumulations (B) 0.3 mM reductively, [ C]methy-lated glycophorin at pH 7.1, after 67,874 accumulations. (Taken from Ref. 63.)]...

Zn(CH3)2 with 83b. It can be deduced from this behaviour that 83a is probably formed as an intermediate which undergoes further reduction/methylation, due to its much higher oxidative power. This assumption has been confirmed by reacting la and Sn(CH3 )4 below 0 °C, which resulted in the formation of 83a (scheme 18). 83a has been characterized by "Tc- and H-NMR, mass spectrometry and i.r. spectroscopy. Two strong vtc=o absorptions were observed at 1002 and 948 cm-1. 83a is not sensitive to oxygen or water but is very volatile and can be sublimed at room temperature even under 1 atm of N2. 

The approach recruited to chemical proteomics in Reference [17] is called SILAC (stable isotope labeling with amino acids in cell culture) and is important in comparative proteomics (Figure 1). SILAC works well with cultured mammalian cells, but prokaryotes defeat it by metabolizing the label (usually supplied in lysine and arginine) into other amino acids. For applications beyond cultured eukaryotic cells, the reductive methylation route to differential labeling [18] is among the alternatives [15]-... 

C]-formaldehyde has been widely used for reductive methylation reaction but because of the marked fluctuation in the reported yields as well as impurities formed in its preparation from 11C02 the tendency has been to use 11CH3I for direct methylation. However, the recent development [99, 100] of a low temperature no-carrier-added method for preparing H11CHO, coupled to the microwave-enhanced Eschwei-ler-Clarke reaction [65-68] has led to a resurgence of interest in the use of H11CHO. 

An attractive feature of this route is that the macrobicyclic intermediate 40a can be readily N-alkylated without affecting the masked thiolate functions (209). Thus, reductive methylation of 40a with formaldehyde and formic acid under Eschweiler-Clarke conditions, followed by deprotection of 40b with Na/NH3 provides the otherwise inaccessible N6S2 ligand H2L19 in nearly quantitative yield (Scheme 1). Several other aza-thioethers 40c-p and their corresponding thiophenolate ligands were prepared by this route (see Fig. 30 and Table I) and some of them will be discussed further in later sections (210-215). 

The reductive alkylation of amines is called the Leuckart-Wallach reaction [112-115]. The primary or secondary amine reacts with the ketone or aldehyde. The formed imine is then reduced with formic acid as hydrogen donor (Scheme 20.27). When amines are reductively methylated with formaldehyde and formic acid, the process is termed the Eschweiler-Clarke procedure [116, 117]. 

The second compound (accedine, C20H24N202, MP 148-149°C, [a]D +72°) showed no carbonyl absorption in the IR, and H-NMR and mass spectra were in full agreement with the almost total existence of ring-closed carbinolamine structure 23. The configuration at C-16 was determined by correlation with 32. Reductive methylation (CH20-H2/Pd) of 23 afforded 29, which on LiAlH4 reduction gave the diol 257 identical in all respects to the product obtained from... 

K Kaljuste, A Unden. New method for the synthesis of V-methylamino acids containing peptides by reductive methylation of amino groups on the solid phase. Int J Pept Prot Res 42, 118, 1993. 

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