Amines methylation with diazomethane

On the basis of fundamental experiments (see Section IV,A,2) some indenobenzazepine alkaloids have been efficiently synthesized from the corresponding protoberberines via 8,14-cycloberbines. For example, the cycloberbine 428 derived from the protoberberine 427 was heated with methanesulfonic acid in aqueous tetrahydrofuran to afford a 2 1 mixture of cis- and trans-indenobenzazepines 429 in 92% yield (Scheme 85). The mixture was methylated with methyl iodide to give the cts-N-methyl derivative 430 and the unchanged trans secondary amine (21%), which was very difficult to methylate and which gave the /V-methyl derivative only in 6% yield even on treatment with dimethyl sulfate for 43 hr. Contrary to the ordinary cases (Section IV,A,2), the trans derivative did not isomerize to the cis isomer 430 under various acidic conditions. Debenzylation of 430 by hydrogenolysis afforded fumarofine (417), which was converted to O-methylfumarofine (316) by methylation with diazomethane (215). 

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). 

Amides can also be methylated with diazomethane in the presence of silica gel however, the reaction requires a large excess of diazomethane (25-60 equiv, eq 16). The reaction primarily provides O-methylated material however, in one case a mixture of O-and A-methylation was reported. Thioamides are also effectively methylated with this procedure to provide S-methylated compounds. Finally, amines have been methylated with diazomethane... 

Note In TLC on cellulose, the free amines or the corresponding salts in the presence of acids yield two substance spots. A single spot appears only when basic solvents are used. It has been found that this is due to the hydroxyl groups of the cellulose, since the effect vanishes when it is methylated with diazomethane. On silica gel G or alumina G layers, whether using acid or neutral solvents, only one spot is always obtained [2],... 

Unexpected reaction products were obtained when compound 206 was treated with diazomethane. After initial methylation of the enol, ring opening and isomerization of the secondary amine to the imine follows, furnishing compound 207 in good yield (Equation 69) <2002JOC6971>. 

Hydrolysis of ( )-colchicine with 0.1 N HC1 affords ( )-colchiceine, and ( )-deacetylcolchiceine is obtained on hydrolysis of ( )-colchicine with 20% H2SO4 and AcOH. Treatment of ( )-deacetylcolchiceine with trifluoroacetic anhydride afforded a trifluoroacetamide which, on methyl-ation with diazomethane, gave a mixture of ( )-trifluoroacetyldeacetyl-colchicine and ( )-trifluoroacetyldeacetylisocolchicine. The latter compounds were separated by chromatography and hydrolyzed with potassium carbonate in acetone/water to give ( )-deacetylcolchicine and ( )-deacetylisocolchicine (37). An easy chemical resolution of ( )-de-acetylcolchicine with 10-camphorsulfonic acid in methanol afforded the optically pure amines, and (+)- and (-)-colchicine after N-acetylation. 

In both cases, only one diastereomer could be detected using high-temperature H NMR spectroscopy. Removal of the oxazolidinone auxiliary from compounds (S,S)-101 and (/ ,R)-101 by treatment with lithium hydroperoxide followed by acidification and treatment with diazomethane generated the corresponding methyl esters (S)-102 and (/ )-102 which have opposite configuration at C2. Amination of either... 

Data on the methyl esters include salts and amines which were converted to the methyl esters with diazomethane for analysis. It should be noted that methylation provides data on the sum of all salts and amines of each phenoxy acid present rather than data on specific formulations. 

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. 

Extension of the C-tether to m = 2 can be achieved by subjecting diazo ketone 58 to the Wolff rearrangement using silver benzoate, triethyl-amine and methanol. Hydrolysis of the resulting methyl 4-methyl-4-[(E)-phenyldiazenyllpentanoate (74) (94%) yields the acid 75 (84%). Conversion of 75 into the mixed anhydride 76 followed by treatment with diazomethane gives 1 -diazo-5-methyl-5-[(E)-phenyldiazenyl]hexan-2-one (77) in low yield (19%) and methyl ester 74 (78%) (Scheme 18). 

A formal total synthesis of ( )-morphine has been achieved by adopting the above synthetic route (Scheme 18). The tetrahydropyridine 91, prepared from the reaction of A/ -methyl-4-piperidone with 2,3-dimethoxy-phenyllithium, followed by dehydration, was converted to the bicyclic en-amine 92 by treatment with the ylic dibromide. Kinetic protonation of 92 with perchloric acid gave the trans-fused immonium salt, which upon dissolution in methanol equilibrated to the thermodynamically prefered cis isomer 93. Treatment of 93 with diazomethane brought about the formation of the aziridinium salt 94, which was readily transformed into the a-amino aldehyde 95 by its oxidation with dimethyl sulfoxide. It is also worth noting that the Komblum oxidation of aziridinium salts leads to the construction of a-amino aldehydes efficiently. Lewis-acid-catalyzed cyclization of 95 afforded the morphinan carbinol 96 in 80% yield. Successive mesylation and reduction of the mesylate derived from 96 with LiBEtjH afforded morphinan (97) in excellent yield. In this instance, direct conversion of 93 to 97 by treatment with diazomethane gave approximately 1 % of the desired product. Lemieux-Johnson oxidation of 97 under acidic conditions furnished the ketone 98, which was previously transformed into ( )-morphine by Gates. In order to confirm the structure of 98, its conversion to the known... 

The presence of a secondary amine and two phenolic hydroxyls in sparsiflorine resulted in the ready formation of an 0,iV -diacetyl derivative (mp 245°), as well as an iV,0,0-triacetyl derivative (mp 196°-197°) under slightly more stringent conditions. Sparsiflorine also slowly formed an iV -methyl methiodide, C19H22O3NI (mp 236°-238° decomp.), which when treated with diazomethane gave i, 0,0-trimethylsparsiflorine methiodide (IV), (mp 218° decomp.), identical by IR-comparison with V,0-dimethyltuduranine methiodide. Sparsiflorine must therefore be a 1,2,10-trisubstituted noraporphine—the three substituents consisting of two phenolic hydroxyls and one methoxyl. 

Reduction with NaBH4 in Me2SO of the Af-3-aminomethyl derivatives has been also proposed as a method for N-methylation of aromatic primary amines.248 Alternatively, N-1- or N-3-aminomethyl derivatives can be obtained by reaction of N-l- or Af-3-halohydantoins with diazomethane and the amine.249... 

Procedure Amines, 10-1000 jug, were acetylated by treatment with 10-20 All of redistilled acetic anhydride and 10-20 /rl of pyridine (distilled over potassium hydroxide). Excess reagents were removed in a vacuum desiccator. Methyl esters of amine acids were prepared by refluxing in methanolic hydrogen chloride. iV-Acetylation of these esters was by treatment with acetic anhydride and pyridine. Esterification of other acids was carried out with diazomethane in ether. The products were dissolved in ethyl acetate, and volumes of 0.1 to 2 ju.1 were injected into the gas chromatograph. Amounts of sample injected were about 0.1 jitg for rapidly eluted compounds and 1 p,g for those with long retention times. In some cases, acetone condensation products of the primary amines were chromatographed. Catecholamines, however, underwent decomposition under these conditions. 

The condensation of the diketone LXXXVIIIa with the amine LXXXVIIIb in hydrochloric acid generated LXXXVIIIc (R = H mp 104°-107°), which on treatment with diazomethane yielded LXXXVIIIc (R = Me mp 176°179°). A-Methylation of the latter and a subsequent Wittig reaction generated racemic ochotensimine (LXXXVIIId) 150). 

Weakly acidic phenols that do not react with diazomethane can be methylated with sodium hydride and methyl iodide in THF at room temperature. The methoxymethyl ether moiety can be used to protect phenols. It is stable to alkali, Grignard reagents, lithium aluminum hydride, and catalytic hydrogenation, and is readily removed by mineral acid. Dimethoxymethane can be used in lieu of the carcinogenic chloromethyl methyl ether for this purpose. Alternatively, phenols may be protected as methyl thiomethyl ethers.The (9-acetylation of phenols in the presence of primary and secondary amines can be carried out with acetyl bromide and TFA. ... 

The reaction of diazo compounds with amines is similar to 10-15. The acidity of amines is not great enough for the reaction to proceed without a catalyst, but BF3, which converts the amine to the F3B-NHR2 complex, enables the reaction to take place. Cuprous cyanide can also be used as a catalyst. The most common substrate is diazomethane, in which case this is a method for the methylation of amines. Ammonia has been used as the amine but, as in the case of 10-44, mixtures of primary, secondary, and tertiary amines are obtained. Primary aliphatic amines give mixtures of secondary and tertiary amines. Secondary amines give successful alkylation. Primary aromatic amines also give the reaction, but diaryl or arylalkyl-amines react very poorly. 

---