Eschweiler-Clarke methylation

To demonstrate the versatility of his S3mthesis strategy Yamada used ketoester 151 as relais substance to S3mthesize two further picrotoxane alkaloids isolated from Dendrobium species, nobilonine (90) and 2-hydroxydendrobine (87) (Scheme 14) (84). Monobromination of 151 with bromine in dioxane and subsequent treatment with water resulted in hydroxy-y-lactam 152, whereas attempts to hydroxylate 151 by Barton oxidation led to rearrangements. Chemo- and stereoselective reduction with zinc borohydride converted 152 into the en fo-alcohol. To counterbalance the unfavorable conformational equilibrium this alcohol had to be converted into the alcoholate to achieve lactonization. Chemoselective reduction of the hydroxylac-tam moiety of lactone 153 again followed Borch s protocol, which led in this case to boron complexed amino compounds necessitating successive acid treatment to obtain racemic 2-hydroxydendrobine (87) in low yield accompanied by dendrobine (82). 2-Hydroxydendrobine (87) was converted into nobilonine (90) by Eschweiler-Clark methylation. 

Both the primary amine funtuphyllamine-A (XXVI) and the secondary base funtuphyllamine-B (XXVII) gave funtuphyllamine-C (XXVIII) on Eschweiler-Clarke methylation. The structure of funtu-phyllamine-B follows from the result of the Ruschig degradation (conversion of a primary or secondary base to a ketone via chloramine and ketimine) (19), which furnished 3 -hydroxy-5 -pregnan-20-one. 0-Acetylfuntuphyllamine-C proved to be identical with the known (20) 3 -acetoxy-20a-dimethylamino-6a-pregnane. Funtuphyllamine-B is... 

This alkaloid was isolated from the leaves of Funtumia elastica its formation by Eschweiler-Clarke methylation of 20a-aminopregn-5-en-3/3-ol provided proof of its structiu e (LIV) which was further confirmed (39) by the result of the catalytic hydrogenation of irehine leading to funtuphyllamine-C (XXVIII). 

The last remaining moot point was the formation of so-called tri-methylconkurchine on methylation of conkurchine and conessidine 114) which result would be inconsistent with the structures CLIII and CLIV. However, later reinvestigation demonstrated conkurchine to yield a mixture of conessine and dimethylconkurchine on Eschweiler-Clarke methylation 79) and thus the claimed formation of trimethylcon-kurchine must have rested on error. 

Alkaloid buxpiine, C25H39NO2 (mp 173° [a]n +158°), is identical with cyclomicrobuxine as follows from preparation of buxpiine by Eschweiler-Clarke methylation of buxtauine oxime, although the melting points of the diacetates differ considerably. [Cyclomicrobuxine diacetate mp 232°-233° fa] + 146° (in chloroform), buxpiine diacetate mp 205° 207° [a]j3 + 99° (in EtOH) and +95° (in chloroform).]... 

The mechanism of all of the above mentioned reactions is essentially the same. However, some steps in the mechanism are still not fully understood. The following steps are believed to be involved in the Eschweiler-Clarke methylation 1) formation of a Schiff-base (imine) from the starting primary or secondary amine and formaldehyde via an aminoalcohol (aminal) intermediate 2) hydride transfer from the reducing agent (e.g., formic acid, cyanoborohydride, etc.) to the imine to get the corresponding A/-methylated amine along with the loss of CO2 and 3) if the starting amine was primary, then steps 1 and 2 are repeated. 

The enantioselective total syntheses of several piperidine and pyrrolidine alkaloids of tobacco were accomplished in the laboratory of J. Lebreton. ° In the final stage of the total synthesis of (S)-A/-methylanabasine, a one-pot Cbz-deprotection-hydrogenation-Eschweiler-Clarke methylation was carried out using a HCHO/MeOH/Pd(C)/H2 system at room temperature with an overall 88% yield. 

C.L. Gibson and co-workers developed an efficient synthesis for chiral ring annulet 2,6-disubstituted 1,4,7-trimethyl-1,4,7-triazamacrocycles. This class of molecules is capable of stabilizing transition metals in their high oxidation states and therefore can be used as oxidation catalysts. The A/-methylation of the three nitrogens in the last step was conducted using the original Eschweiler-Clarke methylation conditions. 

Eschweiler-Clarke methylation One-pot reductive methylation of primary and secondary amines to the corresponding tertiary amines using formaldehyde and a reducing agent. 160... 

Harding, J. R., Jones, J. R., Lu, S.-Y., Wood, R. Development of a microwave-enhanced isotopic labeling procedure based on the Eschweiler-Clarke methylation reaction. Tetrahedron Lett. 2002, 43, 9487-9488. 

Rosenau, T., Potthast, A., Rohrling, J., Hofinger, A., Sixta, H., Kosma, P. A solvent-free and formalin-free Eschweiler-Clarke methylation of amines. Synth. Common. 2002, 32, 457-465. 

An antimicrobial base solacasine has been found in the flowers of S. pseudocapsiaum. In its mass spectrum it showed peaks at m/z 56 and 82, associated with 33-amino-steroids. An azomethine linkage is responsible for its ir-absorption at 1660 cm." on reduction (NaBHi,) a primarysecondary diamine structure results, convertible into a trimethyl derivative on Eschweiler-Clark methylation. Structure (65) has been advanced and confirmed by the formation of dihydrosolacasine by methanolysis of solano-capsine (L. A. Mitscher et al., Experientia, 1976, 415). 

Iminium ion-alkene cyclizations accomplished under standard Eschweiler-Clarke methylation conditions have been employed to prepare five-, six- and seven-membered azacycles (Scheme It is... 

Iminium ion-alkene cyclizations accomplished under standard Eschweiler-Clarke methylation conditions have been employed to prepare five-, six- and seven-membered azacycles (Scheme 25).57,58 It is important to note that under identical conditions amines (62) and (63) did not cyclize but afforded the corresponding IVjV-dimethylamines. With regard to the alkene participant these results are in full accord with Baldwin s rules for ring formation.2 However, the formation of pyrrolidine (61) demonstrates that 5-endo-trig cyclizations2 can take place with respect to the iminium ion n-participant. The observed regioselectivity and the failure of (63) to cyclize are in accord with obligatory formation of an intermediate with tertiary carbocation character. 

Chen and Sung have recently reported a special case where the Eschweiler-Clarke methylation of a-amino amides leads to cyclocondensation products.14... 

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