Eschweiler-Clark conditions

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 five-membered ring can also be formed by intramolecular nucleophilic attack of an alkoxide on a carbamate such as for the formation of 196 from 195 <1997T9553>, by dehydration of fV-carbamate-pipecolic acid derivatives <2002EJO3936>, by treatment of amino-amides under Eschweiler-Clarke conditions <1999TA3371>, or by treatment of hydroxyl aminonitriles with silver trifluoroacetate <2002JA2951> (Scheme 57). 

Thus, Cid and Pombo-Villar have also described the synthesis of (-)-a-skytanthine (201) and (+)-epi-dihydrotecomanine (202) from the common intermediate 200 (195). Treatment of200with (4-toluenesulfonyl)hydrazide and in situ reduction with sodium cyanoborohydride afforded the piperi-done 203 in 44% yield. Debenzylation with Li-NH3 followed by reduction of the lactam 204 [which is formally an aza-analog of (+)-isoiridomyrmecin (205)] with UAIH4 gave 206, and iV-methylation under Eschweiler-Clarke conditions afforded (-)-a-skytanthine (201) (Scheme 12) (195). 

This reaction was initially reported by Eschweiler in 1905, and subsequently by Clarke and co-workers in 1933. It is the preparation of tertiary methylamines from primary or secondary amines by means of the treatment of those amines with an excess amount of aqueous formaldehyde and formic acid. Therefore, it is generally known as the Eschweiler-Clarke methylation. In addition, this reaction is also referred to as the Eschweiler-Clarke condition," Eschweiler-Clarke A -methylation, Eschweiler-Clarke procedure, -) Eschweiler-Clarke reaction, s.3j,7 Eschweiler-Clarke reductive methylation, Eschweiler-Clarke reductive -methylation, Clarke-Eschweiler methylation, Clarke-Eschweiler reaction,or Clarke-Eschweiler procedure. In this reaction, the formate anion donates its proton to reduce the imine or iminium salt, so that carbon dioxide is evolved. Thus the whole process is a reductive amination of formaldehyde. This reaction is very useful for the reductive amination, without the application of hydrogen gas, catalyst (e.g., Pd/C), and high-pressure apparatus and has been widely applied to alkaloid chemistry. A special case of such reductive amination that occurs on phenylethylamine and results in the formation of tetrahydroisoquinolines is also referred to as the Clarke-Eschweiler cyclization. In a few cases, the methylation also occurs on an aromatic ring during the reductive amination. J... 

Cyclization of the hydroxyamide was achieved by treatment of 35 with 2.2 equivalents of sodium hydride followed by the addition of tosyl chloride to the resultant dianion. The dihydropyrrolo[3,2-6]pyridine 36 was isolated in 84% yield by this process. Conversion of 36 to the N-methyl dihydropyrrolo[3,2-fe]pyriine 37 was accomplished by removal of the acetamide with sodium ethoxide followed by methylation of the N-H dihydropyrrolo[3,2-i>]pyridine using Eschweiler-Clark conditions. 

Secondary iV-methylalkylamines can be prepared from primary amines by a multi-step sequence involving first methylation of the benzylidene of the primary amine followed by hydrolytic removal of the benzylidene group (eq 28). An alternative to the methylation procedure using methyl iodide is the employment of Eschweiler-Clarke conditions. Exhaustive (V-methylation of amines results in the production of a quaternized amine. The use of 2,6-LutUine as base is beneficial to carry out quatemization of amines due to the slow rate of methylation of 2,6-lutidine (eq 29). Quaternized ammonium salts are employed in the Hofmaim elimination (eqs 30 and 31). - As in the case of alcohol methylation, silver(I) salts may be used to facilitate the methylation process (eq 32). Finally, conditions for the methylation of indole have been reported (eq 33). ... 

For ammonia and primary amines there are two possible pathways, but when secondary amines are involved, only the hydrogenolysis pathway is possible. Other reducing agents167 can be used instead of hydrogen and a catalyst, among them zinc and HCI, sodium cyano-borohydride NaBHjCN,168 sodium triacetoxyborohydride,169 sodium borohydride,170 iron pentacarbonyl and alcoholic KOH,171 BH -pyridine,172 and formic acid. When the last is used, the process is called the Wallach reaction. In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Eschweiler-Clarke procedure. It is possible to use ammonium (or amine) salts of formic acid,173 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 N-ethylated (e.g., ArNHR —< ArNREt) by treatment with NaBH4 in acetic acid.175... 

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. 

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. 

Kosma et al. have developed a modification of the Eschweiler-Clarke reaction that avoids the use of toxic formaldehyde, and concentrated formic acid.12 In place of these reagents they propose the use of paraformaldehyde and oxalic acid, in solvent-free conditions in addition, this process requires no purification steps. 

The Eschweiler-Clarke reaction represents a synthetically useful method for the methylation of amines that avoids quatemisation and is easy to scale up. The reaction conserves stereocentres present elsewhere, and has been shown to be possible with less toxic reagents, in solvent-free conditions. 

Recently, the application of microwave conditions to reactions that normally proceed thermally, but with long reaction times,16 has led to a much-hastened procedure for the Eschweiler-Clarke reaction.17,18 Harding et a/.18 and Torchy et al 1 have implemented a microwave assisted Eschweiler-Clarke reaction with a 1 1 1 ratio of amine formalin formic acid with severely reduced reaction times of 1-3 minutes, in yields of 70-100 %. 

Another classical alternative is the Eschweiler-Clarke procedure, that involves drastic experimental conditions in which a solution of 88% aqueous formic acid, 35% aqueous formaldehyde and the corresponding primary amine in dimethylformamide is refluxed for 5 hr.10 Moreover, only methylated amines can be prepared. 

We realized that using a low boiling liquid in a microwave environment, even on a small scale, did not constitute best practice and as for hydrogenations our thoughts turned to using formates in a modified Eschweiler-Clarke reaction [79-81] and successfully methylated a number of primary and secondary amines under microwave conditions (Scheme 18.9) [82]. 

When amine (402) was subjected to Eschweiler-Clarke methylation conditions an elimination reaction ensued, leading to (404) neither the C-1 epimer of (402X nor (403),... 

For Petasis borono-Mannich reactions of formaldehyde, methylation of the amine reportedly occurs as a side-reaction, presumably by iminium ion reduction [19]. The hydride source under these conditions may be formic acid, as in the Eschweiler-Clarke methylation reaction. This problem was overcome by the use of potassium trifluoroborate salts and Lewis acids in toluene at 90 °C (the reaction in highly polar solvents such as acetonitrile, DMF and DM SO gives the reduction product). 

A modification of the Leuckart reaction for the preparation of methylated amines which requires less drastic reaction conditions, known as the Eschweiler-Clarke reaction, involves the use of aqueous formaldehyde and an excess of formic acid as reducing agent, along with the appropriate amine. Usually the reaction conditions... 

The reductive alkylation reaction under Clarke-Eschweiler conditions has been shown to proceed through an iminium intermediate (142). 

Grieco s synthesis of cryptopleurine 70 and julandine 68 (see end of section 2.3.1), via an intramolecular imino Diels-Alder reaction for construction of the quinolizidine nucleus, failed in the case of the related indolizidine alkaloid, tylophorine [38]. Submitting phenanthryl amine 113 to the identical aza Diels-Alder conditions used for cryptopleurine only yields by-products (114), as a result of a Clarke-Eschweiler type of cyclization. No tylophorine is detected under these conditions ... 

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