Eschweiler-Clarke Reaction Research Articles

Development of a microwave-enhanced isotopic labelling procedure based on the Eschweiler–Clarke methylation reaction

A number of primary and secondary amines have been rapidly methylated under microwave-enhanced conditions using formic acid-formaldehyde mixtures, providing a route to 2H(D)-containing compounds and the potential for 3H(T), 11C, 13C and 14C labelling.

The Reductive Cleavage of Cyclic Aminol Ethers toN,N-Dialkylamino-derivatives: Modifications to the Eschweiler-Clarke Procedure

The reductive cleavage of cyclic aminol ethers to give N-alkylamino- derivatives in very high yields can be achieved using chlorotrimethylsilane in the presence of sodium cyanoborohydride: in the case of cyclic aminol ethers derived from formaldehyde the Eschweiler-Clarke reaction can be carried out in formic acid heated under reflux in the absence of formaldehyde.

Specific deuteromethylation by the Eschweiler-Clarke reaction. Synthesis of differently labelled variants of trimethylamine and their use for the preparation of labelled choline and acetylcholine.

Reductive methylation (the Eschweiler-Clarke reaction) was used as a route for the synthesis of differently deuterium labelled variants of trimethylamine with the ultimate aim of preparing labelled variants of choline and acetylcholine. Combinations of unlabelled and labelled formaldehyde and formic acid yielded symmetrically labelled trimethylamines of high isotopic purity. The labelled congeners to acetylcholine and choline that were prepared subsequently provide suitable internal standards and tracers to be used in mass spectral analysis and in the evaluation of the pharmacokinetics of the parent compounds.

ChemInform Abstract: SYNTHESIS OF SPIRO(4‐HYDROXYCYCLOHEXANE‐1,4′‐2′,3′‐DIHYDRO‐6′‐METHOXY‐2′‐METHYL‐1′H‐ISOQUINOLINE) AND 4‐DIMETHYLAMINOMETHYL‐4‐(M‐METHOXYPHENYL)CYCLOHEXANOL

AbstractDas Cyclohexanonnitril (I) wird durch eine Meerwein‐Ponndorf‐Reaktion in ein Gemisch der Cyclohexanole (II) und (III) umgewandelt,.aus dem die trans‐Verbindung (II) abgetrennt und durch alkalische Hydrolyse, Acetylierung und Behandlung mit Thionylchlorid in das Säurechlorid (IV) übergeführt wird.

Synthesis of spiro(4-hydroxycyclohexane-1,4'-2',3'-dihydro-6'-methoxy-2'-methyl-1'H-isoquinoline) and 4-dimethylaminomethyl-4-(m-methoxyphenyl)cyclohexanol.

For the purpose of testing the biological activity, spiro-[4-hydroxycyclohexane-1, 4'-2', 3'-dihydro-6'-methoxy-2'-methyl-1'H-isoquinoline] (IV) was synthesized by cyclization of 1-(m-methoxyphenyl)-4-hydroxycyclohexanemethylamine (XIII), which was obtained from the trans-acetoxy-amide (XII), in the presence of excess formic acid and formaldehyde under the conditions of Eschweiler-Clarke reaction. 4-Dimethylaminomethyl-4-(m-methoxyphenyl) cyclohexanol (V) was synthesized by reduction of 1-(m-methoxyphenyl)-4-acetoxycyclohexanecarbonyl dimethylamide (XIV), which was obtained from the trans-acetoxy-acid chloride (XI), with lithium aluminum hydride.

Synthesis of spiro(3-hydroxycyclopentane-1,4'-2'-3'-dihydro-6'-methoxy-2'-methyl-1'H-isoquinoline) (author's transl)

For the purpose of testing their biological activity, hydroxy group epimers of spiro-[3-hydroxycyclopentane-1, 4'-2', 3'-dihydro-6'-methoxy-2'-methyl-1'H-isoquinoline](IV and V) were synthesized by cyclization of 1-(m-methoxyphenyl)-3-hydroxycyclopentane-methylamines (XXIIIa and XXIIIb), which were obtained from the corresopnding carboxamide derivatives, in the presence of excess formic acid in the Eschweiler-Clarke reaction.

Studies on the syntheses of heterocyclic compounds. Part CCCLXXXIII. A total synthesis of (–)(–)-OO-dimethylcurine

Cyclisation of the amide prepared by condensation of 5-bromo-3,4-dimethoxyphenethylamine with methyl 3-bromo-4-methoxyphenylacetate gave a 3,4-dihydroisoquinoline, reduction of which, followed by an Eschweiler–Clarke reaction, afforded a tetrahydroisoquinoline. An Ullmann reaction then gave a mixture of the diastereoisomeric racemates of OO-dimethylcurine (I), tetrandrine (III), and the bisbenzylisoquinolinyl ether (IV). A total synthesis of (–)(–)-OO-dimethylcurine (II) was achieved by a similar route.

Studies on the syntheses of heterocyclic compounds. Part CDI. Rearrangement of β-hydroxylaudanosine

1,2,3,4-Tetrahydro-1-(α-hydroxy-3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methylisoquinoline (β-hydroxylaudanosine)(5) was treated with toluene-p-sulphonyl chloride in the presence of triethylamine to afford 2,3-dihydro-7,8-dimethoxy-5-(3,4-dimethoxyphenyl)-3-methyl-1H-3-benzazepine (6), whose reduction product (9) was also obtained by dehydrative cyclisation of β-hydroxy-3,4-dimethoxy-N-(3,4-dimethoxyphenethyl)phenethylamine (15), followed by an Eschweiler–Clarke reaction of the resulting benzazepine (18).

Synthesis and stereochemistry of 1,2,3,4-tetrahydro-6-methoxy-2-methyl-1-phenylisoquinoline and related compounds

The absolute configurations of (1R,4R)-1,2,3,4-tetrahydro-4-hydroxy-6-methoxy-2-methyl-1-phenylisoquinoline (XIa) and its epimer, which were synthesised by cyclisation of D-(+)-2-amino-1-(3-hydroxyphenyl)ethanol with benzaldehyde, followed by Eschweiler-Clarke methylation, were determined by their n.m.r. spectra. The relationship between the absolute configuration of (1R)-1,2,3,4-tetrahydro-6-methoxy-2-methyl-1-phenylisoquinoline and its o.r.d. curve was also revealed.

Synthesis of spiro [4-hydroxycycloalkane-1,4'-2',3'-dihydro-6'-methoxy-2'-methyl-1-1'H-isoquinoline] derivatives under the conditions of Eschweiler-Clarke reaction

Synthesis of spiro [4-hydroxycycloalkane-1,4'-2',3'-dihydro-6'-methoxy-2'-methyl-1-1'H-isoquinoline] derivatives under the conditions of Eschweiler-Clarke reaction

An alternative total synthesis of N-methylcaaverine through phenolic oxidation

Phenolic oxidation of 1,2,3,4-tetrahydro-7-hydroxy-1-(2-hydroxybenzyl)-6-methoxy-2-methylisoquinoline (Ib) afforded the dienone (IIb) in 2·4% yield, the dimeric benzylisoquinoline (XIa) in 1·1% yield, and an unknown carbonyl compound. Borohydride reduction of the dienone (IIb) gave the corresponding dienol(XVII), whose rearrangement in acidic media gave the 1-hydroxy-2-methoxyaporphine (XVIII). This aporphine was identical with (±)-N-methylcaaverine (XVIII), which was derived from the (±)-caaverine (XIX) by Eschweiler–Clarke reaction.

Syntheses of (plus-minus)-O-demethylstepharotine and (plus-minus)-O-methylstepharotine (studies on the syntheses of heterocyclic compounds. CCCXII)

Treatment of 7-benzyloxy-1-(3-benzyloxy-4, 5-dimethoxybenzyl)-6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline (III) with acetic acid and 37% formaldehyde solution resulted in the progress of the Mannich reaction and protoberberine bases (VI and VII) were obtained. These bases were identified with the authentic sample obtained by the treatment of the hydrochloride of III with 37% formaldehyde solution. Debenzylation of VI and VII gave the phenolic bases, X ((±)-O-demethylstepharotine) and XI, and their methylation with diazomethane gave the same (±)-O-methylstepharotine (XII). XI was also obtained by debenzylation of III to IX and its Mannich reaction. The Eschweiler-Clarke reaction of III gave VI and VII accompanied by a small amount of 7-benzyloxy-1-(3-benzyloxy-4, 5-dimethoxybenzyl)-6-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline (VIII) which was identified with an authentic specimen.

Dimerization of Diphenolic Benzylisoquinolines by Phenolic Oxidative Coupling (Studies on the Syntheses of Heterocyclic Compounds. CXXVIII)

Ferric chloride oxidative coupling of 1, 2, 3, 4-tetrahydro-7-hydroxy-1-(2-hydroxybenzyl)-6-methoxyisoquinoline (IIb) afforded two dimeric benzylisoquinolines, III in 1.6% yield and V in 1.1% yield, respectively. Eschweiler-Clarke reaction of III gave the corresponding N-methyl derivative (IV), which was identified with authentic sample. Ferricyanide oxidative coupling of 1, 2, 3, 4-tetrahydro-7-hydroxy-1-(3-hydroxybenzyl)-6-methoxy-2-methylisoquinoline (IId) also gave the dimeric benzylisoquinoline (VI) in 0.4% yield, which was characterized by microanalysis and spectral data.

Coreximine and related compounds. 3. The formation of coreximine isomers under Eschweiler-Clarke's conditions (studies on the syntheses of heterocyclic compounds. CLXIV.)

The 3, 4-dihydroisoquinoline compound (XII), obtained by the Bischler-Napieralski reaction of the amide (XI), was derived to the 1, 2, 3, 4-tetrahydroisoquinoline compound (XIII) and debenzylated to 1-(4-hydroxy-3-methoxybenzyl)-6-methoxy-1, 2, 3, 4-tetrahydroisoquinolin-7-ol (II). The free base of XII was very labile and easily changed to 1-benzoylisoquinoline (XIV) which was submitted to the Clemmensen reduction to obtain II. In order to obtain 1-(4-hydroxy-3-methoxybenzyl)-6-methoxy-2-methyl-7-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline (I), II was submitted to the Eschweiler-Clarke reaction and an unexpected cyclization to the dibenzoquinolizine base occurred, forming XV, a kind of isomer of coreximine. Methylation of XV with diazomethane gave (±)-norcoralydine (XVI), while treatment of II with sodium borohydride and formaldehyde solution resulted in normal N-methylation to form I.

Aztequine and related compounds. 3. Synthesis of dl-1-(4-bromo-3-hydroxybenzyl)-1,2,3,4-tetrahydro-6-methoxy-2-methyl-7-isoquinolinol. (Studies on the syntheses of heterocyclic compounds. CLXXXIV)

The acid chloride (VI) was derived to diazoketone by treatment with diazomethane, further derived to the homo-ester (VIIIa) according to the method of Newman and others, using silver benzoate, and fusion-condensation of VIIIa and 4-benzyloxy-3-methoxyphenethylamine gave N-(4-benzyloxy-3-methoxyphenethyl)-2-(3-benzyloxy-4-bromophenyl) acetamide (IX). This amide (IX) was submitted to the Bischler-Napieralski reaction to form the 3, 4-dihydro-isoquinoline derivative (X), reduced with sodium borohydride to 1, 2, 3, 4-tetrahydroisoquinoline derivative (XII), and submitted to the Eschweiler-Clarke reaction to obtain the objective compound (IIc). This latter compound was also obtained by rendering X ammonia alkaline, deriving the free base thereby obtained to its methiodide (XI) by treatment with methyl iodide, and its reduction with sodium borohydride. Debenzylation of IIc with 20% methanolic hydrochloric acid afforded the debenzylated compound (IIb), m.p.106∼108°.

クラリン関連化合物の合成研究 (第12報)

The reduction product of 2-ketocularimine (III) with lithium aluminum hydride was submitted to alumina chromatography and cularimine (I), 2-hydroxycularimine (IX), and III were obtained. IX was acetylated with acetic anhydride and pyridine to a diacetyl compound (X), while Eschweiler-Clarke reaction of IX gave the N-methyl compound (XI) and dehydration of IX with phosphorus pentoxide afforded XV, whose reduction produced I. 2, 3, 6-Trimethoxydibenz [b, f] oxepin-10 (11H)-one was synthesized and its Pomeranz-Fritsch reaction with polyphosphoric acid gave 6, 9, 10-trimethoxy-12H benz [6, 7] oxepin-[2, 3, 4-i, j] isoquinoline (XX), whose oxidation with pyridine-chromic acid complex produced a ketone compound (XVII) identical with the product obtained by oxidation of cularimine with pyridine-chromic acid complex. Catalytic reduction of XX gave a product agreeing with authentic sample of cularimine.

Cactus Alkaloids. II. Condensation of Mescaline with Formaldehyde by the Eschweiler—Clarke Reaction

Cactus Alkaloids. II. Condensation of Mescaline with Formaldehyde by the Eschweiler—Clarke Reaction