Laudanosine reaction

Special Reactions of Papaverine. Papaverine undergoes a number of reactions, which are of interest as providing methods of synthesis for other alkaloids, of which examples will be found under laudanosine, laudanine, laudanidine, codamine (pp. 187-195), berberine (p. 331), corydaline (p. 284), and glaucine (p. 311). 

These transformation reactions are similar in part to those previously observed for laudanosine (201) and for the aporphine-benzylisoquinoline alkaloid thalicarpine (202). Laudanosine underwent regiospecific O-demethylation at... 

The synthetic utility of anodic reactions that couple aromatic rings activated by alkoxy groups has been explored for the formation of natural products. Thus laudanosine (78 R1 = R2 = R3 = R4 = CH3) has been oxidized... 

Lactam, ring formation, 288 Lactones, optically active, 31 Lanthanide complexes epoxy ring opening, 234 hetero-Diels-Alder reactions, 217 nitno-aldol reaction, 228 Laudanosine, 36 Leucine hydrocarboxylation, 168 Lewis acid complexes, 212 Ligands ... 

Bromolaudanosine, on treatment with potassamide or sodamide in liquid ammonia, yields the dibenzo[ >,g]indolizinium salt (21), the reaction presumably proceeding through the aryne, together with aminolaudanosine and the indoline (22) and the indole (23).32 Photolysis of laudanosine methiodide yields the base (24 R = Me) in methanol and (24 R = H) in water. The latter, on heating with... 

Sodium thiophenoxide appears to be the best reagent for the selective demethyla-tion of quaternary ammonium salts." 2-Butanone is used as solvent. The reaction involves Sn2 attack by the phenoxide anion on the N-methyl group. An example is the demethylation of ( )-laudanosine methochloride to laudanosine. A limitation... 

The reaction of 6 -nitropapaverine (14) with triethylphosphite has been shown to give a mixture of indolo[2,3-a]benzazepines (15) and (16), but the same treatment of 6 -nitrolaudanosine gives only the carbazole (17), and 6 -nitro-laudanosine methiodide only suffers reduction to the 6 -amino-compound. ... 

Narasimhan and Bhide (59) have also devised an elegant route for transforming laudanosine to tetrahydropalmitine via a directed metalation procedure (Reaction 45). This reaction sequence is important because there was previously no synthetic route for this transformation. 

Kametani et al. (544,545) and other workers (546-561) endeavored to carry out the synthesis of cularine alkaloids by phenolic oxidation (bio-genetic type of synthesis) of the corresponding derivatives of laudanosine. The paper (549) describes the synthesis of these bases via the 6-ethoxycar-bamido-3,4-dihydroisoquinolines, which were converted to 6-amino-isoquinoline. By Ullmann reaction it gives the compound 52 and ( )-cularine (51) (Scheme 18). Cularine-type alkaloids were also synthesized by the intramolecular Ullmann reaction of 7,8-disubstituted isoquinoline obtained by the usual Bischler-Napieralski reaction from the phenolic bromoamide (pathway a) (544, 548). However, in the papers referred to (557,558,561), the rings A, C, and D were formed first (pathway b), and only then was the ring formed during the synthesis of cularine. 

Schopf and Thierfelder (30) isolated two intermediates when this reaction was modified in the following manner. Addition of one mole of sodium ethoxide to an ethanolic solution of methylpapaverinium iodide gave a deep yellow color. This was interpreted as a rearrangement to the benzal derivative XIV. The yellow solution absorbed one mole of hydrogen in the presence of platinum catalysts, and iV-methyl-l,2-dihydroiso-papaverine (XV) (see below) could be isolated (21b). This compound was hydrogenated to DL-laudanosine (XIII) in alcoholic acetic acid solution. 

In all of the syntheses discussed, alkoxy derivatives of a-aminoaceto-phenone or of /3-phenethylamine were employed to supply the main structural outline of the isoquinoline system. Some of these amines are hard to obtain, especially if the resistant aromatic methoxyl groups are replaced by more sensitive substituents which may serve in the preparation of partly demethylated derivatives of papaverine or laudanosine. A significant innovation (60) which avoids the preparation of such unstable amines is the degradation of j3-phenylpropionic acid azides (hydrocinnamic acid azides) to the corresponding isocyanates, which add to the required phenylacetic acids probably with the intermediate formation of four-membered cyclic hemiacetals. The latter are transformed to A-carboxylic acids, which lose carbon dioxide and yield amides needed in the isoquinoline syntheses. In practice, the azide is heated with the phenylacetic acid in benzene solution for several hours, and the amide is isolated from the reaction mixture without difficulty. 

Most of the reactions of laudanosine have been carried out with the racemic mixture obtainable by reduction of quaternary papaverinium salts (p. 36). For instance, Gadamer and Kondo (79) obtained by oxidation with mercuric acetate, veratraldehyde and 4,5-dimethoxy-2-( 3-methyl-aminoethyl) benzaldehyde (XLVI) (or its ring-chain tautomer, laudaline), which resembles cotarnine in its properties. The same products are formed when manganese dioxide is chosen as the oxidizing agent (80). In both... 

Demethylation of racemic laudanosine with 48 % hydrobromic acid (30) or anhydrous aluminum chloride (82) splits all four methoxyl groups and furnishes laudanosoline, but two or three methoxyl groups may be preserved if other reagents and milder conditions are chosen. When heated with 35 % hydrochloric acid at 100° for twenty minutes, all four possible monophenolic isomers are formed and may be isolated from the reaction mixture by fractional extraction and crystallization (83). They are lau-danine (LII) (m.p. 166-167°), pseudolaudanine (LIII) (m.p. 120-121°), DL-codamine (XXII) (oily), and pseudocodamine (LIV) (m.p. 129-130°). A discussion of their structure may be found on pages 57-63. 

Since papaverine has been synthesized by different methods, these reactions constitute syntheses of DL-laudanosine. Pictet and Athanasescu (76) completed the synthesis of the optically active opium alkaloid by resolution of the racemic mixture with quinic acid. 

In 1890, Kauder (93b) worked up the mother liquors of protopine oxalate and isolated an alkaloid which he named tritopine. It was soluble in alkali, and its analysis and color reactions made likely its relation to the monophenolic laudanosine derivatives. Spath and Seka (97) obtained a sample of tritopine, probably from Kauder s original collection, and determined its correct formula, CjoH26N04. It melted at 184° (evac. tube) and exhibited [a] —85.7° (in chloroform). A comparison of tritopine and its salts with (—)-laudanidine and its corresponding salts established the identity of the two samples. 

The two bases described in this section have not been found in plant materials, but are formed by certain chemical reactions from papaverine or laudanosine. 

Aromatic hydroxylation Some isoquinoline alkaloids can be hydroxylated by a method based on a reaction first noted by Buck and Kobrich. The method is illustrated for hydroxylation of laudanosine (1) (equation I). When nitrobenzene... 

Another reaction sequence of the yellow pyridone 8 involves its catalytic reduction to the lactam 13 which was further reduced to norlaudanosine. A related sequence was then adopted to prepare laudanosine itself. ... 

Irradiation of laudanosine methiodide in methanol gives the ether 24 in 807o yield. In aqueous acid, the photolysis reaction provides instead a 547, yield of the alcohol 25. ... 

Reaction of laudanosine with benzyl chloroformate in the presence of sodium hydroxide gave a trans-stilbene which was epoxidized with m-chloro-perbenzoic acid. A benzazepine was then isolated upon acid treatment. 

With laudanosine (16) itself, the reaction takes a different course, and glaucine (17) is produced. This result can best be interpreted in terms of an... 

Miller LL, Stemitz FR. Falck JR (1971) Electrooxidative cyclization of laudanosine. A novel ncmphenolic coupling reaction. J Am Chem Soc 93 5941-5942... 

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