8-Methoxy-1,2,3,4-tetrahydroisoquinolines

Methoxy-1,2,3,4-tetrahydroisoquinoline has been obtained through lithiation with butyllithium between the methoxyl group and the side-chain in N-pivaloyl 2-(3-methoxyphenyl)ethylamine (X = H), formylation with dimethylformamide to give the formyl compound (X = CHO), followed by cyclisation with 10% hydrochloric acid and finally reduction with sodium borohydride (ref. 150). 

The thermal condensetion of p-benzyloxyphenylacetic acid and of 3-methoxy-4-hydroxy-phenethylamine occurs and gives, with a yield of 86% to 92%, the N-(3-methoxy4-hydroxy-phenethyl-p-benzyloxyphenylacetamide from this latter, by cyclization according to Bischler-Napieralski with phosphorus oxychloride in acetonitrile, followed by reduction with sodium borohydride, there is obtained with a yield of 75% to 80% the 1-(p-benzyloxybenzyl)-6-meth-oxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline, which is methylated with formaldehyde and formic acid giving 1 (p-benzyloxybenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline with a yieid of 90%. 

According to polarity alternation the acceptor substituted benzenes should also undergo ipso substitutions [12] Indeed such reactions occur when A = SiMe3, SnRj, HgR. A useful application of the silyl group as site determinant is found in a synthesis of 8-methoxy-iV-methyl-l,2,3,4-tetrahydroisoquinoline [13]. The donor character at the ortho position of the methoxy function is accentuated and steric disfavor is overcome. 

An attempt to utilize this conversion of amines into aldehydes in an isoquinoline synthesis was not successful.439 Instead, reaction between 2-(3,4-dimethoxyphenyl)ethylamine and isatin afforded only the spiro compound 150.439 Reaction between isatin and 2-(3-hydroxy-4-methoxyphenyl)ethylamine gave a mixture of two spiro compounds, while a reaction of isatin, this amine, and benzylamine gave 6-hydroxy-7-methoxy-l-phenyl-1,2,3,4-tetrahydroisoquinoline.439... 

Noscapine (Nectadon ), 2-methyl-8-methoxy-6,7-methylenedioxy-l-(6,7-di-methoxy-3-phtha-lidyl)-l,2,3,4-tetrahydroisoquinoline, is also one of the isoquinoline derivatives present in opium. Next to morphine, it is the most abundant of the opium alkaloids, present to the extent of 6% in the seed capsules. This drug was formerly known as narcotine but, because it is neither chemically nor pharmacologically related to the narcotics, is more appropriately designated as noscapine. 

The aromatic, tetramethoxy-substituted, tetrahydroisoquinoline alkaloid weberine has been isolated recently from extracts of the Mexican cactus Pachycereus weberi (38). The rare occurrence of four adjacent methoxy groups on an aryl moiety prompted the synthesis and examination by crystal-structure analyses of analogs and derivatives with four and five adjacent methoxy groups on the phenyl ring. In contrast to the problem with... 

A-Formylated 1,4-oxazines, including morpholine, can be oxidized anodically in metha-nolic solution to 3-methoxy derivatives, which under acidic conditions lose methanol to N-acylenamines these are of potential synthetic interest [280]. Other acylated secondary amines, such as those from pyrrolidine, piperidine, and tetrahydroisoquinoline, behave similarly (Chapter 24) [281]. 

Kolbe reactions of heterocyclic compounds have been studied in only a few cases. Anodic oxidation of l-azabicyclo[2.2.2]octane-2-carboxylic acid under Kolbe conditions produced 2-methoxy-l-azabicyclo[2.2.2]octane [454]. The primary radical, formed by loss of an electron from the carboxylate ion, decarboxylates and is oxidized further to a carboca-tion, which is attacked by a methoxide ion. A similar pseudo-Kolbe reaction is found in the anodic decarboxylation of 1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid derivatives to 3,4-dihydroisoquinolines [455]. 

Acetyl-7-methoxy- Graphite, MeCN 8-hydroxy-l,2,3,4-tetrahydroisoquinoline... 

Methylation with diazomethane afforded (— )-norcoralydine. The location of the hydroxyl at C-3 was ascertained from the isolation of 6-ethoxy-7-methoxy-l-keto-l,2,3,4-tetrahydroisoquinoline (XL) from the... 

The Faltis theory, which postulates that bisbenzylisoquinoline alkaloids originate in the plant through enzymatic dehydrogenation of the benzylisoquinoline units l-(4 -hydroxybenzyl)-6-methoxy-7-hydroxy-l,2,3,4-tetrahydroisoquinoline (coclaurine) or l-(4 -hydroxy, benzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (norcoclaurine), has been accepted and refined. This theory has played a role in influencing... 

The position of the three phenolic hydroxyl groups in berbamunine was shown to be as in XXVI by subjecting the ethylated alkaloid (XXVIII) to cleavage with sodium in liquid ammonia and identifying the products as (- )-V-methyl-0,0-diethylcoclaurine (V) and (+ )-l-(4 -hydroxy-benzy 1) - 2 - methyl - 6 - methoxy - 7 - ethoxy -1,2,3.4 -tetrahydroisoquinoline iYI) l4). 

The alkaloid was synthesized by the Ullmann condensation of l-(3 -bromo - 4 - benzyloxybenzyl) - 2 - methyl - 6,7 - dimethoxy -1,2,3,4 - tetra-hydroisoquinoline (XXXIV) and l-(4 -benzyloxybenzyl)-2-methyl-6-methoxy-7-hydroxy-l,2,3,4-tetrahydroisoquinoline (IX) followed by removal of the benzyl groups (40). 

The alkaloid was converted to 0,0-dimethylisoliensinine. and 0,0-diethylisoliensinine on treatment with diazomethane and diazoethane, respectively. The former compound was found to be identical with 0,0-dimethylliensinine (LXIV). In order to establish the position of the two hydroxyl groups in isoliensinine the diethyl derivative (LXVII) was bisected by means of the sodium-ammonia reaction. The products obtained were (—) -1-(4 - methoxybenzyl) - 2 - methyl - 6 - methoxy - 7 -hydroxy-1,2,3,4-tetrahydroisoquinoline (IV) and (— )-0,0-diethyl-A -methylcoclam ine (V). The structure of isoliensinine is therefore represented by formula LXVI. 

In order to locate the secondary amino group, the alkaloid was N-acetylated, and the X-acetyltrilobine was subjected to cleavage with sodium-sodium hydride and liquid ammonia (102, 107). The phenolic base CXLVII, obtained by partial cleavage, was methylated and the resulting compound (CXLVIII) was submitted to a second-stage cleavage with sodium in liquid ammonia. There was obtained l-(4 -methoxy-benzyl)-2-methyl-6-methoxy-l,2,3,4-tetrahydroisoquinoline (XXXIII) and l-(4 -methoxybenzyl)-2-acetyl-6-methoxy-8-hydroxy-l,2,3,4-tetra-hydroisoquinoline (CL). These results show that trilobine is represented by CXLII (Ri=H). 

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