1.2.3.4- Tetrahydro-isoquinoline

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%. 

Dihydroisoquinolines are easily reduced to 1,2,3,4-tetrahydro-isoquinoline derivatives catalytically,55 or by means of NaBH4 in the presence of a proton source. Gensler25 ascribes to Robinson and Shinoda79 a report that the reduction of 37a with stannous chloride gives 37b, but the reduction actually described79 is of 38 and is entirely unexceptional. 

It has been reported119 that when 2-methyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylate is heated to about 200° in the presence of benzaldehyde, 4-benzylisoquinoline is formed and can be isolated in 73% yield. It is probable that decarboxylation occurs to form 2-methyl-l,2,3,4-tetrahydroisoquinoline, which then reacts with benzaldehyde via the enamine pathway as before. 

J,5)-Obaberine (Bisbenzvlisoquinoline) (5,5)-Oxandrine (Bisbenzylisoquinoline) Pseudoprotopine (protoberberine isoquinoline) (—)-Salsolinol (= 1-Methyl-6,7-dihydroxy- 1,2,3,4-tetrahydro-isoquinoline) (tetrahydroisoquinoline) Salsolinol main psychoactive in cocoa linked to chocolate craving... 

In earlier investigations by the author, nerve growth agents consisting of 1,2,3,4-tetrahydro-isoquinoline, (I), (3), and azo-amino acid derivatives, (II), (4), were prepared and used in the treatment of neurological disorders. 

Isochroman-3-ones on reaction with HBr/EtOH furnish the bromoesters which on treatment with amines provide isoquinolones. The latter on reduction with LiAlH give 1,2,3,4-tetrahydro isoquinolines... 

Aryl-ethanamines react with aldehydes easily and in good yields to give imines. 1,2,3,4-Tetrahydro-isoquinolines resnlt from their cyclisation with acid catalysis. Note that the lower oxidation level imine, versus amide, leads to a tetrahydro- not a dihydroisoquinoline. Routine dehydrogenation easily converts the tetrahydro-isoqninolines into fnlly aromatic species. 

The Pictet-Spengler reaction is a modification of the Bischler-Napieralski reaction. It is probably the most used method for the synthesis of 1,2,3,4-tetrahydro isoquinoline core. Therefore, phenylethyl amines are used in reaction with carbonyl compounds in the presence of protic or Lewis acids. 

Reaction of phenylethyl amine with aldehyde or ketone forms intermediate imine, which under the acidic conditions is protonated to give the highly reactive iminium ion. Electrophilic substitution on the aromatic ring provides 1,2,3,4-tetrahydro isoquinoline after rapid loss of a proton and... 

Baser KH (1982) Isolation and identification of anisaldehyde and three alkaloids from leaves of Thalictrum minus var. microphyllum. J Nat Prod 45 704-706 Bell EA, Nulu JR, Cone C (1971) L-Dopa and L-3-carboxy-6,7-dihydroxy-1,2,3,4-tetrahydro-isoquinoline, a new amino acid from seeds of Mucuna mutisiana. Phytochemistry 10 2191-2194... 

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