Electrophilic aromatic substitutions isoquinoline

The synthesis of 3-aryltetrahydroisoquinolines was accomplished by electrophilic aromatic substitution of polysubstituted phenols and phenyl ethers with Lewis acid-generated tosyliminium ions of 2-tosyl-3-methoxytetrahydroisoquinoline derivatives <00SL801>. In addition isoquinoline was reported to react with N-tosylated (R)- or (S)-amino acid fluorides to afford optically active dihydroimidazoisoquinolinones. The reaction proceeds via acylation followed by attack of the tosylamino group at Cl of the intermediate 2-tosylaminoacylisoquinolinium salt <00TL5479>. 

Electrophilic aromatic substitutions Quinoline and isoquinoline undergo electrophilic aromatic substitution on the benzene ring, because a benzene ring is more reactive than a pyridine ring towards such reaction. Substitution generally occurs at C-5 and C-8, e.g. bromination of quinoline and isoquinoline. 

As in the Skraup quinoline synthesis, loss of two hydrogen atoms is necessary to reach the fully aromatic system. However, this is usually accomplished in a separate step, utilising palladium catalysis to give generalised isoquinoline 6.14. This is known as the Bischler-Napieralski synthesis. The mechanism probably involves conversion of amide 6.12 to protonated imidoyl chloride 6.15 followed by electrophilic aromatic substitution to give 6.13. (For a similar activation of an amide to an electrophilic species see the Vilsmeier reaction, Chapter 2.)... 

The imine salt is perfectly placed for an intramolecular electrophilic aromatic substitution by the electron-rich dihydroxyphenyl ring. This closes the isoquinoline ring in a Mannich-like process (Chapter 27) with the phenol replacing the enol in the pyrrolidine alkaloid biosynthesis. 

One of the most powerful methods for the construction of tetrahydroisoquinoline systems is the Pictet-Spengler cyclisation. The reaction consists of the condensation of a b-phenylethylamine derivative with a carbonyl compound, generating an imine (Schiffs base), which undergoes cyclisation via an intramolecular electrophilic aromatic substitution yielding the isoquinoline derivative. The Pictet-Spengler reaction is traditionally carried out in a protic solvent with acid catalysts, usually acetic acid or trifluoroacetic acid. 

Tetrahydroisoquinolines were also prepared by an electrophilic aromatic substitution reaction of 2-amidoacroleins. Exposure of IV-aryl-substituted 3-amido-1,3-dioxins 82 to Lewis acids results in retrocycloadditions to afford 2-amidoacroleins 83 and concomitant electrophilic aromatic substitution to afford tetrahydroisoquinolines 84 <01OL3349>. The synthesis of isoquinoline derivatives via cyclization reactions received attention as well. Some examples include the preparation of isoquinolines by a photocyclization of l-methoxy-2-azabuta-l,3-dienes <01TL3575>. The photochemically induced preparation of 1-methyl-1,2,3,4-tetrahydronaphtho[2,l-/ isoquinolines was also reported <01T1981>. 

Quinoline and isoquinoline show that electrophilic aromatic substitution reactions are the more reactive benzene ring because the pyridine ring is less reactive. Indole undergoes electrophilic aromatic substitution primarily in the pyrrole ring because it is much more reactive than the benzene ring 24, 25, 26, 27, 28, 29, 30, 51, 53. 

Reactions with Electrophiles. The structure of isoquinoline 1 is the result of fusing benzene and pyridine together. Electrophilic aromatic substitution predominately occurs on the benzene ring under acidic conditions and usually addition takes place at the 5-position but can sometimes add to the 8-position. The rate of electrophilic aromatic substitution is slower for isoquinoline compared to naphthalene. The nitrogen in isoquinoline reacts similar to a pyridine nitrogen and will add a variety of electrophilic species such as 0-(2,4-dinitrophenyl)hydroxylamine 2 to aminate the nitrogen (eq 1). Friedel-Crafts acylation and alkylation do not work due to the formation of IV-acyl or IV-alkyl isoquinolinium salts. 

The azanaphthalenes (benzopyridines) quinoline and isoquinoline contain an electron-poor pyridine ring, susceptible to nucleophilic attack, and an electron-rich benzene ring that enters into electrophilic aromatic substitution reactions, usually at the positions closest to the heterocyclic unit. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

Here, once again, the cyclising step involves electrophilic attack on the aromatic ring so the method works best for activated rings, and meto-substituted-aryl ethanamides give exclusively 6-substituted isoquinolines. 

Electrophilic substitution (bromination, nitration) of 2-substituted 1,2,3,6,7,116-hexahydro-4//-pyrazino[2,l -a]isoquinolin-4-ones occurred on the aromatic moiety to give either 11- or 8-substituted derivatives the site was not determined (76GEP2441261). The nitro group was reduced to an amino group, which was alkylated, acylated, and converted to different groups via a diazonium group, and involved in diazonium coupling. 

Another useful variation is the Pictet-Spengler isoquinoline synthesis, also known as the Pictet-Spengler reaction. The reactive intermediate is an iminium ion 49 rather than an oxygen-stabilized cation, but attack at the electrophilic carbon of the C=N unit (see 16-31) leads to an isoquinoline derivative. When a p-aryla-mine reacts with an aldehyde, the product is an iminium salt, which cyclizes with an aromatic ring to complete the reaction and generate a tetrahydroisoquinoline." ° A variety of aldehydes can be used, and substitution on the aromatic ring leads to many derivatives. When the reaction is done in the presence of a chiral thiourea catalyst, good enantioselectivity was observed." ... 

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