Synthesis of Isoquinoline Derivatives

The mechanism of palladium-catalyzed intramolecular cyclization of o-bromo(aminoalkyl)benzenes has been discussed earlier (see Scheme 50 in Section IV,A,4). An example illustrating the use of this approach for the synthesis of 2,3,4,5-tetrahydro-l//-2-benzazepin-l-ones is given in Scheme 17386 and examples indicating the synthesis of isoquinoline derivatives are given earlier (see Scheme 146 in Section V,A,4). 

Similarly, ketimines (benzylimines of aromatic ketones) undergo the rhodium-catalyzed ortho-alkenylation with alkynes to give or/ o-alkenylated aromatic ketones after hydrolysis.61 This method is applied to an efficient one-pot synthesis of isoquinoline derivatives by using aromatic ketones, benzylamine, and alkynes under Rh catalysis (Equation (55)). 

The catalytic and chiral efficiency of (S,S)-le was also appreciated in the asymmetric synthesis of isoquinoline derivatives, which are important conformationally constrained a-amino acids. Treatment of 2 with a,a -dibromo-o-xylene under liquid-liquid phase-transfer conditions in the presence of (S,S)-le showed complete consumption ofthe starting Schiffbase. Imine hydrolysis and subsequent treatment with an excess amount of NaHCOs facilitated intramolecular ring closure to give 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butyl ester 38 in 82% yield with 98% ee. A variety of l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives possessing different aromatic substituents, such as 39 and 40, can be conveniently prepared in a similar manner, with excellent enantioselectivity (Scheme 5.20) [25]. 

Nickel(O) complexes catalyse [2+2+2] cycloaddition. Catalytic asymmetric synthesis of isoquinoline derivative 134 is possible based on enantiotopic group-selective formation of the nickelacyclopentadiene 133 from 132 using the Ni(0) complex coordinated by a chiral ligand under acetylene atmosphere [56]. 

A 2-pyridone ring can be a building block for the synthesis of isoquinoline derivatives by acting as a dienophile in a Diels-Alder reaction. An electron-withdrawing group at C-4 is necessary for reaction with various substituted 1,3-butadienes (Equation 109) <2000CPB1814>. 

The same reaction has been developed that allows for in situ olefination in the synthesis of isoquinoline derivatives (Equation 11) <2003JOC980>. Although numerous examples were reported, it was found that the aryl methoxy substituent was necessary for the reaction to be successful. 

The methods discussed in this chapter have made possible the facile synthesis of isoquinoline derivatives oxygenated at the 7-position, the 5,8-positions, the 6,7-positions, the 7,8-positions, and the 6,7,8-positions [Eq. (7)] or having carbon substituents at the 6-position [Eq. (6)]. The starting materials are readily available aromatic aldehydes, and the reactions are experimentally simple. These methods are not suitable for the preparation of isoquinolines with oxygen at the 5-position, the 6-position, or the 5,6-positions. These must still be prepared by the Bischler-Napieralski method,61 the Pictet-Spengler method,83 or the Dieckmann route shown in Eq. (22). 

The chemistry of 4-hydroxy- and 4-oxo-l,2,3,4-tetrahydroisoquinolines has been reviewed. A short chapter on the synthesis of isoquinoline derivatives has appeared. 

Another method for the synthesis of isoquinoline derivatives is the Pomeranz-Fritsch reaction. Simple aniline derivatives can be used but this is very useful for acid sensitive substrates such as thiophene and pyrrole... 

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>. 

SCHEME 11.32. Enantioselective synthesis of isoquinoline derivatives catalyzed by Br0nsted acids. 

The plan was to disconnect reserpine into indole 80 and tri-O-methylgallic acid (81). Indole 80 was to be converted to reserpine using a variant of the well-known Bischler-Napieralski synthesis of isoquinoline derivatives. This transformation (80 79) generates a stereogenic center and thus, there... 

SCHEME 44 Synthesis of isoquinoline derivatives using aryne MCRs [69]. 

A highly efficient Rh(I)-catalyzed one-pot synthesis of isoquinoline derivatives (55 and 56) was achieved from aromatic ketone, benzylamine, and alkyne (Scheme 7.39) [108]. The reaction works well when either electron-donating or electron-withdrawing groups are present in the benzene ring. 

Scheme 7.39 Rh(I)-catalyzed one-pot synthesis of isoquinoline derivatives from aromatic ketone, benzylamine, and alkyne...

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