Regioselectivity isoquinoline synthesis

The cobalt-catalyzed cooligomerization of diynes with nitriles allows a simple one-step synthesis222 of condensed pyridine derivatives including difficultly accessible 5,6,7,8-tetrahydroisoquinolines223 The synthesis is a versatile one in that pyridines condensed with five- and seven-membered carbocyclic rings can also be achieved in moderate yield in similar fashion. Additional attractive features of this simple synthesis are the formation of condensed isoquinolines by the use of functionalized nitriles and the pronounced regioselectivity observed when dissymmetrical diacetylenes are employed (Scheme 148).222... 

Isoquinoline alkaloids. The regioselective allylation of N-acyl heterocycles (13, 10) can be used for synthesis of isoquinoline alkaloids. Thus simultaneous reaction of the dihydroisoquinoline (1) with a diunsaturated acyl chloride (2) and allyltributyltin affords the 1,2-adduct (3), which undergoes a Diels-Alder cyclization... 

The 3 + 2-cycloaddition of 1,2-dithiophthalides with nitrilimines yields benzo[c]thio-phenespirothiadiazoles regioselectively. The azomethineimines isoquinolinium-iV-aryllimide and A-(2-pyridyl)imide readily undergo 1,3-dipolar cycloaddition with electron-deficient dipolarophiles, dimethyl fumarate and dimethyl maleate, to yield tetrahydropyrazolo[5,l-a]isoquinolines in high yield. ° The 1,3-dipolar cycloadditions of electron-poor 1,3-dipoles, bicyclic azomethine ylides (27), with ( )-l-A,A-dimethylaminopropene to yield cycloadducts (28) and (29) are examples of non-stereospecific cycloadductions (Scheme 9). The synthesis of protected... 

Following the proposed biogenetic scheme (see Section IV,A), completion of a first total synthesis of entire alkaloids still required a regioselective coupling of sterically highly crowded naphthalenes with isoquinolines. Thus, as expected, direct methods like the classical Ullmann reaction of 94 and 95 failed, giving the desired mixed coupling product 96 only in traces (7) (see Scheme 22). 

The regioselective ET-sensitized addition of primary amines has been cleverly employed by Yasuda and co-woikers in the synthesis of isoquinolines and related alkaloids. For example, the DCNB-sensitized photoamination of stilbene with 2-hy-doxypropylamine in an acetonitrile-water solution yields the adduct 98, which is converted to the benzylisoquinoline 99 upon treatment with CFjSOjH, The P-hydroxyl group of ethano-lamine can be replaced with acetal or vinyl groups which also can serve as precursors of the carbocation required for the acid-catalyzed ring-forming reaction. Analogous reaction sequences have been used to convert phenanthrene to aporphines. ... 

Konno T, Chae J, Miyabe T, Ishihara T (2005) Regioselective one-step synthesis of 4-fluoroalkylated isoquinolines via carbopalladation reaction of fluorine-containing aflsynes. J Org Chem 70 10172-10174... 

F. Sha, X. Huang, A multicomponent reaction of arynes, isocyanides, and terminal alkynes highly chemo- and regioselective synthesis of polysubstituted pyridines and isoquinolines, Angew. Chem. Int. Ed. 48 (2009) 3458-3461. 

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