Isoquinoline regioselectivity

In the case of the 2-dimethylamino- (or 2-amino-)methylene derivatives, the products were at first thought to be pyrimido[4,5-c]isoquinolines (267), but later work with 6-(N-substituted amino)uracils assigned the structures of the products (268) as belonging to the isomeric pyrimido[4,5-f>]quinoline system (74CB2537), in agreement with the regioselection rules above. 

The Gabriel-Colman reaction can be used to prepare isoquinoline-1,4-diols regioselectively by the use of unsymmetrically substituted phthalimides. Reaction of phthalimide 32 with sodium ethoxide in ethanol provides a 1 7 mixture of 33 34. It was rationalized that attack at carbon b is preferred because of its greater steric accessibility and diminished electron density compared to carbon a. In spite of the reasonable regioselectivity observed m this reaction, the Gabriel-Colman reaction has not been substantially investigated in the preparation of non-symmetrically substituted isoquinolines. 

Strong effects of the catalyst on the regioselectivity have been observed in the cycloadditions of a variety of heterocyclic dienophiles. Some results of the BF3-catalyzed reactions of quinoline-5,8-dione (21) and isoquinoline-5,8-dione (22) with isoprene (2) and (E)-piperylene (3) [25], and of the cycloadditions of 4-quinolones (23a, 23b) as well as 4-benzothiopyranone (23c) with 2-piperidino-butadienes, are reported [26] in Scheme 3.8 and Equation 3.2. The most marked... 

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... 

This reaction proceeds with very high regioselectivity. The other possible regioisomer (coupled at C-7 of the isoquinoline) cannot be detected unless the reaction is performed at higher temperatures (1.2% yield at 130 C). As opposed to the final synthetic target molecules 9/10, which cannot be atropisomerized at higher temperatures, the intermediate lactone exists as helicene-like distorted atropisomers 7 and 8 that interconvert at room temperature with half-lives of less than a minute. 

Quinoline and isoquinoline react in an analogous manner with benzene in conjugated superacids (HCI-AICI3, HBr-AlBr3) to yield predominantly cis-5,1-diphenyl-5,6,7,8-tetrahydroquinoline and <7,v-6,8-diphenyl-5,6,7,8-tetrahydroisoqui-noline, respectively (75-94% yield).297 The regioselectivity observed corresponds to the most stable dicationic intermediates 73 and 74. Unsaturated imides298 exhibit similar behavior in triflic acid (Scheme 5.33). 

Treatment of 1,3,4,6,11,1 la-hexahydro-2//-pyrido[l,2- >]isoquinoline-l, 4-diones with Et3OBF4 in the presence of Na2C03 gave regioselectively 1-ethoxy-3,4,ll,lla-tetrahydro-6//-pyrazino[l,2-6]isoquinolin-4-ones, which were alkylated at position 3 at -78°C in the presence of LDA with cin-namyl chloride and propargyl bromide to give 3-substituted 1,3,4,6,11,11a-hexahydro-2//-pyrido[l,2-h]isoquinoline-l,4-diones (85TL2955). 

Together with syntheses of 2-amino-8,9-dihydrothiazolo[4,5-/ - and [4,5-/ isoquinoline and 2-amino-4,5-dihydrothiazolo[5,4-7j]isoquinoline based upon an a-bromoketone/thiourea condensation similar to that described above, a direct thiazole ring annelation method for an N-protected octahydroquinolin-5-one has been developed. This involves the trapping of a kinetic enolate with TMS—Cl followed by regioselective bromination (NBS) and condensation with thio-... 

Regioselective C- cleavage. When heated in ethyl chloroformate, tetra-hydroberberine (1) is cleaved to 2 as the only product (81% yield). The product was converted by known reactions into ( )-canadaline (3), representative of a new group of isoquinoline alkaloids, the secoberberines. ... 

The classic SsAi substitution of activated aryl halides by protected cyanohydrin anions provides substituted benzophenones. Another procedure for the arylation of protected cyanohydrin anions involves the use of aromatic substrates activated as their rr-chromium tricarbonyl complexes. - Addition of the anion of (32) to the 1,3-dimethoxybenzene complex, for example, leads principally to the meta-suh-stituted isomer (33 equation 20). Preferential meta regioselectivity is also noted with other -rr-chromium tricarbonyl complexes of arenes. Other arylations of cyanohydrin anions include interesting but synthetically limited additions at the a-position of quinoline N-oxides. In a similar manner, cyanohydrin carbonates of aromatic aldehydes react with A -oxides of quinoline and isoquinoline. ... 

Several homogeneous systems have been reported to catalyze the hydrogenation of polynuclear N-heterocycles efficiently the regioselective reduction of the N-containing ring in quinoline, isoquinoline, indole, benzoquinolines, acridine and other related molecules can be achieved with relative ease and under moderate conditions of temperature and pressure. A number of metals are known to be active (Cr, Mo, W, Mn, Fe, Ru, Os, Co, Rh, Ir) but most of the published work has concentrated on ruthenium and rhodium precursors [95-100] as shown in Table 3.3. 

Treatment of isoquinoline /V-oxide under a variety of conditions leads to the formation of 2-regioisomers with the major product arising from arylation of the benzylic position. Significantly, the regioselectivity may be tuned by the choice of ligand. For example, the use of sterically encumbered ligands such as tri-terf-butyl... 

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