Isoquinolines, 3,4-dihydro-, formation

Leptopinine 82 possesses the 3,4-dihydro-isoquinolin-7-ol moiety without further conjugation and was isolated as yellow powder from Hypecoum leptocarpum after several extractions with hydrochloric acid so that this alkaloid was finally isolated as a chloride (Scheme 29). The formation of a mesomeric betaine from this dihydroisoquinoline derivative is unlikely because on addition of base no significant changes of the UV spectra were observed (99P339). A similar structure is Pycnarrhine Pycnarrhena longifolia), which was isolated as a hydroxide (81P323). 

The interaction between pyridine and organolithium compounds in benzene was first reported by Ziegler and Zeiser129 and was attributed to the formation of 1 1 adducts. Indirect evidence for intermediates of this kind was based on the formation of dihydropyridines by treatment of the reaction mixture with water. More definite evidence was obtained with quinoline, isoquinoline, and acridine.130 Phenyllithium reacts quantitatively with quinoline in ether to yield an adduct as a yellow powder that can be recrystallized. In order to define the site of attachment, the adducts were hydrolyzed to dihydro derivatives and the latter dehydrogenated. Because this treatment leads mainly to 2-phenyIquinoIine and l-phenylisoquinoline from quinoline and isoquinoline, respectively, the related adducts can be assumed to have structures 80 and 81. Isolation and characterization of the dihydro derivatives have been carried out, as well as in the case of the reaction of acridine with phenyllithium. 

Pulse polarography has been used to characterize the products of the photochemical oxidation of 3,4-dihydro-1-isoquinolineacetamide to 1-isoquinoline-acetamide (see Fig. 26.5) [73]. After photochemical oxidation, the polarographic activity that the compound had previously demonstrated in acid and neutral supporting electrolytes was destroyed. This was in agreement with the development of fluorescence activity due to the formation of the unsaturated derivative. 

Another set of experiments with 6,7-dicthoxy-3,4-dihydro-l-(2-nitrophenyl)-Ar-substituted-isoquinolinium bromides 191 (Scheme 25) were carried out to confirm the hypothesis depicted in Scheme 24. In all the cases, the isoquinoline-fused indazolc-A-oxide was formed. In one case (191a R = C02Me), the competitive formation of the 1,3-dipolar cycloadduct 192 as a single isomer was observed (ratio 193 192 was ca. 3 1) due to the high reactivity of the electron-deficient C=0 bond of the by-product aldehyde. 

Heteroaromatic cations undergo reduction when treated with 1,4-dihydronicotinamide. An early study showed that the 10-methylacridinium ion (87) was rapidly reduced in a redox reaction to the 9,10-dihydro adduct by 1,4-dihydronicotinamides (M Scheme 18). A variety of systems including py-ridines, isoquinolines, quinolines and phenanthridines have been studied using this and related procedures. The selective reduction of pyridinium and quinolinium salts with 1-benzyl-1,2-dihydro-isonicotinamide (89) has been achieved. The selective conversion to the thermodynamically more stable 1,4-dihydro species (90 Scheme 18) is rationalized by the reversibility in the formation of the kinetic products (i.e. the 1,2-adducts) in the presence of pyridinium ions. In the pyridinium case 1,6-di-hydro adducts were also observed in some cases. Reactivity in such systems is sometimes hindered due to hydration of the dihydropyridine system. This is particularly so in aqueous systems designed to replicate biological activity. Dihydroazines derived from isoquinolines and 3,5-disubstituted pyridines have been reported to overcome some of these difficulties. ... 

UV Irradiation of an 3-aryl-2-azidoacrylic ester (2-azidocinnamate) results in elimination of nitrogen and formation of a 2/f-azirine, which undergoes spontaneous electrocyclic ring opening to give a reactive intermediate which can react as an azomethine ylide dipole or an alk-oxycarbonyl(benzylidenimino)carbene. In favorable cases, the carbene form can be trapped by intramolecular [l-t-2] cycloaddition to an alkene double bond to give a dihydro-cyclopropa[c]isoquinoline, e.g.l, and 2 (Houben-Weyl, Vol. E19b, pi 166). 

Determinations of the ERE of quinoline from thermochemical data have given results which range from 47.3 to 69 kcal mole-1.49-271-272 There appear to be no corresponding estimates for isoquinoline, but a value of 48 9 kcal mole-1 has recently been deduced from a comparison of the equilibrium constants for pseudo-base formation of iV-methylisoquinoline cation and its dihydro analog 73.273 Comparison of these ERE values with those obtained for naphthalene (61-75 kcal mole-1) shows that they parallel the somewhat lower resonance energy of pyridine relative to that of benzene. 

Turning now to the synthesis of isopavines, a required intermediate for this purpose is again an appropriately substituted 1,2-dihydro-A -methylbenzyl-isoquinoline. Hydroboration of the enamine system and oxidative work-up induce formation of a 4-hydroxybenzylisoquinoline which can be cyclized in acid to the isopavine skeleton. A recent example of such a synthesis leads to the new isopavine thalidine ... 

---