Isoquinoline system

An effective synthesis of the pyrido[T,2 l,2]imidazoI5,4-c]isoquinoline system 41 uses the 3-aceta (or benza)mido-2-phenylimidazo[l,2-a]pyridine 40 and phosphorus oxychloride. An alternative approach using the carbodiimide 42, obtained from the corresponding iminophosph(Mane and an isocyanate, is also successful <95H(41)2019>. 

The oxidative degradations of binuclear azaarenes (quinoline, isoquinoline, and benzodrazines) by hydroxyl and sulfate radicals and halogen radicals have been studied under both photochemical and dark-reaction conditions. A shift from oxidation of the benzene moiety to the pyridine moiety was observed in the quinoline and isoquinoline systems upon changing the reaction from the dark to photochemical conditions. The results were interpreted using frontier-orbital calculations. The reaction of OH with the dye 3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro-(l,8)(2//,5//)-acridinedione has been studied, and the transient absorption bands assigned in neutral solution.The redox potential (and also the pA a of the transient species) was determined. Hydroxyl radicals have been found to react with thioanisole via both electron transfer to give radical cations (73%) and OH-adduct formation (23%). The bimolec-ular rate constant was determined (3.5 x lO lmoU s ). " ... 

Several tetra- and pentacyclic systems were prepared from Pro, which was first -substituted with naphthalene or phenanthrene rings whereupon the cyclization took place. Such reactions were used for synthetic ap-proaehes toward alkaloids vinceten from Cynachum vincetoxicum (the tetrahydrobenzo /]pyrrolo[l,2-Z ]isoquinoline system 146) (79LA1212 84AJC819) or tylophorine (65T2573). 

Pictet-Spengler synthesis is another method of preparing isoquinolines. (3-phenylethylamine reacts with an aldehyde to produce an imine, which undergoes acid-catalysed cyclization, resulting in the synthesis of the tetrahydroisoquinoline system. Again, tetrahydroisoquinoline can he aromatized hy palladium dehydrogenation to produce an isoquinoline system. 

Attempts to prepare the isomeric indoloisoquinoline system in the coupling of 3-isoquinolyl triflate and o-anilineboronic acid led to an unexpected result. In the course of the follow-up reactions the nitrogen atom in the isoquinoline ring had to be protected as the A -oxidc to divert the cyclization of the nitrene into the 4-position. The intermediate diazonium salt, however under certain conditions underwent a spontaneous ring closure to the benzofuro[3,2-c]isoquinoline system, which on heating rearranges to the benzisoxazolo[2,3-o]isoquinoline (3.6.),7... 

The 1-amidino substituent on the isoquinoline system in 7 is oxidized at the amino bond with lead(IV) acetate to give 2-(trifluoromethyl)-l,2,4-triazolo[5,l-a]isoquinoline (8).266... 

The isoquinoline system is conveniently prepared from treatment of o-iodobenzylamines with the enolate ions derived from symmetrical ketones (or ketones with one a-position blocked), aldehydes, or the dimethyl acetal of pyruvaldehyde, to give aminocarbonyl compounds which condensed in situ to give 2- and/or 3-substituted 1,2-dihydroisoquinolines. Catalytic dehydrogenation or borohydride reduction of these products then led to the corresponding isoquinolines or tetrahydroisoquinolines in moderate to high... 

The introduction of methoxyl groups at C-6 and C-l into the tetrahydro-isoquinoline system, a common substitution pattern in the alkaloids, as in... 

A synthesis of takatonine-like compounds (25 R = H) has been reported, by Bischler-Napieralski cyclization to (25 R = CH2Ph) followed by routine transformations, and the correlation between chemical shifts in the n.m.r. spectra and the conformation of the isoquinoline system has been examined.38... 

A novel type of bisbenzylisoquinoline alkaloid containing one fully aromatic isoquinoline system is sciadoline, from Sciadotenia toxifera Kruhoff and A. C. Smith (Menispermaceae), which has been shown to have the structure (54) by spectroscopic studies.65 It is related to cycleanine (43 R1 = R2 = Me) and 7-nor-cycleanine (43 R1 = H, R2 = Me). 

The Pd-catalyzed cyclization of appropriate 2-phenethylamine derivatives is a commonly used approach to the isoquinoline system as illustrated by Scheme 111 <2002JOC465, CHEC-III(7.05.2.1)234>. 

If ring D is saturated, as in emetine (177), this process is not possible. Here cleavage occurs at both sides of the methylene bridge connecting the two isoquinoline systems,79,84 (177) -[178], (177)—>[179]. 

The decarboxylation of the complete benzyl isoquinoline system is slightly more complicated as the amine cannot form a simple imine, only an iminium salt. That is quite enough. 

It was also proposed that when an imine function (either as a single C=N bond or as part of an isoquinoline system) was present in these dimers, the imine was found on the right side of the dimer, whereas the left side was of the (S) configuration. 

An isoquinoline system condensed to a tropolone is the skeleton for a tropoloisoquinoline alkaloid. The general structure of the five alkaloids of this type known so far are derivatives of the tautomers of 10-hydroxy-9H-azuleno[l,2,3-i,j]isoquinolin-9-one (42) and 9-hydroxy-10H-azuleno[l,2,3 i,j]isoquinoline-10-one (43) [88]. Recently, the first tropone-isquinoline alkaloid, pareitropone (44) has been isolated from the roots of the South American Menispermaceae, Cissampebs pareira [48]. 

Several mechanisms have been postulated for the transformation of thebaine to morphothebaine of these those of Freund [17], Faltis [18], and Freund and Speyer [19], which are based on erroneous concepts of the structure of thebaine, need not be considered. Gulland and Robinson [20] postulated hydrolytic fission of the 4 5-ether bridge and 0-12 13 bond of thebaine [i] to give [xx], followed by rotation of the isoquinoline system and ring-closure of [xxi], followed by aromatization to [n]. 

C cloadditlon of the electrophilic dienophile 1,4-naphthoquinone with a 2-aza-l,3-diene provides access to the benzo[g]isoquinoline system (F. Sainte et al, J. Amer. chem. Soc., 1982, 1, 1428). 

Several alkaloids of this group have been discovered in which one of the isoquinoline systems rather than being in the dihydro- or tetrahydro-state is fully aromatic as in thalphine... 

In view of the importance of the isoquinoline system in biosynthesis it is surprising that so little effort has been devoted in the past to the biosynthesis of the basic ring system. No doubt the success of this investigation in the peyote cactus will stimulate further work in other systems. It is likely that the normal pattern will involve condensation of a phenethylamine with the appropriate pyruvic acid. However, reference has already been made to ipecoside (27) (Scheme 3) in which the isoquinoline system is formed by condensation of the phenethylamine with an aldehyde [secologanin]. Presumably the corresponding aldehyde, rather than a pyruvic acid, will be found to serve as precursor for the phenethylisoquinolines,3 5 and also for the isoquinoline alkaloids of the Lophophora cactus such as lopho-cerine (66). 

The expansion of smaller rings into the heterocyclic ring of the benzazepines has been achieved with aziridine, indole, quinoline, and isoquinoline systems, usually in high yields, and benzazepines with the highest degree... 

The benzo-fused [l,3,5]-dithiazino[4,5-a]isoquinoline system (271) could be obtained from 1,3-dithietanone (270) with 3,4-dihydroisoquinoline (Equation (59)) <84CB2205>. 

Permanganate oxidation of papaverine in neutral medium furnishes m-hemipinic acid (V), veratric acid (VI), papaverinic acid (a-veratroylcincho-meronic acid) (VII), and pyridine-2,3,4-tricarboxylic acid (VIII). The last-named product (VIII) may serve as evidence for the point of attachment of the nitrogen-free portion of the isoquinoline system. Dimethoxy-isoquinolines are oxidized to pyridine-3,4-dicarboxylic (cinchomeronic) acid, but papaverine yields VIII under analogous conditions, thus marking position 1 as the connecting point. 

In all of the syntheses discussed, alkoxy derivatives of a-aminoaceto-phenone or of /3-phenethylamine were employed to supply the main structural outline of the isoquinoline system. Some of these amines are hard to obtain, especially if the resistant aromatic methoxyl groups are replaced by more sensitive substituents which may serve in the preparation of partly demethylated derivatives of papaverine or laudanosine. A significant innovation (60) which avoids the preparation of such unstable amines is the degradation of j3-phenylpropionic acid azides (hydrocinnamic acid azides) to the corresponding isocyanates, which add to the required phenylacetic acids probably with the intermediate formation of four-membered cyclic hemiacetals. The latter are transformed to A-carboxylic acids, which lose carbon dioxide and yield amides needed in the isoquinoline syntheses. In practice, the azide is heated with the phenylacetic acid in benzene solution for several hours, and the amide is isolated from the reaction mixture without difficulty. 

Oxidation of codamine ethyl ether (LXVI) cleaved the benzylisoquinoline system to 4-methoxy-5-ethoxyphthalic acid (LXVH) and veratric acid (VT). While the formation of these two acids precluded the location of the phenolic hydroxyl in the benzyl residue, LXVTI could have arisen from either a 6- or 7-ethoxy-substituted isoquinoline system. This question was settled by repeating the potassium permanganate oxidation of 0.0085 g. of codamine ethyl ether (LXVI) under gentle conditions. This time, 1-ke-to-2-methyl-6-methoxy-7-ethoxy-l, 2,3,4-tetrahydroisoquinoline (LXVIII) was isolated its structure was confirmed by synthesis, and therefore codamine is XXII. 

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