2.3- Dihydroisoquinolines

Isoquinoline can be reduced quantitatively over platinum in acidic media to a mixture of i j -decahydroisoquinoline [2744-08-3] and /n j -decahydroisoquinoline [2744-09-4] (32). Hydrogenation with platinum oxide in strong acid, but under mild conditions, selectively reduces the benzene ring and leads to a 90% yield of 5,6,7,8-tetrahydroisoquinoline [36556-06-6] (32,33). Sodium hydride, in dipolar aprotic solvents like hexamethylphosphoric triamide, reduces isoquinoline in quantitative yield to the sodium adduct [81045-34-3] (25) (152). The adduct reacts with acid chlorides or anhydrides to give N-acyl derivatives which are converted to 4-substituted 1,2-dihydroisoquinolines. Sodium borohydride and carboxylic acids combine to provide a one-step reduction—alkylation (35). Sodium cyanoborohydride reduces isoquinoline under similar conditions without N-alkylation to give... 

Hydroisoquinolines. In addition to the ring-closure reactions previously cited, a variety of reduction methods are available for the synthesis of these important ring systems. Lithium aluminum hydride or sodium in Hquid ammonia convert isoquinoline to 1,2-dihydroisoquinoline (175). Further reduction of this intermediate or reduction of isoquinoline with tin and hydrochloric acid, sodium and alcohol, or catalyticaHy using platinum produces... 

A methylene base formed from quinaldine ethiodide, l-ethyl-2-methyl-ene-1,2-dihydroisoquinoline (129), exhibits a number of reactions characteristic of enamines (207,209). On treatment with benzoylchloride a dialkylated product (130) is produced by C and subsequent O benzoylation (210). 

The cyclization reaction of some substituted 1,2-dihydroisoquinolines is of interest (255). The reduction of papaverine with tin and hydrochloric acid affords the 1,2-dihydro compound in the form of immonium salt 172, which then undergoes a cyclization reaction in the acidic medium to give compound 173, called pavine (257). 

Knabe et al. (271-274) later observed that 6,7-dimethoxy-2-methyl-1,2-dihydroisoquinolines (175), possessing either a free or a substituted benzyl group in position 1, readily rearrange to 3,4-dihydroisoquinoline salts (176) on treatment with dilute acids. 

The acid-catalyzed cyclization of p-toluenesulfonamides of A/-benzylaminoacetaldehyde usually yields 1,2-dihydroisoquinolines. However, cyclization of intermediates bearing a substitutent a to the carbonyl group affords 3-substituted 2-p-toluenesulfonyl tetrahydroisquinolin-4-ol derivatives, capable of further transformation into the related 1,2,3,4-tetrahydroisoquinolines <95CJC(73)1348>. 

An efficient synthesis of 2-methyl-l-(2-oxoalkyl)-1,2-dihydroisoquinolines 86 via addition of ketone enolates to isoquinolinium methiodide has been reported < 6JCK (61)483Q>. 

The Peterson reactions of amides of bis(trimethylsilyl)methylamines such as 1620 with TBAF in THE afford HMDSO 7 and the 1,2-dihydroisoquinolines 1621... 

A wide variety of other functional groups can be employed in these annulations. For example, this chemistry has been extended to the synthesis of 1,2-dihydroisoquinolines, benzofurans and benzopyrans (Scheme 3).3 One can also employ vinylic halides and triflates in this process.4... 

Several 1-benzylisoquinoline alkaloids have been synthesized utilizing the above reaction sequence. For example, takatonine (34) has been obtained from Reissert compound 27 via alkylation with p-methoxybenzyl chloride and subsequent hydrolysis and quatemarization with methyl iodide 17). Similarly, es-cholamine (37) has been prepared from A-benzoyl-l-cyano-6,7-meth-ylenedioxy-1,2-dihydroisoquinoline (28) and 3,4-methylenedioxybenzyl chloride (77) as shown in Scheme 6. 

The total synthesis of pavinane alkaloid platycerine (89) (Scheme 14) has been accomplished successfully (26) via 1-benzylisoquinoline derivative 91 obtained from Reissert intermediate 90. Quatemarization of 91 with methyl iodide followed by lithium aluminum hydride reduction supplied 1,2-dihydroisoquinoline 92, which on treatment with a 7 5 mixture of formic acid and phosphorous acid gave ( )-platycerine (89) in 60-70% yield. 

The synthetic process leading to pavine formation can now be illustrated as in Scheme 1. It includes quatemization and selective reduction of the iminium bond to afford a 1,2-dihydroisoquinoline (36), which is the key intermediate in the synthesis of pavine bases. Acid-catalyzed cyclization of this enamine furnishes the pavinane framework 38 via the 1,4-dihydroisoquinolinium ion 37. Langhals... 

Nucleophilic addition takes place at C-1, and this is considerably enhanced if the reaction is carried out upon an isoquinolinium salt. Reduction with lithium aluminium hydride [tetrahydroaluminate(III)] in THF (tetrahydrofuran), for example, gives a 1,2-dihydroisoquinoline (Scheme 3.15). These products behave as cyclic enamines and if isoquinolinium salts are reacted with sodium borohydride [tetrahy-droboronate(III)] in aqueous ethanol, further reduction to 1,2,3,4-tetrahydroisoquinolines is effected through protonation at C-4 and then hydride transfer from the reagent to C-3. 

Through a slight modification the Pomeranz-Fritsch synthesis can be made particularly useful for the preparation of 1,2-dihydroisoquinolines. The imine is first reduced with sodium borohydride in 98% ethanol to the corresponding benzylamine, prior to cyclization, by treatment with 6 M hydrochloric acid. When electron-donating groups (such as a methoxyl) are present in the aromatic unit of the benzylamine, the ring-... 

An advantage of the modified Pomeranz-Fritsch synthesis is that the 1,2-dihydroisoquinolines can be reacted in situ with electrophiles, yielding 1,4-dihydroisoquinolinium salts that react with nucleophiles at C-3 (see Section 3.3.3). Such a single pot procedure can be used to form complex 1,2,3,4-tetrahydroisoquinolines. 

A Once the 1,2-dihydroisoquinoline is formed by a Potneranz-Friisch synthesis between the reduced imine, from 4-methoxybenzaldehyde and ami noacetaldehyde diethyl acetal, it is combined directly with the l-(2-bromoethyl)-3-meihoxybenzene in a tandem two-steps-in-one procedure (Scheme 3.21), First the compound acts as an enamine and combines with the alkyl bromide at C-4, and then the methoxylated phenyl ring of the intermediate reacts with the iminium unit at C-3 to form the letracycle. 

The l,3,4-oxadiazin-6-one (240) undergoes cycloaddition followed by a remarkable rearrangement to give the triazole A(-imine 241 and an open-chain product (136). Cycloadditions have also been carried out with the following ring systems 1,2-dihydroisoquinoline (242) (137) dihydro-1,3-oxazine (243) (138,139), 2H-, 3-benzothiazine (244) (140,141), and 27/-l-pyran-2-thione (245) (142). 

Soufiaoui and co-workers (19) reported an intermolecular 1,3-dipolar cycloaddition of tosyl azide with the 1,2-dihydroisoquinoline 81 to give the triazohne 82, which, on extrusion of nitrogen followed by aromatization via elimination of H2 or... 

The ring expansions of quinolines (74JCS(Pl)1828), 1,2-dihydroisoquinolines (80JOC1950) and 1,2-dihydroisoquinolones (80RTC271) by use of dihalocarbenes have some merit for the synthesis of 1- and 2-benzazepines and benzazepinones. However, the report that 1-phenyl-2,3,4-trioxotetrahydroquinoline on treatment with diazomethane ring- expands to 1-phenyl-l//-l-benzazepine-2,4,5-trione is incorrect the product is in fact the spirooxirane (276) (76ZN(B)1716). 

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... 

Rozwadowska and coworkers carried out the asymmetric alkylation of isoquino-line Reissert compounds under phase-transfer conditions using cinchonine-derived quaternary ammonium salts as catalysts. The best enantioselectivity was achieved in the benzylation and allylation of 1 -cyano-2-phenoxy carbonyl-1,2-dihydroisoquinoline (17) catalyzed by 2a (Scheme 2.14) [34]. 

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