3,4-Dihydroisoquinoline

By a modified Bischler-Napieralsky reaction, 6 -nitrophenylaceto-jS-3 4-methylenedioxyphenylethylamide, resulting from the condensation of -3 4-methylenedioxyphenylethylamine with 2-nitrophenylacetyl chloride, was converted into 6 nitro-l-benzyl-6 7-methylenedioxy-3 4-dihydroisoquinoline. The methiodide of the latter was reduced with zinc and hydrochloric acid to 6 -amino-l-benzyl-2-methyl-6 7-methylenedioxy-1 2 3 4-tetrahydro/soquinoline dihydrochloride, which by the Pschorr ring-closure reaction, produced dZ-roemerine (IV, p. 317), m.p. 85-7°. By treatment in succession with d- and Z-tartaric acids, the dZ-base was resolved into Z- and tZ-forms. Synthetic Z-roemerine is dimorphic, m.p. 85-7° and 102°, and has [aju — 79-9° (EtOH), these constants being in good agreement with those of the natural base. 

The piperideine derivatives have not been studied as extensively as the analogous pyrrolines (151,152). The imino structure has been established, for example, for the alkaloid y-coniceine (146) (46). The great influence of conjugation on the structure is seen with l-(a-picolyl)-6,7-methylenedioxy-3,4-dihydroisoquinoline (47), possessing an enamine structure, whereas the analogous 1-methyl derivative (48) possesses an imine structure according to infrared spectra (152,153). 

Imines also react with , -unsaturated aldehydes or ketones (219-221). 3,4-Dihydroisoquinoline reacts, for example, with methyl vinyl ketone to give cyclic ketone 146 (222,223). 

A dimer is formed by the action of hydrogen peroxide on the quaternary salt of 3,4-dihydroisoquinoline (235). The other similar reactions are of small importance. 

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. 

Methyl-1,2-dihydropapaverine (175, R = OMe) rearranges to the 2-methyl-3-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-ium salt (176, R = OMe) under very mild conditions (treatment with 2% hydrochloric acid). A similar rearrangement of l-(3,4-methyl-enedioxybenzyl) - 2 - methyl - 6,7 - dimethoxyisoquinoline (175, R, R = —O—CHj—O—) affords 3-(3,4-methylenedioxybenzyl)-2-methyl-6,7-di-methoxy-3,4-dihydroisoquinolinium chloride (176, R, R = O—CHj—O—) (256). The reaction was shown to be an allylic rearrangement with internal return (275,275). 

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

The synthesis of 3,4-dihydroisoquinolines via intramolecular reactions of phenethyl amides was first reported by August Bischler and Bernard Napieralski in 1893. The authors described the conversion of A-acyl phenethylamide (1, R = Me) and A-benzoyl phenethylamide (1, R = Ph) to 1-methyl-3,4-dihydroisoquinoline (2, R = Me) and 1-phenyl-3,4-dihydroisoquinoline (2, R = Ph), respectively, in the presence of P2O5. This reaction has subsequently proven to be one of the most general methods ever developed for the synthesis of dihydroisoquinolines. 

Asymmetric nucleophilic addition of dialkylzinc to 3,4-dihydroisoquinoline 1-oxides 98YGK11. 

Bischler-Napieralski reaction of 139 to a 3,4-dihydroisoquinoline, oxidation, dehydrogenation and reduction of the nitro to the amino function gave 140 which was subjected to a Pschorr reaction (Scheme 49). Quaternization was accomplished by methyl iodide to furnish the isoquinolininium salt 141 which underwent an ether cleavage on heating a solid sample or benzene or DMF solution to Corunnine (127) (73TL3617). 

All these syntheses form variations of the same reaction. The three-membered ring is formed from an A-halogenoamine with ketone-ammonia mixtures or the Schiff s base 3,4-dihydroisoquinoline. Starting from these first observations the three groups of authors were able to generalize their diaziridine syntheses quickly in the years 1959-1962 they were extended to generally applicable reactions. In numerous variations of the syntheses, large numbers of diaziridincs were prepared. 

Dialkyl-diaziridines are not attacked by lithium aluminum hydride l,2-di-n-butyl-3-n-propyldiaziridine (60) was recovered in 80% yield after treatment with lithium aluminum hydride in boiling ether. A preparative separation of 34 and 3,4-dihydroisoquinoline is possible by treating the mixture with lithium aluminum hydride when compound 34 is unattackcd. ... 

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

The submitters, working on a kilogram scale without purification of reagent or solvent and with no precaution against moisture, obtained 6,7-dimethoxy-l-methyl-3,4-dihydroisoquinoline hydrochloride,2 m.p. 202-203°, instead of the dichlorophosphate at this stage. The checkers obtained this hydrochloride by either treating the free base with... 

This procedure provides a facile method for converting substituted 1-methyl-3,4-dihydroisoquinolines into the corresponding 2-(2-acet-... 

Nucleophilic addition reactions of allylic tin reagents to chiral 3-substituted 3,4-dihydroisoquinolines 89 activated by acyl chlorides afford trans 1,3-disubstituted 1,2,3,4-tetrahydroisoquinolines 90 stereoselectively <95CL1003>. 

Another photochemical method was reported by Kessar et al. (157). l-o-Toluyl-3,4-dihydroisoquinoline 299a, derived from dihydroberberine metho salt (298a), was irradiated and then reduced with sodium boro-hydride to provide the ring D-inverted 11,12-oxygenated protoberberine 482 (Scheme 100). 

The reaction of 2-polyfluoroalkylchromones (e.g., 323) with l,3,3-dimethyl-3,4-dihydroisoquinolines (e.g., 324) gave zwitterionic 6,7-dihydrobenzo[ ]quinolizinium compounds such as 326 (Scheme 70). The mechanism proposed for this transformation involves an addition-elimination displacement of the chromane heterocyclic oxygen by the enamine tautomer of the dihydroisoquinoline, followed by intramolecular cyclization of the intermediate 325 <20030L3123>. 

Dihydroisoquinoline reacts with the appropriate heterocycle-linked dimedone derivatives to give thiazolo-quinolizinium salts such as 467 <1995RJ0271, 1995DOC776> or pyrazoloquinolizines like 468 <1995RJC146> (Scheme 105). 

Another chemotype displaying appreciable isoform selectivity is the 5-benzoyloxy-3,4-dihydroisoquinolin-l(2H)-one (37), displaying ICso = 0.8 and 13 pM against PARP-2 and PARP-1, respectively [36]. Interestingly, 38 is a selective PARP-1 inhibitor, pICso = 7.35, displaying around 100-fold selectivity for PARP-1 over PARP-2 [34],... 

Kobayashi and co-workers have also reported an alternate synthesis of 1,4-disubstituted isoquinolines and a new synthesis of 1,3,4-dihydroisoquinoline derivatives <06BCJ 1126 06S2934>. The 1,4-disubstituted isoquinolines 121 are synthesized in good yields by reacting a variety of organolithiums 122 with different benzonitriles 123. In addition, a variety of lithium dialkylamides 124 were also reacted with different benzonitriles 123 to form 1 -amino-4-substituted isoquinolines 121 in moderate yields. 

The asymmetric addition of different types of nucleophiles at the C-l position of 3,4-dihydroisoquinolines were highlighted in a number of publications. Schreiber et al. described an enantioselective addition of terminal alkynes 136 to 3,4-dihydroisoquinolinium bromide 137 in the presence of triethylamine, catalytic copper bromide, and QUINAP <06OL143>. The resulting 1-substituted tetrahydroquinolines 138 were isolated in high yield and high enantiomeric excess in most cases. 

It is noteworthy that quick and effective formation of diaryl nitrones can be achieved through oxidation of diaryl imines with Oxone (potassium peroxy-monosulfate) in such media as aqueous solution of NaHCC>3 in acetonitrile or acetone. When oxidized under such conditions, dialkyl or monoaryl imines give oxaziridines (17). Oxidation of 3,4-dihydroisoquinoline (9) with Oxone initially leads to the formation of oxaziridine (10) which is easily transformed into the corresponding 3,4-dihydroisoquinoline A-oxide (11) upon treatment with catalytic amounts of p-toluenesulfonic acid (Scheme 2.4) (18). 

I.2. Oxidation of Amines Oxidation of primary amines is often viewed as a particularly convenient way to prepare hydroxylamines. However, their direct oxidation usually leads to complex mixtures containing nitroso and nitro compounds and oximes. However, oxidation to nitrones can be performed after their conversion into secondary amines or imines. Sometimes, oxidation of secondary amines rather than direct imine oxidation seems to provide a more useful and convenient way of producing nitrones. In many cases, imines are first reduced to secondary amines which are then treated with oxidants (26). This approach is used as a basis for a one-pot synthesis of asymmetrical acyclic nitrones starting from aromatic aldehydes (Scheme 2.5) (27a) and 3,4-dihydroisoquinoline-2-oxides (27b). 

The /V -hydroxylamino compounds (404) and (405), obtained from the reaction of tert-butyl acetate with 3,4-dihydroisoquinoline-A-oxide or 5,5-dimethyl-pyrroline-/V-oxide, when boiled in methylene chloride in the presence of triphenylphosphine, carbon tetrachloride and triethylamine, are transformed to (1,2,3,4- tetrahydroisoquinolin-l-ilidene) acetate (406) or (pyrrolidin-2-ilidene) acetate (407) (Scheme 2.181) (645). 

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