Reissert compound from isoquinoline

Treatment of isoquinoline with sulphuryl chloride and potassium cyanide gives 4-chloro-l-cyanoisoquinoline and l-carbamoyl-3-cyanoisoquinoline, the relative yields of the two products depending upon the proportion of reagents. The Reissert compound from 4-methylisoquinoline gives the bromohydrin (172), and this, on treatment with aqueous sodium hydroxide, affords the benzoylimino-compound (173). Hydrolysis of the latter with dilute hydrochloric acid yields 4-methylisocoumarin (174) (Scheme 71). ... 

Reissert compounds (>70%), derived from benzimidazole, phthalazine, quinoline and isoquinoline, have been prepared by a simple catalysed one-pot N-acylation of the appropriate heterocycle, followed by reaction with cyanide ion [e.g. 101-103],... 

The chemistry of Reissert compounds has been the subject of numerous general reviews (3-10). In 1973 Popp gave a summary on the use of Reissert compounds in the synthesis of isoquinoline alkaloids and related compounds (7). We now wish to summarize new results that have appeared from 1973 to the end of 1985 for the application of Reissert compounds in the synthesis of isoquinoline as well as indole alkaloids. 

The synthesis of the basic skeleton of 1-benzylisoquinoline alkaloids has been reported by Uff et al. 15) starting from isoquinoline and benzyl chloride (Scheme 5). The preparation of Reissert compound iV-benzyl-l-cyano-l,2-di-hydroisoquinoline (4) was performed in a dichloromethane-water two-phase system with potassium cyanide and benzoyl chloride in about 64-69% yield. The deprotonation of 4 with sodium hydride in dimethylformamide solution, the subsequent alkylation with benzyl chloride, and the final alkaline hydrolysis could be performed as a one-pot reaction sequence to supply 1-benzylisoquinoline (25) in an overall yield of 75-84%. 

Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7) (78). 6-Methoxy-7-benzyloxyisoquinoline (39), prepared from O-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzyl chloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to ( )-reticuline (38) in about 25% overall yield from 39. 

In the Reissert reaction, 1-benzoylquinolinium ions (formed in situ from quinolines and PhCOCl) and cyanide ions give Reissert compounds thus, quinoline itself forms (313). These Reissert compounds are hydrolyzed by dilute alkali to, for example, quinoline-2-carboxylic acids and benzaldehyde. Isoquinolines also form Reissert compounds (e.g. 314). 

Reactions of quinoline Reissert compounds were less satisfactory than those of the corresponding isoquinolines. The hydrochloride of 64 with DMAD gave 65 in only 7% yield in methylene chloride ethanol, and 10% in DMF. From a study of the mechanism of the 1,3-dipolar addition of Reissert salts to arylpropiolate esters, McEwen et a/.499 concluded that a concerted cyclization was more probable than a two-step process. 

Novel syntheses of the phthalide-isoquinoline alkaloids have been achieved as follows. Condensation of the Reissert compound (289, R R =CH2) with methyl opianate (290) in the presence of sodium hydride gave the isoquinoline (291), which is hydrolysed, reduced and then A -methylated to racemic a and g hydrastine. The isomeric cordrastines are prepared in the same way from the compound (289, R =R =Me) (P. Kerekes, et al., Acta Acad.Sci.Hung., 1978, 97, 353 1980, 105, 283). Hydra-... 

Seubert et al. [25] have reported the first synthesis of praziquantel from the intermediate 37 obtained by the Reissert reaction of isoquinoline and followed by high pressure hydrogenation of the cyano compound 36 [36], Acylation of 37 followed by base catalysed cyclisation of the diacylated product affords praziquantel [25,37,38] (Scheme 2). 

Two new methods of Reissert compound formation have appeared. Silver cyanide and benzoyl chloride in chloroform is eifective in the 1,6-naphthy-ridine series. Reissert compounds have been prepared from quinoline or isoquinoline and an acid chloride, using trimethylsilyl cyanide and a catalytic amount of aluminum chloride in methylene chloride. The Reissert compound of 6,7-dimethoxyphthalazine has also been prepared using this latter method. ... 

Most work has been in the isoquinoline area, principally because of the usefulness of isoquinoline Reissert compounds in the synthesis of isoquinoline alkaloids. Aside from 5-chloro- and 3-acetylaminomethylquinoline and a few halo, methyl, and carbomethoxyisoquinolines, all the substituted quinoline or isoquinoline Reissert compounds have involved oxygen-type functions in one or more of positions 4-, 5-, 6-, 7-, and 8- of the isoquinoline... 

The anion (26) derived from the isoquinoline Reissert compound (2) and the related anions derived from other Reissert compounds have most generally been generated by the use of sodium hydride in dimethylformamide. ... 

A variety of isoquinoline Reissert compounds (2) have been caused to undergo rearrangement of the acyl group from nitrogen to carbon by treatment with sodium hydride in dimethylformamide to give ketones of type similar manner, the bis-Reissert compound 14... 

The mass spectra of Reissert compounds derived from quinoline, isoquinoline, and phthalazine have been discussed. The initial fragmentation involves loss of the N substituent. Additional mass spectral data have also appeared. ... 

A number of other miscellaneous systems that bear some relationship to Reissert compounds have also been reported but will not be covered in depth here. Thus, for example, the reaction of isoquinoline, potassium cyanide, and alkyl chloromethyl ethers give 116. A similar compound was also prepared from quinoline. Compounds of type 117 have been reported to undergo rearrangements similar to Reissert compounds. A... 

The anion of the isoquinoline Reissert compound (26) has also been alkylated with a wide variety of other alkyl halides.519-35 38 48-62-66,90 93 The alkylation product from 26 and allyl chloride undergoes isomerization to 38 on base-catalyzed hydrolysis.90 The phthalazine Reissert compound (3) has also been alkylated, in the presence of sodium hydride, with methyl iodide39 and with benzyl halides40 to give, after hydrolysis, 1-substituted phthalazines. A phthalazine analog of 34 (n = 3) has been prepared.1511 An additional example of the alkylation of the quinoline Reissert compound in the 4-position has appeared.943... 

A route for the synthesis of phthalide-isoquinoline alkaloids from Reissert compounds has been reported. The Reissert compound (111) reacts with methyl opianate in the presence of sodium hydride to give the isoquinoline (112), hydrolysis of which yields dehydrohydrastine (113) this can be reduced in... 

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