Of Reissert compounds

Excellent yields of the former product are also obtained with quinoline N-oxide. Improved yields of Reissert compounds are found under phase-transfer conditions (29). The regiochemistry of the method changes dramatically with /V-alkyl quin olinium salts, eg, /V-methy1quino1inium iodide [3947-76-0] (12), which form 4-cyanoquinoline [23395-72-4] (13) (30), through the intermediary in this example of A[-methyl-4-cyano-l,4-dihydroquinoline... 

Apart from isolated reports summarized in Scheme 47, the chemistry of the fully conjugated ring systems has not been especially developed since CHEC-II(1996). In 1999, Monnier et al. reported the 1,3-dipolar cycloaddition of Reissert compound 160 with acrylates. Addition of triethylamine traps hydrofluoroboric acid and increases the proportion of milnchnone imine 160B the reaction therefore predominantly yields 1,3-adduct 161 which rearranges to 162 (Scheme 47) <1996BSB777, 1999EJ0297>. 

Sonication [130, 131] aids the standard phase-transfer catalysed [e.g. 132, 133] C-alkylation of Reissert compounds. As much as twofold increases in yield are observed with shortened reaction times. No alkylation is observed when sonication is used alone. 

Bischler-Napieralski cyclization of pyridazin-6-one 134 with POCI3, and subsequent hydrogenation of the cyclized product 135 over Pt02, gave rise to 2,3,4,6,7,llZ -hexahydro-l//-pyridazino[6,l-fl]isoquinoline (51) (75CPB3056). Treatment of Reissert compound 136 with NaH gave 116-cyano-l, 2,3,116-tetrahydro-4//-pyrido[2,l-fl]phthalazin-4-one (137) (80JHC433). 

B. Reaction of Reissert Compounds Synthesis of Isoquinoline Alkaloids... 

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 most frequently used method for the preparation of isoquinoline Reissert compounds is treatment of an isoquinoline with acyl chloride and potassium cyanide in water or in a dichloromethane-water solvent system. Though this method could be successfully applied in a great number of syntheses, it has also some disadvantages. First, the starting isoquinoline and the Reissert compound formed in the reaction are usually insoluble in water. Second, in the case of reactive acyl halides the hydrolysis of this reaction partner may became dominant. Third, the hydroxide ion present could compete with the cyanide ion as a nucleophile to produce a pseudobase instead of Reissert compound. To decrease the pseudobase formation phase-transfer catalysts have been used successfully in the case of the dichloromethane-water solvent system, resulting in considerably increased yields of the Reissert compound. To avoid the hydrolysis of reactive acid halides in some cases nonaqueous media have been applied, e.g., acetonitrile, acetone, dioxane, benzene, while utilizing hydrogen cyanide or trimethylsilyl cyanide as reactants instead of potassium cyanide. 

Acid-catalyzed hydrolysis of Reissert compounds results in an aldehyde, a formal reduction product of the acyl halide utilized in the Reissert compound formation (11). The mechanism of the reaction according to McEwen and Cobb (3), is shown in Scheme 2. 

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%. 

Among the great number of different approaches for the synthesis of phthal-ideisoquinoline alkaloids the application of Reissert compounds, developed first by Kerekes et al. (42,43), proved to be one of the most efficient and suitable methods (Scheme 24). Treatment of isoquinoline Reissert compounds 26 or 28 with sodium hydride in dimethylformamide resulted in the formation of the corresponding Reissert anions, which were reacted with dimethoxy- or meth-ylenedioxy-substituted o-formylbenzoic acid ester derivatives 178 and 179, respectively. The presumed mechanism of this reaction involves an initial reaction... 

Successful attempts have been made for the preparation of different emetine analogs 46). For example, 211 has been synthesized by the reaction of Reissert compound 26 with the protoemetine analog 212 (Scheme 26). 

In the early days, greatest interest was focused on the acid-catalyzed hydrolysis (by hydrochloric acid in the presence of 2,4-dinitrophenylhydrazine) of Reissert compounds to aldehydes and the corresponding heterocyclic carboxylic acid derivatives. This reaction is fairly general for compounds of quinoline (178) and isoquinoline (179) (Table 18), but it is not applicable to pyridines as they rarely form Reissert compounds. The 3-hydroxyquino-line Reissert compound does not yield benzaldehyde, probably because acylation of the 3-hydroxy group prevents formation of the required cyclic intermediate (180). Some nitroquinolines and isoquinolines give low yields of benzaldehyde. Rather curiously, disub-stituted quinoline Reissert compounds yield less of the aldehyde than of the corresponding... 

Table 18 Some Examples of Reissert Compound Formation...

Heterocycle Acyl chloride Methoda Yield of Reissert compound (%)... 

The photochemistry of Reissert compounds truly belongs in Section 2.05.8, but it is discussed here to avoid fragmentation. Irradiation of the cyano ester (194) in diethyl ether followed by chromatography on alumina yields ethyl 2-cyanomethylindole-l-carboxylate (Scheme 125) (76JCS(Pl)2587>. The 1-acetyl Reissert compound (195) affords a mixture of... 

This section deals with transformations of heterocyclic rings and includes not only addition of carbenes and nitrenes, but also rearrangements frequently following these additions. Also included are topics such as the synthesis of Reissert compounds as well as miscellaneous oxidations and reductions. 

Koizumi et al.266 have reported the synthesis of Reissert compounds under PT conditions. Ulf and Budrham267 report the same reaction with phthalazines (171). 

The Chemistry of Reissert Compounds F. D. Popp, Bull. Soc. Chim. Belg., 1981, 90, 609-613. 

The mechanism proposed495-497 for the acid-catalyzed hydrolysis of Reissert compounds (l-acyl-l,2-dihydro-2-cyanoquinolines or 2-acyl-1,2-dihydro-1-cyanoisoquinolines) invokes a mesoionic oxazolinium... 

Developments in the chemistry ol furans (1952-1963), 7, 377 of Reissert compounds (1968-1978), 24, 187 Dewar Heterocycles and Related Compounds, 31, 169... 

The reaction of adducts with alkali hydroxides have been studied for cyanoisochromenes 108, which are oxygen analogs of Reissert compounds described for the first time by Balaban and co-workers (87T409). In this case, sodium hydroxide, depending on its concentration in aqueous solutions and on the nature of R3 in 108, may act both as a base and as a... 

Formylisothiazole and 4-formyl-3-methylisothiazole have been prepared by hydrolysis of Reissert compounds.70,137 An alternative... 

---