Reissert compounds reactions

A very useful procedure for introducing a cyano group into a pyridazine ring is the Reissert-type reaction of the A/-oxide with cyanide ion in the presence of an acyl halide or dimethyl sulfate. The cyano group is introduced into the a-position with respect to the A-oxide function of the starting compound. The yields are, however, generally poor. In this way, 6-cyanopyridazines (111) can be obtained from the corresponding pyridazine 1-oxides (Scheme 33). 

Formyl-3-methylisothiazole is prepared by hydrolysis of the appropriate Reissert compound and, as the thiosemicarbazone, in poor yield by the McFadyen-Stevens reaction. 4-Formylisothiazole has been obtained by oxidation of 4-methylisothiazole although no details of the preparation have been reported. 

Heterocyclic structures analogous to the intermediate complex result from azinium derivatives and amines, hydroxide or alkoxides, or Grignard reagents from quinazoline and orgahometallics, cyanide, bisulfite, etc. from various heterocycles with amide ion, metal hydrides,or lithium alkyls from A-acylazinium compounds and cyanide ion (Reissert compounds) many other examples are known. Factors favorable to nucleophilic addition rather than substitution reactions have been discussed by Albert, who has studied examples of easy covalent hydration of heterocycles. 

This reaction is illustrative of a general procedure for the alkylation of active methylene functions in the presence of concentrated aqueous alkali catalyzed by tetraalkylammonium salts. This catalytic method has been used to alkylate arylacetonitriles with monohaloalkanes,2 dihaloalkanes,3 a-chloroethers,4 chloronitriles,.5 haloacetic acid esters,6 and halonitro aromatic compounds.7 It has also been used to alkylate ketones,8 lf/ indene,9 9i/-fluorene,ll) and the Reissert compound.11 The reaction is inhibited by alcohols and by iodide ion.2... 

Several syntheses of secoquettamines have been performed. Seco compounds 234 and 235 were semisynthesized from quettamine (236) by Hofmann and Emde degradations, respectively (179). Chattopadhyay and Shamma (184) conducted a total synthesis of these bases with the intermediacy of quettamine (236) (Scheme 36). In this approach Reissert compound 237 served as substrate. On reaction with 4-benzyloxybenzaldehyde 237 supplied the addition product 238, which after N-methylation and sodium borohydride reduction afforded amino carbinol 239. Compound 239 was cyclized to... 

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>. 

Reinforcing materials, 20 455t Reissert compounds, 22 185, 186, 201 Reissert-Henze reaction, 22 99 Relationships, as an aspect of the technical service function, 24 348 Relative abundance, 25 648, 649-650 Relative atomic ratios, determination of, 24 93-94... 

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],... 

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. 

Cyclizing ca-chloro Reissert compound 136 gives rise to tricyclic lactam 137 (72JHC541). In a study of the cobalt-mediated reaction of pyridones with alkynes, in the case of the N-hexynyl compound, C-H activation with... 

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

A. Synthesis and Reactions of 3,4-Dihydro-P-carboline Reissert Compounds... 

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. 

Isoquinoline Reissert compounds of type 12 could be easily converted to the corresponding 1-cyanoisoquinolines (13) by simple base treatment (4,5) (Scheme 3). This transformation also takes place with high yields when type 12 compounds are oxidized with molecular oxygen in a two-phase system in the presence of phase-transfer catalysts (12-14). It should be mentioned that similar oxidation of dihydro Reissert compounds of type 14 afforded the corresponding dihydroisocarbostyril derivatives (15) (12-14). Base treatment of isoquinoline Reissert eompounds followed by intramolecular rearrangement, due to the absence of a proper intermolecular reaction partner, results in 1-acylisoquinoline derivatives (18) (3). 

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%. 

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. 

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). 

The formation of Reissert derivatives of the antineoplastic agent ellipticine (225) (Scheme 29) and their reactions have been extensively studied by Popp and co-workers 39,49-51). The ellipticine Reissert compound 226 could be prepared either with benzoyl chloride and potassium cyanide in a dichloromethane-water system or, better, with benzoyl chloride and trimethylsilyl cyanide in dichloromethane. In similar manner 9-methoxyellipticine and a number of 6-substituted ellipticines have also been converted to the corresponding Reissert compounds. 

By reacting quinoline first with benzoyl chloride and then with aqueous potassium cyanide, the corresponding Reissert compound is obtained. The reaction is normally carried out in one operation using a two-phase system plus a phase transfer catalyst. The N-benzoy group can then be removed by heating with sodium hydroxide solution, and the reaction is continued to hydrolyse the nitrile function to the acid ... 

In a series of papers, Laude and co-workers (144-149) examined 1,3-dipolar cycloaddition reactions of mtinchnone imines derived from Reissert compounds. For example, mtinchnone imine 241 undergoes a smooth intramolecular 1,3-dipolar cycloaddition with the tethered alkyne unit to afford pyrrole 242 after extrusion of HNCO (144). 

A hydrogen attached to a pyridine or pyridine 1-oxide nucleus cannot be replaced directly by cyanide however, addition of cyanide to various quaternary salts constitutes an important class of reactions of synthetic importance. Before surveying these reactions in detail, the four main classes are outlined. In 1905, Reissert reported the first example, the reaction of quinoline with benzoyl chloride in aqueous potassium cyanide (Scheme 111) (05CB1603). This yielded a crystalline product, C17H12N2O, a Reissert compound (176) which afforded benzaldehyde and quinaldinic acid on acid hydrolysis (Scheme 111). Kaufmann (09CB3776) treated a 1 -methylquinolinium salt with aqueous potassium cyanide and observed 1,4-rather than 1,2-addition (Scheme 112), the Reissert-Kaufmann reaction. Reissert compounds are well known in the quinoline and isoquinoline series, but only rarely have even small yields been found in the pyridine series. On the other hand, cyanide ions add 1,4 with ease to pyridinium salts that have an electron withdrawing substituent at C-3. 

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... 

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