Reissert compounds preparation

The absence of absorption due to a cyano group in the infrared spectra of Reissert compounds was discussed earlier and it is sufficient to note that all of the new Reissert compounds prepared lack absorption in the range 2200-2400 cm . ... 

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. 

The Reissert method15—conversion of an isoquinoline to a 2-benzoyl-1,2-dihydroisoquinaldonitrile (Reissert compound), alkylation, and hydrolysis—has enjoyed wide success in the synthesis of benzyliso-quinoline and related alkaloids.16,17 In particular, aporphines are prepared conveniently by converting isoquinolines to I-(o-nitrobcnzyl)-isoquinolines via a Reissert sequence, followed by A7-alkylation, reduction, and Pschorr cyclization.17... 

Reissert compounds (116) are prepared from the acyl halide by treatment with quinoline and cyanide ion. Treatment of 116 with sulfuric acid gives the... 

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 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. 

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. 

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. 

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. 

Reissert compounds (l-acyl-l,2-dihydro-2-quinolinecarbonitriles) have been prepared on cross-linked polystyrene and C-alkylated in the presence of strong bases (Entry 8, Table 15.25). Treatment of polystyrene-bound C-alkylated Reissert compounds with KOH leads to the release of isoquinolines into solution (Entry 9, Table 15.25). The reaction of support-bound quinoline- and isoquinoline /Y-oxides with acy-lating agents followed by treatment with electron-rich heteroarenes and enamines has been used to prepare alkylated and arylated derivatives of these heterocycles (Entry 10, Table 15.25 see also Table 15.26). 

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

Reissert compounds have been prepared from compounds (21) and (23) using either trimethylsilyl cyanide or potassium cyanide as the cyanating agents. Yields ranged from 57% to 71 % <84JHCl 119, 86JHC545). The N-oxides of some thieno[2,3-6]pyridine derivatives, as shown in Equation (8), have been used in the Reissert-Henze reaction to produce cyano-substituted products <83JHC213>. 

Reissert compounds have been prepared from derivatives of 3,4-dihydro-/ -carboline. Some of the compounds derived from these intermediates, such as the derivative (66), are of interest as potential intermediates in the preparation of indole alkaloid systems (Scheme 18) <81H(15)481, 81JHC909). 

A valuable dimension was added to Reissert compound chemistry with the discovery of the methylene chloride-water solvent system for their preparation. - ... 

Although several new - Reissert compounds were prepared by this method it has been largely displaced by the methylene chloride—water system. The disadvantages of the aqueous method have been discussed. ... 

Although solvents such as dimethylformamide have been tried, the use of anhydrous benzene and anhydrous hydrogen cyanide appears to remain as the most general nonaqueous solvent system and several new Reissert compounds have been prepared by this method. " With the use of anhydrous hydrogen cyanide this method suffers from an obvious disadvantage. 

The failure of pyridine and acridine to yield Reissert compounds has already been discussed. Although many of the arguments advanced for the failure of pyridine to yield a Reissert compound suffer from the fact that analogous compounds have been prepared from pyridine, no one yet appears to have found the proper conditions for formation of a pyridine Reissert compound. 

The previous review noted the formation of Reissert compounds from less than half the quinolines investigated and stated that ... the ease of formation of Reissert compounds is dependent upon steric as well as electronic factors, since the presence of substituents in the 2- and 8-positions of quinoline inhibits the formation of. .. Reissert compounds. That a steric factor does indeed exist is evidenced by the fact that from a total of seven 2-substituted and nine 8-substituted quinolines subjected to the reaction none has yielded a Reissert compound. Using the methylene chloride-water solvent system, however, Reissert compounds have been prepared from 3-, 4-, 5-, 6-, and 7-substituted quinolines and from disubstituted quinolines. Quinolines having various substituents in these positions, including all those previously reported as not giving Reissert compounds, gave positive results in this solvent system. In addition to Reissert compound formation, hydroxyquinolines were esterified and aminoquinolines were converted to the amides. 

Several open-chain analogs of Reissert compounds have been prepared as part of the study of the mechanism of the acid-catalyzed h3 drolysis of Reissert compounds. A-Benzoyl-A-phenylglycinonitrile (49) has been prepared from glycolonitrile. Although the infrared and... 

As noted in Section III, C, a pure sample of 46 has now been obtained and this does not give benzaldehyde on acid hydrolysis.Other dihydro Reissert compounds (52, R = H and R = OCH3) have been prepared bj reaction of the appropriate 3,4-dihydroisoquinoline with... 

Table 9 Yields of Reissert Compounds (31) and (32), and Derived Aldehydes RCHO, Prepared by RCOCl/Amine/CH2Cl2/aq.KCN (Method A) or RCOCl/Amine/HCN/Benzene (Method B) ...

---