Isoquinolines Reissert reaction

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. 

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). 

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... 

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). 

Shibasaki and co-workers applied (BINOL)Al(III)-derived catalyst 5a, previously developed for the cyanation of aldehydes [28], to the asymmetric Strecker reaction. This catalyst proved to be highly enantioselective for both aromatic and a,p-unsaturated acyclic aldimines (>86% ee for most substrates) (Scheme 8) [63-65]. Aliphatic aldimines underwent cyanide addition with lower levels of enantioselectivity (70-80% ee). A significant distinction of 5 relative to other catalysts is, undoubtedly, its successful application to the hydrocyanation of quinolines and isoquinolines, followed by in situ protection of the sensitive cx-amino nitrile formed (this variant of the Strecker reaction is also known as the Reissert reaction [66]). Thus, Shibasaki has shown that high enantioselectivities (>80% ee for most substrates) and good yields are generally obtainable in the Reissert reaction catalyzed by 5b [67,68]. When applied to 1-substituted... 

A chiral auxiliary-mediated Reissert reaction has been demonstrated. Though the diastereomeric ratios are not as high as hoped, the conditions are simple and the products are easily separated by flash chromatography (Equation 63) <2005TL2983>. A catalytic version of the asymmetric Reissert reaction with quinolines, isoquinolines, and pyridines has been developed by Shibasaki and co-workers <2005PAC2047, 2004JA11808>. 

In the third example, the Reissert reaction88 was used by Jackson and Stewart74 to prepare still another l-benzyl-7,8-dioxygenated isoquinoline [Eq. (41)]. The application of a Reissert reaction to a SchifF... 

Scheme 4 Isoquinolines and pyridines in Reissert reactions and related processes...

In 1996 the Kurth group described the first sold-phase Reissert reaction (Scheme 5) [42, 43]. Activation of a carboxylic acid functionalized resin to the corresponding acyl chloride, followed by treatment with isoquinoline and TMS-CN (14) afforded the resin-linked Reissert adduct 16. This intermediate was subsequently alkylated at the a-position by treatment with LDA and alkyl iodides 17. Some of these adducts were further manipulated, and finally the substituted isoquinolines 20 were conveniently released using a traceless cleavage with KOH/THF. 

A solid-phase Ugi-Reissert reaction on chloroformate resin, has been reported. The product, the ot-carbamoylated isoquinoline 230, is released by oxidative cleavage (Scheme 33a). Interestingly, the enamide moiety in the adduct can be exploited to perform this process in tandem with a Povarov MCR [189, 190]. In this way, by interaction of dihydroisoquinoline 231 with aldehydes, anilines and a suitable Lewis acid catalyst, the polyheterocyclic system 232 was prepared (Scheme 33b). The Zhu group devised an innovative approach for the synthesis of this class of compounds. They employed the heterocyclic amine 233, which was oxidized in situ to the dihydroisoquinoline 234 with IBX, to undergo the classic Ugi reaction. Remarkably, all the components are chemically compatible, allowing the sequence to proceed as a true MCR (Scheme 33c) [191]. 

A new synthesis of aporphines has appeared. The key step in this synthesis involves the generation of l-(o-nitrobenzyl)isoquinoline by reaction of a Reissert compound with o-nitrobenzyl chloride in dimethylformamide in the presence of sodium hydride. 

High yields of a-cyanoazines are obtained from pyridine, quinoline or isoquinoline (V-oxides and TMS-CN in acetonitrile/triethylamine or in DMF, and so in THF in the presence of tetrabutylammoni-um fluoride. In another variation TMS-CN together with dimethylcarbamoyl chloride is used. Mechanistically these transformations should be similar to the Reissert reaction and may run through intermediates of type (18) and (19 Scheme 22) ... 

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). 

A number of polymers containing a heterocyclic group have been prepared using the Reissert alkylation sequence. Thus, for example, the reaction of the isoquinoline Reissert anion (26) with poly(vinylbenzyl chloride) and sodium hydride gave 36, which on hydrolysis with base gave A... 

At the time of the last review it was noted that the condensation of ketones with the Reissert anion was a relatively unsatisfactory reaction. It has now been shown that acetone, acetophenone, cyclohexanone, and several N-substituted 4-piperidones ° react with the isoquinoline Reissert compound in the presence of 50% aqueous sodium hydroxide-acetonitrile containing TEB A chloride. Isatin, A(-benzyl-3-piperidone, ° and a variety of N-substituted 4-piperidones ° "° also react with isoquinoline or... 

The anion (26) of the isoquinoline Reissert compound (2) has been used in a Michael-type reaction. Thus, reaction of 26, generated with phenyllithium, with ethyl cinnamate and substituted cinnamates give rise to 63, dimethyl acetylenedicarboxylate yields 64, and 2- and 4-vinylpyridines give rise to 65. Use of cinnamonitrile in this sequence leads to the isolation of 66. The enol ester, vinyl acetate reacts with the isoquinoline Reissert compound in aqueous sodium hydroxide containing TEBA chloride to surprisingly give 67. ... 

The addition of hypochlorous acid to the 3,4-position of the isoquinoline Reissert compound (2 R = Ph) takes place to give the chlorohydrin 71." Use of A -chlorosuccinimide in ethanolic dioxane gave the 0-ethyl derivative. Various reactions of the chlorohydrin led to isochromenes and a rearranged isoquinoline." ... 

An interesting (traceless) example combines the linking with a first-stage reaction by use of a resin acid chloride in a Reissert-reaction-alkylation sequence from isoquinolines, the normal Reissert final-stage hydrolysis being the means of cleavage from the resin. ... 

Finally, a solid phase version of the Reissert reaction has been developed for combinatorial chemistry purposes, and differently substituted isoquinolines have been prepared (Figure 15.16). Starting from polymer-supported benzoyl chloride, isoquinoline was bound and treatment with trimethylsilyl cyanide (TMSCN), followed by alkylation, yielded resin 31. After performing synthetic transformations (carbonylation etc.), Reissert hydrolysis was induced with aqueous NaOH in THF. 

A number of polymers containing a heterocyclic group have been prepared using the Reissert alkylation sequence.92 94 Thus, for example, the reaction of the isoquinoline Reissert anion (26) with polyfvinylbenzyl chloride) and sodium hydride gave 36, which on hydrolysis with base gave 37.92,93 A similar condensation takes place with quinoline, phenanthridine, and benzo-[/Jquinoline Reissert compounds.94 The Reissert anion 26 has also been alkylated with a mixture of m- and p-vinylbenzyl chloride and the product polymerized to a polymer of type 37.93 Copolymerization has also been studied.93... 

Cyanadons. Aluminum complexes of BINOLs (1) that are armed at C-3 and C-3 with diarylphosphine oxide groups possess both Lewis acid and base centers. Asymmetric cyanation of aldehydes and mines with MeaSiCN, and of quinolines and isoquinolines in a manner analogous to the Reissert reaction is successful (ee 70-90%). The asymmetric Strecker synthesis is applicable to conjugated aldimines and the higher reactivity of Me SiCN than HCN in the presence of 10 mol% of PhOH enables its use in catalytic amount while supplying stoichiometric HCN as the cyanide source. 

Isoquinoline Reissert compounds react with 1,1-diarylethenes in the presence of acid to give 3//-pyrroles (122, Scheme 45).6,118 The mechanism of related reactions has been discussed in detail.118 ... 

A base-catalyzed intramolecular nucleophilic substitution reaction on isoquinoline Reissert compounds (222) is the basis of a benzo[a]quinolizidine synthesis developed by Popp et al. (Scheme 42) <72JHC541>. 

The synthetic potential of the Reissert reaction will be discussed in detail together with the corresponding isoquinoline derivatives (see p 338). 

When isoquinoline is refluxed with acetic anhydride, iV-acetyl-l-carboxy-methyl-l,2-dihydroisoquinoline is obtained in analogy with the Reissert reaction. If acetone is also present during the refluxing, 7V-acetyl-l-acetony 1-1,2-dihydro-isoquinoline is formed in addition. ... 

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