Preparation, 286 Reissert reactions

Sydnonimimes are prepared in a similar way to sydnones (Section 5.03.9.2) but rely on the availability of the appropriate aminonitrile (Scheme 8) <2002CRV1091>. Substituted dihydro- and tetrahydrophthalazine 122 and 124, formed from phthalazine by modification of the Reissert reaction, were converted to the novel sydnonimines 123 and 125 (Equation 22) <1995JHC643>. 

While the Reissert reaction is a convenient method for introducing a cyano substituent into the position a to the nitrogen atom in thienopyridines, a method has been developed to introduce substituents into the position y to the nitrogen atom. Thus, acetic anhydride/ethyl cyanoacetate or benzoyl chloride/cyclohexanone enamine reagents were useful for preparing ethyl 2-(4-thieno[2,3-6]pyridyl)cyanoacetate (53) or 2-(4-thieno[2,3-6]pyridyl)cyclohexanone (54), respectively (Scheme 13) <84JHC1135, 87JHC1467). 

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... 

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]. 

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... 

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. 

The long known Reissert reaction involves the kinetic trapping by cyanide of an -acylquinolinium or -isoquinolinium salt in the classical process the acylating agent is benzoyl chloride. Reissert compounds are usually prepared using a dichloromethane/water two-phase medium recent improvements include utilising phase-transfer catalysts with ultrasound or crown ether catalysis. 

Nucleophilic addition of 1005 to an 7V-acyliminium ion, e.g., a Reissert salt, and oxidation of the resulting adduct affords a 2-(heteroaryl)oxazole 1019. Acylation of a nitrogen heterocycle 1016 with ethyl chloroformate generated the intermediate Reissert salts 1017 in situ (Scheme 1.272). Addition of 1005 to 1017 gave adducts 1018, which produced 1019 after oxidative deacylation with o-chloranil. Examples of 2-(heteroaryl)oxazoles prepared from thiazole, benzothia-zole, pyridine, quinoline, and isoquinoUne are shown in Table 1.77. Donodni and co-workers summarized their early work on preparation and reaction of 2-(trimethylstannyl)oxazoles and 2-(trimethylsilyl)oxazoles. 

The main routes to such nitriles have been covered already by primary synthesis (Chapter 8), by the Reissert reaction (Section 9.1.3), by cyanalysis of halogen-ophthalazines (Section 10.3.5), from phthalazine N-oxides (Section 11.6), by cyanolysis of alkylsulfonylphthalazines (Section 12.3), and by dehydration of phthalazinecarboxamides (Section 14.4.2). Other preparative methods are exemplified here. 

Polyhydro-azine preparation with carbanionic species is well known, and many variants using enamines, Michael acceptors, etc. have been described in the past. This year s selection includes work on Reissert reactions of phthalazines (Scheme 43) various enamine annelations leading to alkaloid skeletons [for example... 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

The Reissert-Henze reaction offers a method to prepare cyanopyridines and extends the Reissert and Kaufmann reactions in the quinoline and isoquinoline series. 

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. 

Rawal and Kozmin have utilized a Reissert type reaction in the total synthesis of tabersonine. The requisite nitro ketone is prepared by SNAr reaction of o-nitrophenylphenyliodonium fluoride with ketone silyl enol ether (Scheme 10.10).96... 

Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and l-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained . Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. 

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. 

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). 

Cyanoisoquinolines and 2-cyanoquinolines were recently prepared via the reaction of isoquinolines and quinolines with p-TsCl/KCN.119 The reaction proceeds in two steps, as shown in the example of Scheme 13, and involves Reissert intermediates, which upon treatment with base give the cyano aromatic products in good overall yields.119... 

In order to circumvent the problem of low yields in the usual Ullmann reaction, most syntheses of bisbenzylisoquinoline alkaloids have formed the diphenyl ether linkages at an early stage and confronted the problem of isomer separation later. In the case of phaeantharine (18) (Section II,A,3), which has no asymmetric carbons, this approach was clearly preferred. This synthesis exemplifies the use of Reissert alkylation as a key step (9,269). Several analogs of bisbenzylisoquinoline alkaloids were prepared in an analogous manner (270,271). One... 

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