Reissert reaction heterocycles

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]. 

The Reissert reaction with quinoline-1-oxide which was noted in the previous review has now been extended to a number of additional heterocyclic iV-oxides but is considered to be beyond the scope of this review. 

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. 

Heterocyclic N-oxides such as pyridine, quinoline, or isoquinoline N-oxides can be converted into a mixture of 2- and some 4-cyanopyridines, 2- or 4-cyanoquino-lines, or 1-cyanoisoquinolines, in 40-70% yield, in a Reissert-Henze reaction, by activation of the N-oxide function by O-acylation [1] or O-alkylation [2, 3] followed by treatment with aqueous alkali metal cyanide in H2O or dioxane. 

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],... 

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... 

The reaction of alkyl quaternary salts of pyridine and its benzo analogues with cyanide ion and subsequent loss of the alkyl substituent is known as the Reissert-Kaufmann reaction (Scheme 112). It is not of as much importance for heterocyclic cyanations or alkylations as the other reactions described in this section, chiefly because the N- substituent is such a poor leaving group. 

A solid-phase Suzuki reaction has been described by Kurth et al. in their syntheses of novel isoxazolinoisoquinoline heterocycles via a traceless strategy (Scheme 43).93 The Suzuki coupling was used as an efficient means to introduce extra diversity into the pharmacophore, and a Reissert-based... 

Lorsbach, B. A. Bagdanoff, J. T. Miller, R. B. Kurth, M. J. Isoxazolinoi-soquinoline Heterocycles via Solid-Phase Reissert and Suzuki Reactions, J. Org. Chem. 1998, 63, 2244-2250. 

Reissert chemistry has been employed for polymeric attachment of the isoquinoline heterocycle. Reissert compound (227) reacted with poly(vinylbenzyl chloride) (192) yielding the substitution product (228) in quantitative yield (Scheme 110) (76MI11111). Alkaline hydrolysis of (228) afforded the fully aromatized, polymer-bound isoquinoline derivative (229), again in quantitative yield. In a variation of this reaction (76MI11112), the Reissert... 

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). 

Reissert compounds, 9, I 24, 187 Ring closure of ortlio-substituted t-anilines, heterocycles by, 14, 211 Ring-opening of flve-membered heteroaromatic anions, 41, 41 Ring synthesis of heteroaromatic nitro compounds, 25, 113 Ring transformations and cyclizations on reaction of azines with bifunctional nucleophiles, 43, 301 of five-membered heterocycles, 56, 49... 

Even poor nucleophiles such as the amides 46 can react with azines in the presence of alkynes as activating agents [59, 60]. Various nucleophiles (including alkoxides, thiols, amines and nitrogen heterocycles) were recently employed in a related process with Ai-oxide azaindoles (Reissert-Henze reaction. Scheme 10). In the process, the oxygen is alkylated with dimethyl sulfate and, after the nucleophilic attack, methanol is released to aromatize the initial adduct [61,62]. Following similar mechanistic trends, V-heteroatom-activated azines afford the corresponding substituted adducts. Likewise, W-tosylated isoquinoline [63, 64] and W-fluoropyridinium salts [65] are also reactive substrates in Reissert-Henze type processes. 

In the early work on Reissert compounds the reaction that attracted the greatest attention was the acid-catalyzed hydrolysis to aldehydes plus the corresponding heterocyclic carboxylic acid or acid derivative. 

The hydrochlorides of 64, 65, and 66 were obtained by reaction of iV-phenylbenzimidyl chloride and hydrogen cyanide with the appropriate heterocyclic base. As is typical of the Reissert compounds, these three compounds lack absorption peaks in the region 2200-2400 cm h To further the analogy to Reissert compounds, acid-catalyzed hydrolysis of 64, 65, and 66 gave benzaldehyde. Picolinio acid, quinaldic acid, and isoquinaldic acid, respectively, as well as aniline, are also obtained from the hydrolysis. Nitrobenzene oxidation of the three compounds gave pyridine-2-carboxamide, quinaldonitrile, and isoquinaldonitrile, respectively. ... 

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... 

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... 

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