Reissert anion reaction

It is necessary to hold the reaction temperature below —5° in order to prevent 1,2-rearrangement of the Reissert anion to 1-benzoyliso-quinoline [Isoquinoline, 1-benzoyl-].5... 

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>. 

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... 

Although the data are limited, there is sufficient evidence available to show that the condensation of ketones with Reissert anions is a relatively unsatisfactory reaction. It should be pointed out, however, that the expected tertiary alcohols are available by reaction of Grignard reagents with Reissert compounds as noted below. 

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... 

Although there is little doubt that the esters (45) from the condensation of aldehydes with the Reissert anion normally proceed through 49 and 50, the product 51 has been obtained together with isoquinoline from the reaction of 2-acetyldihydroisoquinaldonitrile and 2-nitrobenzaIdehyde in the presence of phenyllithium. ... 

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... 

Although ketone 53 (R=H) reacts in a normal manner with the Reissert anion to give 54, the reaction of 26 with 53 (R=Me or Et) gives rise to the cyanohydrin 55 and l-benzoylisoquinoline."" "... 

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... 

Makosza et al. recently reported two-step procedure for selective introduction of CF3 or (CF3)2CF group into heteroaromatic ring, using Reissert type reaction between A -acylated heterocycles and the corresponding perfluoroalkyl anions. 

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. 

Reaction of the Reissert compound anion 176 with isatin gave the ester 177.496... 

The Reissert reaction would now require a base-catalysed acylation of the methyl group with dimethyl oxalate to give 42. They say All attempts. .. in the presence of various bases to produce intermediate [42] failed. So they used the radical bromination of 43 with NBS (chapter 24) to give 51, alkylated with the anion of methyl acetoacetate to give 52. 

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... 

The variation of position of substitution caused by electrostatic effects involving the nucleophile is included in Sections I, D, 2, II, B, 1, and II, B, 4. An anionic nucleophile will tend to react more readily adjacent to a cationic azinium-nitrogen than to an azine-nitrogen while an uncharged nucleophile (becoming positive in the transition state) will do so less readily. An entropy of activation effect or built-in solvation (Section I,D,2,b) is involved in reaction of 2-nitrochloro-benzenes with amines. - This effect has been noted in nitro-pyrimidines and -pyridines in which amination displaces substituents adjacent to the nitro group in preference to those in other activated positions (see Section II,E,2,c). Reissert compounds form at the... 

Several classes of carbon nucleophiles have been successfully used in these systems, reflecting the utility of Reissert chemistry for derivatizing azines via carbon-carbon bond formation. Apart from cyanide anion, other classes of carbon nucleophiles have been explored. For instance, addition of indole (51) to A-acyla-zinium salts proceeds selectively at the a-position (Scheme 9). Pyrrole, quinolines and isoquinolines all behave similarly [73-76]. A related reaction, yielding adduct 70 (Scheme 12b) has also been described. In this case, azine activation is promoted by Vilsmeier reagents (generated by reaction of amides with POCI3) [77]. p-Dicarbonyls are reactive inputs in this chemistry, and dialkyl malonates 53... 

B. Reactions Involving the Formation of an Anion of the Reissert Compound... 

The anions of Reissert compounds 19 and 20 undergo reaction with aldehydes to form esters of secondary alcohols containing the 2-quinolyl or 1-isoquinolyl group bonded to the carbinol carbon atom. Thus benzaldehyde, l-benzoyl-l,2-dihydroquinaldonitrile (7), and phenyllithium in ether-dioxan at — 10° gave 29, and benzaldehyde, 2-benzoyl-l,2-dihydroisoquinaldonitrile (8), and phenyllithium in ether-dioxan at —10° (or sodium hydride in refluxing... 

The anion 10, generated from the reaction of 3-benzoyl-3,4-dihydro-2-methylquinazoline-4-carbonitrile (a 2-methylquinazoline Reissert compound) with sodium hydride, undergoes both rearrangement and aromatization (cf. p 84), resulting in the formation of 4-benzoyl-2-methylquinazoline (32%), and 2-methylquinazoline-4-carbonitrile (20%). ... 

Quinazoline 3-oxide differs markedly from the 1-oxide in its behavior towards anionic reagents. Whereas with quinazoline 1-oxide compounds a substituent is introduced into po.sition 2 or 4 (cf. p 104), in quinazoline 3-oxide ring fission occurs between C2 and N3 in the reaction with acetic anhydride, water, alkali hydroxide, and under the conditions of the Reissert reaction.2 -(Hydroxyiminomethyl)formanilide is also formed as a byproduct in the reaction of quinazoline 3-oxide with active methylene compounds. ... 

A novel method for the synthesis of 2-alkylpyridines and 2-pyridine-carbinols starts from pyridine and involves the pyridine Reissert analog 175. Anion formation with sodium hydride and alkylation with alkyl halides afford the 2-alkyl-l-ethoxycarbonyl-2-cyano-1,2-dihydropyridines 176, which on heating with HMPT/Nal (HMPT = hexamethylphosphorous triamide) give 2-alkylpyridines 177. Condensation of the anion with benzaldehyde or o-tolualdehyde leads to 2-pyridinecarbinols (85CI(L)125). The reaction of 1,4-bis(trimethylsilyl)-1,4-dihydropyridine (178) with aldehydes (and ketones) in... 

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. ... 

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