Reissert compound studies. XLV. The phenanthridine reissert compound

A series of phenanthridine Reissert compounds and Reissert analogs have been prepared using the trimethylsilyl cyanide method. The reactions of the conjugate base and fluoroborate salt have been studied and found, generally, to be similar to those of the isoquinoline Reissert compounds.     

Reissert compound studies. LXVII. The pyrido[3,4-b]pyrazine reissert compound

The pyrido[3,4-b]pyrazine systems investigated were found to form Reissert compounds in the presence of an acyl halide (or chloroformate) and trimethylsilyl cyanide. Only the mono Reissert compounds were isolated. In the case of 2,3-diphenylpyrido[3,4-b]pyrazine ( 7 ), its reaction with benzene sulfonyl chloride and trimethylsilyl cyanide gave 5-cyano-2,3-diphenylpyrido[3,4-b]pyrazine ( 16 ). Alkylation of the Reissert compound 11 and analog 12 either directly gave the alkylated hetercyclic base or the alkylated Reissert analog compound.     

Reissert compound studies. XL. The first monocyclic reissert compounds

Pyridazine and pyrimidine have been reacted with trimethylsilyl cyanide and benzoyl chloride to give the first examples of Reissert compounds derived from monocyclic systems.     

Preparation and reactions of mono-reissert compounds and analogs at the 3,4-position of quinazoline

Quinazoline, acid chlorides, and trimethylsilyl cyanide have been converted to mono-Reissert compounds at the 3,4-position of the quinazoline system. Various reactions of these quinazoline Reissert compounds are reported.     

Reissert compound studies LXVI. Regioselective synthesis of pyridine reissert analogs

The reaction of ethyl chloroformate and pyridine with diethylaluminum cyanide as the cyanide source gave the Reissert analog, 1-ethoxycarbonyl-4-cyano-1,4-dihydropyridine and not the expected 1,2-dihydro regio isomer. Under the same conditions, 3-bromopyridine also directly gave the corresponding 1,4-dihydro Reissert analog. Reinvestigation of trimethylsilylcyanide, as the cyanide source, resulted in the observation that both regio isomers are formed and the ratio of these isomers are affected by both solvent polarity and by copper(I) iodide.     

Reissert compound studies. XLI. Synthesis and reactions of the pyrrolo[1,2-α]quinoxaline reissert compound and its analogs

Reaction of pyrrolo[1,2-α]quinoxaline, either by the phase-transfer catalyst method or by the trimethylsilyl cyanide method, yielded the Reissert compound, 5-benzoyl-4-cyano-4,5-dihydropyrrolo[1,2-α]quinoxaline. This Reissert compound rearranged to 4-benzoylpyrrolo[1,2-α]quinoxaline upon sodium hydride treatment. It also underwent methylation with methyl iodide and sodium hydride. A few Reissert analogs of the pyrroloquinoxaline were also prepared and their reactions studied.     

Pyridazines. XXV. Formation of 2-benzoyl-2,5-dihydro-3-pyridazinecarbonitrile derivatives in the reissert reaction of pyridazines

Pyridazines 1a, b on treatment with potassium cyanide/benzoyl chloride in a mixed solvent system gave 2-benzoyl-2,5-dihydro-3-pyridazinecarbonitriles 3a, b together with products resulting from attack of one mole of cyanide ion and three moles of benzoyl chloride ( 5a, b ). The structures of these novel compounds are proved. A plausible reaction mechanism is proposed, involving rearrangement of initially formed 2a, b into 3a, b . Furthermore, the synthesis of the pyridazine Reissert compound 2a is reported.     

Nature of reissert analogs derived from N,N-dialkyl and N,N-diaryl carbamoyl chlorides

Reissert analogs were prepared from the reaction of isoquinoline and phthalazine with carbamoyl chlorides and cyanide using the methylene chloride-water method. Alkylation, condensation, Michael addition, and hydrolysis reactions of these Reissert analogs have been studied and found in many cases, to be similar to those of the isoquinoline Reissert compound.     

Reissert compound studies. XLII. Synthesis and reactions of the 3,4-dihydro-β-carboline reissert compound and observations on α, β, and γ-carbolines

3,4-Dihydro-β-carboline and benzo[α]-γ-carboline yielded Reissert compounds. The 3,4-dihydro-β-carboline Reissert compound, through its acid- and base-promoted reactions, was found to be a very useful intermediate in the synthesis of several β-carboline derivatives including tetracyclic compounds. Reaction of the 3,4-dihydro-β-carboline Reissert compound with dichlorodicyanobenzoquinone (DDQ) resulted in the formation of l-cyano-β-carboline thereby providing the first example of an oxidation of a Reissert compound with DDQ. α-, β- and γ-Carbolines failed to form Reissert compounds under a wide variety of conditions. 7-Azaindole also failed to yield a Reissert compound.     

Reissert compound studies. XXX. Synthesis and alkylation of some new reissert compounds

The synthesis of several new isoquinoline Reissert compounds is described. Alkylation reactions of the anions of these new Reissert compounds and a rearrangement reaction are reported.     

Reissert compound studies. XXXVI. Observations on 1,7-, 4,6-, 4,7-, and 1,10-phenanthrolines

Reissert compounds have been prepared from 1,7-, 4,6-, and 4,7-phenanthrolines. In the case of 4,7-phenanthroline, both mono- and di-Reissert compounds have been prepared. A number of Reissert analogs have also been prepared in this series. 1,10-Phenanthroline fails to give a Reissert compound.     

Reissert compound studies. LXV . Preparation of reissert compounds derived from α,β-unsaturated acid chlorides

Reissert compounds derived from α,β-unsaturated acid chlorides were prepared. The conjugate base obtained from these Reissert compounds exhibited the following carbanion reactions: 1) Alkylation, 2) Condensation with benzaldehyde, 3) Rearrangement to give dimeric compounds rather than simple rearranged compounds. In the case of alkylated isoquinoline Reissert compounds, the attempted rearrangement led to ring annellated amines.     

Synthesis of potential antineoplastic agents. XXVII. (Reissert compound studies. XLIV.). The ellipticine reissert compound as an intermediate in the syntheses of ellipticine analogs

Ellipticine and a number of ellipticine analogs were converted to Reissert compounds. Alkylation of the 6-benzylellipticine Reissert compound gave a series of 1-substituted-6-benzylellipticines. 1-Cyanoellipticine, obtained through the Reissert compound, was hydrolyzed to ellipticine-1-carboxamide hydrochloride which was active against P388 lymphocytic leukemia. Other aspects of the chemistry of the ellipticine Reissert compound are presented.     

2-benzopyrylium salts. xxxi : Analogs of reissert compounds from 2-benzopyrylium salts and sodium cyanide

Nucleophilic addition of a cyanide anion to 2-benzopyrylium salts I takes place at the first position and leads to stable isochromenes II, which are oxygen analogs of Reissert compounds. The structure II was confirmed by IR, ¹H-NMR and ¹³C-NMR spectra. The latter spectra reveal clearly the cyano group (which does not yield any observable stretching band) and give evidence for diastereotopic isopropyl carbons (unlike ¹H-NMR spectra).     

Pyrimido[5,4-b]quinolines. III. Synthesis of 10-alkyl-substituted 10-deazaalloxazines

A general method for the synthesis of 10-alkyl-substituted 10-deazaalloxazines (VIII) and the related chemistry are described. 4-Alkyl-substituted 3-aminoquinolines (IV) were reacted with benzoyl chloride and potassium cyanide in methylene chloride-water mixture to obtain Reissert compounds (V) which were hydrolyzed with a mixture of hydrobromic acid and acetic acid, and subsequently with 20% potassium hydroxide to give the corresponding 3-aminoquinaldic acids (VII). Cyclization with urea gave the 10-deazaalloxazines (VIII). Oxidation, hydroxylation and alkylation reactions of the 10-methyl derivatives (VIIIa,b) and of their quinaldic acid precursors are also reported.     

Reissert compounds and their open-chain analogs in organic synthesis

Reactions of major synthetic interest employing Reissert compounds (1, 2-dihydro-1-acyl-2-cyanoquinolines and 1, 2-dihydro-2-aqyl-1-cyanoisoquinolines) and related heterocyclic species are surveyed. The chemistry of open-chain analogs of Reissert compounds (i.e., derivatives of N-acyl-α-aminoacetonitriles) is described and compared with conventional Reissert compounds.     

Formation of reissert analogs from benzimidazole and use of carboxylic acids in a retro-reissert reactionReissert Analogs from Benzimidazole

Reissert analogs have been formed in high yields from benzimidazole using trimethylsilyl cyanide and chloroformates. A retro-Reissert reaction can be effected on the products, their carbon-2 alkylated derivatives and benzothiazole analogs, by treatment with hexanoic or benzoic acids.     

The Use of 18-Crown-6 As Phase Transfer Catalyst in the Reissert Reaction

Solid-liquid phase transfer of cyanide ion by 18-cro'wn-6 increases the yield of the Reissert reaction and eliminates the undesirable pseudo-base formation.     

Preparation of reissert compounds derived from the thieno[3,2-c]pyridine,thieno[2,3-d]pyridazine and the thieno[2,3-d]pyrimidine ring systems

The use of tributyltin cyanide, trimethylsilyl cyanide and potassium cyanide in the Reissert reaction is contrasted in the furo[3,2-c]pyridine, thieno[3,2-c]pyridine, thieno[2,3-dpyridazine, and thieno[2,3-d]pyrimidine ring systems.     

An unexpected ring-opening in the reissert reaction on 2,3-diphenylquinoxaline-n-oxide.

When quinoxaline-N-oxide 1 is reacted with KCN and benzoyl chloride in water (the Reissert reaction) or methanol, the products are 2-,5- and 6- chloroquinoxaline (the latter being the major product: 42±6 %) and small amounts of 2-cyanoquinoxaline. Using three equivalents of trimethylsilyl cyanide instead of KCN, and dichloromethane as the solvent, leads to a 72 % yield of 2-cyanoquinoxaline. The reaction of trimethylsilyl cyanide and benzoyl chloride with 2,3-diphenylquinoxaline-N-oxide 2 leads to an unexpected ring-opening product 13; its structure is based on spectroscopic data and on an X-ray crystallographic analysis.