Gabor Fodor

Correlation of the von Braun, Ritter, Bischler-Napieralski, Beckmann and Schmidt reactions via nitrilium salt intermediates

Abstract The Bischler-Napieralski dihydroisoquinoline synthesis from N-arylethyl-amides a formerly “one-pot” process was proven to occur via the imidoyl chlorides and the corresponding nitrilium salt. This led to the recognition of using other leaving groups better than chloride (e.g. trifluoroacetate, trifluoromethanesulfonate) and electrophiles better than phosphoryl chloride-POCl 4 − being an unfavorable counterion for the nitrilium ion. Previous facts about better yields with phosphorus pentoxide than phosphorus oxychloride were interpreted in the same light. The two-step process requires much milder conditions, 20–70° vs 110–205°. The “anomaly”, that is, the failure of 1,2-diaryl-ethylbenzamides to undergo cyclization as reported in literature was now rationalized in terms of fragmentation of the nitrilium salts into stilbenes, with formation of the conjugated π-system being the driving force for this product-controlled reaction. This, in fact, was now recognized as a reversal of the Ritter reaction which itself had been used in the synthesis of isoquinolines. The intermediate carbonium ion, from the nitrilium salt can, alternatively, undergo nucleophilic attack by an ionic halogen yielding products, expected from a von Braun reaction. Thus, correlation of the formerly unrelated Ritter, von Braun, Bischler-Napieralski, Beckmann and the Schmidt reactions has been established (Scheme 18) and a few other aspects of nitrilium salt chemistry such as elaboration of a modified Vilsmeier-Haack aldehyde synthesis via nitrilium salt intermediates and an attempt to synthesize compounds with the nitrilium group in a ring are discussed.

A new role for l-ascorbic acid: michael donor to α,β-unsaturated carbonyl compounds

Abstract In a novel Michael-type reaction L-ascorbic acid ( 1 ) undergoes addition to acrolein to give the tricyclic hemiacetal lactone 3 . The constitution and relative configuration of 3 was studied by a combination of NMR and IR spectroscopy. Ultimately, the structure of 3 was determined by X-ray crystallography. The absolute stereochemistry follows from the known chirality of C-4 and C-5 of L-ascorbic acid. A mechanism for the reaction, including its steric course, is proposed. Methyl vinyl ketone reacts with 1 in a similar fashion to give diketo lactone derivative 4 , Upon the action of methanolic hydrogen chloride on 4 one anomer, the tricyclic methyl ketal lactone 5 , forms. Structure 5 is closely related to 3 . Synthetic and possible biological applications of the new reaction are discussed.

Mechanism of the von Braun amide degradations with carbonyl bromide or phosphorus pentabromide

Abstract The isolation of the α-bromobenziminium hexafluoroantimonate 6, the first intermediate in the amide degradation with carbonyl bromide, was previously announced. Present studies reveal that using either COBr2 or PBr5, the very first intermediate is the iminium tribromide (7). Reaction of the crystalline tribromide with cyclohexane gave the monobromide 8 nearly quantitatively and in crystalline form. Heating of the cyclic iminium monobromide 8 to 120° generates in high yield the α,ω-dihalogenoalkane (type 13) and benzonitrile, while heating to 100° in bromobenzene allows isolation of the ω-bromoalkyl benzimidoyl bromide (9 or 10). An independent synthesis of this and other imidoyl bromides is elaborated. the equilibrium of imidoyl bromides with N-alkyl nitrilium (11) can be shifted toward the nitrilium salt by dissolving in liquid sulfur dioxide or reacting with methyl fluorosulfate. All these steps have been monitored by NMR. The ω-bromoalkyl imidoyl bromide at 120° undergoes fragmentation via the nitrilium ion to an α,ω-dibromoalkane and benzonitrile. In addition to gaining mechanistic information (1) we achieved isolation of crystalline n-alkylene-α-bromoiminium bromides, and their smooth thermal decomposition, which makes the von Pechmann-von Braun type of degradation competitive to the Hofmann methylation; (2) new procedure was found for preparing ammonium tribromides and iododibromides using carbonyl bromide; (3) a number of the heterofore unknown imidoyl bromides have been prepared and characterized, and their thermolysis and mass spectra studied.

Absolute configuration of the alkaloid (+)sedridine and of (−)allosedridine

Abstract Details of the correlation of configuration1,2 of natural, (+)sedridine at the OH-bearing carbon with S(+) 2-octanol, 4 → 5 → 6, and some alternate attempts are described. The von Braun amide degradation reaction which has been explored only once before for a similar purpose, led to the conclusion, when applied to 4, that (+)sedridine has the 2S. 2′S absolute configuration, 8. (−)Allosedridine, 10, the C-2′ epimer of (+)sedridine was then converted into the p-nitrophenylpiperidooxazine and both the relative and the absolute configuration of the latter were determined by X-ray diffraction as R at the carbinol carbon and S at the other centers, 9. The configurational assignments are in full agreement with those based on an ORD-CD study3,4 of (+)allosedridine and (−)sedridine. [Sedridine; allosedridine; alkaloids; configuration; correlation; X-ray; anomalous scattering; NMR; spin-decoupling: von Braun reaction; S(+)2-octanol].

THE POWER OF OBSERVATION

Abstract The critical role that observation can play in solving scientific problems is illustrated with several examples.