Hydrogen cyanide adds to a multiple bond in the presence of an appropriate catalyst. The process is called hydrocyanation. The addition to an α,β-unsaturated carbonyl compound gives a 1,2 adduct, α-cyanohydrin, and a 1,4 adduct, β-cyano ketone. Both 1,2 and 1,4 additions are reversible in principle, but in the presence of a base the reverse 1,2 addition is much faster than the reverse 1,4 reaction, leading to the 1,4 adduct as a major (usually sole) product.



In this sense conjugate hydrocyanation is a special case of the Michael reaction. Predominance of 1,2 or 1,4 addition depends on the substrate structure, the reagent, and the reaction conditions. In this chapter 1,2 addition is discussed only when necessary. This chapter deals chiefly with the 1,4 addition and, more generally, with conjugate addition including that on conjugated polyethylenic compounds giving 1,6 or more extended conjugated adducts. Carbonyl substrates include ketones, aldehydes, carboxylic acid derivatives, carbonitriles, and carboimines. Also included are β-functionalized carbonyl compounds, and π-allylpalladium complexes, that generate α,β-unsaturated carbonyl compounds, under hydrocyanation conditions. Although hydrogen cyanide adds to α,β-unsaturated compounds activated by other groups such as nitro and sulfone, these reactions are not considered in this chapter.



The first example of 1,4 addition of hydrogen cyanide to α,β-unsaturated carbonyl derivatives appeared more than a century ago, in 1873, when Claus prepared tricarballylic acid (1,2,3-propanetricarboxylic acid) by heating an ethanolic solution of 2,3-dichloropropene and potassium cyanide in a sealed tube.



The discovery in 1903 that the reactive species in hydrocyanation is the cyanide anion, CN−, and that the rate of the reaction is proportional to the concentration of CN−8, formed the foundation for active study of hydrocyanation chemistry. A fundamental procedure for conjugate hydrocyanation was developed which used 2 molar equivalents of potassium cyanide and 1 molar equivalent of acetic acid in aqueous alcohol. The reaction mode was clarified by Ingold and Michael in the 1930s. Many chemists began extensive application of the reaction to organic syntheses, and attempts were made to explore improved procedures with higher efficiency and fewer side reactions. Detailed reviews cover developments of conjugate hydrocyanations up to the 1950s.



In recent years conjugate hydrocyanation has been used in total syntheses of complex natural products such as terpenes, steroids, and alkaloids. However, conventional procedures using hydrogen cyanide in the presence of a base or an alkali or alkaline-earth metal cyanide were not efficient. Furthermore, the efficiency could not be improved without increasing side reactions. The difficulty was overcome in 1962 when methods using organoaluminum compounds were discovered by Nagata and co-workers. They developed two new hydrocyanation methods, one involving a combination of hydrogen cyanide and an alkylaluminum and the other an alkylaluminum cyanide, both in an aprotic solvent. Applications of the new methods have led to total syntheses of complex natural products having a methyl, a functionalized methyl, or a carbon bridge at an angular position.


Keywords:

hydrocyanation;
conjugated carbonyl compounds;
mechanism;
hydrogen cyanide;
acetone cyanohydrin;
metal cyanides;
organoaluminum cyanides;
side reactions;
incompatible groups;
structure-reactivity relationships;
stereochemistry;
synthetic utility;
ethylenic carboxylic acid derivatives;
ethylenic dicarbonyl derivatives;
ethylenic ketones;
polyenic carbonyls;
acetylenic carbonyls;
scope;
limitations;
experimental procedures

Hydrocyanation of Conjugated Carbonyl Compounds

The catalytic epoxidation by dioxygen with trans-dioxoruthenium(VI)tetramesitylporphyrin [Ru(O)2(tmp)] of the acetic esters of cholesterol, 3-epicholesterol and isocholesterol,† as well as of the 7α-epimer of the latter, is β-stereospecific. Substitution by a methyl group on C-6 of pregnenolone acetate results in reduced reactivity towards catalytic epoxidation and lower β-stereoselectivity. 19-Norsterol esters bearing a double bond at C-8–C-14 or C-14–C-15 are inert towards O2–RU(O)2(tmp) epoxidation. The variable reactivity of these sterol ester substrates is explained by a transition state in which the steroid nucleus approaches the ruthenium–oxo bond approximately perpendicular to the porphyrin ring. The β-selectivity of Δ5-sterol ester epoxidation is accounted for in terms of this transition state geometry which provides a good fit between the porphyrin catalyst and the steroid substrate when the β-side faces the oxo ligand. On the other hand, reaction on the α-side involves unfavourable steric interactions between axial hydrogen atoms on C-3 and C-7 of the substrate and the porphyrin ring and a mesityl substituent of the catalyst, respectively. The crystal and molecular structures of cholesteryl ethyl carbonate and of its 5,6β-epoxide have been determined by single-crystal X-ray diffraction. The overall conformation of the steroid nucleus is nearly planar in the cholesteryl ester, while it is bent at the junction between rings A and B in the 5,6β-epoxide. This change from pseudo-trans- to cis-stereochemistry of the A–B ring junction upon epoxidation is proposed to amplify the β-diastereofacial selection. Variable temperature 1H NMR spectra indicate that in CD2Cl2 solution the 5,6β-epoxide (not the 5,6α-epoxide) of the cholesteryl acetate coordinates the ruthenium atom of Ru(CO)(tmp) with a nearly perpendicular geometry. These results corroborate the orthogonal substrate approach and the steric origin of the β-stereospecificity in Ru(O)2(tmp)-catalysed steroid epoxidations.

Catalytic β-stereospecific epoxidation of unsaturated steroids by trans-dioxoruthenium(VI)tetramesitylporphyrin. Stereochemical grounds for the β-diastereofacial selection

The reaction of 3-bromo-2,5-thiophene-1,1-dioxides with various nucleophiles has been studied. Organolithium derivatives gave hexenynes by a 1,6-Michael addition followed by ring-opening and elimination of sulfur dioxide and lithium bromide. In a competing reaction lithium enyne sulphinates were formed. Grignard reagents gave cage compounds through a series of Michael type additions, while organocopper reagents gave 3-alkyl or 3-aryl substituted derivatives. Reaction with secondary cyclic amines in refluxing benzene resulted in a 1,4-Michael type addition to the exomethylene tautomer providing 3-bromo-6-amino-(2Z,4E)-2,4-hexadienes as main products and dialkylaminomethyl substituted cis 2,3-dihydrothiophene-1,1-dioxides. Reactions in aqueous piperidine on the other hand resulted in a normal 1,4-Michael addition producing 3-bromo-2,5-dimethyl-4-piperidino-4,5-trans-dihydrothiophene-1,1-dioxide. The reaction of the thiophene-1,1-dioxides with thiolates and alkoxides under various conditions were al...

Synthetic Uses of Ring-Opening and Cycloaddition Reactions of Thiophene-1,1-Dioxides

In order to investigate the relation between the structure of mono-branched saturated fatty acids and their physical properties, a three-factor central composite design was constructed. For this purpose sixteen different fatty acids were prepared. The synthetic strategy was to use if possible, a few common starting materials for the preparation of most of the acids. Thus alkylation and hydrolysis of oxazolines were used for the preparation of 2-butylhexanoic acid, 2-methyloctadecanoic acid, 2-hexadecyloctadecanoic acid and 2-pentyloctadecanoic acid. A number of acids were prepared from thiophene derivatives followed by desulfurization with Raney-Nickel alloy under alkaline conditions. Thus, starting from 3-ethylthiophene, 4-ethyl-2-thiophenecarboxylic acid and 4-ethyl-2-methyl-5-thiophenecarboxylic acid were prepared, which upon desulfurization gave the desired 4-methylhexanoic acid. From 3-bromo-2-methylthiophene, 3-ethyl-2-methyl-5-thiophenecarboxylic acid was preparedvia 3-acetyl-2-methylthiophene and 3-ethyl-2-methylthiophene. Desulfurization gave 4-ethylhexanoic acid. Another approach started with 2-acylthiophenes, which were reacted with Grignard reagent to yield the appropriate olefins. By metalation and reaction with carbon dioxide, these were transformed to the corresponding 2-thiophenecarboxylic acids. Upon desulfurization, the desired fatty acids were obtained. In this way 6-propyldecanoic acid, 6-hexyldodecanoic acid, 6-methyldodecanoic acid and 6-pentylpentadecanoic acid were prepared. The remaining four acids were prepared from some of the branched acids described above through Kolbe reactions of dioic acids. Thus 16-methyloctadecanoic acid and 10-methyl-dodecanoic acid were obtained from 4-methylhexanoic acid, 16-ethyloctadecanoic acid from 4-ethylhexanoic acid and 9-pentyloctadecanoic acid from 6-pentylpentadecanoic acid.

On the syntheses of branched saturated fatty acids

Dimedon bildet bei Gegenwart von p-Toluolsulfonsaure mit araliphatischen oder aromatischen Hydrazonen Enhydrazone wie 4, 6, 8 und 10, die zu den Enhydrazinen 12, 13 und 15 hydriert werden konnen. Bei milder Saurekatalyse entstehen aus Dimedon und (auch aliphatischen) Hydrazonen uber die Stufe der Hexahydro-indazolinone-(4) wie 25–28 die Tetrahydro-indazolinone 16–19 und 22.



Enehydrazines, 4. The Reaction of Dimedone with Hydrazones



In the presence of p-toluenesulfonic acid dimedone reacts with araliphatic or aromatic hydrazones to form enehydrazones such as 4, 6, 8, and 10, which can be hydrogenated to the enehydrazines 12, 13, and 15. Under mild acid catalysis dimedone reacts with hydrazones (including aliphatic ones) to yield tetrahydroindazolinones 16 to 19, and 22via hexahydroindazolinones such as 25 to 28.

Enhydrazine, 4 Die Umsetzung von Dimedon mit Hydrazonen

A Simple Synthesis of 8-Aza-D-homo-estrane Analogs



8-Aza-D-homo-estrane analogs containing the angular methyl group at C-13 have been prepared by one step synthesis starting from 4-acetyl-4-methylcyclohex-2-enone and 3,4-dihydroisoquinolines.

Eine einfache Synthese von Analoga des 8-Aza-D-homo-estrans

For the first time we have shown the feasibility of using pentafluoroperoxybenzoic acid for epoxidization ofα,β-unsaturated esters, linear and cyclic dienes, for obtaining sulfoxides, sulfones, and N-oxides, and also for Baeyer-Villiger oxidation.

Pentafluoroperoxybenzoic acid — A new highly active and stable oxidizing reagent

We have examined the dependence of the stereospecificity of epoxidation of Δ5-steroids by p-(methoxy-carbonyl) perbenzoic acid on substrate structure and solvent.

Oxidation with p-(methoxycarbonyl) perbenzqic acid 1. Stereochemistry of epoxidation of Δ5-steroids

1

Electrochemical reduction of several substituted derivatives of thiophene-2-carboxylic acid proceeds strictly selectively under the conditions used in the investigation with the formation of 2,5-dihydroproducts




2

The selectivity of the electrochemical hydrogenation is explained by the inhibited protonation of the products of two-electron transfer due to the formation of ion pairs or their adsorption on the cathode at potentials close to a zero charge potential of the amalgam formed

A. M. Moiseenkov

Papers

Eine einfache Synthese von Analoga des 8-Aza-D-homo-estrans

Pentafluoroperoxybenzoic acid — A new highly active and stable oxidizing reagent

Oxidation with p-(methoxycarbonyl) perbenzqic acid 1. Stereochemistry of epoxidation of Δ5-steroids

Electroreduction in the series of thiophene derivatives: II. Electrosynthesis of 2,5-dihydrothiophene-2-carboxylic acids

Approach to synthesis of 8-azasteroids: Communication 1. Synthesis and some properties of benzo[a]cycloalkano[f]quinolizines