Iontophoretic application of opiates to the locus coeruleus.

Knoevenagel's first papers in this field were concerned with the condensation of formaldehyde with diethyl malonate and with ethyl benzoylacetate. The catalyst was ethylamine. A number of other aldehydes were reported to condense similarly with diethyl malonate, ethyl benzoylacetate, ethyl benzoylpyruvate, and acetylacetone under the influence of various primary and secondary amines. In 1896, Knoevenagel reported benzaldehyde with ethyl aceoacetate condensed at room temperature in the presence of piperdine to give a bis compound, but that when the reaction was run in a freezing mixture, the product was acetoacetate. For the purposes of this chapter, the Knoevenagel condensation is defined as the reaction between an aldehyde or ketone or any compound having an active methylene group, brought about by an organic base or ammonia and their salts.


Keywords:

Knoevenagel condensations;
decarboxylation;
malonic acid;
active methylene component;
stereochemical aspects;
cyanoacetic acid;
ketones;
derivatives. caatalysts;
experimental conditions

The Knoevenagel Condensation

Stereochemical Factors and Receptor Interactions Associated with Narcotic Analgesics

Carbon–carbon bond formation by metal-free cross-coupling of two reactants with low reactivity represents a challenge in organic synthesis. Secondary amides and alkenes are two classes of bench-stable compounds. The low electrophilicity of the former and low nucleophilicity of the latter make the direct coupling of these two partners challenging yet highly desirable. We report herein an unprecedented intermolecular reaction of secondary amides with alkenes to afford α,β-unsaturated ketimines or enones, which are versatile intermediates for organic synthesis and are prevalent in bioactive compounds and functional materials. Our strategy relies on the chemoselective activation of the secondary amide with trifluoromethanesulfonic anhydride (Tf2O)/2-fluoropyridine to generate a highly reactive nitrilium intermediate, which reacts efficiently with alkenes. This metal-free synthesis is characterized by its mild reaction conditions, excellent functional group tolerance and chemoselectivity, allowing the preparation of multi-functionalized compounds without using protecting groups.

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Metal-Free C-H Alkyliminylation and Acylation of Alkenes with Secondary Amides

This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.

Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine dependence.

Cyclohexen-(1)-yl-athylamin wird aus Cyclohexenyl-acetonitril oder Cyclohexenyl-acetamid gewonnen. Es dient als Ausgangsprodukt zur Herstellung von 1-Benzyl-, 1-(p-Methoxybenzyl)-, 1-(3′,4′-Dimethoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isochinolin.

Synthese von Morphinanen. (2. Mitteilung)

1-(p-Hydroxybenzyl)-1, 2,3,4,5,6,7,8-octahydro-isoquinoline has been resolved into the optical antipodes, from which any desired optically active 3-hydroxy-morphinan substituted at the nitrogen atom can easily be obtained. The (-)-3-hydroxy-N-allyl-morphinan thus obtained as well as its ethers and ester counteract the effect of opiates and other potent narcotics. Given in adequate small doses they are able to relieve undesirable side effects.

Hydroxy‐morphinane. 7. Mitteilung. (−)‐3‐Hydroxy‐N‐allyl‐morphinan und verwandte Verbindungen

Oxy-morphinane. (4. Mitteilung). Synthese von Benzyl-octahydro-isochinolinen

It has been shown that synthetic (–)-3-hydroxy-N-methyl-morphinane (I) possesses the same steric configuration at the C-atoms 9, 13 and 14 as the natural mor-phine alkaloids, since it can be degraded to the known (–)-cis- [2-methyl-carboxy-cyclohexyl-(l)]-acetic-acid.

Hydroxy-morphinane. 12. Mitteilung. Die Konfiguration der Morphinane

The structure of the by-products which are formed during the ring closure to morphinans from the corresponding octahydro-iso-quinolines has been elucidated. They are compounds of apomorphine-like structure: 6-methyl- (benzyl- or allyl-)-10-hydroxy-1,2,3,3a,5-6,6a,7,11b, 11c-decahydro-4H-dibenzo-[de, glquinolines] (VII, XV, XVII).

J. Hellerbach

Papers

Synthese von Morphinanen. (2. Mitteilung)

Hydroxy‐morphinane. 7. Mitteilung. (−)‐3‐Hydroxy‐N‐allyl‐morphinan und verwandte Verbindungen

Oxy-morphinane. (4. Mitteilung). Synthese von Benzyl-octahydro-isochinolinen

Hydroxy-morphinane. 12. Mitteilung. Die Konfiguration der Morphinane

Hydroxy‐morphinane. Mitteilung. Über die Konstitution der Nebenprodukte bei Morphinanringschlüssen