Azaheterocycle

Organometallics in coupling reactions of Tr-deficient azaheterocycles 95AHC(62)305. 

Besides simple condensation reactions, valence isomerization reactions, in particular, arc used for the synthesis of unsaturated, eight-membered-ring azaheterocycles. These isomeriz-ations mainly involve rearrangements of nitrogen-containing bicyclo[4.2.0]octatriene or semi-bullvalene systems. 

Aromaticity. The aromaticity indices (based on deviations in peripheral bond orders) for quinoxaline and related azaheterocycles have been calculated and they show good correlation with independently calculated resonance... 

Nishino H (2006) Manganese(III)-Based Peroxidation of Alkenes to Heterocycles. 6 39-76 Nishiwaki N, Ariga M (2007) Ring Transformation of Nitropyrimidinone Leading to Versatile Azaheterocyclic Compounds. 8 43-72... 

In this context, also mentionable are several publications by the groups of Dlaz-de-Villegas [242], Guarna [243], Kunz [244] and Waldmann [245], which describe the formation of six-membered azaheterocycles via treatment of an imine with an appropriate substituted diene. For instance, as described by Waldmann and coworkers, reaction of the enantiopure amino acid-derived imines 2-452 with Danishefsky s diene 2-453 in the presence of equimolar amounts of a Lewis acid provided diastereomeric enaminones 2-456 and 2-457 (Scheme 2.105) [245a]. 

Michael addition to give the azaheterocycles 7-39 through a favorable 6-exo-trig ring closure (Scheme 7.13). Even highly sensible substrates such as aryl-allyl ethers and amines could be transformed to the desired products in excellent yields. 

The intramolecular photoelimination of HC1 from JV-chloroacetyl derivatives of suitable amines is a useful and versatile approach to the synthesis of azaheterocycles. The iV-chloroacetyl derivative 357 has been converted in this way to 7-oxodesethylcatharanthine (358) in 55% yield.300 Investigations in this area have been particularly concerned with the A-chloroacetyl derivatives of benzylamines and phenethylamines the N-chloroacetyl-benzylamine 359 on irradiation affords the two 3-oxo-l,2,3,4-tetrahydroiso-quinolines 360 and 361.301 Competing photocyclizations have been observed in the case of l-[3-(chloroacetylamino)propyl]-3-methylindole (362) which is converted into three photoproducts, 363, 364, and 365.302... 

A related example involves the N-alkylation of azaheterocycles such as imidazole (Scheme 4.8). These reactions are typically performed using 1.5 equivalents of the alkyl halide and a catalytic amount of tetrabutylammonium bromide (TBAB). The reactants are adsorbed either on a mixture of potassium carbonate and potassium hydroxide or on potassium carbonate alone and then irradiated with microwaves (domestic oven) for 0.5 to 1 min. With benzyl chloride, a yield of 89% was achieved after 40 s [18]. 

Scheme 6.120 Nucleophilic aromatic substitution reactions on medicinally relevant azaheterocyclic cores.

Undheim and Benneche reviewed the Pd-catalyzed reactions of pyrimidines, among other ji-deficient azaheterocycles including pyridines, quinolines and pyrazines, in 1990 [1] and 1995 [2], A review by Kalinin also contains some early examples in which C—C formation on the pyrimidine ring is accomplished using Pd-catalyzed reactions [3]. In this chapter, we will systematically survey the palladium chemistry involving pyrimidines. 

Starting materials containing one five-membered azaheterocyclic ring 400... 

Starting materials containing one six-membered azaheterocyclic ring... 

V-methyltransferase, active toward histamine and the catechol neurotransmitters, e.g., norepinephrine, is even more restrictive than COMT in terms of the metabolism of exogenous compounds. A class of compounds that does appear to be susceptible to N-methylation are azaheterocycles, particularly those that contain pyridine as part of the... 

Crooks PA, Godin CS, Damani LA, et al. Formation of quaternary amines by N-methylation of azaheterocycles with homogeneous amine N-methyltransferases. Biochem Pharmacol 1988 37(9) 1673-1677. 

The metabolism of most five-membered azaheterocycles such as pyrrolidines can be described by the scheme given in Fig. 5.23. Thus, nicotine (5.86, Fig. 5.24), tremorine (5.89, Fig. 5.24), a pharmacological reagent used to produce experimental parkinsonism, and the antidepressant prolintane (5.90, Fig. 5.24) are metabolized to both lactam and co-amino acid derivatives [185-187]. 

Fig. 5.23. Mechanism of oxidative opening of azaheterocycles. Hydroxylation at the a-posi-tion (Reaction a) yields an unstable carbinolamine, which is in equilibrium with an open-chain amino aldehyde. The carbinolamine can be converted by aldehyde oxidase to a lactam derivative (Reaction b), while the open-chain amino aldehyde can be converted by aldehyde dehydrogenase to a ft)-amino acid derivative (Reaction c). 

Six-membered azaheterocycles (i.e.,piperidino derivatives) show a metabolic pattern similar to that of pyrrolidine compounds. Thus, the antiemetic drug diphenidol (5.97, Fig. 5.26) and DN-9893 (5.73) are both metabolized to their co-amino acid and lactam derivatives [177]. In contrast, no lactam metabolite was detected for phencyclidine (5.98, Fig. 5.26), a potent analgesic also widely abused [190]. One may assume that, like for piromidic acid (5.91, Fig. 5.24), steric hindrance at the N-atom is unfavorable for the formation of lactam metabolites. 

Sn(ANRORC) Reactions in Azaheterocycles Containing an Inside Leaving Group... 

A. Degenerate Ring Transformations Involving the Replacement of the Nitrogen of the Azaheterocycle by Nitrogen of a Reagent... 

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