Activated pyridines

Ring closure of 2-chloro-l-phenethylpyridinium ion (247) (prepared in situ) to l,2-dihydro-3,4-benzoquinolizium ion involves intramolecular nucleophilic displacement of the chloro group by the phenyl 77-electrons. A related intermolecular reaction involving a more activated pyridine ring and more nucleophilic 7r-electrons is the formation of 4-( -dimethylaminophenyl)pyridine (and benzaldehyde) from dimethylaniline and 1-benzoylpyridinium chloride (cf. Section III,B,4,c). 

Actinides activate pyridine A-oxides to yield cyclometallated products. This may open up new synthetic opportunities (Equation (82)).77... 

An excellent antineoplastic potency against the murine neoplasm Sarcoma 180 has been observed with arylsulphonylhydrazones derived from pyridazine-3-carboxaldehyde 2-oxide (85) [298]. These compounds were prepared in the U.S.A. in order to investigate the effect of the incorporation of an additional nitrogen atom into antitumour active pyridine 1-oxide congeners. Interestingly, the pyridazine-derived compounds (85, R = H, Me, MeO) proved to be superior to the corresponding pyridine derivatives, whereas the analogous pyrimidine-4-carboxaldehyde 3-oxide derivatives were found to be devoid of activity. 

HETE (138) is known to inhibit 5-LO [334]. A group at Revlon created a series of combined 5-LO inhibitors/LT antagonists derived conceptually from the structure of 15-HETE. REV 5901A (139) [335], the best of the series, inhibited 5-HETE release from rat ISN (0.12 //M) and was fairly selective with respect to CO and 12-LO inhibition. The quinoline could be replaced by another lipophilic aromatic group, but potency decreased (naphthalene was 40-fold less potent, and substituted phenyl was 5- to 20-fold less active). Pyridines were active but also less potent 2-pyridyl was only 4-fold less active, while 3- and 4-pyridyl were 20-fold weaker. Ortho-and pnra-substituted phenylene groups were less active. Elimination of the side-chain hydroxyl to the olefin caused a loss of activity, as did the use of shorter alkyl chains. 

The biological properties of heterocycles in general make them one of the prime interests of the pharmaceutical and biotechnology industries. A selection of just six biologically active pyridine or piperidine... 

This reaction is extremely rare, even for activated pyridines and pyridinones. Several preliminary reports have appeared of late on the addition of dichlorocarbene to pyridines, quinolinones and their salts which involve subsequent ring transformation (see Section 2.05.8). There is one example reported of the addition of dichlorocarbene under phase transfer conditions to oxyberberine (94), which gives a stable adduct (95 Scheme 41)... 

Oxidation of Mixtures of Monomers. The method most likely to yield random copolymers of DMP and DPP is the simultaneous oxidation of a mixture of the two phenols, although this procedure may present problems because of the great difference in reactivity of the two phenols. The production of high molecular weight homopolymer from DPP is reported to require both a very active catalyst, such as tetramethylbutane-diamine-cuprous bromide, and high temperature, conditions which favor carbon-carbon coupling and diphenoquinone formation (Reaction 2) from DMP (II). With the less active pyridine-cuprous chloride catalyst at 25 °C the rate of reaction of DMP, as measured by the rate of oxygen... 

The bromination of the tetracyclic compound (30) affords71 the novel compound (31) formed by capture of the Wheland intermediate by die neighbouring carboxylate ion. The intramolecular reaction of some activated pyridines witii A -acyliminium ions led to some novel heterocycles [e.g. (33) from (32) in the presence of p-toluenesulfonic acid in benzene] by cyclization para to an electron-donating substituent.72... 

Application of the known iridium-catalyzed hydrogenation of imines to the pyridine system results in excellent yields and good enantiomeric excess when reaction conditions, catalysts, and activated pyridines are optimized. Among the findings are the use of molecular iodine to oxidize the Ir(l) to Ir(lll) in situ, choice of ligand, and that of a variety of 2-methylpyridines, activated and unactivated, only the A -acyliminopyridinium ylide 193 was hydrogenated (Equation 101) <2005JA8966>. The conditions shown for synthesis of 194 are optimal. 

Activated pyridines will do electrophilic aromatic substitution... 

Dialkyl phosphites such as 49 (Scheme 9) have been reacted as nucleophiles with activated pyridines [69, 70]. The first examples of this chemistry involved either 77-alkyl-pyridinium salts in the presence of DDQ, or pyridine and terminal alkynes as activating agents in a one-step protocol. The reaction proceeds under mild conditions that include AI2O3 catalysis. Quinolines 1 and chloroformates afford the expected adducts 68. The latter structures can be easily oxidized with O3 to provide the substituted indoles 69 (Scheme 12a). Isoquinolinephosphonates obtained this way have been used in Wittig-Homer chemistry. The whole sequence offers ready access to alkyl substituted isoquinolines [71]. Analogously, sUyl substituents have been introduced into A-acylated pyridines by using silylcuprates [72]. 

Hisano developed a solid phase copolymer incorporating the M-oxide functionality that was able to catalyse the reaction, furnishing good yields of thiols [117]. The method has been used recently for the enantio-selective synthesis of thiols catalysed by optically active pyridine M-oxides (Scheme 47) [118]. 

A. E. Hirschler (Sun Oil Co., Marcus Hook, Pa. 19061) I should like to make a comment relating to your statement that activity is not a simple function of acidity. This statement appears to contain the implicit assumption that all acid sites able to protonate pyridine would have the same catalytic activity. Actually, one might expect an intensity factor (acid strength) to be operative in acid catalysis as well as an extensive factor, and the apparent lack of correlation you observed may result from an influence of acid strength on catalytic activity. Pyridine adsorption data alone do not completely define Bronsted acidity. One may need also some measure of acid strength. Acidity measurement with Hr indicators, such as we and others have reported, may supply useful information relative to acid strength as well as number of acid sites. 

The reactivity profile established for pentafluoropyridine, where the 4, 2- and 6-positions are sequentially, regiospecifically substituted by a succession of oxygen-centred nucleophiles, has allowed medicinal chemists to use pentafluoropyridine as a core scaffold for the synthesis of small arrays of biologically active pyridine systems that fall within the Lipinski parameters (see Table 11.3). 

One Nitrogen Atom (it is self-subdivided into Pyridines, Pyridinium Compounds, Ylides, Pyridine N-Oxides, Applications of Pyridines, Bipyridines and Related Systems, Hydropyridines, Biologically Active Pyridines and Hydropyridines, Pyridines Annulated with Carbocycles, Pyridines Annulated with Heterocycles). 

Table 6.8 Asymmetric hydrogenation of activated pyridines with a chiral iridium catalyst.

The starting materials were prepared by electrophilic and nucleophilic substitution on activated pyridines such as 235. The essential boronic acid 238 needed lithiation.35... 

Further studies on the hydroformylation of styrene, x-methylstyrene (2-phenyl-l-propcnc). allylbenzene (3-phenyl-l-propene) and ( >1 -propenylbenzene (1-phenyl-1-propene) catalyzed by octacarbonyldicobalt show that the use of pyridine as a catalyst activator has a marked influence on the chemo- and regioselectivity of the reaction and the isomeric composition of the aldehydes, which is strongly dependent on the temperature23. The base presumably enhances hydride formation, but is obviously not influencing the sterically important step, since with optically active pyridines no asymmetric induction is observed23. 

Aminopyridine Tosic anhydride is used in activating pyridine-A -oxide and homologues for attack by t-butylamine. The resulting 2-t-butylaminopyridine is dealkylated by CF3COOH. 

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