Pyridine halides

The reactivity of pyridine organometallic nucleophiles is of course the same whether they are prepared by direct lithiation or by halogenmetal exchange from pyridine halides. Accordingly, the reactions of these organometallic intermediates are discussed partly here but mainly in Section 3.2.3.11, Reactions of substituents Metals and Metalloid Derivatives. 

The nucleophile [Nu (or NuH)] may include H2O, ROH, OH, RO, RCOO, NO3, SCN", SeCN , CH3CN, NO2", N3", OCN", pyridine, halide ion, and CN the electrophile [ ] is most commonly H", but could be a carbocation or an alkoxonium ion. The case in which the electrophile is CO2 (the Kolbe reaction) is treated in Chapter 14 and will not be dealt with here. Anodic substitution reactions therefore allow for a net substitution by a nucleophile, a reaction not easily achieved by ordinary chemical means. Specifically, this makes possible the direct formation of a C-O or C-N bond by substitution of a C-H bond. This is of considerable synthetic interest. 

These considerations, however, cannot exclude the possibility that a vibration of a pyridine-halide-metal (atom or surface) complex is responsible for the debated Raman feature. This would explain the shift of the frequency from that of a metal-halide frequency, the stability to cathodic potentials" (and, perhaps, the relative insensitivity to the metal itself). One should mention in this context that Krasser et reported a band at 240 cm in the Raman spectrum of pyridine-silver cluster complexes, which they associate with a pyridine-Ag mode. 

Reactions of pyridylboranes with l-bromo-2-phenylethyne give the alky-nylated product 254 (84H2475). An analogous series of reactions has been described in pyridine halides with diethyl(4-isoquinolinyl)borane as substrate for the preparation of255. The reactions proceed in the same manner with comparable product yields (87H1603). 

Synthetic Applications of Phase-tranter Processes 311 Tab. 6.27. Solvent-free PTC SfjAr of pyridine halides. 

Among all the methods of introducing a pyridine moiety into a drug-like molecule, metal-catalyzed carbon-carbon or carbon-nitrogen bond formation reactions of C-metallated pyridines or pyridine halides are the most important and widely used. 

The kinetic acidity of the ortho-hydrogen atoms in the pyridine halides has the following order 4- > 3- > 2-position, which the same order as the kinetic acidity of the hydrogens in the pyridine. Gribble and Saulnier first reported the DoM of 2-, 3-, and 4-halo-pyridines with LDA." ... 

Castanet and his team demonstrated a palladium-catalyzed carbonylative Suzuki reaction of pyridine halides in 2001. Under their conditions, pyridine halides reacted with aryl boronic acids to 2-pyridyl ketones in good yields (81-95 % Scheme 4.8). The proper choice of solvent, catalyst precursor, and CO pressure enabled the selective transformation of mono- and dihalopyridines. Later on, they... 

E. Maerten, M. Sauthier, A. Mortreux, Y. Castanet, Tetrahedron, 2007, 63, 682-689. Palladium-N-heterocyclic carbene an efficient catalytic system for the carbonylative cross-coupling of pyridine halides with boronic acids. 

In most nucleophilic substitutions of pyridines, halides are leaving groups, the 2- and 4-halopyridines being particularly reactive. 

PPha, pyridine) organic groups (olefines, aromatic derivatives) and also form other derivatives, e.g. halides, hydrides, sulphides, metal cluster compounds Compounds containing clusters of metal atoms linked together by covalent (or co-ordinate) bands, metaldehyde, (C2H40) ( = 4 or 6). A solid crystalline substance, sublimes without melting at I12 1I5" C stable when pure it is readily formed when elhanal is left in the presence of a catalyst at low temperatures, but has unpredictable stability and will revert to the monomer, ft is used for slug control and as a fuel. 

A wide class of aiyl-based quaternary surfactants derives from heterocycles such as pyridine and quinoline. The Aralkyl pyridinium halides are easily synthesized from alkyl halides, and the paraquat family, based upon the 4, 4 -bipyridine species, provides many interesting surface active species widely studied in electron donor-acceptor processes. Cationic surfactants are not particularly useful as cleansing agents, but they play a widespread role as charge control (antistatic) agents in detergency and in many coating and thin film related products. 

The monomers are electron pair acceptors, and donor molecules are often able to split the dimeric halide molecules to form adducts thus, whilst the dimeric halides persist in solvents such as benzene, donor solvents such as pyridine and ether appear to contain monomers since adduct formation occurs. Aluminium halides, with the one exception of the fluoride, resemble the corresponding boron halides in that they are readily hydrolysed by water. 

Acyl halides, both aliphatic and aromatic, react with the sodium derivative, but the product depends largely on the solvent used. Thus acetyl chloride reacts with the sodium derivative (E) suspended in ether to give mainly the C-derivative (t) and in pyridine solution to give chiefly the O-derivative (2). These isomeric compounds can be readily distinguished, because the C-derivative (1) can still by enolisation act as a weak acid and is therefore... 

The cross-coupling of aromatic and heteroaromatic rings has been carried out extensively[555]. Tin compounds of heterocycles such as oxazo-lines[556,557], thiophene[558,559], furans[558], pyridines[558], and seleno-phenes [560] can be coupled with aryl halides. The syntheses of the phenylo.xazoline 691[552], dithiophenopyridine 692[56l] and 3-(2-pyridyl)qui-noline 693[562] are typical examples. 

The presence of a cyano group seems to be important[649]. The reaction has been successfully applied to halides of pyridine, quinoline, isoquinoline, and oxazoles[650]. An interesting application is the synthesis of tetracyanoquino-dimethane (789) by the reaction of / -diiodobenzene with malononitrile[65l]. 

Nickel halide complexes with amines give mixtures of linear polymer and cychc trimers (30). Nickel chelates give up to 40% of linear polymer (31). When heated with ammonia over cadmium calcium phosphate catalysts, propargyl alcohol gives a mixture of pyridines (32). 

Unlike simple alkyl halides, ethyl chloroformate appears to react with primary and secondary amino groups in any position to give directly the corresponding urethane, e.g. (258) (64JMC364). Such alkylations proceed in pyridine, aqueous alkali or even warm benzene (62JOC982). 

Sulfonate esters are especially useful substrates in nucleophilic substitution reactions used in synthesis. They have a high level of reactivity, and, unlike alkyl halides, they can be prepared from alcohols by reactions that do not directly involve bonds to the carbon atom imdeigoing substitution. The latter aspect is particularly important in cases in which the stereochemical and structural integrity of the reactant must be maintained. Sulfonate esters are usually prepared by reaction of an alcohol with a sulfonyl halide in the presence of pyridine ... 

Oxidations usually proceed in the dark at or below room temperature in a variety of solvents ranging from aqueous bicarbonate to anhydrous benzene-pyridine. Base is quite commonly used to consume the hydrogen halide produced in the reaction, as this prevents the formation of high concentrations of bromine (or chlorine) by a secondary process. The reaction time varies from a few minutes to 24 hours or more depending on the nature of the reagent and the substrate. Thus one finds that NBS or NBA when used in aqueous acetone or dioxane are very mild, selective reagents. The rate of these oxidations is noticeably enhanced when Fbutyl alcohol is used as a solvent. In general, saturated, primary alcohols are inert and methanol is often used as a solvent. 

Ester eliminations are normally one of two types, base catalyzed or pyrolytic. The usual choice for base catalyzed j5-elimination is a sulfonate ester, generally the tosylate or mesylate. The traditional conditions for elimination are treatment with refluxing collidine or other pyridine base, and rearrangement may occur. Alternative conditions include treatment with variously prepared aluminas, amide-metal halide-carbonate combinations, and recently, the use of DMSO either alone or in the presence of potassium -butoxide. 

Various sources of fluoride ion have been investigated, of which highly nucleophilic tetraalkylammonium fluorides ate the most effective Thuf, fluoro alkyl halides and N (fluoroalkyl)amines are efficiently synthesized by treatment of the corresponding trifluoromethanesulfonic esters with tetrabutylammonium fluoride trihydrate in aprotic solvents [5fl] (equation 34) The displacement reactions proceed quantitatively at room temperature within seconds, but tail with hydrogen fluoride-pyridine and give reasonable yields only with hydrogen fluo ride-alkylamine reagents... 

Vinylic fluorines offluoralkenes are replaced with chlorine or bromine when treated with lithium halide salts in methoxyethanol, dimethylformamide, and pyridine [77]. 

The cyclic sulfur imides readily undergo condensation reactions in the presence of a base, e.g., pyridine. For example, the reaction of S7NH with sulfur halides, S Cla or SOCI2, produces the series (S7N)2Sx (x = 1, 2, 3, 5), or (S7N)2S0, respectively. The bicyclic compound S11N2 (6.6) is obtained by treatment of 1,3-S6(NH)2 with The reaction... 

The formation of quaternary salts from benzyl halides and related compounds occurs readily and has been known for many years. More recently, Krohnke and co-workers, who have studied the reactions of many heterocyclic quaternary salts, reported the formation of 5 from pyridine and benzylidene dibromide on heating the reactants together for 1 hr at 100°. The salt is sufficiently stable to be recrystallized from methanol containing a trace of hydrogen bromide. Isoquinoline gives a similar salt. 

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