Pyridine product

Hydrogenation of i-butyl nicotinate methobromide, followed by hydrolysis of the 1-methyl-3-tert-butoxycarbonyl-1,4,5,6-tetrahydro-pyridine product (205) in the presence of indole affords, on decarboxylation, the -substituted derivative (206) (325). The formation of... 

Van der Eycken and coworkers have presented a study describing the microwave-assisted solid-phase Diels-Alder cycloaddition reaction of 2(lH)-pyrazinones with dienophiles [69]. After fragmentation of the resin-bound primary cydoadduct formed by Diels-Alder reaction of the 2(lH)-pyrazinone with an acetylenic dieno-phile, separation of the resulting pyridines from the pyridinone by-products was achieved by applying a traceless linking concept, whereby the pyridinones remained on the solid support with concomitant release of the pyridine products into solution (Scheme 7.58). 

Tebbe reagent to form 2-methyl pyridine products (32) has recently been reported by Nicolaou <00AG(E)2529>. 

B. General Oxidation Procedure for Alcohols. A sufficient quantity of a 5% solution of dipyridine chromium (VI) oxide (Note 1) in anhydrous dichloromethane (Note 7) is prepared to provide a sixfold molar ratio of complex to alcohol. This excess is usually required for complete oxidation to the aldehyde. The freshly prepared, pure complex dissolves completely in dichloromethane at 25° at 5% concentration to give a deep red solution, but solutions usually contain small amounts of brown, insoluble material when prepared from crude complex (Note 8). The alcohol, either pure or as a solution in anhydrous methylene chloride, is added to the red solution in one portion with stirring at room temperature or lower. The oxidation of unhindered primary (and secondary) alcohols proceeds to completion within 5 minutes to 15 minutes at 25° with deposition of brownish-black, polymeric, reduced chromium-pyridine products (Note 9). When deposition of reduced chromium compounds is complete (monitoring the reaction by gas chromatography or thin-layer chromatography analysis is helpful), the supernatant liquid is decanted from the (usually tarry) precipitate and the precipitate is rinsed thoroughly with dichloromethane (Note 10). 

Comparison of the different types of cobalt catalysts shows that the in situ system [Eq.(2)] is most accessible while the Rep-, R(ind)-, and bori-ninato ligands having electron-withdrawing substitutents are the most active. The difference between the 14e" and the 12e core complexes makes itself apparent in the chemoselectivity of the reaction. Catalysts containing a 14-electron core favor pyridine formation, whereas those containing a 12-electron core (i.e., the rj -allylcobalt systems) favor the formation of benzene derivatives by cyclotrimerization of the alkynes. For example, in the reaction of propyne and propionitrile at 140°C in the presence of a 12-electron system (5), a 2 1 ratio of benzene to pyridine product is formed, whereas a catalyst containing the cpCo moiety (a 14-electron system) leads (under identical conditions) to the predominant formation of pyridine derivatives (84HCA1616). 

Table I details representative examples of the [4 + 2] cycloaddition of triethyl 1,2, 4-triazine-3,5,6-tricarboxylate with pyrrolidine enamines and related electron-rich olefins. Cycloaddition occurs across carbon-3 and carbon-6 of the 1,2,4-triazine nucleus, and the nucleophilic carbon of the dienophile attaches to carbon-3 (eq 1). Loss of nitrogen from the initial adduct and aromatization with loss of pyrrolidine affords pyridine products.

Chloro-3-hydroxypyridine is a readily available starting point for the synthesis of furo[2,3- ]pyridines via iodina-tion followed by a palladium cross-coupling reaction with alkynes to afford alkynylpyridines, 107. Cyclization of compound 107 leads to furo[2,3- ]pyridine products <1998JME1357, 1998JOC7851 Similarly, reaction of 5-bromo-... 

Thieno[3,4- ] and [3,4-f]pyridine derivatives can be generated from a cycloaddition reaction of oxazinones with l,4-dichloro-2-butyne to afford polyhalogenated pyridine products which cyclize to thienopyridines (Scheme 39) <2001T4203>. In a similar reaction, pyrazinones, 122, containing alkynyl substituents cyclize to form thieno[3,4-3] and [3,4-i ]pyridine derivatives <2002TL799, 2004T429>. 

Selenazole and the 1,2,4- and 1,2,5-selenadiazoles serve as heterodienes in the Diels-Alder reaction. [l,4]Cycloaddition of the active dienophiles to these selenaheterocyclic compounds, followed by deselenation, is a convenient means of synthesis of a nonselenium azaaromatic ring. Cycloaddition of 2,4-disubstituted 1,3-selenazole (131) with DMAD forms a bicyclo intermediate (132) that undergo extrusion of elemental selenium liberating the pyridine product (133) (Scheme 42) [110]. 

The application of Diels-Alder methodology to pyridine formation can take different approaches. The heteroatom can be sourced from the diene or the dienophile and by varying its position in the starting materials can lead to strategies for different substitution patterns in the pyridine product. While such approaches are well documented, recent reports have both extended the range of derivatives available and incorporated new technology to assist in the optimization of reactions. 

Pyridine production from acetaldehyde, formaldehyde and ammonia,... 

In the 2,3-dihydro-5-oxo-5Ff-oxazolo[3,2-c]pyrimidinium salt (207) there are three sites for reactions with nucleophilic reagents, viz. C-2, C-8a and C-7. Products resulting from attack at C-2 are observed with DMSO, water, alcohols, benzoate, chloride, diethylamine and pyridine. Products resulting from attack at C-8a are observed with water, hydroxide, alcohols, alkoxide and isopropylamine. Diethylamine also causes attack at C-7 of the cation, which results in cleavage of the pyrimidine ring (75JOC1713). 

Intermolecular [4+2] cycloaddition strategies have also been used successfully. Moody and co-workers have reported the synthesis of a core piece of the thiopeptide antibiotics through a [4+2] cycloaddition <02CC1760>. For example, 2-azadiene 7 and 2-thiazolyl dienophile 8 were submitted to microwave heating (180 °C) for 15 minutes. The substituted pyridine product 9 was isolated in modest yield. Palacios has also reported an intermolecular [4+2] approach involving 2-azadienes <02JOC2131>. 

In the 1,4-dihydropyridine series, there has been much discussion on detailed mechanism. In a study of reduction of-cyanocinnamates with a 4,4-dideutero Hantzsch dihydropyridine, a product that was singly deuterated at only the benzylic position together with the oxidized pyridine product 503 was obtained. This seems to show that the mechanism involves hydride transfer from the 4-position of the 1,4-dihydropyridine followed by proton extraction from the nitrogen of the dihydropyridine <2000J(P2)1857>. 

It is clear that (3-picoline formation is a higher order reaction than pyridine formation, since the reactions involve 5 and 4 molecules respectively. Since a lower order reaction is favored in a more shape-selective environment, pyridine production is highest on ZSM-5 zeolites. Alternatively, one might try to maximize the fraction of (3-isomers in the picoline products. With a H-Beta zeolite, more than 98% of the picolines consist of (3-picoline, which highly simplifies the product purification (12) ... 

Oxazoles represent the most widely recognized heteroaromatic azadiene capable of [4 + 2] cycloaddition reactions. The course of the oxazole Diels-Alder reaction and the facility with which it proceeds are dependent upon the dienophile structure (alkene, alkyne), the oxazole and dienophile substitution, and the reaction conditions. Alkene dienophiles provide pyridine products derived from fragmentation of the [4 + 2] cycloadducts which subsequently aromatize through a variety of reaction pathways to provide the substituted pyridines (Scheme 14). In comparison, alkyne dienophiles provide substituted fiirans that arise from the retro Diels-Alder reaction with loss of R CN from the initial [4 + 2] cycloadduct (Scheme 15,206 Representative applications of the [4 + 2] cycloaddition reactions of oxazoles are summarized in Table 14. Selected examples of additional five-membered heteroaromatic azadienes participatiitg in [4 + 2] cycloaddition reactions have been detailed and include the Diels-Alder reactions of thiazoles, - 1,3,4-oxadiazoles, isoxazoles, pyrroles and imidazoles. ... 

The cycloadducts obtained in the oximinosulfonate Diels-Alder reaction are best converted directly to pyridines without purification. Exposure of the spiro-fused cycloadducts to a combination of NCS and sodium methoxide brings about cleavage of the dioxanedione ring with concomitant elimination of acetone and carbon dioxide. Elimination of tosylate from the resulting ester enolate then generates a dihydropyridine, and subsequent chlorination by NCS and elimination of HCl finally provides the desired aromatic pyridine product. 

In the laboratory of P. Kocovsky, novel pyridine-type P,A/-ligands were prepared from various monoterpenes. The key step was the Krohnke pyridine synthesis, and the chirality was introduced by the a,(3-unsaturated ketone component, which was derived from enantiopure monoterpenes. One of these ligands was synthesized from (+)-pinocarvone which was condensed with the acylmethylpyridinium salt under standard conditions to give good yield of the trisubstituted pyridine product. The benzylic position of this compound was deprotonated with butyllithium, and upon addition of methyl iodide the stereoselective methylation was achieved. The subsequent nucleophilic aromatic substitution (Sw/ r) gave rise to the desired ligand. 

Sulfanilides.A convenient route to sulfanilides involves reaction of an aniline with sulfuryl chloride in pyridine at 0° (in the absence of pyridine products of oxidation and chlorination are produced). 

Scheme 1) that undergoes extrusion of elemental selenium liberating the pyridine product (25)... 

A-Protected 4-hydroxy-4-hexenamines undergo similar cyclizations however, the cis- and /ra v-octahydro-2-oxofuro[3,2-6]pyridine products are formed nonstereoselectively16. 

Thiazoles have been shown to be much more reluctant than oxazoles to participate in Diels-Alder reactions, and only two successful intermolec-ular Diels-Alder reactions have been described. Like oxazoles, olefinic dienophiles provide pyridine products via a Kondrat eva dehydration [Eq. (9)].60... 

The course of and facility with which the Diels-Alder reaction of oxazoles proceed are dependent on the dienophile structure, the oxazole/dienophile substitution, as well as the reaction conditions. Olefinic dienophiles provide pyridine products derived from the fragmentation of the initial [4 + 2] cycloadducts 2 to provide 3 which subsequently aromatize to provide the substituted pyridines [Eq. (1)]. 

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