Preparation of pyridines

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An alternative one-step polar cyclization procedure involves the condensation of n nucleophiles with amides to efficiently produce highly substituted pyridines 07JA10096 . As shown below, acetylenes 5 or enol ethers 6 react with electron-poor and electron-rich N-vinyl and A-aryl amides 7 that are activated with triflic anhydride in the presence of 2-chloropyridine. This novel method employs mild reaction conditions and provides rapid access to highly substituted pyridines 8 with good regiocontrol. 

Alternative one-pot [4+2] cycloadditions producing highly-substituted pyridines have also been reported. For example, a practical and effective procedure adaptable to preparative scale utilizes silica gel to facilitate the elimination-aromatization of dihydropyridines, as shown below 07SL2217 . Substituted and unsubstituted 1,2,4-triazines 21 react with enamines, derived from pyrrolidine 22, and substituted ketones 23, to form highly substituted pyridines 24 in good to excellent yields. 

In addition, the efficiency of inverse electron demand Diels-Alder reactions with 1,2,4-triazines has been improved to include microwave-activated procedures 07T8286 . The approach allows access to higher reaction temperatures, which results in shorter reaction times. Several highly substituted dihydrofuro- and dihydro-2//-pyranopyridines 25 are produced from alkylnol-substituted triazines 26 in excellent yields via a one-pot cycloaddition/ aromatization protocol. 

The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels Alder reactions has expanded to include 3-phosphinyl-l-aza-l,3-butadienes, 3-azatrienes, and l,3-bis(trimethylsiloxy)buta-l, 3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively 06T1095 06T7661 06S2551 . In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-l-aza-1,3-butadiene 15 (conveniently prepared from p-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields 06T5454 . 

Likewise, an efficient one-pot multicomponent synthesis of annelated 2-amino pyridines (e.g., 17) utilizing [4+2] cycloadditions has been described 06JOC3494 . The process involves the in situ generation of 1-aza-1,3-butadiene from a palladium-catalyzed coupling-isomerization reaction of aryl halides (e.g., 18) with propargyl V-tosylamines (e.g., 19). The resulting butadiene then undergoes cycloadditions with V.S -ketene acetals (e.g., 20) to form annelated pyridines (e.g., 17). 

Recently, a method for synthesizing substituted pyridines incorporating 3-azadienynes as substrates in ruthenium-catalyzed cycloisomerizations was described 06JA4592 . This route is a two-step process that first converts readily available JV-vinyl or JV-arylamides (e.g., 26) to the corresponding C-silyl alkynyl imines (e.g., 27) and subsequent ruthenium-catalyzed protodesilylation and cycloisomerization results in the formation of the corresponding substituted pyridines (e.g., 28). 

The [4+2] discoimection is a common approach for the synthesis of pyridines. Lipihska has presented an extensive report of Diels-Alder-retro-Diels-Alder reactions of 1,2,4-triazines with enamines to produce cycloalkylpyridines 05T8148 . Triazines have been used as efficient 

The reaction proceeds through initial Diels-Alder reaction of 2-pyrazinones 4 with an acetylene forming bicyclic intermediate 5. This is followed by spontaneous elimination of cyanogen chloride or an isocyanate to obtain 2-pyridone 6 and pyridine 7, respectively. Additionally, continuous flow reactors have been designed for microwave reactions, which improve the energy efficiency. The eontinuous flow microwave reaction was illustrated using a mierowave assisted Bohlmann-Rahtz pyridine synthesis 05JOC7003 . 

The Bohlmann-Rahtz reaction is a classic pyridine synthesis that has been studied and modified in many ways. Bagley et al. has elaborated on his previous work and reported an iodine-mediated catalytic Bohlmann-Rahtz reaction of aminodienone intermediates 05SL649 . This modified process is reported to be rapid at ambient temperatures resulting in good yields. Moreover, Bagley and co-workers presented a one-pot, three-component Bohhnann-Rahtz reaction to synthesize 2,3,6-trisubstituted and 2,3,4,6-tetrasubstituted pyridines 8 and 9 from P-ketoesters 10 and alkynes 11 as shown in Seheme 3 05JOC1389 . 

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The oxidation of Hantzsch 1,4-dihydropyridines has been a long standing method for preparation of pyridines. The development of mild oxidants that do not affect other functional groups about the ring has been a specific point of interest. Yadav and co-workers... 

The oxidation of substituted pyridines to iV-oxides was reported by Sharpless and coworkers to proceed with yields between 78 and 99% (Scheme 154). A variety of substituents like electron donor as well as acceptor groups and alkenyl substituents are tolerated. In 1998, Sharpless and coworkers reported an alternative method for the preparation of pyridine-A-oxides in which the MTO/H2O2 catalyst could be replaced by cheaper inorganic rhenium derivatives (ReOs, Re207, HOReOs) in the presence of bis(trimethylsilyl) peroxide (equation 73). Yields of the prepared A-oxides after simple workup (filtration and bulb to bulb distillation) ranged from 70-98%. Molecular sieves slowed down the reaction while small amounts of water (0-15%) were essential for the reaction. Both electron-poor or electron-rich pyridines give high yields of their A-oxides and while para-... 

As explained in Chapter 3.2, the reactivity of six-membered rings containing two heteroatoms bears the same relationship to six-membered rings containing one heteroatom as do the latter to benzene. Hence many of the methods listed for the preparation of pyridines by substituent introduction and modification in Table 1 of Section 4.2.4.1 are also applicable to the preparation of analogous azines. 

Table 15.22. Preparation of pyridines by palladium-mediated vinylation and arylation of other pyridines.

Preparation of Pyridine Dodecasil-3C. A 2.2 M aqueous HF solution was prepared by dilution of 8.84 mL of 49 wt% HF solution with 108 mL of deionized water. A... 

A rapid, mild, and efficient method for the preparation of pyridine A-oxides has been reported using zn-CPBA in DMF/MeOH solvent in the presence of HF <95F1(41)323>. Metallation of pyridine A-oxides at the 2- or 6-position has been used in the preparation of a-substituted pyridine A-oxides <95H(40)809> <95JCS(P1)2503>. 

The preparation of pyridine compounds from a,o>-dinitrile systems has been studied by several workers. Johnson et al.101 found that 3-hydroxyglutaronitriles (128) or glutacononitriles (129) react readily with anhydrous hydrogen bromide or iodide to yield the 2-amino-6-halopyridines (130) as their salts, although in no case does hydrogen chloride cause cyclization to the expected 2-amino-6-chloropyridine. 

This method has found particular use in the preparation of pyridine-substituted dithiolene complexes, which exhibit pH sensitive luminescence properties (263). The a-halocarbonyl starting materials could include related precursors used in the synthesis of unsaturated dithiocarbonates described in Section II.C. 

Vinamidinium salts are important intermediates in the synthesis of heterocycles. The 2-chloro-l,3-bis(dimethylamino)trimethinium hexafluorophosphate salt has been used in the preparation of the highly selective Cox-2 inhibitor etoricoxib (Scheme 1). This method describes a straight-forward preparation of the hexafluorophosphate salt which is a crystalline, thermally and shock-stable, non-hygroscopic solid. The submitters have extensively studied the preparation of vinamidinium salts and demonstrated that the method is applicable to substituted acetic acids that contain an electron-withdrawing group (Table 1)." The annulation reaction is also general and useful for the preparation of pyridines, pyridones and pyridine N-oxides. ... 

The remarks regarding the preparation of pyridine derivatives in the introduction to the preceding section apply also to the formation of quinoline derivatives. 

The substituent on the alkyne and the cyano group can be widely varied. The basic catalytic reaction (eq. (2)) was developed into a general synthetic method for the selective preparation of pyridines. Only small amounts of benzene derivatives are formed as the by-product. 

Kresze, G., Albrecht, R. Heterocycles by diene synthesis. Dienophilic azomethines and their diene adducts. Ber. 1964, 97,490-493. Albrecht, R., Kresze, G. Heterocycles by diene synthesis. II. N-Carbobutyloxymethylene-p-toluenesulfonamide, a new dienophile for the preparation of pyridine, piperideine, and piperidine derivatives by the Diels-Alder synthesis. Chem. Ber. 1965, 98,1431-1434. 

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