Synthesis of Pyridines

There are very many ways of achieving the synthesis of a pyridine ring the following section describes the main general methods. 

Ammonia reacts with 1,5-dicarbonyl compounds to give 1,4-dihydropyridines which are easily dehydrogenated to pyridines. With unsaturated 1,5-dicarbonyl compounds, or their equivalents (e.g. pyrylium ions) ammonia reacts to give pyridines directly. 

5-Diketones are accessible via a number routes, for example by Michael addition of enolate to enone (or precursor Mannich base ), by ozonolysis of a cyclopentene precursor, or by reaction of silyl enol ethers with 3-methoxyallylic alcohols. They react with ammonia, with loss of two mol equivalents of water to produce a cyclic bis-enamine, i.e. a 1,4-dihydropyridine, which is generally unstable but can be easily and efficiently dehydrogenated to the aromatic heterocycle. 

The oxidative final step can be neatly avoided by the use of hydroxylamine, instead of ammonia, when a final 1,4-loss of water produces the aromatic heterocycle. In an extension of this concept, the construction of a 1,5-diketone 

It follows, that the use of an unsaturated 1,5-dicarbonyl compound will also afford aromatic pyridine directly a number of methods are available for the assembly of the unsaturated diketone, including the use of pyrylium ions or 2-pyrones (see chapter 8) as synthons, or the alkylation of an enolate with a 3,3-bis(methylthio)-enone.  

Ammonia reacts with 1,5-dicarbonyl compounds to give 1,4-dihydropyridines which are easily dehydrogenated to pyridines. 

In 2008, our group disclosed a novel method that involved the one-pot synthesis of multisubstituted pyridines 92 by Rh-catalyzed oxime-assisted alkenyl C-H bond functionalization of a, -unsaturated oximes with alkynes [48]. The scope includes a variety of a, -unsaturated oximes and symmetrical alkynes. This report is one of a few examples of Rh(I)-catalyzed alkenyl C-H bond functionalization. The mechanism is thought to occur by oxime-directed oxidative insertion of the Rh catalyst into the alkenyl C-H bond to form the hydrometalacycle LI. Hydrorhodation onto the alkyne then occurs to give L2, followed by reductive elimination to provide L3. Intermediate L3 can undergo a 6. r-electrocyclization and then a dehydration reaction to form pyridine (Eq. (5.89)). Overall, this Rh(I)-catalyzed reaction is a redox neutral. 

There has been a considerable focus on the development of reliable conditions for Rh-catalyzed C-N bond formation in the absence of metal oxidants. The first example of Rh(III)-catalyzed oxidative annulation reactions of a, -unsaturated oximes and alkynes was described by Rovis in 2011 for the construction of pyridine derivatives (Eq. (5.90)) [49a]. Equations (5.91)-(5.96) illustrate subsequent modifications of these reactions for the synthesis of various substituted pyridines in good yields. Catalytic amounts of Rh, alkyne/alkene substrates, and a stoichiometric amount of a cooxidant, such as AgOAc or Cu(0Ac)2-H20, were required to facilitate catalyst turnover [49b-g]. 

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Pyridine ring syntheses (48) can be classified into essentially two categories ring synthesis from nonheterocyclic compounds, and synthesis from other ring systems. The synthesis of pyridine derivatives by transformations on the pyridine ring atoms and side-chain atoms have been considered in the previous section. 

The vapor-phase synthesis of pyridines and picolines from formaldehyde, acetaldehyde, and ammonia falls in the category of four-bond formation reactions (Fig. 1). Reactions are performed in the vapor phase with proprietary catalysts. 

Commercial Manufacture of Pyridine. There are two vapor-phase processes used in the industry for the synthesis of pyridines. The first process (eq. 21) uti1i2es formaldehyde and acetaldehyde as a co-feed with ammonia, and the principal products are pyridine (1) and 3-picoline (3). The second process produces only alkylated pyridines as products. 

Acrolein (CH2=CHCHO) can be substituted for formaldehyde and acetaldehyde in the above reaction to give similar results, but the proportion of (3) is higher than when acetaldehyde and formaldehyde are fed separately. Acrolein may be formed as one of the first steps to pyridine (1) and P-picoline (3) formation. There are many variations on the vapor-phase synthesis of pyridine itself. These variations are the subject of many patents in the field. 

By-Products. Almost all commercial manufacture of pyridine compounds involves the concomitant manufacture of various side products. Liquid- and vapor-phase synthesis of pyridines from ammonia and aldehydes or ketones produces pyridine or an alkylated pyridine as a primary product, as well as isomeric aLkylpyridines and higher substituted aLkylpyridines, along with their isomers. Furthermore, self-condensation of aldehydes and ketones can produce substituted ben2enes. Condensation of ammonia with the aldehydes can produce certain alkyl or unsaturated nitrile side products. Lasdy, self-condensation of the aldehydes and ketones, perhaps with reduction, can lead to alkanes and alkenes. 

Raw Material and Energy Aspects to Pyridine Manufacture. The majority of pyridine and pyridine derivatives are based on raw materials like aldehydes or ketones. These are petroleum-derived starting materials and their manufacture entails cracking and distillation of alkanes and alkenes, and oxidation of alkanes, alkenes, or alcohols. Ammonia is usually the source of the nitrogen atom in pyridine compounds. Gas-phase synthesis of pyridines requires high temperatures (350—550°C) and is therefore somewhat energy intensive. 

The current paradigm for B syntheses came from the first report in 1957 of a synthesis of pyridines by cycloaddition reactions of oxazoles (36) (Fig. 5). This was adapted for production of pyridoxine shordy thereafter. Intensive research by Ajinomoto, BASF, Daiichi, Merck, Roche, Takeda, and other companies has resulted in numerous pubHcations and patents describing variations. These routes are convergent, shorter, and of reasonably high throughput. 

Dihydropyridines not only are intermediates for the synthesis of pyridines, but also are themselves an important class of N-heterocycles an example is the coenzyme NADH. Studies on the function of NADH led to increased interest in the synthesis of dihydropyridines as model compounds. Aryl-substituted dihy-dropyridines have been shown to be physiologically active as calcium antagonists. Some derivatives have found application in the therapy of high blood pressure and angina pectoris. For that reason the synthesis of 1,4-dihydropyridines has been the subject of intensive research and industrial use. The Hantzsch synthesis has thus become an important reaction. 

The rapid synthesis of heteroaromatic Hantzsch pyridines can be achieved by aromatization of the corresponding 1,4-DHP derivative under microwave-assisted conditions [51]. However, the domino synthesis of these derivatives has been reported in a domestic microwave oven [58,59] using bentonite clay and ammoniiun nitrate, the latter serving as both the source of ammonia and the oxidant, hi spite of some contradictory findings [51,58,59], this approach has been employed in the automated high-throughput parallel synthesis of pyridine libraries in a 96-well plate [59]. In each well, a mixture of an aldehyde, ethyl acetoacetate and a second 1,3-dicarbonyl compound was irradiated for 5 min in the presence of bentonite/ammonium nitrate. For some reactions, depending upon the specific 1,3-dicarbonyl compound used. 

Scheme 56 Synthesis of pyridines and pyrimidines from alkynyl ketones...

Borabenzene complexes of cobalt such as Co(C5H5BPh)(COD) (51) and its 5-ethyl analog show the same type of catalysis but improved activity and chemoselectivity (77). Thus, 51 as the catalyst precursor gave the hitherto best results in the catalytic synthesis of the valuable 2-vinylpyridine from C2H2 and CH2=CHCN (120°C, 51 bar, 2 hours, turnover number 2164) (77,101). Furthermore, this catalyst for the first time allowed the synthesis of pyridine from C2H2 and HCN under mild conditions (110°C, 23 bar, 60 minutes, turnover number 103) (77). 

Transition metal complexes have been used in a number of reactions leading to the direct synthesis of pyridine derivatives from acyclic compounds and from other heterocycles. It is pertinent also to describe two methods that have been employed to prepare difficultly accessible 3-alkyl-, 3-formyl-, and 3-acylpyridines. By elaborating on reported194,195 procedures used in aromatic reactions, it is possible to convert 3-bromopyridines to products containing a 3-oxoalkyl function196 (Scheme 129). A minor problem in this simple catalytic process is caused by the formation in some cases of 2-substituted pyridines but this is minimized by using dimethyl-formamide as the solvent.196... 

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>. 

Scheme 6.227 The Bohl mann—Rahtz synthesis of pyridines.

Reaction of Lithioacetonitriles 85.1-85.2 and p-Lithioamino-(3-substituted acrylonitriles 85.3-85.10 with 6 A New General Synthesis of Pyridines and their Condensed Variants... 

Methods for the synthesis of substituted pyridines remains an intense topic of research. One of the most popular approaches to substituted pyridines remains cycloaddition reactions. While this strategy is not new and many examples are in the current literature <00TL10251>, the state-of-the-art has been expanded. Weinreb and co-workers have reported the regioselective synthesis of pyridines (3) via intramolecular oximino malonate hetero Diels-Alder reactions (1 - 2) <00OL4007>. Similarly, the intramolecular [4 + 2] cycloaddition of... 

Scheme 29.9 Synthesis of pyridine-derived ligands for catalysts 30.

F. X. Woolard, J. Paetsch, J. A. Ellman, A Silicon Linker for Direct Loading of Aromatic Compounds to Supports. Traceless Synthesis of Pyridine-Based Tricyclics , J. Org Chem. 1997, 62, 6102-6103. 

The Hantzsch reaction that allows the synthesis of pyridine derivatives, is a condensation involving two equivalents of a yS-ketoester or a yS-ketoamide, one equivalent of an aldehyde and ammonia. The Hantzsch reaction was used by Patel et al. for the synthesis of a 300 member dihydropyridine library (Scheme 3.27) [287]. 

Andrews, D.M., Gibson, K.M., Graham, M.A., Matusiak, Z.S., Roberts, C.A., Stokes, F.S.F. et al. (2008) Design and campaign synthesis of pyridine-based histone deacetylase inhibitors. Bioorganic ej Medicinal Chemistry Letters, 18, 2525-2529. 

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