Pyridine from acrolein

P-Picoline may serve as an important source of nicotinic acid [59-67-6] for dietary supplements. A variety of substituted pyridines may be prepared from acrolein (75—83). 

Variations on this theme include the use of acrolein/ammonia (72GEP2224160) and acrolein/acetaldehyde/ammonia (64BRP963887,69BRP1141526). Ketones can also be utilized. For example, 2,6-dimethylpyridine is obtained in 36% yield from combination of for-malin/acetone/ammonia (71GEP2064397) (Scheme 3). This general reaction has recently been extended to include the preparation of 2,6-disubstituted (78BEP858390) and 2,3-disubstituted (78GEP2712694) pyridines from aromatic or heteroaromatic ketones/aliphatic aldehydes and ammonia. 

Figure 14.5 Flow diagram of the synthesis of pyridine from ammonia and acrolein...

A number of routes are available for the synthesis of 2,2 -bipyridines where one of the pyridine rings is built up from simpler entities. For example, condensation of 2-(aminomethyl)pyridine (31) with acetaldehyde or acetylene over a silicon-alumina catalyst at 450°C gives 2,2 -bipyridine, ° whereas 2-cyanopyridine reacts with acetylene at 120°C in the presence of a cobalt catalyst to afford 2,2 -bipyridine in 95% yield.2-Acetylpyridine with acrolein and ammonia gives 2,2 -bipyridine in the presence of dehydrating and dehydrogenating catalysts, and related condensations afford substituted 2,2 -bipyridines. ° In a similar vein, condensation of benzaldehyde with 2 mol of 2-acetylpyridine in the presence of ammonia at 250°C affords 2,6-di(2-pyridyl)-4-phenylpyridine, ° and related syntheses of substituted 2,2 6, 2"-terpyridines have been described. Likewise, formaldehyde with two moles of ethyl picolinoylacetate and ammonia, followed by oxidation of the product and hydrolysis and decarboxylation, affords a good... 

Like 2,2 - and 2,3 -bipyridines, 2,4 -bipyridine is formed by a number of reactions where one of the pyridine rings is built up from simpler components. Thus 4-(aminomethyl)pyridine with acetylene or acetaldehyde at 450"C affords 2,4 -bipyridine and 4-cyanopyridine reacts with acetylene at 120 C under pressure in the presence of a cobalt catalyst to give 2,4 -bipyridine in over 90% yield. 4-Acetylpyridine with acrolein and ammonia in the presence of dehydrating and dehydrogenating catalysts also gives 2,4 -bipyridine. A number of minor routes to 2,4 -bipyridine are worthy of... 

As in the synthesis of other bipyridines, several routes to 4,4 -bipyridine have been devised where one of the pyridine rings is built up from simpler components. For example, a dimer of acrolein reacts with ammonia and methanol in the presence of boron phosphate catalyst at 350°C to give a mixture of products including 4,4 -bipyridine (3.4% yield), and in a reaction akin to ones referred to with other bipyridines, 4-vinylpyridine reacts with substituted oxazoles in the presence of acid to give substituted 4,4 -bipyridines. ° ° Condensation of isonicotinaldehyde with acetaldehyde and ammonia at high temperatures in the presence of a catalyst also affords some 4,4 -bipyridine, and related processes give similar results,whereas pyran derivatives can be converted to 4,4 -bipyridine (56% conversion), for example, by reaction with ammonia and air at 350°C with a nickel-alumina catalyst. Likewise, 2,6-diphenyl-4-(4-pyridyl)pyrylium salts afford 2,6-... 

There are a very large number of patented processes for the synthesis of pyridines, often in very small yields, from ketones and ammonia. Most of the syntheses must involve the condensation of two molecules of the carbonyl compound to give an a,/3 -unsaturated aldehyde or ketone, and such unsaturated compounds can be used directly. The early work on the vapour-phase catalytic processes dates from the 1920s and a series of papers by Chichibabin. In one of these (24JPR(107)154) he records the use of acrolein, acetaldehyde, and ammonia over an alumina catalyst at 370-380 °C to give a poor yield of pyridine and a very poor yield of 3-methylpyridine. The major problems are to separate the mixtures of products from the considerable amount of tarry material. Many catalysts and many mixtures of ketones have since been used a few of the better yields are reported here. 

Various alkyl-substituted pyridine derivatives are formed from the condensation of butyraldehyde with ammonia at high temperatures. For example, cocondensation of -butyraldehyde with acrolein [107-02-8] and ammonia at 400°C over a borosilicate zeolite gives 3-ethylpyridine [536-78-7] in 70% yield... 

Instead of acetates also free aldehydes may be oxidized The oxidation of acrolein is carried out at 313 K in benzene For polyCu- and polyFePc, pyridine is needed to activate the oxidation. From benzaldehyde and others a mixture of benzoic acid and peroxybenzoic acid is produced with Cu- and FePc derivatives (95) (prepared from TCB and metal dilorides in ethylene glycol) (Eq.45) The reactions were carried out in various solvents at %3 K. 

A comparison of the ratio of l-d 3,3-d2-acrolein formed from the reaction of bl-dj-allyl alcohol with Bi2O3 3MOO3 in the presence of pyridine (reaction only on acrolein-forming sites) and for the corresponding reactions of a 50 50 mixture of 1,1 3,3-d2-allyl alcohol and Ul-dj-propylene (Table IV) shows that only the 50 50 mixture produces the ratio observed for propylene-hl-dj. In terms of the mechanism for selective propylene oxida-... 

A mixture of the pyrroles 45 and 46, the pyridine 47 and the dihydro-2-pyridone 48 is obtained when the oxazolinone 44 is heated with 4-phenyl-l-tosyl-l-azabuta-l,3-diene (94JCS2499). The anion of the oxazolinone 49 functions as a masked ynthon of the formyl anion. Thus treatment of 49 with triethylamine and an electrophile E- derived from acetaldehyde, benzaldehyde, acrolein, methyl acrylato etc yields 50, which is cleaved to a mixture of the keto acid 51 and an aldehyde 52 by mild acidic hydrolysis (Scheme 2) (93TL3907). 

Apart from Ci and C2-aldehydes, Ca-aldehydes are also used in the production of pyridine. The process carried out by Daicel in Japan employes acrolein. 

The monomer is soluble in numerous solvents however, the polymer precipitates from most of these solvents at about 15% conversion during radical polymerization. Molecular weights up to 100,000g/mol and aldehyde contents above 65% can be achieved when the polymerization is carried out in polar solvents such as DMF, y-butyrolactone, or pyridine by means of hydroperoxides and nitrous acid derivatives as redox catalysts [68]. Deviations from this behavior are observed if DMF is used as solvent and the polymerization is initiated by AIBN. A microgel is formed here after 16% conversion the clear reaction solution turns into a transparent gel [69]. Polymerization in the presence of methanol initiated by means of azo compounds or peroxides does yield soluble poly(acrolein), presumably because of the polymer s molecular weight [70]. 

The retro-Hofmann consideration is based on the availability of pyridine-3-carboxamide on a large scale. Actually, this compound, known as nicotinamide or vitamin B3, is produced in multi-ton quantities from 3-methylpyridine [20, 21]. For this building block, the catalytic industrial process is based on the one-pot cyclization of acrolein, ammonia and propanal in the presence of oxides of Sb(II), Ti(IV) or V(V) as catalysts. 3-Methylpyridine is submitted to amoxidation, the combined action of oxygen and ammonia to obtain 3-cyanopyridine (Scheme 8.9) [22]. 

The l-fiT-pyrano[3,4-c]pyridine nucleus is found extensively amongst alkaloids and a short photochemical synthesis has been reported, starting from readily available 4-acetoxy- or 4-alkoxy-2-pyridones (54). Under photochemical stimulation, these compounds react with the diethyl acetal of acrolein. Treatment of the head-to-tail adducts (55) with a base gives the cyclobuta[c]pyridone derivative (56), which rearranges (upon heating in acid) to produce the H-pyrano[3,4-c]pyridone (57). The method is claimed to be general. 

An alternative asymmetric Diels-Alder reaction was reported by the Fukuyama group in which a dihydropyridine derivative and acrolein were used to build the cyclohexene ring (Scheme 16.2). Dihydropyridine 10 was synthesized from pyridine 9 by NaBH4 reduction in the presence of Cbz-Cl. An asymmetric Diels-Alder reaction between the dihydropyridine 10 and the acrolein in the presence of MacMillan catalyst 11 at room temperature... 

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