Condensations pyridines and

The one-pot reaction of a piperidin-4-one, carbon disulfide, and 1,1-dicyanomethane generates condensed thio-pyranthiones (Scheme 46). These products are reactive to ring opening and react with amines to give condensed pyridines and ultimately [2,7]naphthyridines <1999CHE799>. 

Over the last twenty years, the cycloaddition reactions of 1,2,4-triazines have been studied intensively. 1,2,4-Triazincs arc clcctron-dcficicnt systems and readily undergo Diels-Alder reactions with inverse electron demand with electron-rich dienophiles, such as enamines and ynamines, or with systems containing strained double bonds. Inter- and intramolecular cycloaddition reactions have been observed, giving pyridines and pyrimidines or condensed pyridines and pyrimidines. 

In addition to the trihalo compounds, many other 1,2,4-triazines have been found to react with cyclopentene, cyclohexene, cycloheptene and cyclooctene to give condensed pyridines. In most cases, 1,4-benzoquinone is added to oxidize the initially formed dihydropyridines and to prevent a second [4 I 2] cycloaddition.386 Other 1,2,4-triazines also react with bicyclo[2.2.1]hept-2-ene to give either the condensed pyridines and/or the bisadducts. The ratio of the two products depends on the reaction conditions and the relative proportions of the reactants.386 For a detailed survey, see Houben-Weyl, Vol. E7b, p471ff. 

There are numerous examples of construction of condensed pyridines (and also quinolines and acridines) via cascade reactions, involving conversion of the adducts of benzylic or allylic carbanions to nitroarenes followed by their intramolecular cyclization to form the pyridine ring. Thus, the reaction between 4-chloronitrobenzene and phenylacetonitrile, which is known to produce in protic media the corresponding 2,1-benzisoxazole via conversion of the intermediate adduct into nitrosoarene and its further condensation reaction [80], can proceed in aprotic media along another way. The same o adduct formed in tetrahydrofuran, when treated with trialkylchlorosilanes or pivaloyl chloride, undergoes cycUzatiOTi into acridine derivative (Scheme 85) [208]. 

Note that p-acetamidobenzenesulphonyl chloride will similarly react with primary and secondary amines, and the products, after hydrolysis of the acetyl group, may furnish notable drugs e.g., the condensation products with 2-amino-pyridine and 2-aminothiazole, after remo al of the acetyl groups, provide the drugs commonly known as sulphapyridine (M B 693) and sulphathidzole respectively. 

Aminopyridine. In a 1 litre three-neoked flask, equipped with a sealed mechanical stirrer, reflux condenser, thermometer and inlet tube for nitrogen, place 300 ml. of dry toluene (1) aud 75 g. of fine granular sodamide (2) bubble a steady stream of nitrogen thi ough the toluene. Stir the mixtiue vigorously and heat the flask in an oil bath until the internal temperatime is 110° (the bath temperatime required is approximately 130°). Add 100 g. of pure dry pyridine (compare Section 11,47,22)... 

Reactions with Ammonia and Amines. Acetaldehyde readily adds ammonia to form acetaldehyde—ammonia. Diethyl amine [109-87-7] is obtained when acetaldehyde is added to a saturated aqueous or alcohoHc solution of ammonia and the mixture is heated to 50—75°C in the presence of a nickel catalyst and hydrogen at 1.2 MPa (12 atm). Pyridine [110-86-1] and pyridine derivatives are made from paraldehyde and aqueous ammonia in the presence of a catalyst at elevated temperatures (62) acetaldehyde may also be used but the yields of pyridine are generally lower than when paraldehyde is the starting material. The vapor-phase reaction of formaldehyde, acetaldehyde, and ammonia at 360°C over oxide catalyst was studied a 49% yield of pyridine and picolines was obtained using an activated siHca—alumina catalyst (63). Brown polymers result when acetaldehyde reacts with ammonia or amines at a pH of 6—7 and temperature of 3—25°C (64). Primary amines and acetaldehyde condense to give Schiff bases CH2CH=NR. The Schiff base reverts to the starting materials in the presence of acids. 

N -Heterocyclic Sulfanilamides. The parent sulfanilamide is manufactured by the reaction of A/-acetylsulfanilyl chloride with excess concentrated aqueous ammonia, and hydrolysis of the product. Most heterocycHc amines are less reactive, and the condensation with the sulfonyl chloride is usually done in anhydrous media in the presence of an acid-binding agent. Use of anhydrous conditions avoids hydrolytic destmction of the sulfonyl chloride. The solvent and acid-binding functions are commonly filled by pyridine, or by mixtures of pyridine and acetone. Tertiary amines, such as triethylamine, may be substituted for pyridine. The majority of A/ -heterocycHc sulfanilamides are made by simple condensation with A/-acetylsulfanilyl chloride and hydrolysis. 

Historical. Pyridines were first isolated by destructive distillation of animal bones in the mid-nineteenth century (2). A more plentifiil source was found in coal tar, the condensate from coking ovens, which served the steel industry. Coal tar contains roughly 0.01% pyridine bases by weight. Although present in minute quantities, any basic organics can be easily extracted as an acid-soluble fraction in water and separated from the acid-insoluble tar. The acidic, aqueous phase can then be neutrali2ed with base to Hberate the pyridines, and distilled into separate compounds. Only a small percentage of worldwide production of pyridine bases can be accounted for by isolation from coal tar. Almost all pyridine bases are made by synthesis. 

Dimethylquinoxaline reacts with pyridine and iodine to form quinoxaline-2,3-bis(methylenepyridinium iodide) (55). Condensation of (55) with p-nitrosodimethylaniline in the presence of potassium carbonate yields the bis-(p-dimethylaminonitrone) (56) and this on acid hydrolysis gives quinoxaline 2,3-dialdehyde (57) in high over-all yield. The dialdehyde is also obtained by selenium dioxide oxidation of 2,3-dimethylquinoxaline. ... 

In contrast to the iV-imines 11, which yield solely bicyclic 1,2-diazepines 12 on irradiation, the [c]-fused pyridine /V-imincs 13 give mixtures of condensed 1,2- and 1,3-diazepines, 14 and 15, accompanied by condensed pyridines 16 (if R3 = H).145... 

Pyrido- and pyrimido[l, 4]diazepinones have been produced by condensing pyridinediamines and a pyrimidinediamine with esters of /i-oxo acids. Because of the unsymmetrical structures of the diamines the reactions may take two courses, as exemplified by the action of ethyl acetoacetate on pyridine-2,3-diamine.308... 

B. 2-Acetyl-6,l-dimethoxy-l-methylene-l,2,3,4-tetrahydroisoquinoline [Isoquinoline, 2-acetyl-l,2, A,4-tetrahydro-6,7-dimethoxy-l-methylene-]. A 1-1., three-necked, round-bottomed flask equipped with a mechanical stirrer, a reflux condenser topped with a calcium chloride drying tube, and a thermometer is charged with 110 ml. of acetic anhydride, 110 ml. of pyridine, and 45.0 g. (0.22 mole) of the dihydroisoquinoline prepared in Part A. The reaction mixture is stirred and heated at 90-95° for 30 minutes, stored at room temperature overnight, and concentrated by distillation at 50° using a rotary evaporator. The residue is diluted with 20 ml. of ethyl acetate, and another evaporation under reduced pressure gives material that can be crystallized from 75 ml. of ethyl acetate to yield 38.5 41.0 g. (72-77%) of product, m.p. 106-107° (Note 11). 

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

The condensation of pyridine and trimethylphosphine complexes of borabenzene with dimethyl acetylenedicar-boxylate leads to the corresponding 1-borabarrelene complexes 146 and 147 (Scheme 58). 

The cobalt-catalyzed cooligomerization of diynes with nitriles allows a simple one-step synthesis222 of condensed pyridine derivatives including difficultly accessible 5,6,7,8-tetrahydroisoquinolines223 The synthesis is a versatile one in that pyridines condensed with five- and seven-membered carbocyclic rings can also be achieved in moderate yield in similar fashion. Additional attractive features of this simple synthesis are the formation of condensed isoquinolines by the use of functionalized nitriles and the pronounced regioselectivity observed when dissymmetrical diacetylenes are employed (Scheme 148).222... 

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... 

Condensation of active methylene compounds with cyanoacetic hydrazide-derived hydrazones led to a one-pot formation of pyridine and triazole rings. 

These ketones were utilized in various addition and condensation reactions (78). The expected pyridines and pyrimidines were easily formed, while hydrazine failed to give the corresponding pyrazoles. 

Pyridine and its derivatives are technically-important fine chemicals. Their isolation from coal tar is decreasing, whereas their manufacture by synthetic methods has increased rapidly. The classical pathways to pyridine have been discussed by Abramovitch (74HC14-1-4). Many of them rely on the reaction of aldehydes or ketones with ammonia in the vapor phase. However, the condensation processes used suffer from unsatisfactory selectivity. Using soluble organocobalt catalysts of the type [YCoL] allows pyridine and a wide range of 2-substituted derivatives to be prepared selectively and in one step from acetylene and the appropriate cyano compound [Eq.(l)]. 

Another example of a MCR-based strategy for the synthesis of pyridines was reported by Kantevari et al. in 2007. Thus, the three-component condensation of enaminones, 1,3-dicarbonyls, and ammonium acetate in the presence of a catalytic amount of a tangstocobaltate salt as heterogeneous catalyst, either in refluxing solvent or under solvent-free conditions, allowed the regioselective formation of 2,3,6-trisubstituted pyridines and 2,7,7-trisubstituted tetrahydroquinolin-5-ones (Scheme 55) [155]. This methodology combines shorter reaction times and... 

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