Pyridines 4- alkyl- from

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 most efficient routes to the cationic oxazolo[3,2- ]pyridine ring system 351 rely on the method of Bradsher and Zinn <1967JHC66> involving the cyclocondensation of iV-phenacyl-2-pyridones 349 obtained by alkylation of readily available 2-pyridones 347 (Scheme 95). This method has been used by Babaev et al. to prepare a series of 6-nitro-oxazolo[3,2- ]pyridines 355 from 5-nitro-2-pyridone 352 in excellent yields <2003MOL460>. Similarly, tricyclic oxazolo[3,2- ]pyridines 359 have been prepared from the corresponding quinolin-2(177)-ones 356 <2003H(60)131>. 

The most efficient route to the cationic oxazolo[3,2- ]pyridine ring system 69 relies on the cyclocondensation of N-phenacyl-2-pyridones 68 obtained by alkylation of 2-pyridones 67 (Scheme 41) <1967JHC66, CHEC-III(11.10.7.8) 479>. The use of this method is exemplified by the preparation of tricyclic oxazolo[3,2- ]pyridines 71 from the corresponding quinolin-2(l//)-ones 70 (Scheme 42) <2003H131>. 

Radical nucleophile oxidation based on one-electron oxidation, known as the Minisci reaction, is employed for the functionalization of /V-heterocycles with acidic hydrogen peroxide in the presence of iron(II) salts (Figure 3.112).472 A range of A-heterocycles (pyridines, pyrazines, quinolines, etc.) which are activated towards attack by nucleophilic radicals when protonated are suited to this chemistry. The Minisci reaction is suitable for the preparation of carboxylic amides (from formamide), carboxylic esters (from pyruvic esters via a hydroxyhydroperoxide), aldehydes (from 1,3,5-trioxane) and alkylated pyridines (either from carboxylic acids or from alkyl iodides in dimethyl sulfoxide).473 The latter reaction uses dimethyl sulfoxide as the source of methyl radical (Figure 3.112). 

A 16 membered ring carbodiimide is obtained in the reaction of Me2SiCl2 with cyanamide." In addition to the tetramer, oligomers with n = 2 to 7 are detected. Also, higher oligomeric carbodiimides are formed in the reaction of alkyl- and dialkyl silicon chlorides with cyanamide in the presence of pyridine." Also, from bis(trimethylsilyl)carbodiimide and silicon tetrachloride in the presence of pyridine, the silicon polycarbodiimide 34 is obtained." ... 

Table 8 Examples of 3-Alkyl- and 3-Aryl-[l,2,4]triazolo[4,3-a]pyridines Prepared from 2-Hydrazinopyridines and Carboxylic Acids, Anhydrides, Esters or Ortho Esters <66JOC25i, 78JHC439.7OJHC703,70JHC1019)...

In principle, the interaction of a phosphorus(III) ester with an co-haloalkylamine should lead to an (co-aminoalkyl)phosphonic diester or a phosphinic acid analogue (Scheme 11). Such examples in the classical Michaelis-Arbuzov mould have been widely reported, but success in their outcome depends on the relative nucleophilicities of nitrogen and phos-phorus(III) centres towards the displacement of halogen. The interaction of triethyl phosphite and a halogen-substituted tertiary amine, such as 2-chloroethyldiethylamine, does not lead to a phosphonic diester, and in this particular case the product is a piperazinium diquaternary salt. However, successful Michaelis-Arbuzov reactions have been carried out between the bis(bromomethyl)phthalazines 130 (to both the mono- and di-phosphonic acid stages) and the series of [co-(2-cyano-4-pyridine)alkyl]phosphonic diesters 132 (n = 1-4) have been prepared from the 4-pyridinealkyl bromides 131 as precursors to the phosphonoalkylpiperidinecarboxylic acids 133 . ... 

Niphatesines A-H (4-11). Niphatesines A-D (4-7) showed antineoplastic activity and they were found in another Niphates species from the sea around Okinawa [123]. The total synthesis of 4-7 has been approached by two different research groups. A first regio/enantioselective synthesis was achieved (see Scheme 1) by making use of the extremely versatile Pd(0) chemistry, which assisted the 3-pyridine alkylation in the key step. At the same time the absolute configuration of niphatesin C (6) and D (7) was established [24]. A different, thiophene-based approach was used to complete the total synthesis of both enantiomers of niphatesin C (see Scheme 2). In this case the absolute configuration was established on the basis of the comparison of the sense of optical rotation with that of the natural product [25]. Niphatesin A (4) was also synthesized in a simple manner via an alkyne derivative (see Scheme 6). 

Ultraviolet irradiation of pyridines can produce highly strained species which may lead to isomerised pyridines or can be trapped. From pyridines " and from 2-pyridones 2-azabicyclo[2.2.0]hexadienes and -hexenones are obtained in the case of pyridines these are usually unstable and revert thermally to the aromatic heterocycle, but 2-alkylpyridines with an electron-withdrawing group on the alkyl substituent give stable products by base-catalysed proton shift. Pyridone-derived bicycles are relatively stable, 4-alkoxy- and -acyloxypyri-dones are converted in particularly good yields. 

Unfortunately, Vertex s initial foray into varying the quinolinone moiety on 2 (ECso = 2.1 aM) came empty-handed. Replacing the quinolinone with quinolone, pyridine, alkylation of the NH on quinolone 2, and replacing the quinolinone moiety with pyridopyrimidine core structure all yielded analogs with inferior potentiator activities. Meanwhile, the naphthanol derivative 3 retained the potentiator activity (ECso = 3.5 jM). The lesson learnt from this SAR exercise is that the two features are essential to the potentiator activity (i). The hydrophobic phenyl ring is needed, and (ii). The quinolinol tautomer 2 (which is more stabilized via hydrogen bond) is favored. 

It has been pointed out (p. 265) that nucleophilic attack upon a quaternary salt may have various consequences the nucleophile may replace substituents from the pyridine nucleus, it may attack and open the ring and it may displace the pyridine ring from the quaternizing group. Numerous examples of the first two kinds of reaction (pp. 200-51, 265), and of the third the important case of the formation of 4-substituted pyridines from 4-pyridyl-pyridinium chloride (pp. 210, 239,251) have been quoted. This last kind is a particular case of arylation of nucleophiles by arylpyridinium salts, and the general case of this reaction and analogous alkylations will now be considered. These are presumably Sjn2 reactions (but see p. 269). 

A wide class of aiyl-based quaternary surfactants derives from heterocycles such as pyridine and quinoline. The Aralkyl pyridinium halides are easily synthesized from alkyl halides, and the paraquat family, based upon the 4, 4 -bipyridine species, provides many interesting surface active species widely studied in electron donor-acceptor processes. Cationic surfactants are not particularly useful as cleansing agents, but they play a widespread role as charge control (antistatic) agents in detergency and in many coating and thin film related products. 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

The synthesis of these disubstituied thioureas takes place in three steps. First the alkyl bromide is prepared by the action of hydrobromic acid on the corresponding alcohol (518). Then the dialkylcyanamide is obtained by treatment at 25°C with calcium cyanamide. The yields are of the order of 30 to 60%. Thioureas are obtained in a third step from the cyanamide by reaction at 40 C with HjS in the presence of pyridine. Yields ranged from 57 to 90% (518),... 

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. 

Etherification. The reaction of alkyl haUdes with sugar polyols in the presence of aqueous alkaline reagents generally results in partial etherification. Thus, a tetraaHyl ether is formed on reaction of D-mannitol with aHyl bromide in the presence of 20% sodium hydroxide at 75°C (124). Treatment of this partial ether with metallic sodium to form an alcoholate, followed by reaction with additional aHyl bromide, leads to hexaaHyl D-mannitol (125). Complete methylation of D-mannitol occurs, however, by the action of dimethyl sulfate and sodium hydroxide (126). A mixture of tetra- and pentabutyloxymethyl ethers of D-mannitol results from the action of butyl chloromethyl ether (127). Completely substituted trimethylsilyl derivatives of polyols, distillable in vacuo, are prepared by interaction with trim ethyl chi oro s il an e in the presence of pyridine (128). Hexavinylmannitol is obtained from D-mannitol and acetylene at 25.31 MPa (250 atm) and 160°C (129). 

Key intermediates in the industrial preparation of both nicotinamide and nicotinic acid are alkyl pyridines (Fig. 1). 2-Meth5l-5-ethylpyridine (6) is prepared in ahquid-phase process from acetaldehyde. Also, a synthesis starting from ethylene has been reported. Alternatively, 3-methylpyridine (7) can be used as starting material for the synthesis of nicotinamide and nicotinic acid and it is derived industrially from acetaldehyde, formaldehyde (qv), and ammonia. Pyridine is the principal product from this route and 3-methylpyridine is obtained as a by-product. Despite this and largely due to the large amount of pyridine produced by this technology, the majority of the 3-methylpyridine feedstock is prepared in this fashion. 

The alkyl pyridines (6) and (7) can be transformed either to nicotinic acid or nicotinonitrile. In the case of nicotinic acid, these transformations can occur by either chemical or biological means. From an industrial standpoint, the majority of nicotinic acid is produced by the nitric acid oxidation of 2-meth5i-5-ethylpyridine. Although not of industrial significance, the air oxidation has also been reported. Isocinchomeronic acid (10) (Fig. 2) is formed as an intermediate. 

Various alkyl-substituted pyridine derivatives are formed from the condensation of butyraldehyde with ammonia at high temperatures. For example, cocondensation of //-butyraldehyde with acroleia [107-02-8] and ammonia at 400°C over a borosiUcate 2eohte gives 3-ethylpyridine [536-78-7] ia 70% yield... 

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