3 substituted pyridine derivatives

Reaction of Alkyl- and Aryllithidm Compounds with 3-Substituted Pyridine Derivatives (108)... 

Scheme 10.39 Asymmetric hydrogenation process of 3 substituted pyridine derivatives.

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... 

The vast majority of syntheses of pyrido[2,3-t/]- and pyrido[3,4-t/]-pyridazines fall into this category, resulting from the cyclization of various o-substituted pyridine derivatives (2,3- or 3,4-, respectively) with hydrazine or its congeners. 

The Boger pyridine synthesis involves the reaction of triazine 1 with activated alkene 2 in a hetero-Diels-Alder fashion. The intermediate bicyclic species 3 is unstable and a facile cycloreversion takes place due to the loss of nitrogen gas to afford the appropriately substituted pyridine derivative 4. 

In addition to their reactions with amines, Zincke salts also combine with other nitrogen nucleophiles, providing various A -substituted pyridine derivatives. Pyridine A -oxides result from the reaction with hydroxylamine, as exemplified for the conversion of Zincke salt 38 to the A -oxide 39 Reactions of Zincke salts with hydrazine, meanwhile, lead... 

Those reactions of halogenopyridines with potassium amide and lithium piperidide which proceed via 3,4-pyridyne form the 3- and 4-substituted pyridine derivatives in ratios of 1 2 and 1 1, respectively (see Section II, A, 1). It appears that the ring nitrogen atom has an orienting effect on these additions, but the quantitative divergence of the addition of ammonia and piperidine is not understood at present. 

Rayama, A., Rinoshita-Nagaoka, J., Rawano, H., Rameda, S. and Mukuriya, M. (1998) Cycloauration of 2-substituted pyridine derivatives. Synthesis, structure and reactivity of srx-membered cycloaurated complexes of 2-anilino-, 2-phenoxy- and 2-(phenylsulfanyl)-pyridine. Journal of the Chemical Society Dalton Transactions, (24), 4095. 

The complex, one of a series of substituted pyridine derivatives, exploded violently during microanalytical combustion. 

The [Fe(diimine)2X2] system has been modified by replacing the diimines by unidentate nitrogen donors. [Fe(diimine)(py)2(NCS)2] is a crossover system when the diimine is 2,2 -bipyrimidine or phen [99] but [Fe(py)4(NCS)2] is purely high spin [100]. However, [Fe(py)4(NCS)2] systems containing substituted pyridine derivatives have been shown to exhibit thermal SCO [101], while 4,4 -bipyridine derivatives are able to bridge Fe(II) centres and form polynuclear structures containing SCO [Fe(py)4(NCS)2] centres [102]. SCO is maintained in certain instances when the diimines are replaced by an N4 quadridentate [103,104]. 

Effectively, this is another example of the addition of a functional aromatic compound to an alkene, as the Murai reaction, but the mechanism is different. Alkyl substituted pyridine derivatives are interesting molecules for pharmaceutical applications. The a-bond metathesis reaction is typical of early transition metal complexes as we have learnt in Chapter 2. 

The cobalt-catalyzed pyridine synthesis is the only known one-step process for the selective preparation of the industrially significant 2-substituted-pyridine derivatives. Moreover, the method is applicable to a broad variety of substituted alkynes and nitriles, thereby giving access to a whole range of pyridine derivatives having 1,2,3 or 5 substituents in the ring. Selected examples follow and are compared to the prior state of the art. 

Movassaghi et al. [21[ reported the synthesis of substituted pyridine derivatives via ruthenium-catalyzed cycloisomerization of 3-azadienynes. To avoid the isolation of the chemically active alkynyl imines, trimethysilyl alkynyl amines served as initial substrates, as shown in Scheme 6.19. The formation of ruthenium vinylidene intermediates is accompanied by a 1,2-silyl migration according to controlled... 

Table 9. Sigma and pi populations of the Nitrogen atom in substituted pyridines, derived from nuclear quadrupole...

Reaction of 2-amino-3,5-dicyano-6-substituted pyridine derivatives with formamide led to pyridopyrimidines 365 <1993JHC253>. 

Acetyl hypofluorite also appears to be a very convenient reagent for the conversion of the pyridine ring into 2-substituted pyridine derivatives 34,35. and 36, which are otherwise difficult to access. This functionalization is very sensitive to the nature of the group present in the pyridine ring.30-32... 

According to reaction (559) these reactions can occur by an oxidation reaction of platinum(II). With one-electron oxidants, the intermediate formation of platinum(III) complexes occurs. The best early example of this type of reaction is in the oxidation of PtCi - and Pt(en)2+ by IrIVCl - in the presence of free chloride ion. The presence of platinum(III) intermediates has been inferred from the rate law.2036 For the oxidation of platinum(II) by gold(III) the kinetic data are consistent with a mechanism requiring a complementary two-electron transfer,2037 with a rate independent of chloride ion. For the substituted pyridine derivatives PtCkLj (L = substituted pyridine) however, the third-order rate law is found with first-order dependencies on PtCl I, Aum and Cl-.2038 Comparisons have been made with the amine complexes PtC L (L = NH2R).2039... 

Clearly therefore, Tables II, III, and IV indicate the large difference between the uncharged and positive pyridine nitrogen atom stems almost entirely from the inductive effect. The discrepancy between the Oy values reported for azonium in nucleophilic substitution41 and from the second pK, value of 4-aminopyridine1 is large and hard to interpret it has a bearing on the mode of correlation of the pKJs of substituted pyridine derivatives with o values and will be discussed in Section II, A, 2. 

Two derivatives of the fully conjugated 1,2-diazocine system 8 were reported in the past decade but in poor yields (14-20%) from the reaction of 2-methyl-7-tosylfuro[2,3-r/]pyridazine 101 with ynamines by a [2+2] cycloadditionring-expansion sequence (Equation 4). From the reaction mixture, the penta-substituted pyridine derivatives (14%) by an N-N bond cleavage of the pyridazine ring and benzofuranes, as the major products (31-34%) by a [4+2] cycloaddition-denitrogen reaction, were also isolated <1996H(43)199>. 

Warshakoon NC, Wu S, Boyer A, Kawamoto R, Sheville J, Bhatt RT, Renock S, Xu K, Pokross M, Zhou S, Walter R, Mekel M, Evdokimov AG, East S. Design and synthesis of substituted pyridine derivatives as HIF-lalpha prolyl hydroxylase inhibitors. Bioorg. Med. Chem. Lett. 2006 16 5616-5620. 

Yamazaki s complex (Structure 5) contains two alkyne molecules linked together to form a five-membered metallacycle. Arene-solvated cobalt atoms, obtained by reacting cobalt vapor and arenes, have been used by Italian workers to promote the conversion of a,w-dialkynes and nitriles giving alkynyl-substituted pyridines [20]. -Tolueneiron(0) complexes have also been utilized for the co-cyclotrimerization of acetylene and alkyl cyanides or benzonitrile giving a-substituted pyridine derivatives. However, the catalytic transformation to the industrially important 2-vinylpyridine fails in this case acrylonitrile cannot be co-cyclotrimerized with acetylene at the iron catalyst [17]. 

Chambers, R. D., Hoskin, P. R., Sandford, G., et al. (2001) Synthesis of multi-substituted pyridine derivatives from pentafluoropyridine. J. Chem. Soc., Perkin Trans 1, 2788-2795. 

Pyridine and substituted pyridine derivatives were shown to react with spiro-activated electrophilic cyclopropanes to give ring-opened zwitterions. 11 ss -157 jjjgjg reactions were mainly studied for theoretical reasons. 

Commercially, pyridine is prepared by the gas phase, high-temperature reaction of crotonaldehyde, formaldehyde, steam, air, and ammonia over a silica-alumina catalyst in 60-70% yield. However, in the laboratory, the challenge is in the preparation of substituted pyridine derivatives in a process that allows one to control regioselectivity and chemoselectivity in the most efficient manner. In this regard the utility of palladium-catalyzed cross-coupling reactions has enabled synthetic chemists by providing the ability to construct highly diversified pyridine derivatives in an efficient fashion [2]. 

---