Pyridine and Quinoline Derivatives

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

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The order NO2 > Cl, which is known for the reactions of nitro-activated aromatic compounds, is also found for pyridine and quinoline derivatives. In the reaction of 2-chloro-4-nitroquinoline with methoxide ion, only the 4-methoxide derivative is formed, as shown by gas-chromatography, whereas 2,4-dichloroquinoline yields a mixture of the isomeric chloro-methoxy derivatives in comparable amounts. ... 

Virus replication comprises numerous biochemieal transformations that might provide suitable targets for antiviral therapy. The antiviral effect of thiosemicarbazones was first demonstrated by Hamre et al. [53, 54], who showed that p-aminobenzaldehyde-3-thiosemicarbazone and several of its derivatives were active against vaccinia virus in mice. These studies were extended to include thiosemicarbazones of isatin, benzene, thiophene, pyridine, and quinoline derivatives, which also showed activity against vaccinia-induced encephalitis. The nature of the aldehyde/ketone moiety was not as significant as the presence of the thiosemicarbazide side chain the latter was deemed essential for antiviral activity. 

Recently, a series of pyridine- and quinoline-derived catalysts 31 (Fig. 29.18) have been developed. Ligands 31a-k were obtained by reduction of pyridyl ke-... 

Catalyst 58, in which the oxazoline ring has been replaced with an imidazoline, gave ee-values in the low 90% region for substrates 36 and 38-40 [42]. However, for certain substrates (see Section 30.5), replacement of the oxazoline by an imidazoline has resulted in significantly higher enantioselectivity. Recently, a number of pyridine- and quinoline-derived iridium complexes 59-62 have been developed, which gave promising enantioselectivities with substrates 36-39 [43, 44]. However, these catalysts cannot yet compete with the most efficient oxazoline-based complexes and complex 14. 

In contrast with the azoles, diazoles and their benzo derivatives tend to react with dichlorocarbene to yield the tris(diazolyl)methanes, presumably via the initial formation of the N-dichloromethyl derivative [6, 13]. Only in more activated polymethyl derivatives does reaction occur at a ring carbon atom. In a similar manner (7.7.1.B), 2-chloropyridine and 2-chloroquinoline react with dichlorocarbene at the ring nitrogen atom to yield, after nucleophilic displacement of the chloro group, the 1 -dichloromethyl-2-oxo derivatives (13-25%) [14] (Scheme 7.38). 2-Chlorobenzothiazole reacts in an analogous manner, but other pyridine and quinoline derivatives fail to react. It is also noteworthy that the dichloromethyl group is unusually stable and is not converted into the formyl group. 

Kobayashi S, Ishitani H, Nagayama S (1995) Ln(OTf)3- or Sc(OTf)3-catalyzed three components coupling reactions between aldehydes, amines, and dienes or alkenes efficient synthesis of pyridine and quinoline derivatives. Chem Lett 423 f24... 

Addition of dichlorocarbene to benzofuran affords the tricyclic species (118) (63JOC577). The furan ring subsequently expands to a pyran, affording 2,3-dichlorochromene (119). This reaction is reminiscent of those shown by pyrrole and indole, which yield pyridine and quinoline derivatives, respectively. However, the product could not be purified and on hydrolytic work-up the dichromenyl ether (120) was isolated. 

The use of pyridine and quinoline derivatives in the growth of poultry and related animal industries is described in CHEC(1984) <1984CHEC(2)511>. In CHEC-II(1996) <1996CHEC-II(5)245>, discussion of veterinary products had subsections covering anthelmintics, antiparasitics, and antibacterials. It is pointed out in CHEC-II(1996) <1996CHEC-II(5)245> that drugs developed for human use often find a place in veterinary medicine. 

Another one-pot synthesis uses reaction of an aldehyde, an amine, and an alkene to give pyridine and quinoline derivatives via the imino-Diels-Alder route. 

The formation of bonds c and b can take a couple of forms, either a Darzens-type approach (i.e., addition of a nucleophile bearing a leaving group) or addition of a carbene. Both of these routes have been used in the synthesis of fused-ring aziridines as well as monocyclic aziridines. The addition of a carbene or nucleophile such as an ylide to an imine can provide a nice route to fused-ring aziridines. The necessary cyclic imines are sometimes more readily obtained and used than the acyclic imines. These methods have largely been used on pyridine and quinoline derivatives. 

Heteroaromatic compounds such as pyridine and quinoline derivatives give complexes with five-membered rings ... 

Pyridine and quinoline derivatives substituted with methyl groups in the a or y position also form carbanions readily. In the presence of a strong base, such as phenyl lithium, one of the aliphatic hydrogen atoms of a-picoline is replaced and the useful synthetic intermediate (XIX) is formed.11 Although organo-lithium compounds show many of the prop-... 

Where one has a pyrrole-type nitrogen I /(N-CI > 10 Hz. Relatively large absolute values of /(N-C) are also observed in unsaturated N-oxides, and in protonated pyridine and quinoline derivatives. (122)... 

Moreover, the three-component coupling reactions proceeded smoothly in aqueous solution, and commercial formaldehyde water solution could be used directly. Most lanthanide triflates tested were effective in the three-component coupling reactions (Table 23). These reactions provide very useful routes for the synthesis of pyridine and quinoline derivatives. 

Thus, a new type of Lewis acid, lanthanide triflates, is quite effective for the catalytic activation of imines, and has achieved imino Diels-Alder reactions of imines with dienes or alkenes. The unique reactivities of imines which work as both dienophiles and azadienes under certain conditions were also revealed. Three-component coupling reactions between aldehydes, amines, and dienes or alkenes were successfully carried out by using Ln(OTf)3 as catalysts to afford pyridine and quinoline derivatives in high yields. The triflates were stable and kept their activity even in the presence of water and amines. According to these reactions, many substituted pyridines and quinolines can be prepared directly from aldehydes, amines, and dienes or alkenes. A stepwise reaction mechanism in these reactions was suggested from the experimental results. 

I2 with pyridine and quinoline derivatives shows that a reasonably linear correlation exists between log (K equilibrium constant) and pK for donors bearing no orthp-substituents. Sambhi and Khoo have reported their estimates of the magnitude of the contribution of effects other than charge transfer to AH of amine-l2 complexes. The 1 1 and 1 2 adducts of hexamethylenetetramine with I2 have been investigated by X-ray crystallography. Both compounds belong to the class of n-cr donor-acceptor complexes. The I—I distances are 2.830 in the orange 1 1 adduct and 2.791 and 2.771 0.002 A in the red-brown... 

Very mobile nitro groups can be replaced directly by chlorine or bromine, a reaction that has preparative importance for bromo- and chloro-pyridine and -quinoline derivatives. 5-Ethoxy-2-nitropyridine gives 2-bromo-5-ethoxy-pyridine when heated with HBr in glacial acetic acid in a sealed tube for 3 hours at 130°,1260 and 2-bromo-3-ethoxypyridine is obtained from the corresponding nitro compound and boiling 48% HBr.1261 It is particularly easy to introduce Cl or Br in place of a 4-nitro group in pyridine 1-oxide or quino-... 

Reactions of hexafluoropropene with iV-oxides of various pyridine and quinoline derivatives provide an interesting process for introducing a polyfluoroalkyl group. The mechanism of the process has not been easy to formulate, but the most likely one now seems to be that shown in Scheme 12. The primary step in the addition of Al-oxides to unsaturated fluorocarbons could be formulated as either a nucleophilic attack or a concerted 1,3-dipolar... 

Alkylation Using Alkanes. Direct alkylation of pyridines and quinolines using simple alkanes and terf-butyl peroxide as oxidant was developed. This C-C bond forming reaction was carried out by using Sc(OTf)3 as a Lewis acid to increase the reactivity of pyridine and quinoline derivatives (eq 37). Scandium triflate demonstrated the best catalytic activity among the Lewis acids tested. While bis-alkylation product was obtained using quinoline, only mono-alkylation products were afforded when isoquinoline was used. Cycloheptane, cyclohexane, and norbornane were determined to be suitable reaction partners. 

The Beilstein test is very sensitive. Salt in sweat on plastics can also produce a green flame. Test results can also be confused by halogen-free materials. Some halogen-free compounds such as pyridine and quinoline derivatives, purines, acid amides and cyano compounds decompose in the flame to produce cyanides which also give a blue-green flame. 

A catalyst system composed of Ni(COD)2, amino-NHC (38) and AlMes was demonstrated to promote C-4 selective alkenylation of pyridine and quinoline derivatives. A small amount of C-3 alkenylation species was also obtained as side products in most cases (Scheme 14.63). Stoichiometric reaction of Ni(COD)2 with amino-NHC/AlMcg results in complex 39. Complex 39 can react stoichiometrically or catalytically with allgmes to generate the alkenylated product in good yield. The coordination mode of this intermediate may account for the paraMeta-selectivity over orffto-selectivity. ... 

Polar adsorbents, especially silica, are widely used for the separation of alkaloids and basic drugs, such as barbiturates, benzodiazepines, and other pyridine and quinoline derivatives. Because of strong interactions of basic nitrogen with surface silanols, solvents with high eluent strength are used as mobile phases. In a review ... 

Pyridine and quinoline derivatives and amino-acids frequently give chnnictcristic copper and nickel saltsy... 

Imino Diels-Alder reactions synthesis of pyridine and quinoline derivatives... 

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