Extended Pyridine Derivatives

Conformation in such macrocycles is of most interest when there are interactions between the pyridine nitrogens and other components of the macrocyclic ring. This is demonstrated by the difference in conformational preference between the two isomeric pyridinophanes 55 and 56. In the case of the 2,6-disubstituted pyridinophane 55, the attractive interactions between the pyridine nitrogens and the amino protons of the macrocyclic bridge result in the boat-boat conformation shown. For the isomeric case 56, the chair-boat and boat-boat forms have the same stability as shown by variable temperature NMR spectroscopic studies and ab initio calculations 2002J(P2)393 . 

It is worth noting that pyridines are also often used as rigid components in cyclophanes, though they will not be discussed here since in these cases the properties of the cyclophane are not substantially effected by the presence of the pyridine nitrogen (i.e., the replacement of a benzene moiety with a pyridine moiety has limited effect on the structure of the system). 

Similar arrangements of hydrogen bonds in diaminobipyridines result in the formation of C3-symmetrical discs. In the case of the systems such as the chiral 61, aggregation into a dynamic helix in apolar solvents is observed 2005JA5490 . 

In addition to these helical polymers, phenylene-pyridinylenes have been investigated as linear oligomers held in place by intramolecular hydrogen bonds. This is demonstrated by the oligomer 62, and is expressed in terms of its optical properties 2005CEJ5889 . 

Much of the impetus for considering the pyridine systems described above and their assembly in solution is the 

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Extended pyridine derivatives have also been considered in the development of new materials as they present rigid systems with different electronic character than benzene. Self-assembled multilayers (SAMs) of stilbazolium derivatives, such as those based on compound 63, have been investigated <1996JA8034> and shown to have very high structural regularity and subsequently be very smooth. These show promise for nonlinear optical materials, as they have very high second-order susceptibility. 

Pyridine-based N-containing ligands have been tested in order to extend the scope of the copper-catalyzed cyclopropanation reaction of olefins. Chelucci et al. [33] have carefully examined and reviewed [34] the efficiency of a number of chiral pyridine derivatives as bidentate Hgands (mainly 2,2 -bipyridines, 2,2 6, 2 -terpyridines, phenanthrolines and aminopyridine) in the copper-catalyzed cyclopropanation of styrene by ethyl diazoacetate. The corresponding copper complexes proved to be only moderately active and enantios-elective (ee up to 32% for a C2-symmetric bipyridine). The same authors prepared other chiral ligands with nitrogen donors such as 2,2 -bipyridines 21, 5,6-dihydro-1,10-phenanthrolines 22, and 1,10-phenanthrolines 23 (see Scheme 14) [35]. 

Three different fused systems have been reported in the literature thieno[3, 2 4,5]thieno[2,3-c]pyridine (f/r-thiophenes), thieno[2, 3 4,5]thieno[2,3-c]pyridine (tram- thiophenes) and thicno[3,2-g]thicno [3,2-d pyridine derivatives. So far, the parent thienothienopyridines have only been prepared via the corresponding pyrylium salts (see below) all others are benzo or extended carbocyclic derivatives, for example, thienothienoquinolines. 

Next, in chronological order, Acheson and his group, in his series Addition reactions of heterocyclic compounds (cf. 63AHC(1)125), extended the range of substrates to pyridine derivatives and initially believed to have found numerous pyridoazepines. The contents of six experimental articles (1968-1975), however, were for the most part revised... 

A somewhat similar method of cyanide preparation is applicable in the aromatic series aromatic sulphonic acid potassium salts, on fusion with potassium cyanide or potassium ferrocyanide, yield aromatic nitriles. The reaction can be extended to derivatives of pyridine. 

In a paper recently published 2>, we point out that, except for a bromine-benzene complex studied by Duchesne, the results reported in the literature do not offer any clear evidence for charge transfer. A systematic observation of both nitrogen and chlorine resonances in some complexes led us to admit the existence of a small transfer (0.05 electron) in chloroform complexes with amines and pyridine derivatives. Though the number of compounds studied is still small, the observed effects are not thought to be due to mere coincidence, and it appears very desirable to extend such experiments especially for stronger complexes. 

How pyridine derivatives can be used to extend pyridine s reactivity... 

Subsequent protic workup releases the aromatic compound. The metalative Reppe reaction can also be used to prepare iodo-substituted or homologated aromatics by treatment of the titanium aryl compound with iodine or an aldehyde, respectively. This procedure has recently been extended to include pyridine derivatives (254 and 255), where the titanacyclopentadiene intermediate can be treated with sulfonylnitriles to afford pyridines after protic workup.192 As with the alkyne cyclotrimerizations, treatment with the appropriate electrophiles affords iodo- and homologated pyridines. 

Treatment of 2-alkyl- or 2-hydroxymethyl-l-aminopyridinium salts with acyl or aroyl chlorides in the presence of base causes cyclization to pyrazolo[l,5-a]pyridine derivatives. If the 3-position is unsubstituted, acylation occurs at this position under the reaction conditions (Eq. 13).18141 There is good evidence that the initial step is acylation of the iV-amino group. This reaction has been extended to the synthesis of various bridgehead nitrogen heterocyclic systems including pyrazolodiazines (11),9 pyrazolo[5,l- ]thiazole (12),142 and imidazo[l,2-h]pyrazole (13).142... 

Heterocyclic o-quinodimethanes are unstable and reactive dienes that must be generated in situ. In solution and in the pre.sence of a dienophile the -quinodimethanes can be intercepted in a Diels-Alder reaction, often in high yield. Most of the dienophiles investigated so far have been electron deficient A-phenylmaleiinide. acrylonitrile, methyl vinyl ketone, acrylate, ftimarate and acetylenedicarboxylic esters are typically used. However, since the objective of most of the work was simply to establish that the o-quinodimethane was being formed, the scope of the reaction has not been adequately explored. The pyridine derived o-quinodimethane 12 has recently been shown to undergo cycloaddition to ethyl vinyl ether (Scheme 2) and to dihydroftiran <96T11889>, and it is thus clear that the scope of the Diels-Alder reaction extends beyond electron deficient alkenes and alkynes. Heterodienophiles (azodicarbonyl compounds and nitrosobenzene) have been added to indole-2,3-quinodimethanes <91T192,S> and this type of hetero Diels-Alder reaction is also potentially of wider application. 

The reaction can be extended to the case in which two alkynes and a nitrile are trimerized to give a pyridine or two alkynes and an isocyanate are tri-merized to give an a-pyridone, also shown in Eq. 14.63, as exemplified in syntheses of vitamin 85, a pyridine derivative, and the antitumor agent, camptothecin, an a-pyridone. 

A variety of l,2,3,4-tetrahydro-j8-carbolines have been prepared from 3-piperidone phenylhydrazone derivatives. Used initially to obtain pentacyclic derivatives (35) related to the yohimbe alkaloids, this route was later extended to the synthesis of tetracyclic compounds (36). l-Methyl-5,6,7,8-tetrahydro-j8-carboline (37) was prepared in low yield by heating cyclohexanone 2-methyl-3-pyridylhydrazone with zinc chloride, a synthesis probably based on the similar preparation of the tetracyclic compound 38 starting from the corresponding quinolylhydrazine. Abramovitch and Adams extended this approach to the cyclization of cyclohexanone 3-pyri-dylhydrazone (39) itself. The main product was 6,7,8,9-tetrahydro-8-carboline (40), a smaller amount of the j8-isomer (41) also being obtained. This provides a convenient and readily reproducible route to the otherwise difficultly accessible 8-carboline ring system. The favored attack at carbon-2 over carbon-4 of the pyridine nucleus... 

It is only recently that the chloromethylation reaction, well known in the benzene series, has been extended to isoxazoles. It has been thereby found that this reaction results in 4-chloromethyl derivatives (69), their yield decreasing as follows 5-phenyl > 3,5-dimethyl > 5-methyl > 3-methyl isoxazoles > isoxazole. To prove the position of the chloromethyl group these compounds were oxidized to the known isoxazole-4-carboxylic acids (70). It is especially noteworthy that pyridine and its homologs do not undergo chloromethylation. 

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