Quinolines isoquinolines and

Chan and coworkers applied catalysts based on (R) P Phos (16, Table 6.4, entries 3 and 4) [118], BINAPO (17 and 18, entries 5 and 6) [119], and atropisomeric (13, entry 7) [ 120] ligands to the reaction. Ligand 16 was particularly interesting because its polar nature allowed the catalyst to be immobilized and recycled. After using [Ir(COD)Cl[2/ I6/I2 to catalyze the hydrogenation of 2 methylquinoline in biphasic mixtures of hexane and dimethyl poly (ethylene glycol) (dmpeg), the authors decanted off the 

The catalysts shown in Table 6.4 have also been used to hydrogenate a variety of 

Quinoline and isoquinoline can also be viewed as being formally derived from naphthalene 

Quinoline 6.1 and isoquinoline 6.2 are two isomeric heterocyclic systems, which can be envisaged as being constructed from the fusion of a benzene ring at the C2/C3 and C3/C4 positions of pyridine respectively. They are both ten Jt-electron aromatic heterocycles. Like pyridine, they are moderately basic (p/fa quinoline = 4.9, pKa isoquinoline = 5.1). Indeed quinoline is sometimes used as a high boiling-point (237°C) basic solvent. 

As with pyridine, the nitrogen atoms of quinoline and isoquinoline each bear a lone pair of electrons not involved in aromatic bonding which can be protonated, alkylated, or complexed to Lewis acids. This chapter should be read in conjunction with the chapter on pyridines as several points discussed at length there are also relevant to the chemistry of quinoline and isoquinoline. 

The classical Skraup synthesis of quinolines is exemplified by the reaction of aniline 6.3 with glycerol 6.4 under acidic/oxidative conditions to produce quinoline 6.1. 

At first sight this reaction appears to be another one of those ancient heterocyclic syntheses that owe more to alchemy than to logic, but in fact the processes involved are relatively straightforward. 

Quinoline and isoquinoline are heterocycles in which a benzene ring and a pyridine ring are fused through carbon. The isomeric heterocycles 1- and 2-azanaphthalene, better known by their trivial names quinoline and isoquinoline, have been the subject of extensive studies since their discovery in the extracts of coal tar at the beginning of nineteenth century. Since then their heterocyclic ring systems were found incorporated in several hundreds of natural products and were used as pharmacophore units in dozens of pharmaceuticals especially anti-bacterials, better known under the general name of Quinolones .  

3-Carboxylic acid substituted quinolin-4-one derivatives constitute another class of biologically active compounds often known under the collective name quinolones . The development of quinolone antibacterials since the discovery of naphthyridine agent, nalidixic acid, has progressed with periods of great innovation. 

Pyranoquinoline alkaloids are another important group of quinoline derivatives that possess strong biological activities, from potent inhibitors of platelet aggregation such as zanthodioline, to cytotoxic compounds acting selectively to breast cancer cells such as huajiaosimuline.  

Exchange in the hydroxy derivatives of quinoline and isoquinoline has been studied. For exchange at the 3-position of 4-quinolone, the rate is roughly invariant with acidity below // - 7 but increases rapidly at higher acidity. This rate-profile slope alteration is due to a change-over from reaction on the free base to reaction on the conjugate acid and relative 

Comparison of the exchange data for 4-quinolone and 4-pyridone indicated that benzo annelation increases the reactivity of the latter by 102 for the free base and I05 for the conjugate acid [67JCS(B)1226]. Again, the factor is greatest for the less reactive system, in keeping with the reactivity-selectivity principle. 

For exchange in l-hydroxyisoquinolinewith61 wt%D2S04at 180°C, the positional reactivity order was 4 5 7 8 3 6 (68CPB715), which is almost exactly the order for the free base of isoquinoline (Section 7). 

However, the conjugate acid is almost certainly the exchanging species in 3-hydroxyisoquinoline, so this agreement is probably fortuitous and may reflect near cancellation of the effects of the OH substituent and N-protonation. 

Rate profiles have been obtained for exchange in 6- and 7-aminoquin-olines at the 5- and 8-positions, respectively [71 JCS(B) 11]. These rate profiles are fairly similar and show the expected changes in slope corresponding to the first and second protonations at the appropriate pK values. 

Early work on the amination of quinoline and substituted quinolines showed that the parent compound gave only a 32% yield of 2-aminoquinoline (78) in aromatic hydrocarbons (20MI1). Many derivatives, including quinoline carboxylic acids and amides, formed amino products more readily. However, amino- and hydroxyquinolines do not participate in the Chichibabin reaction (78RCR1042). 

In a similar manner, 7-methylquinoline was treated with sodium amide to give 2-amino-3,4-dihydro-7-methylquinoline, isolated as 3,4-dihydro-7-methylcarbostyril (4%). Attempts to isolate the normal product, 2-amino-7-methylquinoline, failed (68CPB367). Continuing the investigation. 

Quinoline easily forms a-adducts 22 and 23 in liquid ammonia containing excess sodium or potassium amide (Section II,A,3). The cr-adducts are time 

7- amino-3//-pyrrolo[3,2-/]pyrroloquinoline (135) and 33% 9-amino-3H-pyrrolo[3,2-/]quinoline (136) 3H-pyrrolo[2,3-/)]quinoline (137) gave 39% 

8- amino-3//-pyrrolo[2,3-/i] quinoline (138) and 31% 6-amino-3/f-pyrrolo-[2,3-/i]quinoline (139) and lH-pyrrolo[3,2-/i]quinoline (140) gave 43% 8-amino-l//-pyrrolo[3,2-/z]quinoline (141) and 24% 6-amino-l//-pyrrolo-[3,2-/i]quinoline (142) (81JOU1371). 

Replacing one carbon atom of naphthalene with an a2omethene linkage creates the isomeric heterocycles 1- and 2-a2anaphthalene. Better known by their trivial names quinoline [91-22-5] (1) and isoquinoline [119-65-3] (2), these compounds have been the subject of extensive investigation since their extraction from coal tar in the nineteenth century. The variety of studies cover fields as diverse as molecular orbital theory and corrosion prevention. There is also a vast patent Hterature. The best assurance of continuing interest is the frequency with which quinoline and isoquinoline stmctures occur in alkaloids (qv) and pharmaceuticals (qv), for example, quinine [130-95-0] and morphine [57-27-2] (see Alkaloids). 

The close chemical relationship among these stmctural entities, as well as the uniqueness of (1) and (2), have been evident from the time of the earhest stmctural studies. Permanganate oxidation of (1) (2) produces 2,3-pyridinedicarboxyhc acid (quinolinic acid [89-00-9]) (3), whereas similar treatment of (2) (3) yields a mixture of 3,4-pyridinedicarboxyhc acid (cinchomeronic acid [490-11 -9]) (4) and phthaUc acid. 

The continuing impoitance of these compounds has led to a number of general and specific reviews. Five volumes of Weissberger s The Chemistyy of 

Kirk-Othmer Encyclopedia of Chemical Technology (4th Edition) 

HeteroQic/k Compounds are essential reading for studies through 1977 and, in many instances, to 1990 (4). 

Just a few quinoline derivatives have been prepared from AAs. Upon condensation with p-benzyloxyaniline, ethyl formylhippurate yielded the 4-hydroxyquinoline 96 after some transformations (82JMC501). 

For biosynthetic studies of the formation of the macrocyclic peptide antibiotic thiostrepton, isotopically labeled [ C]-AAs were employed. The quinaldic acid moiety 97 of this antibiotic was shown to be biosynthesized from 3-methyltryptophan, and a mechanism has been proposed (93JA7992). 

An enantioselective synthesis of the natural venom pumiliotoxin C 98 and its unnatural enantiomer was achieved from (/ )-norvaline in a multistep 

SYNTHETIC METHODS FOR SOME PROMINENT HETEROCYCLIC FAMILIES 

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The first quantitative studies of the nitration of quinoline, isoquinoline, and cinnoline were made by Dewar and Maitlis, who measured isomer proportions and also, by competition, the relative rates of nitration of quinoline and isoquinoline (1 24-5). Subsequently, extensive kinetic studies were reported for all three of these heterocycles and their methyl quaternary derivatives (table 10.3). The usual criteria established that over the range 77-99 % sulphuric acid at 25 °C quinoline reacts as its cation (i), and the same is true for isoquinoline in 71-84% sulphuric acid at 25 °C and 67-73 % sulphuric acid at 80 °C ( 8.2 tables 8.1, 8.3). Cinnoline reacts as the 2-cinnolinium cation (nia) in 76-83% sulphuric acid at 80 °C (see table 8.1). All of these cations are strongly deactivated. Approximate partial rate factors of /j = 9-ox io and /g = i-o X io have been estimated for isoquinolinium. The unproto-nated nitrogen atom of the 2-cinnolinium (ina) and 2-methylcinno-linium (iiiA) cations causes them to react 287 and 200 more slowly than the related 2-isoquinolinium (iia) and 2-methylisoquinolinium (iii)... 

Unlike quinoline and isoquinoline which are of comparable stability the compounds indole and isoindole are quite different from each other Which one is more stable Explain the reason for your choice... 

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