4-Quinoline derivatives

A quinoline derivative, 8-hydroxyquinoline (27) was the first fungicide with systemic properties, but it did not find a wide application. It is a white crystalline substance, slightly soluble in water but readily soluble in alkalies and acids, with the formation of salts. It is of medium toxicity, its acute oral being 1000 mg/kg for 

The preparation of 8-hydroxyquinoline has long been known. The basis of the preparation is Skraup s synthesis, which essentially involves the reaction of primary aromatic amines with unsaturated carbonyl compounds and the oxidation of the 

With fuming sulfuric acid quinoline gives quinoline-8-sulfonic acid, from which 

8-hydoxyquinoline can be prepared by decomposition with sodium hydroxide (Magidson and Rubtzov, 1935). 8-Hydroxyquinoline can be obtained in a single step from o-aminophenol by Skraup s synthesis (Das and Mukherjee, 1951 Kanevskaya and Melenteva, 1953). 

Powell (1946) and Mason (1948) found that the 2 1 complex of 8-hydroxyquinoline with copper, oxine-copper, has a stronger fungicidal action than 8-hydroxyquinoline. Albert et al. (1953) attributed this to the fact that the organic part of the compound makes copper lipoid-soluble and thus accelerates its penetration into the cell. Inside the cell the 2 1 complex dissociates into a 1 1 complex and free 8-hydroxyquinoline. The active toxic agent is the ionised 1 1 complex of nonlipoid properties, which reacts with the enzymes in the fungus and blocks their function. This theory is also supported by the research work of McNew and Gershon (1969). 

There are also a few compounds belonging to the 7,8-dione system 238. 8-unsubstituted 7-hydroxyquinolines are oxidized with Fremy s salt to 238. Because the formation of these quinones is slow, other reactions can take place. In acid solution, dimeric compounds are formed and, in neutral solution, ethers similar to those in the 5,6-dione series (237) are formed (67CB2077). 

There are also some special syntheses. For example, in an attempted acid-catalyzed hydrolysis of a benzobis(oxazole) into a diaminobenzoquinoline-quinone, 240 was obtained instead. This compound has two more carbon atoms than expected. In addition, in the presence of acetaldehyde, the yield of 240 increased whereas addition of propionaldehyde generated compound 241. During these transformation, 2 equivalents of the aldehyde are incorporated in what is explained as a retroaldol reaction of benzobis(oxazole) during deprotection (85JOC4276). 

Another approach is a palladium-catalyzed cyclization. 2-Allyl-3,6-diamino-5-methyl-l,4-benzoquinone was transformed into the 5-amino-6-methyl analog of 289 (85JOC4276). Oxidative cyclization with chloranil was also effective. 

Quinone 239 adds hydrogen chloride to give the 6-chloro compound after subsequent oxidation the 7-chloro isomer is obtained as a by-product (870PP249). Reactions with pyridine have been described (58MI3 71JMC1029). With dienes, adducts are formed that can be isomerized with acid into hydroquinones, which can be reoxidized with silver oxide to quinones (67JHC133 73JCS(P 1)2374). 

6-7-Dichloroquinoline-5,8-dione is converted by peroxytrifluoroacetic acid into the N-oxide in low yield. This compound is also obtainable directly from 8-hydroxyquinoline with a mixture of concentrated hydrochloric and nitric acids (86JMC1329). The 6,7-dichloroquinone reacts also with imidazole to give the disubstituted product (72LA131). 

The historical importance and utility of quinine was known in the medical practice for a long time as a potent antipyretic in addition to its remarkable effect against the malarial fever. The basic quinoline nucleus, present in the quinine molecule, contributes to antipyretic activity to a certain extent. Therefore, an attempt was made to synthesize a number of quinoline derivatives which might exhibit better antipyretic activity. 

Two quinoline derivatives first synthesized though possessed significant antipyretic action, yet could not gain cognizance as a drug because of their high toxic effects on the red blood corpuscles and damaging after-effect on kidneys. These were, thalline and 6-methoxy quinoline. 

2-Phenyl-cinchoninic aeid 2-PhenyIquinoIine-4-carboxyIie aeid Quinophan Atophan B.P 

It may be prepared by any one of the following three methods Method-I From o-Amino benzaldehyde cyanohydrin 

Condensation of o-aminobenzaldehyde cyanohydrin and methylphenyl ketone yields dnchophen. Method-II From Isatin 

Various bioisosteric replacements for a phenolic hydroxyl have been explored. One such, a lactam NH, is incorporated into the design of the 3-adrenergic blocker, carteolol O)- The fundamental synthon is carbostyril derivative K This is reacted in the usual manner with epichlorohydrin to give which is in turn reacted with t-butylamine to complete the synthesis of carteolol (3 ), a drug that appears to have relatively reduced nonspecific myocardial depressant action. Carrying this de- 

Friedel-Crafts alkylation of 8-hydroxycarbostyrils, such as leads to substitution at the C-5 position, namely, In this case an a-haloacyl reagent is employed. Displacement with isopropylamine and careful sodium borohydride reduction (care is 

Droxacin (16) is a carbabioisostere of the clinically useful antimicrobial agent, oxolinic acid. Its synthesis 

An interestingly complex analogue in this family is f1ume-quine (17). As might be expected from the knowledge that the bacterial target is an enzyme (DNAtopoisomerase II), one of the 

Nantradol (25) is an especially interesting agent in that it 1l a potent analgesic that does not act at the morphine receptorSi 

---

Doebner-von Miller reaction Condensation of an aromatic amine with an aldehyde or ketone in the presence of hydrochloric acid to form a quinoline derivative. A general method, thus aniline and ethanal give 2-methyl-quinoline (quinaldine) and p-phenetidine. 

Quinoline derivatives may be synthesised by heating aii aromatic amine with an aldehyde or a mixture of aldehydes in the presence of concentrated hydrochloric or sulphuric acid this synthesis is known as the Doebner - Miller reaction. Thus aniline and paraldehyde afford 2-methylquinohne or quinaldine. 

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

Economic Aspects. There is little evidence of large-scale demand for either quinoline or isoquinoline in 1996. The U.S. Tariff Commission reports no longer show separate production or sales data for any quinoline derivative. A number of these compounds are available as fine chemicals representative examples are found in Table 2. The principal suppHer of quinoline and quinoline still residue is Koppers Chemical. 

Quinoline derivatives are also dangerous for example, 8-quinolinol is especially toxic intraperitoneaHy, with an LD q (mouse) of 48 mg/kg. This... 

Table 3. Quinoline-Derived Drugs Marketed in the United States ...

The synthesis of meconin has been referred to already (p. 201). Cotarnine has been synthesised by Salway from myristicin (I) as a starting-point. This was transformed into jS-3-methoxy-4 5-methylenedioxy-phenylpropionic acid (II), the amide of which was converted by Hofmann s reaction into )S-3-methoxy-4 5-methylenedioxyphenylethylamine, and the phenylacetyl derivative (HI) of this condensed, by heating it in xylene solution with phosphoric oxide, giving rise to the two possible dihydroiso-quinoline derivatives. The first of these substances, 8-methoxy-6 7-methylenedipxy-1-benzyl-3 4-dihydroiioquinoline (IV), on conversion into the methochloride and reduction with tin and hydrochloric acid, gave... 

Because of the similarity of the substituent effects in s-triazine and quinoline derivatives, it seems probable that in the former sequence hydrogen falls between the chlorine atom and the methoxy group. 

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. ... 

The rate of the corresponding reaction of naphthoic derivatives was greater than that of quinoline derivatives. 

Under similar conditions, as in the case of 5-amino-2,l,3-benzothiadiazole, and starting from 6-amino-l,2,3-benzothiadiazole 72, the l,2,3-thiadiazolo[5, 4-/ quinoline derivatives 73 resulted (Scheme 28) and were tested for antibacterial properties (74JAP(K)1). 

Amino-2-phenyl-2//-benzotriazole reacted with epichlorhydrin in chlorobenzene at 140-145°C to give the A-benzyl-7-hydroxy-6,7,8,9-tetrahydrotriazolo-quinoline derivative 194. This was benzylated and rearranged by heating in DMSO to give the isomeric 7-benzyloxy derivative 195 (Scheme 59) (77MI2). 

Quinoline derivatives of formula 115 are outstandingly active as microbiocides and can be preferentially used as agricultural fungicides and bactericides for the control of undesired plant pathogens (96EUP703234). 

In the reaction of 4-methoxybut-3-en-2-one with amines 223 and 226, the products of methoxy group substitution 224 and 227 were isolated. Under subsequent intramolecular dehydration these products give quinoline derivatives 225 (50°C, H2SO4, 15 min, yield 25%) (61GEP1017613) and 228 (0°C, 35% KOH, 10 min, yield 88.7%) [65NEP6401199 80MI2]. 

Dialkylquinolinyl boranes 83 and 86 were prepared from halogen/metal exchange of 3-bromoquinoline (70) with n-BuLi followed by quenching with Et2BOMe and Br-9-BBN, respectively. They are then coupled with bromides 84 and 87 to give 3-substituted quinoline derivatives 85 and 88, respectively (85H2375). 

Cacchi and Palmier (83T3373) investigated a new entry into the quinoline skeleton by palladium-catalyzed Michael-type reactions. They found that phenyl mercurial 134 was a useful intermediate for the synthesis of quinoline derivatives, and that by selecting the reaction conditions the oxidation level of the heterocyclic ring in the quinoline skeleton can be varied. On such example is shown in Scheme 16. PdCla-catalyzed coupling between organomercurial reagent 134 and enone 135 delivered adduct 136 which was subsequently cyclized to quinoline 137 under acidic conditions. 

The Reisert compound 93, prepared from quinoline derivatives 92, gave upon reaction with dimethyl acetylenedicarboxylate the pyrroloquinoline 95. Reduction of 93 gave the tetrahydro derivative that upon reaction with dimethyl acetylenedicarboxylate afforded 96 (85JOC722). Reaction of 94 with acrylonitrile in presence of base gave pyrroloquinoline 97 (77JCS(P1)2018) (Scheme 18). 

Bromination of the diphenyl indole derivative 316 with bromine in DMF or trimethylammonium bromide afforded the 7-bromo derivative 317. Reaction with allyl bromide or its derivatives gave A-allyl derivatives 318 that upon cyclization with palladium acetate gave 7,9-dimethoxy-l,2-diphenylpyrrolo[3,2,l-// ]quinoline derivatives 319 (92T7601) (Scheme 57). 

This ring system was prepared by treatment of quinoline derivative 786 with antimonyl chloride to give 787. Quinoline derivative 786 was prepared by Mannich reaction on 2,8-dihydroxylepidine with diethylamine and formaldehyde to afford the respective diethylaminomethyl derivative that followed by subsequent nitration. The schistosomicidal activity of 787 was studied (80MI66) (Scheme 138). 

Hydroxy-3-(4-biphenyl)perhydropyrido[l,2-c][l,4]oxazine was obtained in the reaction of 2-piperidinemethanol and 4-bromoacetylbiphenyl in a mixture of acetone and Et20 at room temperature (00JMC609, 00MIP13). Perhydropyrido[l,2-c][l,4]oxazin-l-one 298 was obtained in the reaction of quinoline derivative 297 and chloroacetyl chloride (OOMIPl). 

Since various substituents are tolerated, the Friedlander reaction is of preparative value for the synthesis of a large variety of quinoline derivatives. The benzene ring may bear for example alkyl, alkoxy, nitro or halogen substituents. Substituents R, R and R" also are variable. The reaction can be carried out with various carbonyl compounds, that contain an enolizable a-methylene group. The reactivity of that group is an important factor for a successful reaction. 

By reaction of a primary aromatic amine—e.g. aniline 1—with glycerol 2, and a subsequent oxidation of the intermediate product 4, quinoline 5 or a quinoline derivative can be obtained.As in the case of the related Friedlander quinoline synthesis, there are also some variants known for the Skraup synthesis, where the quinoline skeleton is constructed in similar ways using different starting materials. ... 

A partially reduced quinoline derivative with antiulcerative and antisecretory activities is isotiquimide (14). It may be synthesized by metallating (with n-BuLi) 4-methyl-5,6,7,8-tetrahy-droquinoline and condensing this with dimethylmethoxysilylisothiocyanate to produce the desired thioamide isotiquimide (14) [4],... 

Heteroatom rings, such as that found in quinoline derivatives, can be generated from amino-ketones with [hydroxy(tosyloxy)iodo]benzene and perchloric acid. Cyclic imines are converted to pyridine derivatives with NCS and then excess sodium methoxide. ... 

Polycyclic aromatic hydrocarbons, indole and quinoline derivatives, naphthylamines, azulenes Silica gel G Formation of oxidation products via the initially formed iodine complexes [15]... 

The [4+2] cycloaddition reaction of N-atylaldimines with vinyl ethers is effectively catalyzed by ytterbium(III) triflate to give quinoline derivatives (e.g., 50) in good yield <95S801>. 

Recently Rabon et al. [100] reported on a new conformational probe of H,K-ATPase. This fluorescent quinoline derivative MDPQ was shown to be a reversible luminal K -site inhibitor of both K -ATPase and K -pNPPase activity. High-affinity MgATP binding induced a conformational change with fluorophore movement into a more hydrophobic environment. 

---