Quinine reaction

On the other hand, the high importance of Knorr reaction in drug design is highlighted in the synthesis of quinine. Reaction of jp-anisidine and acetoacetic ester in the presence of sulfuric acid provides 6-methoxylepidine. Substitution of hydroxyl group with chloride and subsequent reduction provides the 2-unsubstituted quinoline. Condensation and oxidation affords a quininic ester, which is just three steps away from the synthesis of strong anti-malarial compound quinine. ... 

In the following decades, chemists tried to utilize more and more the knowledge on reactions which had already been gained. A number of landmark syntheses represent the change to modern chemistry, such as the synthesis of the estrogenic steroid equilenin (W. Bachmann, 1939), of pyridoxine (K. Folkers, 1939), and of quinine (R.B. Woodward, W. von E. Doering, 1944) [23]. 

Detection. Cinchonidine is distinguished from quinine and quinidine by not being fluorescent in dilute sulphuric acid, and by not giving the thalleioquin reaction and from cinchonine in being laevorotatory and more soluble in ether, and in the sparing solubility of its tartrate. 

In the cases of quinine and quinidine there is an additional complication, except for reaction (c), owing to partial de-methylation of the methoxyl group, thus in the action of sulphuric acid on quinine there may be four products of formula E, viz., the two geometrical isomerides apoquinine and isoapoquinine (for which Q is 6-hydroxyquinolyl) and their methyl ethers, j8-isoquinine and a-isoquinine respectively (for which Q is 6-methoxyquinolyl). 

EtOH) was examined in detail by Mead and Koepfli, who, from its reactions and the resemblance of its absorption spectrum to that of 2-hydroxy-6-methoxy-4-methylquinoline, regard it as Z-2 -hydroxyquinine (2 -hydroxy-6 -methoxy-3-vinylruban-9-ol). According to P. B. Marshall, this metabolite is inactive in chick malaria, but Kelsey efaZ. (1946) find that at a dosage of 40-70 mgm./kilo./day, it exercises about the same degree of suppression as 15 mgm./kilo./day of quinine, and quote E. K. Marshall for the observation that it has about one-twentieth the activity of quinine in the malaria of ducks. 

The initial observation that menthone reacts with amyl nitrite in the presence of base to give a good yield of an open-chain oximino ester was not expanded for synthetic purposes until Woodward almost forty years later utilized this reaction for the cleavage of a 7-keto-decahydroisoquinoline in the course of his total synthesis of quinine. 

Subs tituted-1,2,3-oxadiazolo[4,5-/]quinoline 47 originated after nitration, reduction, and diazotization of alkaloid quinine during the study of its stmcture and reactions (53RZC495, 54RZC61). 

Following Uskokovic s seminal quinine synthesis [40], Jacobsen has very recently reported the first catalytic asymmetric synthesis of quinine and quinidine. The stereospecific construction of the bicyclic framework, introducing the relative and absolute stereochemistry at the Cg- and expositions, was achieved by way of the enantiomerically enriched trans epoxide 87, prepared from olefin 86 by SAD (AD-mix (3) and subsequent one-pot cyclization of the corresponding diol [2b], The key intramolecular SN2 reaction between the Ni- and the Cg-positions was accomplished by removal of the benzyl carbamate with Et2AlCl/thioanisole and subsequent thermal cyclization to give the desired quinudidine skeleton (Scheme 8.22) [41],... 

Scheme 8.22 Intramolecular Sn2 reaction in the catalytic asymmetric total synthesis of quinine.

The use of quinine can cause cinchonism at full therapeutic doses. Cinchonism is a group of symptoms associated with quinine, including tinnitus, dizziness, headache, gastrointestinal disturbances, and visual disturbances. These symptoms usually disappear when the dosage is reduced. Other adverse reactions include hematologic changes, vertigo, and skin rash. 

The thalleiochin reaction for the specific detection of quinine alkaloids carrying an oxygen group at C-6 of the quinoline nucleus (e. g. quinine and quinidine) [17], or the... 

Irreversible reaction of [18] iodine with acetylsalicylic acid, aethaverine, amidopyrine, ascorbic acid, benzo-caine, quinine, dihydrocodeine, fluorescein, glycine, hydrocortisone acetate, isoni-azid, metamizole, papaverine, paracetamol, phenacetin, phenol-phthalein, piperazine, resorcinol, salicylic acid, salicylamide, sulfaguanidine, thymol, triethanolamine, tris buffer detection by reaction chromatography... 

Note It is possible to differentiate amino acids by color on the basis of the markedly different shades produced [2, 3]. Proline and hydroxyproline, that only react weakly with ninhydrin, also yield pink-red colored derivatives [2]. Ergot alkaloids and LSD are detected by spraying with 10% hydrochloric add and then heating to 110°C for 20 min after they have been treated with the reagent [9]. Ergot alkaloids and LSD yield red to purple zones when treated in this manner other alkaloids, e.g. reserpine, emetine, quinine, strychnine, pilocarpine, atropine, scopolamine, cocaine and opium alkaloids, do not give a reaction [9]. 

Only a few other cobalt complexes of the type covered in this review (and therefore excluding, for example, the cobalt carbonyls) have been reported to act as catalysts for homogeneous hydrogenation. The complex Co(DMG)2 will catalyze the hydrogenation of benzil (PhCOCOPh) to benzoin (PhCHOHCOPh). When this reaction is carried out in the presence of quinine, the product shows optical activity. The degree of optical purity varies with the nature of the solvent and reaches a maximum of 61.5% in benzene. It was concluded that asymmetric synthesis occurred via the formation of an organocobalt complex in which quinine was coordinated in the trans position (133). Both Co(DMG)2 and cobalamin-cobalt(II) in methanol will catalyze the following reductive methylations ... 

Humans have used dyes to create color since the dawn of history. Until the mid-nineteenth century, all dyes were of natural origin. Many came from plants, such as indigo, a dark blue dye that was extracted from the leaves of a native East Indian plant. In 1856, the young English chemist William Perkin stumbled upon the first synthetic dye. Perkin was trying to synthesize quinine, a valuable antimalaria dmg. None of his experiments met with success. As he was about to discard the residue from yet another failed reaction, Perkin noticed that it was colored with a purple tinge. He washed the residue with hot alcohol and obtained a purple solution from which strikingly beautiful purple crystals precipitated. Perkin had no idea what the substance was or what reactions had created it, but he immediately saw its potential as a new dye. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

Interestingly, Jacobsen et al. have also reported that addition of a /3-hydroxy ammonium salt to the reaction medium accelerates the isomerization in the presence of an /V-benzylated quinine salt epoxidation of cw-stilbene with (27) gives Zrarax-stilbene oxide with 90% ee as the major product (trans cis= >96 4).109 In 2000, Adam et al. reported that the isomerization ratio was related to the triplet-quintet energy gap of the radical intermediate which was affected by the... 

Scheme 6.103 Intramolecular SN2 reaction in the total synthesis of quinine.

Another microwave-mediated intramolecular SN2 reaction forms one of the key steps in a recent catalytic asymmetric synthesis of the cinchona alkaloid quinine by Jacobsen and coworkers [209]. The strategy to construct the crucial quinudidine core of the natural product relies on an intramolecular SN2 reaction/epoxide ringopening (Scheme 6.103). After removal of the benzyl carbamate (Cbz) protecting group with diethylaluminum chloride/thioanisole, microwave heating of the acetonitrile solution at 200 °C for 2 min provided a 68% isolated yield of the natural product as the final transformation in a 16-step total synthesis. 

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