Quinolines and isoquinolines

Quinoline forms part of the structure of quinine, the malaria remedy found in cinchona bark and known since the time of the Incas. The quinoline in quinine has a 6-MeO substituent and a side chain attached to C4. In discussing the synthesis of quinolines, we will be particularly interested in this pattern. This is because the search for anti-malarial compounds continues and other quinolines with similar structures are among the available anti-malarial drugs.

We shall also be very interested in quinolones, analogous to pyridones, with carbonyl groups at positions 2 and 4, as these are useful antibiotics. A simple example is pefloxacin, which has typical 6-F and 7-piperazine substituents.

When we consider the synthesis of a quinoline, the obvious disconnections are, fi rst, the C–N bond in the pyridine ring and, then, the C–C bond that joins the side chain to the benzene ring. We will need a three-carbon (C3) synthon, electrophilic at both ends, which will yield two double bonds after incorporation. The obvious choice is a 1,3-dicarbonyl compound.

The choice of an aromatic amine is a good one as the NH2 group reacts well with car bonyl compounds and it activates the ortho position to electrophilic attack. However, the dialdehyde is malonic dialdehyde, a compound that does not exist, so some alternative must be found. If the quinoline is substituted in the 2- and 4-positions this approach looks better.

The initially formed imine will tautomerize to a conjugated enamine and cyclization now occurs by electrophilic aromatic substitution. The enamine will normally prefer to adopt the fi rst configuration shown in which cyclization is not possible, and (perhaps for this reason or perhaps because it is difficult to predict which quinoline will be formed from an unsymmetrical 1,3-dicarbonyl compound) this has not proved a very important quinoline synthesis. However, the synthetic plan is sound, and we shall describe two important variants on this theme, one for quinolines and one for quinolones.

In the synthesis of pyridines it proved advantageous to make a dihydropyridine and oxidize it to a pyridine afterwards. The same idea works well in probably the most famous quinoline synthesis, the Skraup reaction. The diketone is replaced by an unsaturated carbonyl com pound so that the quinoline is formed regiospecifically. The first step is conjugate addition of the amine. Under acid catalysis the ketone now cyclizes in the way we have just described to give a dihydroquinoline after dehydration. Oxidation to the aromatic quinoline is an easy step accomplished by many possible oxidants.

Traditionally, the Skraup reaction was carried out by mixing everything together and let ting it rip. A typical mixture to make a quinoline without substituents on the pyridine ring would be the aromatic amine, concentrated sulfuric acid, glycerol, and nitrobenzene all heated up in a large flask at over 100 °C with a wide condenser.

The glycerol was to provide acrolein (CH2=CH⋅CHO) by dehydration, the nitrobenzene was to act as oxidant, and the wide condenser...? All too often Skraup reactions did let rip—with destructive results. A safer approach is to prepare the conjugate adduct first, cyclize it in acid solution, and then oxidize it with one of the reagents we described for pyridine synthesis, particularly quinones such as DDQ.

The more modern style of Skraup synthesis is used to make 8-quinolinol or ‘oxine’. ortho Aminophenol has only one free position ortho to the amino group and is very nucleophilic, so acrolein can be used in weak acid with only a trace of strong acid. Iron(III) is the oxidant, with a bit of boric acid for luck, and the yield is excellent.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشعائر يواصل تحضيراته لتنظيم عمل المواكب الحسينية في زيارة الأربعين

قسم شؤون المعارف يناقش تحضيرات المؤتمر العلمي الأول لمركز تراث البصرة

قسم الشؤون الفكرية يقيم دورة تطويرية لملاكات هيأة المساءلة والعدالة في الأرشفة الإلكترونية

المجمع العلمي ينظم مجلس عزاء في قضاء الهندية

المزيد

الآخبار الصحية

نصائح عملية للحد من التعرق المفرط في الصيف

أطباء يحذرون: مكمل غذائي شائع قد يدمر الجهاز العصبي

تحذير طبي من تأثير جانبي "غير متوقع" لحقن التخسيس

حمامات الثلج قد تكون خطيرة وأحيانا مميتة.. ما السبب؟

المزيد

الآخبار التكنلوجية

أكبر جدارية شمسية في العالم تدخل موسوعة غينيس.. مشروع ضخم

تسارع دوران الأرض يثير القلق.. وتحذيرات من "كوارث محتملة" ؟

"سوذبيز" تطرح أكبر قطعة من المريخ على الأرض في مزاد علني

أوبن أيه آي تعتزم إطلاق متصفح إنترنت يعمل بالذكاء الاصطناعي

المزيد

مواضيع ذات صلة

Aziridine: ring strain promotes ring opening

Reactions of saturated heterocycles

More heteroatoms in fused rings mean more choice in synthesis

Quinolones also come from anilines by cyclization to an ortho position

Pyrimidines can be made from 1,3-dicarbonyl compounds and amidines

Pyrazoles and pyridazines from hydrazine and dicarbonyl compounds

Thermodynamics is on our side

There are thousands more heterocycles out there

Fusing rings to pyridines: quinolines and isoquinolines

Putting more nitrogen atoms in a six-membered ring

Benzo-fused heterocycles-Indoles are benzo-fused pyrroles

Five-membered rings with two or more nitrogen atoms Imidazole