Skraup cyclization

The Skraup cyclization is another reaction principle that provides rapid access to the quinoline moiety. Theoclitou and Robinson have published the preparation of a 44-member library based on the 2,2,4-trisubstituted 1,2-dihydroquinoline scaffold by the Lewis acid-catalyzed cyclization of substituted anilines or aminoheterocyc-les with appropriate ketones (Scheme 6.237) [420], The best results were obtained using 10 mol% of scandium(III) triflate as a catalyst in acetonitrile as solvent at... 

The Skraup reaction is a good illustration of this common approach, as illustrated by the series of syntheses of 5,7-difluoro- and 5,6,7-trifluoroquinolines 2a,b proceeding in high yields on the basis of 3,5-difluoro- and 3,4,5-trifluoro-anilines la,b (Scheme 3) [5]. In a similar way 5,6,8-trifluoroquinolines 4a,b have been obtained from 2,4,5-trifluoro substituted acetanilide 3 and acrolein or crotonic aldehyde [6-8]. 5,7,8-Trifluoroquinoline has also been obtained from 2,3,5-trifluoro-acetanilide, while 6-trifluoromethyl-5,7,8-trifluoroqumoline - from 2,3,5-trifluoro-4-trifluoromethyl acetanilide, respectively [6]. The Skraup cyclization is also an effective synthetic took to transform 2,3,4,5-tetrafluoro substituted aniline 5 into... 

Skraup proposed a simple mechanism involving imine formation followed by an acid-mediated cyclization. Unfortunately the observed regioselectivity is not consistent with the proposed mechanism when, for example, electron-rich aniline 4 reacts with a, 3-unsaturated aldehyde 5 to give quinoline 6. ... 

Recently, solvent-free Skraup/Doebner-von Miller reactions have been developed under microwave radiation. For example, aniline 34 and enone 35 are reacted in the presence of silica gel impregnated with indium trichloride to give the corresponding quinoline 36 in good yield. It was subsequently shown that both electron-rich and electron-poor anilines undergo cyclization in a similar fashion. 

Skraup synthesis starting from 4- and 5-aminobenzothiadiazole afforded only angularly annelated products thiadiazolo[5,4-/i]- and [4,5-/]quinoline, respectively. Attempts to cyclize 4-chloro-5-aminobenzothiadiazole failed (37LA38). 

Combes synthesis with pentan-2,4-dione that led to 157, was ascribed to unfavorable steric hindrance in the alternative orientation in the Combes synthesis. 2-Amino-l,4-dimethylcarbazole underwent the Skraup reaction in the only orientation available to it. Finally, the carbazol-1-yIhydrazone of ethyl pyruvate underwent normal Fischer indolization giving 158 its 3-isomer gave an indole by cyclization at C-4 producing 159. ... 

Several of the well known cyclization reactions of aromatics that are used for the preparation of benzoheterocycles also work for pyridines (66AHC(6)229). 3-Aminopyridine undergoes the Skraup reaction (equation 59), and the substituted 3-amino derivative (97) undergoes intramolecular Friedel-Crafts reaction (equation 60). Further examples of these reactions can be found in the appropriate part of Chapter 2.06. 

Attempts to prepare tricyclic homologues of the naphthyridines have been partially successful. 4-Amino-1,5-naphthyridine (109) reacts under Skraup conditions to give 4,5,9-triazaphenanthrene (110), and 1,8,9-triazaanthracene derivatives (111) can be isolated from the mixtures of products obtained by treatment of 2-amino-l,8-naphthyridin-7-one and its derivatives with ethyl ethoxymethylenemalonate, acetylacetone and alkyl /3-oxoglutarates (72JHC801) (see also earlier papers in that series). However, 2-amino-1,8-naphthyridine (112 R = H) reacts under Skraup conditions to give the 2-oxo derivative (113 R = H) instead of a 1,8,9-triazaanthracene, and 2-amino-1,6-naphthyridine behaves similarly (75MI21103). Under non-hydrolytic conditions, naphthyridines (112 R = Aik, Ar, H) cyclize... 

The Skraup and related quinoline syntheses are the method of choice for the cyclization of an appropriate aniline in generally good yield (see, for example, Chapter 7.23.8.3.2 in CHEC-II(1996) < 1996CHEC-II(7)921 >). Formation of this class of compounds by formation of two bonds is generally achieved by condensation of a 1,2-diketone and a 1,2-diamine in excellent yield (see, for example, Equation 52). 

The mechanism is similar to that of the Skraup synthesis (Problem 20.37) in that carbonyl O is protonated and the electrophilic C attacks the benzene ring in cyclization, to be followed by dehydration and oxidation. 

The Skraup reaction and Friedlander synthesis have found application in the preparation of pyrazolo[3,4-fc]pyridines. Cyclization of l-benzyl-5-aminopyrazoles (51 R1 = CH2Ph R2 = H,Me)88,89 under usual Skraup conditions gave the 1-benzyl derivatives (73) in moderate yield. The 1 -H derivative (73, R1 = H, R2 = Ph), however, was isolated only in poor yield.89... 

The unsubstituted compound, 1,5-naphthyridine, can easily be prepared by application of the Skraup reaction to 3-aminopyridine. This reaction has been modified several times,17,59,60 and a yield of 60-70% may now be realized. Rapoport and Batcho16 have shown that cyclization takes place exclusively at the 2-position of the 3-aminopyridine in the Skraup reaction since none of the isomeric 1,7-naphthyridine is formed in the absence of a blocking group at that site. 

It is of interest that, although the Skraup reaction62 on 3-amino-pyridine 1-oxide affords 1,5-naphthyridine, the EMME synthesis on this compound affords the l,7-naphthyridine-7-oxide.28 It has been suggested that the 3-aminopyridine 1-oxide is deoxygenated prior to the Skraup reaction so that, in fact, it is 3-aminopyridine that is directly converted to the 1,5-naphthyridine. The EMME cyclization, on the other hand, follows the expected direction of cyclization. 

The Skraup reaction is successful with 3-aminopyridines but fails with 2- and 4-aminopyridines (although it has been successful with 4-aminoquinaldine420). The product of cyclization at the a-position is invariably obtained in the Skraup reaction with 3-aminopyridines. Thus, 3-aminopyridine itself gives 1,5-naphthyridine,421 and various substituted 3-aminopyridines give the corresponding 1,5-naphthyrid-ines. In only one case has a 1,7-naphthyridine been isolated.422,423-423°... 

When 3-aminopyridine A-oxide was subjected to the conditions of the Skraup reaction, 1,5-naphthyridine itself was obtained, presumably due to prior deoxygenation of the starting material followed by cyclization.424... 

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. 

Dipeptides, cyclization to piperazinediones, 57, 189 Diphenylamine, in Skraup reaction, 55, 302 Diphosphabenzvalene,... 

Eisch, J. J., DIuzniewski, T. Mechanism of the Skraup and Doebner-von Miller quinoline syntheses. Cyclization of -unsaturated N-aryliminium salts via 1,3-diazetidinium ion intermediates. J. Org. Chem. 1989, 54, 1269-1274. 

Several examples have been reported of the preparation of 4,7-phenanthrolines from substituted 6-aminoquinolines by the Skraup and related reactions. In this way, 5-methoxy-, 5-chloro-, 3-methyl-6-methoxy-, l-methyl-, and l,2,3,4-tetrahydro-4-methyl-4,7-phenanthrolines have been synthesized while improvements have been made to the synthesis of the 3-methyl derivative. The Skraup reaction has also been applied to quaternary salts of 6-aminoquinolines. For example, 5-chloro-4-methyl-4,7-phenanthrolinium iodide (36) was obtained from the methiodide of 6-acetamido-8-chloroquinoline (35). Cyclizations starting from aminocarbostyrils have also been reported. Thus, 6-amino-1-methylcarbostyril (37) was condensed with paraldehyde in the presence of concentrated hydrochloric acid to afford 3,4-dihydro-4,8-dimethyl-3-oxo-4,7-phenanthroline (38), while under Skraup conditions, with glycerol as condensing agent, 6-amino-4-methylcarbostyril afforded 3,4-dihydro- l-methyl-3-oxo-4,7-phen-... 

General synthetic methods used to prepare various types of naphthyridines include the Skraup, Friedlander and some other name reactions. They include cyclization, cyclocondensation, dimerization reactions, etc. 

Cyclization. Aniline, nitrobenzene, and glycerol react under acid catalysis (Skraup synthesis) to form quinoline [91-22-5] (27). 

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 compound 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. 

The great majority of quinolines and isoquinolines have been prepared by ring construction, instead of transformation of preexisting derivatives. They are obtained by variants of two main routes. The first route involves the cyclization of mono-substituted benzene rings, usually A-substituted anilines (Skraup, Doebner-von Miller, Knorr, Conrad-Limpach), and the second route involves the intramolecular condensation of o-disubstituted benzenes for the formation of the requisite pyridine ring (Friedlander, Pfitzinger reaction, etc.). 

Although the Skraup/Doebner-von Miller reaction represents one of the most common reaction for the synthesis of quinoline core for more than a century, its mechanism is still dedebated. To date, both of the two more popular mechanistic explanations are involving fragmentation-recombination pathways. In the first one, initially the amine reacts with the aldehyde or ketone under acidic conditions to form an imine. Dimerization and Pictet-Spengler type cyclization forms a diazetine core. Protonation and subsequent cyclization-ring cleavage reaction assembles the isoquinoline nucleus. 

Various substituted 3-aminopyridines have been cyclized to 1,5-naphthyri-dines. jhree products, IX-104 to IX-106, have been isolated from the Skraup reaction with 3,5-diaminopyridine Czuba has suggested that 3-amino-l,5-naphthyridine (IX-104) was the logical precursor to IX-105 and... 

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