Modified Skraup reaction

The Skraup reaction, in all of its modifications, has proved to be unsuccessful as a method of obtaining anthyridines. Thus when 2-amino-l,8-naphthyridine (112 R = H) and 3-amino-l,5-naphthyridine (127) are subjected to the modified Skraup reaction using sulfo-mix the products are either triazaphenanthrenes or naphthyridine by-products (75MI21103). Similarly 3,5-diaminopyridine (126) gives 1,5,9-triazaphenanthrene (129) as the only tricyclic product (see Section 2.11.5.3) (67MI21102). 

Amino-2( 1 //)-pyridinone (37) underwent a modified Skraup reaction to give l,7-naphthyridin-8(7//)-one (38) (see original for considerable detail (20%).1048... 

Theoclitou, M.-E., Robinson, L. A. Novel facile synthesis of 2,2,4-substituted-1,2-dihydroquinolines via a modified Skraup reaction. 

In recent years, a modified Skraup reaction (20% oleum, nitrobenzene, FeS04 7H20, H3BO4) has been used to synthesize fused naphthyridines. Thus, 3-aminobenzo[/z]quino-line 7 was converted in this way into naphtho[2,l-6]-l,5-naphthyridine 8(1989H2109). 

Also the synthesis of 6,8-difluoro-7-chloroqumoline 10 has been perfonned in a high yield by means of the modified Skraup reaction from 3-chloro-2,4-difluoro-aniline 9 [5]. Similarly 5-fluoro-6-methoxy-8-nitroquinoline 12 was obtained from 3-fluoro-4-methoxy-6-nitroaniline (Scheme 4) 11 [9]. 

In view of the high reactivity and sensitivity to oxidation of o-phenylone-diamine, the normal experimental conditions of the Skraup reaction are modified the condensation is carried out hi the presence of glycerol, arsenic acid solution and dilute sulphuric acid. 

Dijbner-von Miller Synthesis. A much less violent synthetic pathway, the Dn bner-von Miller, uses hydrochloric acid or 2inc chloride as the catalyst (43). As in the modified Skraup, a,P-unsaturated aldehydes and ketones make the dehydration of glycerol uimecessary, and allow a wider variety of substitution patterns. No added oxidant is required. With excess aniline the reaction proceeds as follows ... 

Modified Skraup/Doebner-von Miller reaction — Dihydroquinolines... 

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. 

As in the case of the 1,5-naphthyridines, the Skraup reaction can be modified to prepare various methyl derivatives. The use of crotonalde-hyde, methacrolein, and methyl vinyl ketone affords the 2-methyl-,40 3-methyl-,41 and 4-methyl-l,6-naphthyridines,40 respectively. 

A modified Skraup method, namely, the reaction of 4-aminoisoquinoline with methyl vinyl ketone in the presence of As205 and concentrated sulfuric acid, was used to prepare 4-methylbenzo[c]-l,5-naphthyridine (1994AJC2129). 

This reaction was initially reported by Doebner and von Miller in 1881 as a modification of the original Skraup Reaction, and it was subsequently modified by Beyer in 1886 It is an acidic condensation between primary aromatic amines (e.g., anilines) and Q ,j8-unsaturated carbonyl compounds (mostly o ,y3-unsaturated aldehydes) to give 2,3-disubstituted quinolines. Therefore, this reaction is generally known as the Doebner-Miller reaction, or Doebner-Miller synthesis." In addition, this reaction is also referred to as the Doebner-von Miller quinoline synthesis, Skraup-Doebner-von Miller reaction, Skraup-Doebner-von Miller quinoline synthesis, Doebner-Miller condensation, and Doebner-Miller Quinaldine Synthesis. For comparison, the modification from Beyer, known as the Beyer method for quinoline, is an acidic condensation between anilines and Q ,j8-unsaturated carbonyl compounds generated in situ from aldehyde or aldehyde and methyl ketone to afford 2,4-disubstituted quinolines." The optimal condition of this reaction is to heat the mixture of aniline/aldehyde (1 2) at 100°C for 6 h with hydrochloric acid and zinc chloride in addition, an oxidizing reagent is also needed in this reaction, such as nitrobenzene. However, it has been reported that A -alkylanilines are also formed in this reaction. The nature and... 

Quinolines 3 can be obtained from reaction of orr/zo-aminobenzaldehydes or o-aminoarylketones 1 with a-methylene carbonyl compounds.Various modified procedures are known a related reaction is the Skraup quinoline synthesis. 

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