Anthranils, reduction

Nitroketene dithioacetal reacts with anthranilic esters to afford quinolone derivatives, which are converted into diazepinones by reductive cyclization. The review by Kolb covers synthetic application of nitroketene dithioacetal for heterocyclic compounds (see Scheme 10.26).145... 

Reduction of anthranilic acid (5) to o-aminobenzylalcohol (6). The expensive LiAlH4 can be used as reducing agent for valuable fine chemicals, e.g. pharmaceuticals [31]. 

Scheme 70 Cathodic reduction of nitrocarhonyl compounds to anthranilic derivatives. Ph...

Reduction of aromatic carboxylic acids to alcohols can be achieved by hydrides and complex hydrides, e.g. lithium aluminum hydride 968], sodium aluminum hydride [55] and sodium bis 2-methoxyethoxy)aluminum hydride [544, 969, 970], and with borane (diborane) [976] prepared from sodium borohydride and boron trifluoride etherate [971, 977] or aluminum chloride [755, 975] in diglyme. Sodium borohydride alone does not reduce free carboxylic acids. Anthranilic acid was reduced to the corresponding alcohol by electroreduction in sulfuric acid at 20-30° in 69-78% yield [979],... 

The above procedure is essentially that of Ullmann and Bleier.2 2-Aminobenzophenone has also been prepared by reduction of 2-nitrobenzophenone,3 by the Hofmann reaction of the amide of o-benzoylbenzoic acid with sodium hypobromite,4 by the action of an excess of benzoyl chloride on aniline at 220°,6 and by hydrolysis of the acetyl derivative which is obtained by the action of phenylmagnesium bromide on 2-methyl-3,l,4-benzoxaz-4-one (from anthranilic acid and acetic anhydride).6 Various methods for the preparation of 2-aminobenzophenones have been summarized critically by Simpson, Atkinson, Schofield, and Stephenson.7... 

The discovery that the cyclization of one of the sulfonamide groups and the adjacent amine in classic monocyclic diuretics leads to an increase in potency is discussed in the next section. A similar increase in potency is also observed in the anthranilic acid based diuretics. Thus the fusion of anthranilic acid (87-1), which may show diuretic activity in its own right, with propionamide leads to the ring closure and formation of (87-2). Reduction of the unsaturation in the heterocyclic ring then affords the diuretic quinethazone (87-3) [97]. 

Condensations of anthranilic acid derivatives lead to the 6,12-diamino- and 6,12-dioxo-dibenzodiazocines, and the dichloro compound (279) is available from the latter (54JCS3429). Reduction of (279) via the dihydrazino compound was used to prepare the parent dibenzo[6,/][l,5]diazocine (280) (67CC1077). The NMR value (5 8.53 p.p.m.) of the 6(12) proton is indicative of the diazocine structure, presumably in a tub form, rather than the valence isomeric dibenzodiazapentalene (281). 

Diphenic acid has been prepared by the reduction of diazotized anthranilic acid with cuprous ion,5 Ullman coupling of potassium... 

An alternative but equally cumbersome synthesis utilizes the more accessible bis(2-carboxyphenyl)disulfide, easily prepared from anthranilic acid. Byconversion to the corresponding anilide, then by successive reduction with zinc dust and acetic acid (yielding 2-mercaptobenzoyl anilide) and lithium aluminum hydride, the aldehyde (6) is obtained in fair overall yield.Although... 

Examples of this ring system (263) were prepared by cyclocondensation of anthranilic acid with the 1,3-thiazole derivatives 262 (82MI1 83AP394). Reductive cyclization of the 4-ethylamino-3-(2-nitrobenzyl)thiazolidines (264) was affected by heating with iron filings and acetic acid to give 4//-3,3a-dihydrothiazolo[4,3- >]quinazoline (265) (87JHC107). 

On the other hand, the two heterocyclic rings of the title compounds (587) were formed upon synthesis from anthranilic acids and 2-nitrophenoxyacetyl chloride (585) followed by reduction and cyclization (84J1C721). 

Reduction of the benzil (170) and the anthranil (171) (original structure assigned incorrectly see Section III,A,1) has been reported to give the corresponding indolones (158 R = 2-aminophenyl, 2-amino-... 

It was previously mentioned1 that cinnoline and 3-substituted cinnolines (94) could be prepared from the condensation products (95) between an o-nitrobenzaldehyde and a nitroalkane by electrochemical reduction. The reaction has been further studied,138 and it was noticed that when the reduction was carried out stepwise, anthranils (96) were formed, especially at elevated temperatures. The final ring closure was catalyzed by traces of oxygen, whereas too much oxygen produced the cinnoline JV-oxide (97) the ring closure was believed to be a radical chain reaction where the formation of the aromatic cinnoline was part of the driving force [Eq. (76)]. 

The reduction of oxaziridines, anthranils, and benzoxazines was discussed in Part I. 

The moist cake is mixed with 27 g. of zinc dust and 300 cc. of glacial acetic acid in a x-1. round-bottom flask, and the mixture is refluxed vigorously for about four hours (Note 4). When the reduction is complete, the mixture is cooled and filtered with suction. The filter cake is washed once with water and then transferred to a i-l. beaker. The cake is suspended in 200 cc. of water and the suspension is heated to boiling. The hot solution is made strongly alkaline by the addition of about 40 cc. of 33 per cent aqueous sodium hydroxide solution. The alkaline solution is boiled for about twenty minutes to insure complete extraction of the product from the filter cake, filtered from the insoluble material (Note 5) and the thiosalicylic acid is then precipitated by the addition of sufficient concentrated hydrochloric acid to make the solution acid to Congo red paper. The product is filtered with suction, washed once with water and dried in an oven at 100-110°. The yield of a product which melts at 162-163° is 110-130 g. (71-85 per cent of the theoretical amount based on the anthranilic add). 

Of the several methods described for the production of thiosalicylic acid, only the following are of preparative interest heating of o-halogenated benzoic acids with an alkaline hydrosulfide at i50-200° in the presence of copper or copper salts,1 5 or by substitution of sodium sulfide at 200° 2 by reduction of dithiosalicylic add with glucose,3 or metals 4,5 in alkaline solution. The dithiosalicylic add is prepared by treating diazo-tized anthranilic acid with sodium disulfide in alkaline solution.4... 

The stirrers are started, the current (no volt D.C.) turned on, and the resistance so adjusted that the ammeter records io-i 2 amperes. The temperature of the solution in the cells is maintained at 20-30° by surrounding them with a bath of cool water (Note 4). The reduction is complete after 60-70 ampere-hours. This fact is indicated by the increased evolution of hydrogen and the complete solution of the anthranilic acid. 

The anthranilic acid derivative 4, prepared from isatoic anhydride and L-proline, on Birch reduction and alkylation affords pure 5, which is hydrolyzed by acid to the aminolactone 6, with the absolute configuration opposite to that of 3. 

Reductive removal of the Nj-oxide oxygen atom of the triazinium betaines (76) can be readily accomplished either by heating the betaine N-oxides in ethanol, or, more efficiently, by treatment with stannous chloride. Further reduction of the resultant betaines (77) with tin/hydrochloric acid results in ring cleavage and formation of arylhydrazides or anthranilic acid.87... 

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