Cyclisation of 2-amino-or 2-acetamido-2'-methoxybenzophenones occurred in the presence of sodium hydride to give 9-acridones. This is a method of wide applicability for the synthesis of substituted acridones. A mechanism Department of Chemistry, University of Aberdeen AB9 2U E, Scotland for the cyclisation is discussed.IN connection with studies on the synthesis of natural products under biomimetic conditions we became interested in the synthesis of naturally occurring 9-acridones, a group of alkaloids found only in the plant family Rutaceae.2 The similarity in ring number, ring size, and substituent pattern of the acridone alkaloids to xanthones 3 suggested that oxidative coupling of 2-aminobenzophenones might give the 9-acridone system in an analogous manner to that reported for the conversion of 2-hydroxybenzophenones into ~a n t h o n e s . ~ The poor yields which were obtained for this type of cyclisation 5 led us to investigate alternative methods for the ring closure of 2-aminobenzophenones. In our earlier oxidative experiments 2'-amino-2,3,4-trimethoxybenzophenone (1) cyclised to 3,4-dimethoxy-9-acridone (2) in 7% yield, whereas reduction of 2,4,6-trihydroxy-2'nitrobenzophenone (3) gave 1,3-dihydroxy-9-acridone (6; R = H , R 1 = R 2 = OH), quantitatively, presumably via the amine Our interpretation of these cyclisations involved intramolecular displacement of the adjacent ortho-methoxy-group by nucleophilic nitrogen, or, in the case of the amine (4), a Schiff-base-type condensation with the keto-form of the phloroglucinol ring (5). To establish the utility of this type of cyclisation a
Die Reformatsky-Reaktion zwischen Cyclohexenoxyd und Bromessigester wurde erneut untersucht und die Ausbeute an P-Hydroxy-P-cyclopentyl-propionsaure-athylester (I) verbessert. Fur die Ringverengung wird ein Reaktionsmechanismus vorgeschlagen. I spaltet mit Phosphoroxychlorid in Pyridin Wasser ab zum 6-Cyclopentyl-acrylsaureester, der bei der Michael-Addition mit Acetessigester 4-Carbathoxy-5-cyclopentyl-cyclohexandion-(l.3) ergibt. 5-SubstituierteResorcine werden bequem iiber die entsprechenden 5-substituierten Dihydroresorcine (Cyclohexandione-( 1.3)) erhalten, die im allgemeinen entweder durch Michael-Addition eines a-Diesters an ein a.P-ungesattigtes Keton') oder eines P-Ketoesters an einen =.a-ungesattigten Ester % 3 ) und anschlieBende Dieckmann-Cyclisierung der Addukte hergestellt werden.
of Aberdeen. Scotland AB9 2UECyclisations of 2'-amino-, 2'-acetylamino-. or 2'-methylamino-2-methoxybenzophsnones occur in thz presence of sodium hydride in dimethyl sulphoxide to give acridone alkaloids. This cyclisation has relevance to the biosynthesis of these alkaloids. An alternative cyclisation can occur, giving 4-arylquinolines or 4-arylquinolones.THE acridone alkaloids compiise ca. 35 members pro-mild reduction of 2,4,6-trihydroxy-2'-nitrobenzophenone duced only by the Rutaceae family of higher plants. (5) with zinc dust in ethanol to give solely 1,3-dihydroxy-Their mode of biosynthesis was postulated by Sir Robert 9-acridone (4), presumably via the 2-aminobenzo-R~b i n s o n ,~ who suggested that anthranilic acid con-phenone (6), the keto tautomer (7) of which could underdensed with acetic acid to give the tricyclic acridone go a Schiff's base type condensation.* Methylation of system.one or more of the hydroxy-functions in (5) prevented the early observation that 2-aminobenzaldehyde (1) cyclisation concomitant with reduction. Cyclisation condensed easily with phloroglucinol (2) t o give 1,3-of 2-methoxyaminoor 2-methoxyacetamido-benzodihydroxyacridine (3). Compound (3) can be con-phenones can be achieved at room temperature through verted through oxidation into 1,3-dihydroxy-9-acridone the use of sodium hydride in dimethyl sulphoxide (4) (Scheme 1).whereby 2'-acetamido-2-methoxybenzophenone and related compounds yield g-acridone~.~ Application of this This postulate may have been prompted byIn modern terms this sequence could involve the I reaction of an activated anthranilic acid (as its co-type of cyclisation has now enabled the synthesis of a enzyme) with a triketide to produce an aminobenzo-number of acridone alkaloids. phenone which on cyclisation produces a dihydroxy-Thamnosma montana lo, If. contains both acridone (8 ;9-acridone. In support of this hypothesis, both an-R1 = R2 = R3 = H) and its 10-methyl derivative (8;thranilic and N-methylanthranilic acid have been shown R1 = R2 = H, R3 = Me); the synthesis of acridone experimentally t o be precursors of the acridone alkaloids from 2'-amino-2-niethoxybenzophenone proceeds in 47% in Acronychia baueri and in Glycosmis arborea,' and the yield.g FOI N-methyl-9-acridone (8; R1 = R2 = H, cyclisation step has been achieved quantitatively by Stirling, December 17th, 1974. R.A. Watt, Chem. and Ind., 1,975, 744.
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