Enamines from 1,3-diones

H-l,4-Benzodiazepine-3,5(lH,4H)-diones from anthranilamides Enamines from acetylene derivs. 

NMR data have been recorded for numerous compounds with exocyclic enamine double bonds (79JHC1335). Examples of exocyclic imine double bonds are found in furan-2,3-dione 3-oxime and a related 5-oxime the vie proton coupling constant in the former is 5 Hz and so larger than expected, perhaps because of electron release from the hydroxy oxygen atom (72JCS(P1)2527). 

Sequential oxidation and hydrolysis of the enamine derived from the reaction between 4-methylpent-3-en-2-one and pyrrolidinium pyrrolidinedithiocarbamate affords 6,6-dimethylthiopyran-2,4-dione (Scheme 222) <2003RJ0235>. 

Several important examples of ring transformation are referred to elsewhere in this chapter. These include the extrusion of nitrogen from tetraazaphenanthridines and S02 from dipyridothiophene dioxides to yield diazabiphenylenes (Section 7.23.8.1.1), the benzylic-type ring contraction of phen-anthridine diones to give diazafluorenones (Section 7.23.8.2.1), and the extrusion of nitrogen from the Diels-Alder adducts formed from enamines and pyridazo[4,5-d]pyridazines (Section 7.23.8.3.2). 

The stereochemical course of the annulation process has been determined by reaction of acryloyl chloride with the morpholine enamine of 4-f-butyl-2-methylcyclohexanone. The bicyclic dione was obtained in 76% yield as a 4 1 mixture of two isomers (Scheme 150). X-ray analysis of the main isomer showed that reaction had occurred by axial attack from the same side as the C-2 methyl group. In order for regeneration of the enamine system to occur under conditions of stereoelectronic control, the intermediate ketene-iminium salt presumably adopts a twist conformation. Cyclization of the ketene... 

Similar a,a -annulations were achieved from reaction of oc,/ -unsaturated acid chlorides with cyclic ketone enamines which afforded bicyclo[3.3.1]nonane-2,9-diones41,60 65 or bicyclo[4.3.1]decanones66. In this reaction, 7V-acylation of the enamine 109 occurs as the first step giving 110, followed by a [3,3] sigmatropic rearrangement to a ketene intermediate (111). Ketene 111 subsequently cyclized via 112 to a bicyclic immonium salt (113) which after hydrolysis gave the corresponding dione 11463. If there is an axially oriented electrophilic substituent at C-4 of the enamine (for example, R = COPh) the enolate anion 115 may cyclize to an adamantane derivative 116 (equation 20). 

Various accounts report the synthesis of heterocyclic androstane derivatives. 17)8-Acetoxy-4-oxa-androst-2-ene (215) has been prepared in three steps from the hemiacetal (214). Since various 4-aza-steroids exhibit antimicrobial activity, several new 4-aza-androstanes have been prepared. The reduction of ring a enamine lactams, such as 4-aza-androst-5-ene-3,17-dione (216a), under conditions of the Leuckart-Wallace reductive amination, provided 17/ -(iV-methyl-... 

The enantioselective total synthesis of 1 commences with the formation of the enamine of morpholine and cyclohexane-1,2-dione (6), which actually exists almost entirely in the enolic form. Constant removal of water shifts the equilibrium to the side of the product. 2-Siloxyaniline 7, " which can be easily prepared from 2-aminophe-nol, reacts with the morpholine enamine in an acid-catalyzed transamination to give enamine 8. 

Heterocyclic Synthesis. - The reactions of phosphorus ylides with phenan-threne-9,10-quinone (113) have been used to prepare phenanthrene [9,10-x]-fused compounds with four, five, and six membered heterocyclic rings. (E)-4-carbethoxymethylene-l,2,3,4-tetrahydro-2-quinolones 114 have been obtained from the stereoselective reaction of 3-hydroxy-1,2,3,4-tetrahydroquinoline-2,4-diones and ethyl(triphenylphosphoranylidene)acetate. A -trifluoroacetylanilines 115 react with Ph3P=C02Et producing enamine derivatives 116 as a mixture of (E)- and (Z)-isomers. Enamines 116 are useful precursors for the synthesis of indoles and quinolones. 

Reaction of DBD with 1-A-morpholino- or 1-iV-piperidinocyclohexene gives the 1,3,4-oxadiazine (170), hydrolysis of which gives the monosubstitution product (171) or cyclohexane-1,2-dione (172) (Scheme 179). The analogous adduct to 170 from the pyrrolidine enamine could only be isolated by working with an excess of the enamine. Otherwise, further reaction occurred to give the products of 2,6-disubstitution (173 and 174) on hydrolysis however, the main product was the oxadiazine (175) derived by 2,2-disubstitution and isolated in 50-80% yield Such is the reactivity of DBD that simply heating with cyclohexanone gives 171 . With 2-methylcyclohexanone enamines the normal product 176 of 2,6-disubstitution is, however, formed (Scheme 180). 

Hickmott and coworkers have shown that the reaction of crotonoyl chloride with the pyrrolidino enamine of 4-benzoyl-4-methylcyclohexanone 117 gives a mixture of the three adamantane dione derivatives 118, 119 and 120 (equation 21). Surprisingly the main product obtained was the sterically most crowded 119, with the 6-phenyl and 9-methyl in mutually 1,3-diaxial position. This could be explained if the [3,3] sigmatropic rearrangement of 121 to 122 occurs via a boat transition state conformation from the same face of the cyclohexene moiety as the benzoyl group (equation 22). Although a boat conformation (125 126) normally is preferred for this type of rearrangement,... 

Enamines derived from cyclohexane-1,2-dione react readily with azodicarboxylic esters but the enamine products are very resistant to hydrolysis.249... 

Chromones.- Enamines have previously been converted into chromones and in another approach, the enamine (104) reacted with thionyl chloride to give the chromone (105 n=2) in moderate yield. The sulphinic acid was readily oxidized to the sulphonic acid (105 n=3) by 3-chloroperoxybenzoic acid.110 A convenient synthesis has been described of 2-methylchromene-4-thione in 57% yield from 4-(2-hydroxyphenyl)butane-1,3-dione.111 The t-amino-methylchromones (106) have been synthesized and shown to be central nervous system depressants. A new synthesis of 2-substituted chromones (including flavones) uses 2-acetoxyphenacyl bromide (107) which is converted into its phosphorane (108). Heating this with an alkanoyl or aroyl chloride or anhydride in pyridine gave good yields of the chromone (109).113... 

Thiochromone reacts with 2-piperidinobuta-1,3-diene to give a single diastereoisomeric thioxanthene-3,9-dione. Reaction of 4-silyloxy-l-benzothiopyrylium triflate, derived from thiochromone, with enamines involves regioselective 1,2-addition leading to 2-substituted thiochromanones <97JCS(P1)2807>. 

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