Diketone equivalents

Aminobenzylamine (1, R1 = H) reacts with benzil in refluxing acetic acid for 24 hours to give the yellow 2,3-diphenyl-5//-l,4-benzodiazepine (2) in 47% yield, but the reaction is not general. However, 2-chloro-2//-azirines function as diketone equivalents, yielding the benzodiazepines 3, when treated with equivalent amounts of the diamines 1 in pyridine at 20 C. Further details were not reported.192... 

The resin-bound 1,3-oxazinium salt 116, obtained by oxidation of 4//-l,3-oxazines 115 with 2,3-dicyano-5,6-dichloro-p-benzoquinone (DDQ), behaved as /3-diketone equivalents and formed pyrazoles 117 through a functionalizing release process on treatment with hydrazines (Scheme 18). When the hydrazines were substituted (R = Me, Ph), the oxazinium salts reacted selectively to afford one regioisomer 117 <2004JC0846>. 

This suggests very little additional destabilization arising from an array of /1-diketones. Equivalently, there is insignificant enthalpic consequence of e- or greater separation on the energetics of ketones, a finding consonant with the energetics of reaction 54. 

The oxidative final step can be neatly avoided by the use of hydroxylamine instead of ammonia, when a final 1,4-loss of water produces the aromatic heterocycle, hi an extension of this concept, the construction of a 1,5-diketone equivalent by tandem Michael addition of an iV,Af-dimethylhydrazone anion to an enone, then acylation, has loss of dimethylamine from nitrogen as the final aromatisation step. ... 

II, 14, 15. Here intramolecular cycloadditions of enol esters, dioxinones and vinylogous esters and amides as /1-diketone equivalents will mainly be discussed. The examples shown belong to the de Mayo reaction in the broader sense as mentioned above. For more details see references 12 and 13. 

Cyclocondensations of hydroxylaminc with P-diketone equivalent three carbon 13-difunctionalized units continue to be an important route for the synthesis of isoxazoles. A regioseicctive method affording directly 3-phenyl-5-substitutcd isoxazoles 26 employed as starting material a-benzotriazolyl-a,P-unsaturated ketones 24. stereoselectively generated in good yields from benzotriazolylacetophenone 23, and the corresponding aldehyde in the presence of piperidine <01JOC6787>. 

The photocycloaddition of tetronates is analogous to that of vinylgous esters as P-diketone equivalents (vide supra). The MEM-protected tetronate 155 is irradiated in the presence of cyclopentene, cyclohexene and cw-cyclooctene, and the resulting adducts 156 are immediately deprotected with titanium tetrachloride to give the hydroxyl lactones 157 as mixture of diastereomers in about 50% yield. These adducts are subjected to cesium carbonate in THF under microwave irradiation to give the ring-opened oxepanediones 158 in 74-84% yield. 

This reaction consists of the condensation of two molecular equivalents of a 1,3 diketone (or a J3-keto-ester) with one equivalent of an aldehyde and one of ammonia. Thus the interaction of ethyl acetoacetate and acetaldehyde and ammonia affords the 1,4-dihy dro-pyridine derivative (1), which when boiled with dilute nitric acid readily undergoes dehydrogenation and aromatisation" to gb e the diethyl ester of collidine (or 2,4,6-trimethyl-pyridine-3,5 dicarboxylic acid (II)). For the initial condensation the solid aldehyde-ammonia can conveniently be used in place of the separate reagents. 

Heating of -keto esters or of 1 3-diketones with an equivalent amount of phenylhydrazine often yields substituted pjrrazolones or pjrrazoles respectively. The latter may serve as derivatives of enols. 

Decant the liquid layer into a 2 5 litre flask, and dissolve the sodium derivative of acetylacetone in 1600 ml. of ice water transfer the solution to the flask. Separate the impiue ethyl acetate layer as rapidly as possible extract the aqueous layer with two 200 ml. portions of ether and discard the ethereal extracts. Treat the aqueous layer with ice-cold dilute sulphimic acid (100 g. of concentrated sulphiu-ic acid and 270 g. of crushed ice) until it is just acid to htmus. Extract the diketone from the solution with four 200 ml. portions of ether. Leave the combined ether extracts standing over 40 g. of anhydrous sodium sulphate (or the equivalent quantity of anhydrous magnesium sulphate) for 24 hours in the ice chest. Decant the ether solution into a 1500 ml. round-bottomed flask, shake the desiccant with 100 ml. of sodium-dried ether and add the extract to the ether solution. Distil off the ether on a water bath. Transfer the residue from a Claisen flask with fractionating side arm (Figs. II, 24, 4r-5) collect the fraction boiling between 130° and 139°. Dry this over 5 g. of anhydrous potassium carbonate, remove the desiccant, and redistil from the same flask. Collect the pure acetji-acetone at 134r-136°. The yield is 85 g. 

Akylsilanes are more reactive than vinylskanes in Friedel-Crafts reactions, as shown in the selective acylation of 2,3-disilylalkenes. The akylsilanes, a-skyloxyakyltrialkylsilanes, have been used as enolate equivalents in the preparation of 1,4-diketones (178). The mild reaction conditions required for these reactions tolerate many other functional groups, providing valuable synthetic routes. 

The course of the acid catalyzed dehydration of 1,4-diketones to furans, known as the Paal-Knorr method (1884CB2756), entails the formal addition of the enol of one carbonyl group to the other carbonyl. Examples which illustrate some of the routes used to make the necessary 1,4-diketones are shown in Scheme 13. Few examples are known of the preparation of the other heterocycles by this general approach using isolated intermediates, although some of the ring closures discussed in Section 3.03.3.1.1 are mechanistically equivalent. One example of the preparation of a hydroxypyrrole is included in Scheme 13 <59AC(R)2075). 

Selective hydroxylation with osmium tetroxide (one equivalent in ether-pyridine at 0 ) converts (27) to a solid mixture of stereoisomeric diols (28a) which can be converted to the corresponding secondary monotoluene-sulfonate (28b) by treatment with /7-toluenesulfonyl chloride in methylene dichloride-pyridine and then by pinacol rearrangement in tetrahydrofuran-lithium perchlorate -calcium carbonate into the unconjugated cyclohepte-none (29) in 41-48 % over-all yield from (27). Mild acid-catalyzed hydrolysis of the ketal-ketone (29) removes the ketal more drastic conditions by heating at 100° in 2 hydrochloric acid for 24 hr gives the conjugated diketone (30). 

Compound A has the formula C K)Hi6. On catalytic hydrogenation over palladium, it reacts with only 1 molar equivalent of H2. Compound A also undergoes reachun with ozone, followed by zinc treatment, to yield a symmetrical diketone, B (CjoH C )-... 

The reaction of crotonaldehyde and methyl vinyl ketone with thiophenol in the presence of anhydrous hydrogen chloride effects conjugate addition of thiophenol as well as acetal formation. The resulting j3-phenylthio thioacetals are converted to 1-phenylthio-and 2-phenylthio-1,3-butadiene, respectively, upon reaction with 2 equivalents of copper(I) trifluoromethanesulfonate (Table I). The copper(I)-induced heterolysis of carbon-sulfur bonds has also been used to effect pinacol-type rearrangements of bis(phenyl-thio)methyl carbinols. Thus the addition of bis(phenyl-thio)methyllithium to ketones and aldehydes followed by copper(I)-induced rearrangement results in a one-carbon ring expansion or chain-insertion transformation which gives a-phenylthio ketones. Monothioketals of 1,4-diketones are cyclized to 2,5-disubstituted furans by the action of copper(I) trifluoromethanesulfonate. ... 

This is a l,4 diketone and disconnection of the central bond separates the two rings. We require a specific enol equivalent lor (4) - they used activated ketone (6) - and a reagent for unnatural synthon (5) -they used a-chloroketone (7). 

The cyclobutane ring was then cleaved by hydrolysis of the enamine and ring opening of the resulting (3-diketone. The relative configuration of the chiral centers is unaffected by subsequent transformations, so the overall sequence is stereoselective. Another key step in this synthesis is Step D, which corresponds to the transformation 10-IIa => 10-la in the retrosynthesis. A protected cyanohydrin was used as a nucleophilic acyl anion equivalent in this step. The final steps of the synthesis in Scheme 13.11 employed the C(2) carbonyl group to introduce the carboxy group and the C(l)-C(2) double bond. 

The reductive animation of 1,4-diketones in the presence of an equivalent of ammonia opens an avenue to 2,4-disubstituted pyrrolidines. Since Stetter s thiazolium salt chemistry allows the preparation of 1,4-diketones from a, 3 unsaturated enones and aldehydes, a large variety of pyrrolidines may be prepared. Two examples of such syntheses have recently been published by the T. H. Jones group (Scheme 27) (132, 170). 

An intramolecular aza-Wittig reaction of 1,3-diketones (134) and hydra-zinobis(iminophosphoranes) (133) gives pyrazole (135) on elimination of two equivalents of triphenylphosphane oxide, as shown in Scheme 53 (75CB623). 

Cyclic 1,3-diketones can also participate in this MCR. Thus, utilization of two equivalents of 1,3-cyclohexanedione or dimedone instead of (3-ketoesters led to hydrogenated acridine derivatives. However, when only one equivalent of cyclic 1,3-dicarbonyl is used in combination with one equivalent of (3-ketoester, unsym-metric 1,4-DHPs may be obtained (Scheme 3). For example, this reaction was applied to the synthesis of ZD0947, a potassium chaimel opener [20]. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

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