Aldol condensation with diketones

The 1,2-diketone undergoes an aldol condensation with the a-CH-acidic ester furnishing the intermediate 12 which is cyclized by N2H4, similar to the formation of 9. In another combination of this three-component system, the monohydrazones of the 1,2-dicarbonyl compounds 13 or hydrazides with a reactive a-CH2 group 14 can be employed for the pyridazin-3(2//)-one synthesis. 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Acetoxy-l,7-octadiene (40) is converted into l,7-octadien-3-one (124) by hydrolysis and oxidation. The most useful application of this enone 124 is bisannulation to form two fused six-membered ketonesfl 13], The Michael addition of 2-methyl-1,3-cyclopentanedione (125) to 124 and asymmetric aldol condensation using (5)-phenylalanine afford the optically active diketone 126. The terminal alkene is oxidi2ed with PdCl2-CuCl2-02 to give the methyl ketone 127 in 77% yield. Finally, reduction of the double bond and aldol condensation produce the important intermediate 128 of steroid synthesis in optically pure form[114]. 

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

Problem 23.9 > Treatment of a 1,3-diketone such as 2,4-pentanedione with base does not give an aldol condensation product. Explain. 

Intramolecular Claisen condensations can be carried out with diesters, just as intramolecular aldol condensations can be carried out with diketones (Section 23.6). Called the Dieckmann cyclization, the reaction works best on 1.6-diesters and 1,7-diesters. Intramolecular Claisen cyclization of a 1,6-diester gives a five-membered cyclic /3-keto ester, and cyclization of a 1,7-diester gives a six-membered cyclic /3-keto ester. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

Intramolecular aldol condensation.1 This base can be effective for intramolecular aldol condensation of extremely hindered diketones that resist cyclization with the usual bases. 

In the Clemmensen reduction of 1,4-cyclohexanedione, all the products isolated from the reduction of 2,5-hexanedione were found in addition to 2,5-hexanedione (20%) and 2-methylcyclopentanone (6%). The presence of the two latter compounds reveals the mechanism of the reduction. In the first stage the carbon-carbon bond between carbons 2 and 3 ruptured, and the product of the cleavage, 2,5-hexanedione, partly underwent aldol condensation, partly its own further reduction [927], The cleavage of the carbon-carbon bond in 1,4-diketones was noticed during the treatment of 1,2-diben-zoylcyclobutane which afforded, on short refluxing with zinc dust and zinc chloride in ethanol, an 80% yield of 1,6-diphenyl-1,6-hexanedione [75<5]. 

Conseqnently, the magnesinm chelate 71 can also react as a nucleophilic donor in aldol reactions. In the chemistry involving magnesium chelates, these two aspects model their mode of action as nucleophilic partners in aldol condensations. This is exemplified in aldol condensations of y-diketones . Thus, sodium hydroxyde catalyzed cyclization of diketone 73 to give a mixtnre of 3,5,5-trimethyl-cyclopent-2-enone 74 and 3,4,4-trimethyl-cyclopent-2-enone 75 in a 2.2/1 isomeric ratio (equation 100). When treated with magnesinm methanolate, the insertion of a a-methoxy carbonyl group as control element, as in 76, allows the formation of a chelated magnesium enolate 77, and the major prodnct is now mainly the aldol 78. This latter treated with aqueous NaOH provides the trimethylcyclopent-2-enones 74 and 75 in a 1/49 ratio. 

Isoniazide, the hydrazide of pyridine-4-carboxylic acid, is still, well over half a century after its discovery, one of the mainstays for the treatment of tuberculosis. Widespread use led to the serendipitous discovery of its antidepressant activity. This latter activity is retained when pyridine is replaced by isoxazole. The requisite ester (45-4) is obtained in a single step by condensation of the diketo ester (45-1), obtained by aldol condensation of acetone with diethyl oxalate, with hydroxylamine. One explanation of the outcome of the reaction assumes the hrst step to consist of conjugate addition-elimination of hydroxylamine to the enolized diketone to afford (45-2) an intermediate probably in equilibrium with the enol form (45-3). An ester-amide interchange of the product with hydrazine then affords the corresponding hydrazide (45-5) reductive alkylation with benzaldehyde completes the synthesis of isocarboxazid (45-6) [47]. 

Step, aldol condensation to form the benzylidene derivative (12-3). Conjugate addition of a second mole of acetoacetate would then afford the 1,5-diketone (12-4). Reaction of the carbonyl groups with ammonia will lead to the formation of the dihydropyridine ring. Alternatively, acetoacetate may go on to form the imine (12-5) reaction of this with the aldol product (13-3) will give the same dihydropyridine. The product, nifedipine (12-6) [13], has been used extensively for the treatment of angina and hypertension. 

Aldol reactions are often used to close five- and six-membered rings. Because of the favorable entropy (p. 211), such ring closures generally take place with ease, even where a ketone condenses with a ketone. An important example is the Robinson annulation reaction which has often been used in the synthesis of steroids and terpenes. In this reaction a cyclic ketone is converted to another cyclic ketone, with one additional six-membered ring containing a double bond. The substrate is treated with methyl vinyl ketone (or a simple derivative of methyl vinyl ketone) and a base.551 The enolate ion of the substrate adds to the methyl vinyl ketone in a Michael reaction (5-17) to give a diketone that undergoes or... 

An efficient general synthesis of a variety of 3(2i/)-furanones has been developed. Aldol condensation of aldehydes with the enolate derived from 3-methyl-3-(trimethylsiloxy)-2-butanone (183) followed by Collins oxidation afforded 1,3-diketones (184). Acid catalyzed cyclodehydration leads to the corresponding 3(2//)-furanones (185) (Scheme 43)... 

When an a-chloroaldehyde or an a-chloroketone is condensed with a /3-ketoester, in the presence of aqueous base, a furan is produced bearing an ester substituent at the /3-position. It is thought that the reaction is of the aldol type intermediate dihydrofurans (256) have been isolated in certain cases (Scheme 70) (74BSF519). The condensation of ethyl bromopyru-vate and sodium oxaloacetate follows a similar mechanism (54JOC1671). The one-pot synthesis of 2,4,5-trisubstituted furans (257) from ketones and ethyl 3,4-dibromo-2-butenoate is a useful addition to a well known route (80S52). The analogous reaction of cyclic /3-diketones, i.e. cyclohexane-1,3-dione and 5,5-dimethylcyclohexane-l,3-dione, results in the formation of the condensed furans (258) and (259). These reactions are preformed either in ethanol with sodium ethoxide or in DMF with potassium carbonate. 

The simplest approach which can be envisaged to 4/f-pyrans involves the ring closure of 1,5-diketones. However, such molecules are frequently able to undergo a facile intramolecular aldol condensation leading to cyclohexenones, which competes successfully with cyclization to the pyran. 

Wenkert and coworkers have reported several applications of this chemistry to the synthesis of alkaloids and terpenes.110 A recent example, leading to die methyl ether of tetrahydropyrethrolone (97), is illustrated in Scheme 19.116 Reaction of 1,2-dimethoxypropene with 1 -diazo-2-heptanone (98) resulted in the formation of the labile cyclopropane (99), which was directly converted to the 1,4-diketone (100). Base-induced aldol condensation of (100) readily formed (97). Stereoselective syntheses of prostaglandins1 17 and dicranenone A118 have also been developed using acid-induced ring-opening reactions. 

Di- and polysubstituted pyrrolizines are uncommon. The only pyrrolizine isolated from the intramolecular aldol condensation of 2-acetyl-l-(butan-3-on-l-yl)pyrrole was the 6,7-disubstituted compound 223.122 A small amount of the 5,6-disubstituted pyrrolizine (145d) was obtained when the 2-formylpyr-ryl anion was condensed with l,2-di(phenylsulfonyl)ethene.90 By contrast with the production of the single isomer (223), the homologous diketone 224... 

In the Weiss reaction (Scheme 4), an 7-dicarbonyl compound (38) condenses with two molecules of dimethyl 3-oxoglutarate (39 E = CC Me) to give a c w-bicyclo [3.3.0] oct-ane-3,7-dione tetraester (40) the one-pot reaction produces considerable complexity, with the sequential formation of four C—C bonds. Simple acid treatment removes the carbomethoxy groups, if deshed. While die reaction involves aldol and Michael sequences, die intermediacy of a cyclopentenone [4-hydroxycyclopent-2-enone (41)] has up to now been unproven. A series of such 1 1 adducts has now been reported for a variety of diketones, together with evidence diat diey are indeed intermediates en route to the bicyclo system.62 Electronic and steric effects on the reaction are also discussed in detail. 

The polymer was imprinted with dibenzoyl-methane (42), a 1,3-diketone able to be held in place by formation of a complex with the Co(II) ion, and structurally similar to the product of the cross-aldol condensation. A schematic representation of this approach is given in Scheme 7. 

On the basis of a catalytic system previously developed by the same group, Nicholls and collaborators [51] reported the preparation of an imprinted polymer for enantioselective formation of a C-C bond with properties of a metallo-enzyme aldolase type II. Polymers were imprinted using the two enantiomers of a 1,3-diketone, the (l.S, 35,45)-(75), and the corresponding (l/ ,3/ ,4/ )-(75), together with two 4-vinyl-pyridine held in place by a Co(II). The cross-aldol condensation... 

Hydrogenation of 1,4- and 1,5-diketones over platinum metals may be accompanied by cyclization to give tetrahydrofurans and terahydropyrans, respectively.133,134 The hydrogenation of 2,6-heptanedione over Pt-C at 200°C in cyclohexane gave 40% of 2,6-dimethyltetrahydropyran, together with 43% of 3-methylcyclohexanone and 15% of 3-methylcyclohexanol, which resulted by an intramolecular aldol condensation and subsequent hydrogenation.134... 

Pentanedione is in equilibrium with two enolate ions after treatment with base. Enolate A is stable and unreactive, while enolate B can undergo internal aldol condensation to form a cyclobutenone product. But, because the aldol reaction is reversible and the cyclobutenone product is highly strained, there is little of this product present when equilibrium is reached. At equilibrium, only the stable, diketone enolate ion A is present. 

When you need to synthesize a p-hydroxy ketone or aldehyde or an a,p-unsaturated ketone or aldehyde, use an aldol reaction. When you need to synthesize a p-diketone or p-keto ester, use a Claisen reaction. When you need to synthesize a 1,5-dicarbonyl compound, use a Michael reaction. The Robinson annulation is used to synthesize polycyclic molecules by a combination of a Michael reaction with an aldol condensation. 

Aldol condensation reactions are catalyzed by amines and the active sites of many aldolases contain an essential lysine residue. Using a strategy of reactive immunization with a 1,3-diketone (18 in Fig. 5.8), Wagner et al. were able to generate antibodies with aldolase activity. These were shown to possess a highly reactive lysine residue in... 

---