Intramolecular aldol condensation reactions

The reaction is carried out in vapour phase (250°C) using a flow system (see methods section). This procedure turned out to be essential in order to mantain the hydrogen transfer as the main reaction pathway. A batch experiment carried out in an autoclave actually showed a wide range of condensation products besides some saturated ketone [6]. Reactions of ketones over oxide catalysts can lead to a variety of products due inter alia to aldol condensation, intramolecular dehydration and intermolecular disproportionation [16]. However, the presence of a good hydrogen donor such as a secondary alcohol and vapour phase conditions favour the transfer hydrogenation as the major reaction [16,17]. In our reaction conditions, products attributable to crotonic condensations and subsequent 1,4 Michael addition [18] were observed by g.l.c.-m.s. (Table 1). 

The first transformation is an intramolecular aldol condensation. This reaction was carried out under conditions of base catalysis. 

Intramolecular Mukaiyama aldol condensation. This reaction can be used to obtain six-, seven-, and eight-membered rings. Thus the reaction of the r /.v-dioxolanc la with TiCL (1-2 equiv.) gives 2a as the exclusive product. The isomeric /ran.v-dioxolane lb under similar conditions gives a I I mixture of 2a and 2b (72% yield). No cyclization products are obtained with SnCL or ZnCL. 

Cp 2La CH(SiMe3)2 reacts with 3-pentanone to form the solvated enolate, Cp 2La —O—C(Et)=CHMe Et2CO (equation 9a), while with acetone it forms a chelate (equation 9b) after intramolecular aldol condensation. The reaction of the precursor bistrimethylsi-lyhnethyl organometallic with hydroxyketone, preformed from the pentanone, yields the enolate ketone solvate. This difference between acetone and 3-pentanone presumably reflects the difference in strain in the condensation product because the ethyl groups in 3-pentanone are rather much bigger than the methyl groups in acetone. 

Benzene derivatives can also be obtained from pyrylium salts 43 which are substituted by R-CH2 in the 2- or 6-position. This is effected by C-2 addition of hydroxide ions, leading to a base-catalysed intramolecular aldol condensation. The reaction produces highly substituted phenols 44, which incorporate the R-CH2 carbon in the benzene ring ... 

The formation of orcin 7 in addition to 6 is the result of a subsequent deprotonation of 6 to the enolate 8 which recyclizes by an intramolecular aldol condensation. This reaction gave rise to the hypothesis of the biosynthesis of aromatic compounds from polyketides (Collie 1907) [34]. 

Cyclic ketob. Rubezhov has reported the reaction of dibenzylideneacetone (1) with this osmium salt and zinc to give 2 in almost quantitative yield. The reaction involves reductive coupling followed by intramolecular aldol condensation. Similar reactions are observed with other a, 8-unsaturated ketones. 

The plausible biosynthesis of camptothecin is outlined in Scheme 22.6. Strictosamide 45 may undergo oxidative cleavage of double bond giving diketo derivative 46 which provides pumiloside 47 after intramolecular aldol condensation (similar reaction sequence executed by chemical transformation was reported by Hutchinson [169]). Reduction of quinolone part in 47 afforded 48, which forms CPT after double-bond rearrangement and hydrolytic cleavage of glucose. 

In fact, there are sound reasons for doing the Michael reaction first. Aldol condensation products of ketones are not generally favored at equilibrium, for example, and doing the Michael reaction makes the subsequent aldol condensation intramolecular, and thus more favorable. 

C)5W=C(0Et)CH=C(0Et)CH=CR(02CR)]. Aldehydes or ketones react with the [diosphine complexes, [(OC)4(PR3)Cr=C(OMe)Me] to give aldol condensation products. Reaction with the amino carbene complexes [(OC)sCr=C(NMe2)Me] results in aldol addition products. Aldol reactions of optically active aminocarbene complexes proceed with moderate to high diastereoselectivity. Photolysis of chromium alkoxycaibene complexes with aldehydes in the presence of Lewis acids produces -lactones in low yield. Intramolecular reaction by incorporation of the aldehyde into either side chain of the carbene complex is considerably more efficient. ... 

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]. 

Both the conjugate addition step and the intramolecular aldol condensation step can be carried out in one synthetic operation without isolat mg any of the intermediates along the way For example consider the reaction... 

Comforth has reviewed literature reports and independently studied the special cases of reaction of 1 with salicylaldehyde and with 2-acetoxybenzaldehyde. Coumarins (10) are afforded in the condensation of 1 with salicylaldehyde or its imine, whereas when 2-acetoxybenzaldehyde is used, acetoxy oxazolone 12 is the major product. The initial aldol condensation product between the oxazolone and 2-acetoxybenzaldehyde is the 4-(a-hydroxybenzyl)oxazolone 11, in which base-catalyzed intramolecular transacetylation is envisioned. The product 9 (R = Ac) can either be acetylated on the phenolic hydroxy group, before or after loss of acetic acid, to yield the oxazolone 12, or it can rearrange, by a second intramolecular process catalyzed by base and acid, to the hydrocoumarin, which loses acetic acid to yield 10. When salicylaldehyde is the starting material, aldol intermediate 9 (R = H) can rearrange directly to a hydrocoumarin. Comforth also accessed pure 4-(2 -hydroxyphenylmethylene)-2-phenyloxazol-5(4//)-one (13) through hydrolysis of 12 with 88% sulfuric acid. 

The reaction of hexa-2,4-diyn-l-al (64) with mercaptoacetaldehyde leads to 2-formyl-5-(prop-l-ynyl)thiophene (65). The addition direction is governed by the aldehyde group via intramolecular aldol condensation in the intermediate (77HOU947). 

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). 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

The aldol reaction is a carbonyl condensation that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible, leading first to a /3-hydroxy aldehyde or ketone and then to an cr,/6-unsaturated product. Mixed aldol condensations between two different aldehydes or ketones generally give a mixture of all four possible products. A mixed reaction can be successful, however, if one of the two partners is an unusually good donor (ethyl aceto-acetate, for instance) or if it can act only as an acceptor (formaldehyde and benzaldehyde, for instance). Intramolecular aldol condensations of 1,4- and 1,5-diketones are also successful and provide a good way to make five-and six-inembered rings. 

How could you prepare the following cvclohexenones by combining a Stork enamine reaction with an intramolecular aldol condensation (See Problem 23.53.)... 

The intramolecular Michael addition of acyclic systems is often hampered by competing reactions, i.e., aldol condensations. With the proper choice of Michael donor and acceptor, the intramolecular addition provides a route to tram-substituted cyclopentanones, and cyclopentane and cyclohexane derivatives. Representative examples are the cyclizations of /3-oxo ester substituted enones and a,/J-unsaturated esters. 

The aldol reaction can be applied to dicarbonyl compounds in which the two groups are favorably disposed for intramolecular reaction. Kinetic studies on cyclization of 5-oxohexanal, 2,5-hexanedione, and 2,6-heptanedione indicate that formation of five-membered rings is thermodynamically somewhat more favorable than formation of six-membered rings, but that the latter is several thousand times faster.170 A catalytic amount of acid or base is frequently satisfactory for formation of five- and six-membered rings, but with more complex structures, the techniques required for directed aldol condensations are used. 

Base-catalyzed aldol reactions have been carried out intramole-cularly.241 The aqueous acid-catalyzed intramolecular aldol condensation of 3-oxocyclohexaneacetaldehyde proceeded diastereoselectively (Eq. 8.95).242... 

A SN reaction-based domino route to clerodane diterpenoid tanabalin (2-488) [258] has been described by Watanabe s group (Scheme 2.111) [259]. This natural product is interesting as it exhibits potent insect antifeedant activity against the pink bollworm, Pectinophora gossypiella, a severe pest of the cotton plant The domino sequence towards the substituted trans-decalin 2-487 as the key scaffold is induced by an intermolecular alkylation of the (5-ke toes ter 2-484 with the iodoalkane 2-483 followed by an intramolecular Michael addition/aldol condensation (Robin-... 

A trifold anionic/pericyclic domino reaction was used for the synthesis of the dioxapyrrolizidine 2-655 combining a nitro aldol condensation, SN-type cyclization, SN-type etherification, and an intramolecular 1,3-dipolar cyclization as described by Rosini and coworkers (Scheme 2.148) [339]. 

The reaction of diaryl compounds 2-974 with 3 equiv. of DB U at r. t. results initially in an intramolecular aldol condensation to give 2-975 this is followed by an oxidation to give the 3,4-diaryl disubstituted maleic anhydride or maleimide derivatives 2-976 when the reaction is conducted under atmospheric oxygen (Scheme 2.219). 

Recently, Trost et al. reported the vanadium-catalyzed addition reaction of 2,3-allenols [180], Here the oxygen in 401 served as an intramolecular nucleophile to attack the center carbon atom of allene to form a vanadium enolate 402. Aldol condensation of 402 with an aldehyde afforded (2-hydroxy)alkyl vinylic ketones 403. 

Simple reactivity inversion" implies using an umpoled synthon whose origin has, in principle, nothing in common with the synthon with "unnatural" polarity. An example of this type of reactivity inversion is found in one of the possible synthesis of cw-jasmone (3) in which the nitroethane (4) is used as an equivalent of an "acetyl anion" and reacts with an a,P-unsaturated ketone to give the corresponding 1,4-bifunctional system which can then be transformed by a Nef-type reaction into the dissonant 1,4-dicarbonyl system [5]. An intramolecular aldol condensation finally affords the target molecule (Scheme 5.3). 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

The iridium-catalyzed addition of water could be applied to the reaction of a,03-diynes. Thus, 1,7-octadiyne 125 was converted to l-(2-methylcyclopent-l-enyl)ethanone 127 (Equation 10.32). The formation of 127 was explained by assuming intramolecular aldol condensation of the resulting 2,7-octadione by Lewis acid. 

The proline-mediated intramolecular aldol condensation of dialdehyde substrates was also reported by List in 2003, affording enantioselective synthesis of cyclic p-hydroxy aldehydes via a 6-e ofexo-aldolization reaction (Scheme 11.7d). 

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