Intramolecular aldol condensations

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). 

Adenosine 5 -(tr1hydrogen diphosphate), 5 5 ester with 3-(ami nocarbonyl)-alcohol dehydrogenase, 63, 17 Adogen 464 [50934-77-5], 60, 11 Alanine, L-, N-carboxybenzyl ester, 63, 182 ALANINE, PHENYL-, N-tert-BUTOXYCARBONYL-, L-, 63, 160 Alanine, N-[(phenylmethoxy)carbonylL- [1142-20-7], 63, 182 Alcohols, alkynyl-, synthesis of, 63, 61 Alcohols, amino-, by reduction of acids, 63, 138 Aldol condensation, intramolecular, asymmetric, 63, 26, 37 Aldol condensation, diastereoselectlve, 63, 94, 104 ALIPHATIC B-KETOESTERS, 61, 5 Alkene photodimerization, 62, 125... 

Intramolecular aldol condensation The dicarbonyl compound gives a cyclic product by the intramolecular aldol condensation. Intramolecular aldols are facile when a five- or six-membered ring can be formed as shown below ... 

Ring fragmentation s.a. Aldol condensation, intramolecular-ring fragmentation... 

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. 

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

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]. 

Category Ih cyclizations effect closure of the C2 C3 bond. Scheme 3.1 depicts retrosynthetic transformations corresponding to syntheses in category lb. Included are three variations of the intramolecular aldol condensation and reductive coupling of o,/V-diacylanilines,... 

The product of this Michael addition has the necessary functionality to undergo an intramolecular aldol condensation... 

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... 

A combination of conju gate addition of an enolate anion to an a p unsaturated ketone with subsequent intramolecular aldol condensation... 

Give the structure of the product denved by intramolecular aldol condensation of the keto aldehyde shown... 

Robinson annotation (Section 18 13) The combination of a Michael addition and an intramolecular aldol condensation used as a synthetic method for nng formation... 

Original Synthesis. The first attempted synthesis of i7-biotin in 1945 afforded racemic biotin (Fig. I). In this synthetic pathway, L-cysteine [52-90-4] (2) was converted to the methyl ester [5472-74-2] (3). An intramolecular Dieckmaim condensation, during which stereochemical integrity was lost, was followed by decarboxylation to afford the thiophanone [57752-72-4] (4). Aldol condensation of the thiophanone with the aldehyde ester [6026-86-4]... 

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. 

Forty years after the initial proposal, Sweet and Fissekis proposed a more detailed pathway involving a carbenium ion species. According to these authors the first step involved an aldol condensation between ethyl acetoacetate (6) and benzaldehyde (5) to deliver the aldol adduct 11. Subsequent dehydration of 11 furnished the key carbenium ion 12 which was in equilibrium with enone 13. Nucleophilic attack of 12 by urea then delivered ureide 14. Intramolecular cyclization produced a hemiaminal which underwent dehydration to afford dihydropyrimidinone 15. These authors demonstrated that the carbenium species was viable through synthesis. After enone 13 was synthesized, it was allowed to react with N-methyl urea to deliver the mono-N-methylated derivative of DHPM 15. 

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. 

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