Aldol 2-butanone

Aldol reaction of the campholenic aldehyde with 2-butanone gives the intermediate ketones from condensation at both the methyl group and methylene group of 2-butanone (Fig. 6). Hydrogenation results in only one of the two products formed as having a typical sandalwood odor (160). 

In the condensation of 2-butanone with citral, if the reaction temperature is kept at 0—10°C, higher yields of the isomethyl pseudoionones, which are the more thermodynamically stable isomers, are obtained. The aldol iatermediates have more time to equilibrate to the more stable isomers at the lower temperature. The type of base used and a cosolvent such as methanol are also very important ia getting a high yield of the isomethyl pseudoionones (168). 

In contrast, highly stereoselective aldol reactions are feasible when the boron etiolates of the mandelic acid derived ketones (/ )- and (5,)-l- t,r -butyldimethylsiloxy-l-cyclohexyl-2-butanone react with aldehydes33. When these ketones are treated with dialkylboryl triflate, there is exclusive formation of the (Z)-enolates. Subsequent addition to aldehydes leads to the formation of the iyn-adducts whose ratio is 100 1 in optimized cases. 

Surprisingly, the size of the silyl protecting group significantly influences the stereochemical outcome of aldol additions performed with the lithium enolates of (S )-l-trimethylsiloxy-and (S)-l-f< rt-butyldimethylsiloxy-l-cyclohexyl-2-butanone. Thus, the former reagent attacks benzaldehyde preferably from the Si-face (9 1), which is the opposite topicity to that found in the addition of the corresponding titanium enolates of either ketone ... 

Both the titanium4, d and the lithium enolate47c of (S)-l-benzoyl-l-cyclohexyl-2-butanone deliver the srn-aldol 6c, predominantly. 

Scheme 6 Complementary regioselectivities in direct aldol couplings of 2-butanone and corresponding hydrogen-mediated reductive aldol couplings of MVK...

In general, the product ratio of a mixed aldol condensation will depend upon the individual reaction rates. Most ketones show a pattern similar to butanone in reactions with aromatic aldehydes. Base catalysis favors reaction at a methyl position over a methylene group, whereas acid catalysis gives the opposite preference. 

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)... 

A wide range of donor ketones, including acetone, butanone, 2-pentanone, cyclopentanone, cyclohexanone, hydroxyacetone, and fluoroacetone with an equally wide range of acceptor aromatic and aliphatic aldehydes were shown to serve as substrates for the antibody-catalyzed aldol addition reactions (Chart 2, Table 8B2.6). It is interesting to note that the aldol addition reactions of functionalized ketones such as hydroxyacetone occurs regioselectively at the site of functionaliztion to give a-substitutcd-fi-hydroxy ketones. The nature of the electrophilic and nucleophilic substrates utilized in this process as well as the reaction conditions complement those that are used in transition-metal and enzymatic catalysis. 

HYDR0XY-3-NETHYL-1-PHENYL-1-BUTAN0NE BY CROSSED ALDOL REACTION (1-Butanone, 3-hydroxy-3-methyl -1-phenyl -)... 

HYDROXY-3-METHYL-1-PHENYL-1-BUTANONE BY CROSSED ALDOL REACTION... 

S)-Proline-catalyzed aldol reactions involving 2-butanone afforded the products of C-C bond formation at the methyl group, the less substituted a-position of the ketone as the major regioisomers (Fig. 2.1) [6, 9]. The regioselectivity of the aldol reaction of 2-butanone was reversed using a proline amide derivative as the catalyst, as shown in Scheme 2.2 [13]. The (S)-proline-catalyzed aldol reactions of cyclohexanone and of cyclopentanone afforded both anti- and syn-products (anti syn 2 1) with moderate enantioselectivities (63-89% ee) [6]. The selectivity... 

Fig. 2.1 Products of (S)-proline 1- and 4-catalyzed aldol reactions of 2-butanone [6, 9].

In the aldol reaction between butanone and benzaldehyde it is important to note that butanone can form more than one enolate. Under the reaction conditions given, formation of the more substituted and thermodynamically more stable enolate will be produced, and this can be either E- or Z-configured. Moreover, nucleophilic attack at the aldehyde group of the planar benzaldehyde can take place both from the Re or Si sides. Four products are therefore obtained. From the Z enolate the /-configured enantiomers A and B are the preferred products, whilst the E enolate gives predominately the w-configured enantiomers C and D. 

Reaction of phenacyl iodide with indium metal gives 3,4-epoxy-1,3-diphenyl-1-butanone which, on treatment with silica gel, gives 2,4-diphenylfuran and 2,4-diphenyl-4-oxobutanal (Scheme 92). Metallic indium as well as indium(i) iodide mediate the aldol condensation between ce-halo ketone and aldehyde.333... 

Gennari et al. developed a computational model to reproduce the experimental syn/anti setereoselectivity for the aldol reactions of Z and E enol borinates of butanone with acetaldehyde.13 For the reaction of Z-enol borinate 8Z, the chair transition state TS Z-chair A dominates over other three-transition states (Scheme 2.XI). When a Boltzmann distribution was calculated for the competing transition structures, a complete syn/anti selectivity of 99 1 was predicted. The aldol reaction of E-enol borinate 8E with acetaldehyde is, however, calculated to have four transition structures of similar energy (Scheme 2.XII). Although... 

Their more directed approach to hirsutic acid utilized 341 as starting material (Scheme 53).335 This diketo ester was the major product obtained from alkylation of the pyrrolidine enamine of340 with 3-bromo-2-butanone and aldolization in aqueous base. Reesterification with diazomethane and catalytic hydrogenation generated the cis-fused bicyclooctane nucleus. The subsequent Claisen alkylation of 342 proved to be stereoselective, affording 343 as the major product. Cyclization as before furnished 344 whose further transformations are currently being examined. 

This selective route to quinolines choice here either you first form an enol(ate) from butanone and do an aldol reactic ... 

Scheme 2. Pathway of the aldol addition reaction of 3,3-dimethyl-2-butanone with lithiuin-3,3-diinethyl-2-butanolate.

Swinholide A. The swinholides are a series of complex macrodiolides isolated from the marine sponge Theonella Swinhoei, which display potent cytotoxicity against a range of human tumour cell lines. Swinholide A (71) provided an excellent opportunity to showcase the synthetic utility of a range of aldol reactions. For its total synthesis by our group in 1994 [50] the fully protected preswinholide A 72 was considered to be an essential late-stage intermediate, which appeared accessible via two directed aldol reactions of a suitable butanone equivalent with aldehydes 73 and 74 (Scheme 9-24). 

With aldehydes 73 and 74 in hand, two alternatives were considered for the completion of the synthesis of preswinholide A, i.e. carrying out the butanone aldol reaction on either the methyl or the ethyl side first (see Scheme 9-24). Initially, the former option was investigated. While the reaction of the kinetic boron enolate of butanone with aldehyde 73 did not favour the desired Felkin adduct 83, the addition of allyl silane 84 (a masked butanone equivalent) proved selective in the desired sense (Scheme 9-27). This change in selectivity indicates the stereochemical reversal possible when switching from a cyclic to an acyclic transition state. 

Given this problem, the attachment of the butanone synthon to aldehyde 74 prior to the methyl ketone aldol reaction was then addressed. To ovenide the unexpected. vTface preference of aldehyde 74, a chiral reagent was required and an asymmetric. syn crotylboration followed by Wacker oxidation proved effective for generating methyl ketone 87. Based on the previous results, it was considered unlikely that a boron enolate would now add selectively to aldehyde 73. However, a Mukaiyama aldol reaction should favour the desired isomer based on induction from the aldehyde partner. In practice, reaction of the silyl enol ether derived from 87 with aldehyde 73, in the presence of BF3-OEt2, afforded the required Felkin adduct 88 with >97%ds (Scheme 9-29). This provides an excellent example of a stereoselective Mukaiyama aldol reaction uniting a complex ketone and aldehyde, and this key step then enabled the successful first synthesis of swinholide A. 

Since the enolization is not restricted to the 2 and 3 positions, a number of products are formed that undergo subsequent aldol condensations and the Cannizzaro oxidation. They are all 2-hydroxy-3-methyl, 3,4-dimethyl-2-hydroxy, 3,5-dimethyl-2-hydroxy, and 3-ethyl-2-hydroxy-2-cyclopenten-l-ones sugar acids acetic acid hydroxyacetone three isomeric hydroxy-2-butanones y-butyrolactone and such furan derivatives as furyl alcohol, 5-methyl-2-furyl alcohol, and 2,5-dimethyl-4-hydroxy-3(2H)-furanone. They are food flavoring agents. 

Butanone 29 was also investigated as an aldol donor. The reactions of 2-buta-none 29 with nitro-substituted benzaldehydes afforded the aldol product 30 with excellent stereoselectivity (up to 93 7 of dr and 98% ee). However, the reaction also occurred unselectively at the Cl position of the ketone, leading to the concomitant formation of 31 (Scheme 8.10). 

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