Cyclohexanone aldol reactions

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

The Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexenones. For example, reaction of the pyrrolidine enamine of cyclohexanone with 3-buten-2-one. followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each. 

A DFT study found a corresponding TS to be the lowest energy.167 This study also points to the importance of the solvent, DMSO, in stabilizing the charge buildup that occurs. A further computational study analyzed the stereoselectivity of the proline-catalyzed aldol addition reactions of cyclohexanone with acetaldehyde, isobu-tyraldehyde, and benzaldehyde on the basis of a similar TS.168 Another study, which explored the role of proline in intramolecular aldol reactions, is discussed in the next section.169... 

Fig. 2.P25. Top Reaction energy profile for alanine-catalyzed aldol reaction of benzaldehyde and cyclohexanone. Bottom Diastereomeric transition structures. Reproduced from Angew. Chem. Int. Ed. Engl., 44, 7028 (2005), by permission of Wiley-VCH...

Classical Aldol. Aldol reaction is an important reaction for creating carbon-carbon bonds. The condensation reactions of active methylene compounds such as acetophenone or cyclohexanone with aryl aldehydes under basic or acidic conditions gave good yields of aldols along with the dehydration compounds in water.237 The presence of surfactants led mainly to the dehydration reactions. The most common solvents for aldol reactions are ethanol, aqueous ethanol, and water.238 The two-phase system, aqueous sodium hydroxide-ether, has been found to be excellent for the condensation reactions of reactive aliphatic aldehydes.239... 

In a similar manner, a new strategy to access the fumagilol skeleton was reported. RCM of diene 29, which was synthesized by the Evans aldol reaction, was carried out using Ic in the presence of Ti(0 Pr)4 to give a key cyclohexanone intermediate 30 [Eq. (6.22)]. This compound was readily converted to fumagilol " ... 

Typical starting materials, catalysts, and products of the enamine-catalyzed aldol reaction are summarized in Scheme 17. In proline-catalyzed aldol reactions, enantioselectivities are good to excellent with selected cyclic ketones, such as cyclohexanone and 4-thianone, but generally lower with acetone. Hindered aldehyde acceptors, such as isobutyraldehyde and pivalaldehyde, afford high enantioselectivities even with acetone. In general, the reactions are anti selective, but there are aheady a number of examples of syn selective enamine aldol processes [200, 201] (Schemes 17 and 18, see below). However, syn selective aldol reactions are still rare, especially with cychc ketones. 

Application of this work to a domino process using 51 involves Michael addition of P-ketoesters [91], p-diketones or P-ketosulfones [92] to a,P-unsaturated ketones followed by an intramolecular aldol reaction provides highly functionalised cyclohexanone building blocks with up to four contiguous chiral centres. Gryko has also reported examples of this domino Michael/intramolecular aldol reaction in the coupling of 1,3-diketones and methyl vinyl ketone using L-proUne as catalyst [93],... 

Appendix 7.C Aldol reaction between cyclohexanone and 4-nitrobenzaldehyde (Entries in bold indicate favourable catalyst properties)... 

It is thus possible to look at a molecule such as A below and recognize that it is a ft-hydroxy ketone and thus could be formed in a crossed-aldol reaction between enolate B and aldehyde C. Likewise D could potentially be produced by dehydration of the aldol product of cyclohexanone... 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

In direct nitroso aldol reactions of a-branched aldehydes, an L-prolinamide (50) catalyses to give a-hydroxyamino carbonyl compounds which are otherwise dis- favoured ees up to 64% were found.149 Another prolinamide derivative gives similar results in a nitrosobenzene reaction.150 For proline-catalysed cases involving highly substituted cyclohexanones, DFT calculations have highlighted the roles of electro- static and dipole-dipole interactions in the level of de achieved.151 (g)... 

In another study Feringa et al. [20] reported a catalytic enantioselective three-component tandem conjugate addition-aldol reaction of dialkyl zincs. Here, zinc enolates were generated in situ via catalytic enantioselective Michael addition of dialkylzinc compounds to cydohexenone in the presence of a chiral Cu catalyst. Their diastereoselective reaction with an aldehyde then gave trans-2,3-disubstituted cyclohexanones in up to 92% yields and up to >99% ees (Scheme 9.11). 

An aldol reaction is also involved in the synthesis of 4-(tetrahydro-477-thiopyran-4-cyclohexylidene-4 -ylidene)-tetrahydro-4/7-thiopyran 284 from tetrahydro-477-thiopyran-4-carboxylic acid and 4-(tetrahydro-477-thiopyran-4-ylidene)cyclohexanone (Scheme 39) <2000JOC4584>. 

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... 

In addition, the combination of KF and 1 H-crown-6 in the presence of BINAP-AgOTf, which was effective in accelerating the allylation reaction using allyltrimethoxysilane, could be used for the aldol reaction (Scheme 9.11).20 Thus, the reaction with the silyl enol ether derived from cyclohexanone and benzaldehyde in the... 

Enolate D of Figure 10.62 can undergo an aldol reaction with the C=0 double bond of the ketone. The bicyclic compound A is formed as the condensation product. It is often possible to combine the formation and the consecutive reaction of a Michael adduct in a one-pot reaction. The overall reaction then is an annulation of a cyclohexanone to an enolizable ketone. The reaction sequence of Figure 10.62 is the Robinson annulation, an extraordinarily important synthesis of six-membered rings. 

The diastereoselective aldol reaction of the tributyltin enolate of cyclohexanone with benzaldehyde in the presence of a catalytic amount of various metal triflates has been studied. The highest A-selectivity is observed with Pd(OTf)2, while Zn(OTf)2 in THF shows moderate yy -selectivity (Equation (68)).222 OSnBu3... 

Procter used the cleavage of an aryloxy substituent with Sml2 to initiate aldol-type reactions.154 For example, treatment of ketone 139 with Sml2 in the presence of cyclohexanone and tetrahydropyran-4-one resulted in efficient aldol reaction to give adducts 140 and 141, respectively (Scheme 5.98). Again, an... 

First, chemoselective (Chapter 24) conjugate addition of the silyl ketene acetal on the enone is preferred to direct aldol reaction with the aldehyde. Then an aldol reaction of the intermediate silyl enol ether on the benzaldehyde follows. The stereoselectivity results, firstly, from attack of benzalde-hyde on the less hindered face of the intermediate silyl enol ether, which sets the two side chains trans on the cyclohexanone, and, secondly, from the intrinsic diastereoselectivity of the aldol reaction (this is treated in some detail in Chapter 34). This is a summary mechanism. 

The stereoselective chelation-controlled aldol reaction of unsubstituted lithium ester enolates with (7 s)-2-(p-tolylsulfinyl) cyclohexanone A (Figure 16) led to a high enantio-face differentiation (> 90 < 10), while the simple diastereoselection was rather low for prochiral enolates567. The role of the lithium cation acting as a template is here essential, since sodium, potassium, HMPA or even added ZnCl2 resulted in decreased yield and selectivity. 

Scheme 5.63. Ab78H6 catalyzed intramolecular aldol reaction to generate 2-benzyl-3-hydroxy-cyclohexanone.

Use of fluorous pyrrolidine sulfonamides 5 for enantioselective aldol reactions and Michael additions are shown in Fignre 1.4. The aldol reaction of cyclohexanone and 4-nitrobenzaldehyde under 10 mol% of the catalyst gave product 6 in 90% yield with a 70% ee and a 2 1 syn/anti ratio. The catalyst can be recovered by F-SPE and reused up to 6 times without significant loss of catalytic activity. 

Aldol condensation (8, 467). Complete details have been published concerning the fluoride-ion-catalyzed aldol reaction of enol silyl ethers with aldehydes. I hc primary product is the silyl ether of the aldol, and yields can be markedly improved by addition of FSi(CHj), to the reaction. The reaction exhibits only slight anti-syn selectivity, but does show high axial selectivity when the substituent is added to the a-position of a cyclohexanone (equation I). 

The hydrophobicity-driven association of reactant molecules in aqueous solution has even been found in aldol reactions. The trimethylsilyl ether of cyclohexanone adds to benzaldehyde in aqueous solution at 20 °C in the absence of a catalyst to give aldol addition products with a synlanti stereoselectivity opposite to that of the acid-catalyzed reaction carried out in dichloromethane [746]. 

Houk next examined the aldol reaction of cyclohexanone with benzaldehyde (Reaction 6.20) and isobutyraldehyde (Reaction 6.21) with (6)-proline as the catalyst. Four diastereomeric TSs starting from the enamine formed from cyclohexanone and proline were optimized at B3LYP/6-31G for each reaction. These transitions states, 53 and 55, are shown in Fignre 6.23. In all of these TSs, proton transfer from the carboxylic acid group to the carbonyl oxygen accompanies the formation of the new C-C bond, creating a carboxylale and alcohol product. 

A zirconium complex, bis(cyclopenta(Uenyl)zirconium(IV) hydride will function as a catalyst for the chemoselective Oppenauer oxidation of primary alcohols in the presence of a hydrogen acceptor (cyclohexanone, benzaldehyde or benzophenone). This method appears to be of some value, since it also allows for the selective monooxidation of primary (and secondary) diols (Scheme 3). 1,2-Diols are not cleaved under these conditions and retro-aldol reactions appear not to be a problem. 

---