Aldol-type reactions diketones

Aldol-type reactions of nitrones (303) occur with electron-deficient ketones, such as a-keto esters, a, 3-diketones, and trifluoromethyl ketones. These reactions are catalyzed by secondary amines. The use of chiral cyclic amines A1-A7 leads to a-(2-hydroxyalkyl)nitrones (304) in moderate yields and rather high optical purity (Scheme 2.120) (381). The mechanism of the nitrone-aldol reaction of iV-methyl-C-ethyl nitrone with dimethyl ketomalonate in the absence and presence of L- proline has been studied by using density functional theory (DFT) (544). 

Other removal procedures include reaction of the bicyclic lactam 4 with hydride (R6 = H) or an alkyl metal (R6 = alkyl). After hydrolysis of the bicyclic azahemiketal 5, ketoaldehydes or diketones 6 result. These can then be used in intramolecular aldol-type reactions to furnish enantiomerically pure cyclopentenones 7 (n = 1). The same reaction sequence can be used to prepare cyclohexenones (see Table 9)3-6 7l 1 ... 

The titanium(IV) chloride-promoted reactions of enol silyl ethers with aldehydes, ketones, and acetals, known as Mukaiyama reaction, are useful as aldol type reactions which proceed under acidic conditions (eq (23)) [20], Enol silyl ethers also undergo the Michael type reactions with enones or p.y-unsaturated acetals (eq (24)) [21]. Under similar reaction conditions, enol silyl ethers are alkylated with reactive alkyl halides such as tertiary halides or chloromethyl sulfides (eq (25)) [22], and acylated with acid halides to give 1,3-diketones (eq (26)) [23]. 

Although ketones are not generally considered to be reactive carbonyl partners in MBH reactions (except under high pressure), the enhanced reactivity of certain a-diketones towards aldol-type reactions make them suitable partners for reaction with MBH-type vinyl carbanion equivalents. Indeed, a-keto esters have been found to possess the requisite reactivity and are very reactive electrophiles for the MBH reaction of acrylate, methyl vinyl ketone, acrylonitrile and acrolein in the presence of a tertiary amine, such as DABCO (Scheme 1.66). " ... 

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]. 

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 reaction of tin enolates with a-chloro or bromoketones gives 7-diketones (1,4-diketones) catalyzed by zinc halides. In contrast to the exclusive formation of 1,4-diketones under catalytic conditions, uncatalyzed reactions afford aldol-type products. NMR studies indicate that the catalyzed reaction includes precondensation between tin enolates and cr-haloketones providing aldol-type species and its rearrangement of the oxoalkyl group with the substitution of the halogen to produce 1,4-diketones (Equation (90))/ ... 

The synthons of porphyrin syntheses are the pyrroles, which in turn must be made from 1,4-difunctional synthons. These carbon skeletons are available by an aldol-type condensation of the enol of a 1,3-diketone with an a-nitrosylated acetoacetate (Knorr pyrrole synthesis. Scheme 1.3.4). The final reductive ring closure by Schiff base formation is again a reversible condensation reaction. After dehydration, however, a stable 7i-electron sextet is formed, which gives the resulting pyrrole aromatic stability. Hydrolysis of this enamine can now only occur in very strong acid. In water of modest acidity or basicity it is perfectly stable. 

Similar conditions have been successfully applied to 2-alkyl-1,3-diketones by Cossy s group, leading to the corresponding jy -2-alkyl-3-hydroxyketones. These reactions offered an alternative preparation of aldol-type intermediates by a non-aldol pathway under easily-scalable conditions (Scheme 2.23). 

Alkyl halides are less investigated in this protocol. a-Halo ethers, thioethers, and lactones can be used in this protocol. a-Halocarbonyl compounds react abnormally with allyl- and acetonyltins to give oxiranes via the attack at the carbonyl followed by the cyclization (Scheme 34).p°]-P3] -pjjg reaction appears to be a variation of a simple Lewis-acid-catalyzed aldol-type condensation. On the other hand, if a catalyst without phosphine ligand is used, 1,4-diketone is formed (Scheme 35). 

A green chemistry variation makes use of solventless conditions to minimize the waste stream from reactions of this type. To a mortar are added aldehyde 67, ketone 68 and solid sodium hydroxide. The mixture is ground and within 5 minutes aldol product 69 is produced. Addition of the second ketone and further grinding affords the 1,5-diketone 70, which can be isolated and cyclized to pyridine 71 with ammonium acetate. The authors report that this method can substantially reduce the solid waste (by over 29 times) and is about 600% more cost effective than previously published procedures. 

With a synthesis of 58 completed, the key intramolecular diketone aldol cyclization was investigated. Precedent for this type of 1,8-dicarbonyl aldol reaction is rare, although an aldol reaction has been proposed in the biosynthetic pathway to the hypocrellins. The only reported examples of such diketone aldol cyclizations involve multicyclic or bridged bicyclic systems, and of these no examples exist for 1,8-diketones forming 7-membered rings. MM2 calculations indicated that a... 

In 2008 Resmini et al. [76] presented their work on the synthesis of novel molecularly imprinted nanogels with Aldolase type I activity in the cross-aldol reaction between 4-nitrobenzaldehyde and acetone. A polymerisable proline derivative was used as the functional monomer to mimic the enamine-based mechanism of aldolase type I enzymes. A 1,3-diketone template, used to create the cavity, was... 

The Claisen-type condensation reaction of cyclic vinylogous carboxylic acid triflates with lithium enolates and their analogues has provided acyclic alkynes bearing a 1,3-diketone-type moiety.19 The reaction mechanism has been proposed to proceed via a 1,2-addition of the enolate to the vinylogous acyl triflate, followed by fragmentation of the aldolate intermediate (Scheme 2). 

Desymmetrization via proline-catalyzed asymmetric intramolecular aldol reaction can, however, also be performed with acydic diketones of type 109 as has been reported by the Agami group [106], In the first step a prochiral acyclic diketone reacts in the presence of L-proline as catalyst (22-112 mol%) with formation of the aldol adduct 111 (Scheme 6.49). In this step reaction products with two stereogenic centers, 110, are formed. These chiral hydroxyketones 110 are subsequently converted, via dehydration, into the enones 111, by treatment with p-toluenesulfonic acid. 

Transition metal catalysis of the Michael reaction of 1,3-dicarbonyl compounds with acceptor activated alkenes has been known since the early 1980 s 2>3 It is a valuable alternative to the classic base catalysis of the reaction. Because of the mild and neutral conditions, the chemoselectivity of these reactions is superior to that provided by base catalysis, since the latter suffers from various unwanted side or subsequent reactions, such as aldol cyclizations, ester solvolyses or retro-Claisen type decompositions. A number of transition metal and lanthanide compounds have been reported to catalyze the Michael reaction, but FeCb 6 H20 is one of the most efficient systems to date. A number of 3-diketones or p-oxo esters and MVK are cleanly converted to the corresponding Michael reaction products within a few hours at room... 

One possible reaction for 60 is an intramolecular condensation with the other carbonyl (see Chapter 22, Section 22.6, for reactions of this type), but that would lead to a four-membered ring product, 61. The activation barrier to form this strained ring is high, so this reaction is slow (see Chapter 8, Section 8.5.3). The reaction conditions favor thermodynamic control (protic solvent, hydroxide, heat see Chapter 22, Section 22.4.2), which means that enolate anion 60 is in equilibrium with the neutral diketone. Further reaction with hydroxide generates the kinetic enolate anion 62 as part of the equilibrium mixture. If 62 attacks the carbonyl in an intramolecular aldol reaction (Chapter 22, Section 22.6), a six-membered ring is formed (63) in a rapid and highly favorable process. 

Dibenzoylmethane undergoes a de Mayo-type photoaddition reaction at the carbonyl group of BQ, NQ, and 9,10-anthraquinone to give hydroxyoxetanes that, on further irradiation, afford 1,5-diketones in reasonable yield by a retro-Aldol process. " The reaction is outlined in Figure 87.5 for NQ and the addition is reported to be reversed by 254-nm radiation, as is the conversion of the hydroxyoxetane to the 1,5-diketone with 300-nm radiation. 

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