Type Aldol Reactions

The Mukaiyama reaction is an aldol-type reaction between a silyl enol ether and an aldehyde in the presence of a stoichiometric amount of titanium chloride. The reaction, which displays a negative volume of activation, could be performed without acidic promoter under high pressure [58]. In this case, the major product is the syn hydroxy ketone, not as for the TiCl4-promoted reactions which lead mostly to the anti addition product. Since the syn or anti selectivity is the result of two transition states with different activation volumes (AV n AVfnti), it was of great interest to investigate the aldol reaction in water. Indeed, the reaction of the silyl enol ether of cyclohexanone with benzaldehyde in aqueous medium was shown to proceed without any catalyst and under atmospheric pressure, with the same syn 

Solvent Temp. [ C] Time Conditions Yield [%] syn anti 

To improve the yields and therefore the scope of this aqueous aldolization, the use of lanthanide triflates as water-tolerant Lewis acids was recommended [9, 60]. After completion of the reaction nearly 100% of the catalyst is recovered from the aqueous layer and can be re-used quite easily. Other water-tolerant Lewis acids, including indium chloride [61] and tris(pentafluorophenyl) boron [62], were proposed as catalysts in the aqueous aldol reaction. 

The Henry reaction is an aldol-type reaction between a nitroalkane and an aldehyde in the presence of a base. Since basic reagents are also catalysts for the aldol condensation, the nitroaldol reactions must be strictly controlled. An interesting alternative lies in the use of surfactants to perform the reaction in an aqueous medium [63], The Reformatsky reaction, which involves a-haloketones and aldehydes, can be mediated by zinc, tin or indium in water in the latter case the proportion of undesirable reduction products could be strongly reduced [64]. 

Considerable rate enhancements have been observed when water is used as solvent compared with alcoholic or hydrocarbon media for Mannich reactions, i.e. condensations of ketones with secondary amines in the presence of formaldehyde [65]. Allylsilanes [66] and allylstannanes [67] in aqueous media were used in organic synthesis under Mannich-like conditions. More recently, Kobayashi reported the catalysis of the reaction of vinyl ethers with iminium salts by ytterbium triflate in tetrahydrofuran-water mixtures [68]. 

A clean, high-yielding asymmetric Baylis-HiUman reaction has been reported employing Oppolzer s sultam,63ab it couples acrylates witii a variety of aldehydes at 0 °C, with 99% ee in all cases described.630 Another new, practical variant of the reaction employs a phosphine catalyst,64 and here the temperature effect is critical the rate increases in either direction from room temperature, with a dramatic improvement observed at 0 °C. This unusual observation is explained in tenns of a temperature-dependent equilibrium between efficient and inefficient intermediates. 

The mechanism of addition of lithium pmacolone enolate, H2C=C(OLi)Bu. to benzaldehyde has been investigated by the determination of kinetic isotope effects69 (phenyl-ds and carbonyl-13C) C—C bond formation occurs in the rate-determining step (a result supported by MO calculations), in contrast to addition of MeLi or PhLi, which proceed via electron transfer. Further carbonyl-13 C isotopic studies on substituted benzaldehydes (including equilibrium effects) by the same authors confirmed these conclusions.70 

Homer-Wadsworth-Emmons reactions of ketones and aldehydes with phosphono-acetate esters, (R20)2P(=0)CH2C02R1, produce E/Z mixtures of a, /Tunsaturated esters. Use of the conventional reagent, sodium hydride, gives some selectivity. The combination of tin(II) triflate and A -cthylpipcndine enhances—and sometimes also reverses—the selectivity in most cases studied.71 Six-membered oxo-coordinated tin intermediates are proposed to control the selectivities observed. A similarly selective synthesis of trisubstituted exocyclic alkenes from cyclic ketones has been reported.72 

The Henry reaction (addition of a nitroalkane to a carbonyl) is synthetically very useful, as the nitro group of the nitro alcohol product provides many routes to a variety of functional groups. An ah initio study of the stereochemical outcomes of the reaction yields the following 73 

The mechanism, stereoselectivity, and synthetic applications of the nitrile aldol reaction have been reviewed.75 

The effect of a remote chiral center in this reaction has also been investigated. In most cases the reaction turned out to be controlled mainly by the chiral catalyst (e.g., 79), whereas the resident center generally exercised a weak to modest influence [76], 

As a further reflection of their high nucleophUicity, silyl ketene acetals, such as 88, proved to be reactive not only towards aromatic, heteroaromatic, and cinnamyl aldehydes buL very importantly, even to aliphatic aldehydes. Furthermore, the catalyst loading can be reduced to 1 mol% without erosion of enantio-selectivity [80]. 

In stark contrast to trichlorosilyl enol ethers (76 and 88, etc), their more readily obtainable trimethylsilyl counterparts, such as 90, are insensitive to the presence of Lewis bases, owing to the lower Lewis acidity of the silicon atom. Therefore, a different approach was required if these nucleophiles were to be used in aldol chemistry. Here, Denmark turned to the well-estabUshed electrophilic activation of the aldehyde but in an interestingly innovative way. He employed SiCU, which 

Benzaldehyde (1, R = Ph) (100pi, 2,0mmol, 1.0 equiv) was added in one portion to a solution ofbis-phosphoramide R,R)-81 (84mg, 0.1 mmol, 0.05 equiv) at-78°C under nitrogen in a flame-dried, round-bottom flask with a magnetic stirrer, followed by SiCh (252 pi, 2.2 mmol, 1.1 equiv) and the mixture was stirred at -78 °C 

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Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

In antithetical analyses of carbon skeletons the synthon approach described in chapter I is used in the reverse order, e.g. 1,3-difunctional target molecules are "transformed" by imaginary retro-aldol type reactions, cyclohexene derivatives by imaginary relro-Diels-Alder reactions. 

Difunctional products often come from aldol type reactions. The following example, 2- hydroxymethyl)-2-methylbutanal, needs no further comment (F. Nerdel, 1968). 

Formaldehyde condenses with itself in an aldol-type reaction to yield lower hydroxy aldehydes, hydroxy ketones, and other hydroxy compounds the reaction is autocatalytic and is favored by alkaline conditions. Condensation with various compounds gives methylol (—CH2OH) and methylene (=CH2) derivatives. The former are usually produced under alkaline or neutral conditions, the latter under acidic conditions or in the vapor phase. In the presence of alkahes, aldehydes and ketones containing a-hydrogen atoms undergo aldol reactions with formaldehyde to form mono- and polymethylol derivatives. Acetaldehyde and 4 moles of formaldehyde give pentaerythritol (PE) ... 

Reaction With Carbonyl Compounds. Primary and secondary nitroparaffins undergo aldol-type reactions with a variety of aldehydes and ketones to give nitro alcohols (11). Those derived from the lower nitroparaffins and formaldehyde are available commercially (see Nitro alcohols). Nitro alcohols can be reduced to the corresponding amino alcohols (see Alkanolamines). 

Katada rearrangement, 3, 289 synthesis, 3, 305 Lumazine, 7-methyl-aldol-type reactions, 3, 302 synthesis, 3, 311 Lumazine, 8-methyl-structure, 3, 277... 

Besides the aldol reaction in the true sense, there are several other analogous reactions, where some enolate species adds to a carbonyl compound. Such reactions are often called aldol-type reactions the term aldol reaction is reserved for the reaction of aldehydes and ketones. 

Thomson W Click Organic Interactive to use a web-based palette to design syntheses utilizing aldol-type reactions. 

Another example of a [4S+1C] cycloaddition process is found in the reaction of alkenylcarbene complexes and lithium enolates derived from alkynyl methyl ketones. In Sect. 2.6.4.9 it was described how, in general, lithium enolates react with alkenylcarbene complexes to produce [3C+2S] cycloadducts. However, when the reaction is performed using lithium enolates derived from alkynyl methyl ketones and the temperature is raised to 65 °C, a new formal [4s+lcj cy-clopentenone derivative is formed [79] (Scheme 38). The mechanism proposed for this transformation supposes the formation of the [3C+2S] cycloadducts as depicted in Scheme 32 (see Sect. 2.6.4.9). This intermediate evolves through a retro-aldol-type reaction followed by an intramolecular Michael addition of the allyllithium to the ynone moiety to give the final cyclopentenone derivatives after hydrolysis. The role of the pentacarbonyltungsten fragment seems to be crucial for the outcome of this reaction, as experiments carried out with isolated intermediates in the absence of tungsten complexes do not afford the [4S+1C] cycloadducts (Scheme 38). 

Aldol-Type Reactions between Carboxylic Esters or Amides and Aldehydes or Ketones... 

Another interesting example is SHMT. This enzyme catalyzes decarboxylation of a-amino-a-methylmalonate with the aid of pyridoxal-5 -phosphate (PLP). This is an unique enzyme in that it promotes various types of reactions of a-amino acids. It promotes aldol/retro-aldol type reactions and transamination reaction in addition to decarboxylation reaction. Although the types of apparent reactions are different, the common point of these reactions is the formation of a complex with PLP. In addition, the initial step of each reaction is the decomposition of the Schiff base formed between the substrate and pyridoxal coenzyme (Fig. 7-3). 

In Section 3.5 on alkene isomerization, it was mentioned that Li and co-workers reported a RuCl2(PPh3)3-catalyzed shuffling of functional groups of allylic alcohols in water (Eq. 3.35).140 Since the reaction proceeds through an enol intermediate, allyl alcohols can thus be considered as enol equivalents.203 This has been developed into an aldol-type reaction by reacting allyl alcohols with aldehyde (Scheme 3.11).204 The presence of In(OAc)3 promoted the aldol reaction with a-vinylbenzyl alcohol and aldehyde.205... 

Rychnovsky and coworkers very recently described a so-far unknown domino Michael addition/2 -oxonia Cope/aldol-type reaction to give tetrahydropyran rings [475]. The transformation has as its origin an annulation process (see Section 2.1) which was discovered by the same group. 

It can be assumed that, upon irradiation, tautomer 5-40-II reacts with the alkene 5-41 in a highly regioselective [2+2] cycloaddition to give the cyclobutane 5-42 as an intermediate. Subsequent retro-aldol-type reaction and hemiacetal formation produces 5-44 via 5-43. After addition of the Lewis acid (BF3-Et20), cyclization takes place to give the desired products. It should be noted that the excess of alkene must be removed under reduced pressure before addition of the Lewis acid in order to avoid polymerization. 

Nagao, Y., Hagiwara, Y., Kumagai, T., Ochiai, M., Inoue, T., Hashimoto, K., and Fujita, E. (1986). New C4-chiral l,2-thiazolidine-2-thiones Excellent chiral auxiliaries for highly diastereocontrolled aldol-type reactions of acetic acid and a,b-unsaturated aldehydes. J. Org. Chem. 51, 2391-2393. 

The mechanism of epoxide formation (Scheme 7) has not been established but the intermediacy of nickel enolates and ensuing aldol type reactions are suspected28 (cf. Zn-mediated formation of furans from a-bromoketones29). A limitation on the synthesis is that R cannot be aryl for these cases, the products are 2,4-diarylfurans (see Section IV,B,1).30... 

The use of an anionic reagent for addition at carbonyl carbon rather than a fully esterified form of a trivalent phosphorus acid obviates a troublesome aspect of the Abramov reaction. Specifically no dealkylation step is required. Mechanistic investigations257 258 indicate that the reaction proceeds much as a simple "aldol"-type reaction in which the anionic phosphorus site adds directly to the carbonyl center. While the initial efforts concerned with the "Pudovik reaction"259 were directed toward the use of sodium salts of the simple dialkyl phosphites, as shown in Equation 3.17,260 266 with a, 5-unsaturated carbonyl systems (vide infra) competition between sites for addition can occur. Addition at the carbonyl carbon site is the kinetically favored route.267-270... 

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). 

Recent developments of aldol-type reactions with titanium enolates include the a- and /3-C-glycosidation of glycals73 and the diastereoselective addition to 2-acetoxytetrahydrofurans.74 Mukaiyama and co-workers have developed a one-pot procedure for the preparation of unsymmetrical double aldols.75... 

Various examples for the preparation of zirconium enolates131 and their use in aldol-type reactions are described in 132 133 134... 

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

Chiral bis-phosphine acylplatinum complex 210 with a strong acid such as TfOH serves as an effective enantio-selective catalyst for aldol-type reactions of aldehydes with ketene silyl acetals (Equation (127)).486 The presence of water and oxygen in the catalyst preparation step is required to obtain the highly enantioselective catalyst. The intermediacy of a C-bound platinum enolate was suggested by IR and 31P NMR spectroscopies. 

Oxazolidones as Chiral Auxiliaries Chiral Auxiliary-Mediated Aldol-Type Reactions... 

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