Aldol under neutral conditions

Allyl aryl ethers are used for allylation under basic conditionsfh], but they can be cleaved under neutral conditions. Formation of the five-membered ring compound 284 based on the cyclization of 283 has been applied to the syntheses of methyl jasmonate (285)[15], and sarkomycin[169]. The trisannulation reagent 286 for steroid synthesis undergoes Pd-catalyzed cyclization and aldol condensation to afford CD rings 287 of steroids with a functionalized 18-methyl group 170]. The 3-vinylcyclopentanonecarboxylate 289, formed from 288, is useful for the synthesis of 18-hydroxyestrone (290)[I7I]. 

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]. 

As shown in Eq. 6.59, Rapoport has prepared sinefungin, nucleoside antibiotics, via nitro-aldol reaction, dehydration, and reduction with Zn in acetic add.115a [i-Nitrostyrenes are selectivity reduced to the corresponding oximes by indium metal in aqueous methanol under neutral conditions.11515... 

Allylic alcohols react with aldehydes, in the presence of catalytic amounts of Fe(CO)s under photochemical activation conditions, to give mainly aldol products (Scheme 11).33 This novel tandem iosmerization-aldolization reaction is a process with a perfect atom economy, proceeding under neutral conditions. 

Aromatic and a-substituted aliphatic aldehydes react with oxiranes under neutral conditions to yield 1,3-dioxoIanes [35] whereas a-unsubstituted aldehydes undergo a simple aldol condensation under such conditions. In a somewhat similar manner, perfluorocarboxylic esters react with oxiranes to produce cyclic orthoesters (-50%) [36]. The corresponding reaction with non-fluorinated esters fails. 

Boron enolates react with aldehydes and ketones under neutral conditions to give intermediates which hydrolyze to aldol products. The reaction proceeds via a cyclic transition state (Equation B5.2) and is analogous to the allylborane reactions discussed above. 

The use of C-H bonds is obviously one of the simplest and most straightforward methods in organic synthesis. From the synthetic point of view, the alkylation, alkenylation, arylation, and silylation of C-H bonds are regarded as practical tools since these reactions exhibit high selectivity, high efficiency, and are widely applicable, all of which are essential for practical organic synthesis. The hydroacylation of olefins provides unsymmetrical ketones, which are highly versatile synthetic intermediates. Transition-metal-catalyzed aldol and Michael addition reactions of active methylene compounds are now widely used for enantioselective and di-astereoselective C-C bond formation reactions under neutral conditions. 

Various methods, many with an eye towards industrial application, have been examined to accelerate Cannizzaro reactions. For example copper-silica catalysts,Na2S, Na2S203 or NaaSOs supported on AI2O3, and ultrasound all have been reported to accelerate certain Cannizzaro processes. An extremely promising development is the use of transition metal catalysts, which may be employed under neutral conditions in the absence of strong base. This permits the use of enolizable aldehydes like (28), which under basic conditions would immediately be consumed via aldol reactions. For example, in the presence... 

Enol silyl ethers undergo aldol reactions with aldehydes, acetals and their equivalents with the aid of a Lewis acid catalyst. These reactions are discussed in Volumes 2-4. Enol silyl ethers prepared by hydro-silylation of a, 3-unsaturated ketones with a rhodium catalyst can be used for aldol reactions with aldehydes or ketones in situ under neutral conditions (equation 60)." ... 

Aldol reaction and alkylation of ketones at the a-position via enol silyl ethers (11) under neutral conditions are good examples [8]. Ortho-quinodimethane (15) is afforded at room temperature and undergoes [4 + 2] cycloaddition [10]. In contrast, the thermal ring opening of benzocyclobutane requires a much higher temperature (180-190°C) [11]. The fluorine-mediated Si—C activation protocol was the preferred method for the formation of tetrafluoro-para-quinodimethane (19), which then dimerizes to octafluoro-para-cyclophane (20) [12]. Azomethine ylide (22) can be generated from 21 byAgF catalysis and is used for heterocycles syntheses [13]. 

The basic mechanistic outline is presented in Scheme 16. H-Phosphonates exist as two tautomers. Under neutral conditions the equilibrium lies toward the phosphonate tautomer, which is not the reactive form for the phospho-aldol process. The equihbrium must be forced toward the phosphite tautomer, where a lone pair of electrons on phosphorus permit nucleophilic attack at the carbonyl carbon of a suitable substrate. A catalyst is required to... 

Pd(OAc)2, combined with DPPE, catalyzes aldol condensation of aldehydes or ketones with ketene silyl acetal (Mukaiyama reaction) under neutral conditions. The ketene silyl acetal of methyl isobutyrate (10) reacted smoothly with methyl pymvate (9) or benzaldehyde (12) in THF or MeCN using 0.1 % of the catalyst. In this reaction the Pd enolate 14 is generated by transmetallation of the ketene silyl acetal with Pd(OAc)2, and the Pd moiety as a Lewis acid activates the carbonyl group to facilitate the attack by the enolate to provide 11 and 13 [2]. 

Lubineau, A., Water-promoted organic reactions aldol reaction under neutral conditions, J. Org. Chem., 1986,51,2142-2144. 

A study of the oxidation of /3-hydroxyketones has shown that Collins reagent and dimethylsulphoxide-oxalyl chloride are suitable oxidants for the preparation of l,3-diketones. Using these reagents, neither /3-elimination nor retro-aldol fragmentation were observed. a-Diazo-/3-hydroxyketones are transformed into diketones on treatment with acid, but the need for an acidic medium can limit the generality of the method. However, it has been reported that this transformation occurs rapidly under neutral conditions in the presence of a catalytic amount of rhodium(ii) acetate. ... 

Yamamoto, H. Maruyama, K. Matsumoto, K. (1983) Organometallic high-pressure reactions. 2. Aldol reaction of silyl enol ethers with aldehydes under neutral conditions, J. Am. Chem. Soc., 105,6963-5. 

Thus, boron enolates prepared under mild conditions enable aldol-type reactions essentially under neutral conditions. Stereocontrolled synthesis of acyclic molecules has been achieved by employing boron enolate-mediated aldol reactions this method has been extensively applied to the synthesis of natural products. 

A bifimctional chiral phase-transfer 1,1-binaphthyl catalyst has promoted aldol reaction of a-substituted nitroacetates with aqueous HCHO under neutral conditions 0 Aza-Henry reaction of N-protected imines (R CH=NPg) with bromonitromethane to yield nitroamines and bromonitroamines has been promoted by Sml2 and Nal, respectively, in THF.20 ... 

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) ... 

During 1989-93 lithium perchlorate iethyl ether (LiC104 EtiO, LP-DE) was studied as a reaction medium in organic synthesis when it was observed that cycloadditions, sigmatropic rearrangements, Michael additions and aldol condensations carried out in LP-DE occurred quickly and selectively under mild reaction conditions [33]. In addition, LP-DE allowed the reaction and subsequent work-up to be carried out under essentially neutral conditions. 

We have explored two types of carbon-carbon bond forming reactions operated under almost neutral conditions. Both reactions are initiated by the formation of an H-Rh-Si species through oxidative addition of a hydrosilane to a low-valence rhodium complex. Aldol-type three-component couphngs are followed by the insertion of an a,yS-unsatu-rated carbonyl compound into a Rh-H bond, whereas silylformylation is accomplished by the insertion of an acetylenic moiety into a Rh-Si bond. 

Some other catalytic events prompted by rhodium or ruthenium porphyrins are the following 1. Activation and catalytic aldol condensation of ketones with Rh(OEP)C104 under neutral and mild conditions [372], 2. Anti-Markovnikov hydration of olefins with NaBH4 and 02 in THF, a catalytic modification of hydroboration-oxidation of olefins, as exemplified by the one-pot conversion of 1-methylcyclohexene to ( )-2-methylcycIohexanol with 100% regioselectivity and up to 90% stereoselectivity [373]. 3. Photocatalytic liquid-phase dehydrogenation of cyclohexanol in the presence of RhCl(TPP) [374]. 4. Catalysis of the water gas shift reaction in water at 100 °C and 1 atm CO by [RuCO(TPPS4)H20]4 [375]. 5. Oxygen reduction catalyzed by carbon supported iridium chelates [376]. - Certainly these notes can only be hints of what can be expected from new noble metal porphyrin catalysts in the near future. 

Recently, Corey and coworkers prepared the cinchonidine-derived bifluoride 20 from the corresponding bromide by passage of a methanolic solution through a column of Amberlyst A-26 OH- form, and subsequent neutralization with 2 equiv. of 1 N HF solution and evaporation (the modified method C in Scheme 9.5). The catalytic activity and chiral efficiency of 20 (dried over P205 under vacuum) have been demonstrated by the development of a Mukaiyama-type aldol reaction of ketene silyl acetal 21 with aldehydes under mild conditions, giving mostly syw-P-hydroxy-a-amino esters 22 as the major diastereomer with good to excellent enantiomeric excesses (Table 9.4) [23],... 

In place of active methylene compounds having a nitrile group, malonates, 13-ketoesters, 1,3-diketones, 1,1-disulfones, nitro compounds, Mel drum acid, and anthrone can also be used as the Michael donors for these ruthenium-catalyzed aldol and Michael reactions. The reaction proceeds well in acetonitrile under mild and neutral conditions (Eq. 9.59) [83]. 

Proton abstraction of the polar C-H bond with base is a well-established heteroly-tic C-H bond cleavage to obtain carbanion. Ruthenium complexes can act as a base in nonpolar media to provide highly selective catalyses, as in the Murahashi aldol and Michael reactions. These reactions are highly chemoselective under neutral and mild conditions, where cyanoesters preferentially react over 2,4-pentanedione with nucleophiles (Scheme 14.12) [26]. The mechanistic basis of this reaction is described in Section 14.2.2. 

In combination wifh t-butyldimethylsilyl chloride, InClj catalyzes the aldol reaction between aldehydes and t-butyldimethylsilyl enol ethers in anhydrous organic solvents [140]. It has recently been found that the InCh-catalyzed Mukaiyama aldol reaction proceeds in water (Tab. 8.26) [141]. The reaction proceeds cleanly under almost neutral conditions to give /1-hydroxy ketones. The aqueous phase with IriClj can be reused. Water-soluble aldehydes such as glyoxylic acid and a commercial formaldehyde solution can be used directly for these reactions. 

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