Unsaturated Aldehydes, Acids, and Esters

Nielsen developed a set of rules for a, 8-unsaturated acids and esters that are similar to those for enones (Table 10.9). 

Double bond is in a six-membered ring, adds nothing 

With or or yS alkyl groups With a,p or P,P aUcyl groups With OC,p,P alkyl groups 

The absorptions that result from transitions within the benzene chromophore can be quite complex. The ultraviolet spectrum contains three absorption bands, which sometimes contain a great deal of fine structure. The electronic transitions are basically of the n- - n type, but their details are not as simple as in the cases of the classes of chromophores described in earlier sections of this chapter. 

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Lithium aminoborohydrides are obtained by the reaction of -BuLi with amine-boranes [FF2, FH5, NT2]. They can be generated in situ as THF solutions or as solids when formed in diethylether or hexane (n-BuLi must then be used in sub-stoichiometric amounts). They are stable under dry air and are slowly decomposed by water [NT2] or methanol so that workup of the reactions mixtures can be carried out with 3M HCl. They reduce alkyl halides (Section 2.1), epoxides (Section 2.3), aldehydes, and ketones (Section 3.2.1) (in the latter case with an interesting stereoselectivity [HFl]), and esters to primary alcohols (Section 3.2.5). a,(3-Unsaturated aldehydes, ketones, and esters are reduced to allyl alcohols (Section 3.2.9) [FF2, FS2]. Depending on the bulkiness of the amines associated with the reagent and to the substrate, tertiary amides give amines or alcohols (Section 3.2.8) [FFl, FF2]. Amines are also formed from imines (Section 3.3.1) [FB1 ] and from azides (Section 5.2) [AFl]. However, carboxylic acids remain untouched. 

The primary site of electrophilic attack on 5(4//)-oxazolones is at position C-4. The oxazolones are activated by deprotonation. For example, a variety of 2,4-disubstituted-5(4.H)-oxazolones (80) react with l-fluoro-2,4-dinitrobenzene and sodium carbonate to give 2,4,4-trisubstituted products <88CB67>. When the products are refluxed in methanol containing a catalytic amount of p-toluene-sulfonic acid, they rearrange to 1-hydroxyindazoles (81) (Scheme 24). Apparently, under certain conditions the site of electrophilic attack may be diverted to the 2 position <93TL3907>. Methylene chloride solutions of a, -unsaturated aldehydes, ketones, and esters containing a catalytic amount... 

A question of regiochemistry arises with O-silylated dienolates derived from a, -unsaturated aldehydes, ketones and esters. The silylated dienolates of crotonaldehyde and its 3-methyl derivative (108) react with acetals in Lewis acid catalyzed conditions at the y-position. This high regioselectivity has been used in the synthesis of vitamin A acetate (Scheme 41). ... 

Simple a,/3-unsaturated aldehydes, ketones, and esters participate preferentially in inverse electron demand (LUMOdlcne controlled) Diels-Alder reactions with electron-rich, strained, or simple olefinic and acetylenic dienophiles.3 5 The thermal reaction conditions for promoting the [4 + 2] cycloadditions of simple 1-oxabutadienes (R = H > alkyl, aryl > OR), cf. Eq. (1), are relatively harsh (150-250°C), and the reactions are characterized by competitive a,/3-unsaturated carbonyl compound dimerization or polymerization. Usual experimental techniques employed to compensate for poor conversions include the addition of radical inhibitors to the reaction mixture and the use of excess 1-oxabutadiene for promoting the [4 + 2] cycloaddition. Recent efforts have demonstrated that Lewis acid catalysis and pressure-promoted reaction conditions28-30 may be used successfully to conduct the [4 + 2] cycloaddition under mild thermal conditions (25-100°C). 

Catalysts suitable specifically for reduction of carbon-oxygen bonds are based on oxides of copper, zinc and chromium Adkins catalysts). The so-called copper chromite (which is not necessarily a stoichiometric compound) is prepared by thermal decomposition of ammonium chromate and copper nitrate [50]. Its activity and stability is improved if barium nitrate is added before the thermal decomposition [57]. Similarly prepared zinc chromite is suitable for reductions of unsaturated acids and esters to unsaturated alcohols [52]. These catalysts are used specifically for reduction of carbonyl- and carboxyl-containing compounds to alcohols. Aldehydes and ketones are reduced at 150-200° and 100-150 atm, whereas esters and acids require temperatures up to 300° and pressures up to 350 atm. Because such conditions require special equipment and because all reductions achievable with copper chromite catalysts can be accomplished by hydrides and complex hydrides the use of Adkins catalyst in the laboratory is very limited. 

In 2004, List reported that several ammonium salts including dibenzylammonium trifluoroacetate catalyzed the chemoselective 1,4 reduction of a, 5-unsaturated aldehydes with Hantszch esters as hydride sources [40]. It is assumed that substrate activation via iminium ion formation results in selective 1,4 addition of hydride. Subsequently, List [41] and MacMillan [42] reported asymmetric versions of this reaction promoted by chiral imidazoUdinone salts. In this context, several reports of this metal-free reductive process catalyzed by chiral phosphoric acids have appeared in the recent literature. 

Catalytic oxidation of ozonides over platinum appears to be accompanied by the same ester by-product disadvantage found in the thermal process. Chain degradation by other reactions is less serious, however, and transesterification does not occur. The method can therefore be used to prepare a half-ester of a dicarboxylic acid from an ester of a suitable unsaturated acid. If ozonide autoxidation occurs by the route, ozonide — aldehyde — peracid, with the latter acting as precursor of both acid and ester products (20-24), it is interesting to compare reaction rates observed in the present study with the rate of uptake of oxygen by... 

Methyl 8-oxooctanoate-4,5-D2, 35, and methyl 12-oxododecarbate-4,5,8,9-D4, 36, have been synthesized32 as shown in equations 13 and 14 by monoozonization and sodium acetate cleavage of 1,5-cyclooctadiene and 1,5,9-cyclododecatriene, respectively. The resultant unsaturated aldehydic acids 37 and 38 have been converted to the corresponding acetal esters, which have been deuteriated with Wilkinson s catalyst33 and hydrolysed to the deuterium-labelled aldehydic esters 35 and 36 in 47% and 49% overall yields and... 

This reaction type leading to oc,/ -unsaturated acids and esters is exemplified in the Perkin reaction (Section 6.12.3, p. 1036) and the Knoevenagel reaction (Section 5.11.6, p. 681). The Doebner reaction, which is illustrated in this section, is the condensation of an aldehyde with malonic acid in pyridine solution, often in the presence of a trace of piperidine. The reaction mechanism involves the addition of a malonate anion to the aldehydic carbonyl carbon atom followed by the elimination of water accompanied by decarboxylation. 

Aromatic carboxylic acids, a,/f-unsaturated carboxylic acids, their esters, amides, aldehydes and ketones, are prepared by the carbonylation of aryl halides and alkenyl halides. Pd, Rh, Fe, Ni and Co catalysts are used under different conditions. Among them, the Pd-catalysed carbonylations proceed conveniently under mild conditions in the presence of bases such as K2CO3 and Et3N. The extremely high toxicity of Ni(CO)4 almost prohibits the use of Ni catalysts in laboratories. The Pd-catalysed carbonylations are summarized in Scheme 3.9 [215], The reaction is explained by the oxidative addition of halides, and insertion of CO to form acylpalladium halides 440. Acids, esters, and amides are formed by the nucleophilic attack of water, alcohols and amines to 440. Transmetallation with hydrides and reductive elimination afford aldehydes 441. Ketones 442 are produced by transmetallation with alkylmetal reagents and reductive elimination. 

In summary, a stereoselective 10-step total synthetic route to the antimalarial sesquiterpene (+)-artemisinin (1) was developed. Crucial elements of the approach included diastereoselective trimethylsilylanion addition to a,p-unsaturated aldehyde 16, and a tandem Claisen ester-enolate rearrangement-dianion alkylation to afford the diastereomerically pure erythro acid 41. Finally, acid 41 was converted in a one-pot procedure involving sequential treatment with ozone followed by wet acidic silica gel to effect a complex process of dioxetane formation, ketal deprotection, and multiple cyclization to the natural product (+)-artemisinin (1). The route was designed for the late incorporation of a carbon-14 label and the production of a variety of analogues for structure-activity-relationship (SAR) studies. We were successful in preparing two millimoles of l4C-l73 which was used for conversion to I4C-arteether for metabolism75 and mode of action studies.76,77... 

For the study of the physical and chemical properties of triply unsaturated fatty acids and for the comparison with y-linolenoic acid [6Z,9Z.12Z)-6,9,l2-octadeca-trienoic acid] coworkers of the Unilever Research Centre in Vlaardingen (Netherlands) synthesized some methyl esters of ( ,Z,Z)-trisunsaturated fatty acids 73). For the preparation of the esters of (2E,9Z, 12Z)-2,9,12-octadecatrienoic acid and of (2 ,11Z,14Z)-2,11,14-eicosatrienoic acid (68 a and b) they used the Wittig reaction to introduce the ( )-2-double bond into the starting diunsaturated aldehyde. Reduction of the acid chlorides of (7Z,10Z)-7,10-hexadecadienoie acid and of linolenoic acid (65a and b) with lithium tri-tert-butoxyaluminium hydride affords the corresponding aldehydes 66 a and b which can be olefinated with the stable ylide 67 to methyl ( ,Z,Z)-alkatrienoates 68a, b with a (Z)-2-isomer content of 4.6%73) (Scheme 13). 

The alkylhydroperoxides are also interesting because of their formation in natural products. Unsaturated fatty acids and their esters (plant oils) are oxidized in air to peroxides (auto-oxidation). This leads to a stepwise breaking of the double bonds leading to the formation of aldehydes, ketones and fatty acids, all of which make their presence known through their strong odor intensities (e.g. rancid oil). 

Diisobutylaluminum benzenetellurolate, prepared from diphenyl ditellurium and diisobutylaluminum hydride, adds in a 1,4-fashion to a,/i-unsaturated aldehydes, ketones, and carboxylic acid esters to give as intermediates /i-phenyltelluro-substituted aluminum enolates that can be hydrolyzed to the carbonyl compounds or reacted with aldehydes to produce aldol adducts2. 

A range of nucleophiles will undergo conjugate additions with a, 3-unsaturated carbonyl compounds, and six examples are shownbelow. Note the range of nucleophiles, and also the range of carbonyl compounds esters, aldehydes, acids, and ketones. 

Ionic liquids were initially developed as solvents for electrochemical applications. The electrochemical window of clean ionic liquids can be huge/11 allowing for a wide range of redox reactions/2,31 It has further been demonstrated that they are also suitable solvents for enzymatic oxidations14 71 but both topics are beyond the scope of this book. Only transformations that involve the metal-catalysed addition of oxygen to unsaturated carbon bonds as well as the oxidation of alcohols, aldehydes and ketones to their corresponding ketones, carboxylic acids and esters shall be discussed in this chapter. 

The alkene reduction reactions most frequently observed are of a,3-unsaturated aldehydes, ketones, acids and esters. Examples of stereospecific reductions of acyclic substrates are given in Scheme 50.148.157-159 (j, (, e formation of (123), the double bond of (122) is reduced prior to the aldehyde function. The conversion of (124) to (125) involves oxidation of the intermediate alcohol to the carboxylic acid by bubbling air into the fermentation medium. Stereospecific reductions of a, 3-unsaturated ketones may be similarly effected (Scheme 61). The reduction of the chloro ketone (126) gives (127) initially. This epimerizes under the reaction conditions, and each enantiomer is then reduced further to (128) and (129), with the predominance of the (128) stereoisomer increasing with the size of the R-group. Reduction of ( )-(130) leads to (131) and (132). ... 

Anionic activation of Si—H bonds " by fluorides, such as KF or CsF, or by potassium phthalate, KHCO3, KSCN, etc., yields powerful hydridic reagents that reduce the carbonyl group of aldehydes, ketones and esters, " and 1,2-reductions of a,p-unsaturated aldehydes and ketones occur with high selectivity. " The analogous activation of hydridosllanes by fluoride ions is also achieved under acidic conditions with boron trifluoride etherate, in which the latter compound is consumed and fluorosilanes are formed. ... 

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