Unsaturated aldol-type reactions

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 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... 

Scheme 120 illustrates aldol-type reaction of aldehydes and silyl ene-thiolates catalyzed by 20 mol % of Sn(II) triflate-chiral diamine combined system in propionitrile or dichloromethane (291). A variety of aldehydes such as aliphatic, ,/3-unsaturated, and aromatic aldehydes are usable. The reaction is facilitated by high affinity of the Sn atom to sulfur atoms and the weak Si—S bond. A binaphthol-containing Ti oxo... 

As for the unsaturated carbonyl compounds, the most significant groups are the oc,/ -unsaturated acids or esters. Some of their methods of formation are closely analogous, for example, (a) the Horner-Emmons or Wadsworth-Emmons reaction, and (b) the aldol-type reactions. Rather more specific methods are considered below for the formation of a,/ -acetylenic acids, and for the conversion of the unsaturated dicarboxylic acid, maleic acid, into its anhydride or into fumaric acid. 

Tandem radical addition-aldol-type reaction of a,/3-unsaturated oxime ethers bearing an Oppolzer sultam auxiliary leads to stereoselective incorporation of alkyl groups in the 5- and 3-positions in tetrahydrofurans (Scheme 77) <2005AGE6190>. The observed /ra r,/ra r-stereoselectivity was explained by invoking a cyclic six-membered ring transition state. 

Another possibility to obtain thioamides from thioamides is via electrophilic attack in the a-position (Scheme 6). Thus, aldol-type reactions are feasible and proceed with high erythro selectivity providing (30), or even allowing optically active products (c/. Volume 2, Chapter 1.6). Heating with a form-amide 0,V-acetal gives an a,3-unsaturated thioamide (31) in a sequence of electrophilic attack and elimination. ... 

Spectacular enantioselection has been observed in hydrogenation (cf. Section 2.2) [3] and hydrometallation of unsaturated compounds (cf. Section 2.6) [4], olefin epoxidation (cf Section 2.4.3) [5] and dihydroxylation (cf Section 3.3.2) [6], hydrovinylation (cf Section 3.3.3) [7], hydroformylation (cf Section 2.1.1) [4a, 8], carbene reactions [9] (cf Section 3.1.10), olefin isomerization (cf Section 3.2.14) [10], olefin oligomerization (cf Section 2.3.1.1) [11], organometallic addition to aldehydes [12], allylic alkylation [13], Grignard coupling reactions [14], aldol-type reactions [15], Diels-Alder reactions [12a, 16], and ene reactions [17], among others. This chapter presents several selected examples of practical significance. 

The Knoevenagel condensation is a base-catalyzed aldol-type reaction, and the exact mechanism depends on the substrates and the type of catalyst used. The first proposal for the mechanism was set forth by A.C.O. Hann and A. Lapworth Hann-Lapworth mechanism) In 1904." When tertiary amines are used as catalysts, the formation of a p-hydroxydlcarbonyl Intermediate is expected, which undergoes dehydration to afford the product. On the other hand, when secondary or primary amines are used as catalyst, the aldehyde and the amine condense to form an Imlnlum salt that then reacts with the enolate. Finally, a 1,2-ellmlnatlon gives rise to the desired a,p-unsaturated dicarbonyl or related compounds. The final product may undergo a Michael addition with the excess enolate to give a bis adduct. 

Sulfonyl carbanions undergo aldol-type reactions with aldehydes and ketones to give p-hydroxy sulfones which can be converted into alkenes (the Julia reaction) (see Chapter 10, p. 197). With allyl methyl sulfones (75) and a,p-unsaturated carbonyl compounds (63),... 

Cp 2Sm(THF)2 has been used as an efficient catalyst for the acylation of alcohols with vinyl esters to give the corresponding esters in moderate to good yields (Scheme 317). In addition, Sml2 was found to catalyze an aldol-type reaction of imines in the presence of a formiate to the corresponding a,/3-unsaturated imines in satisfactory yields.1109... 

The Claisen-Schmidt Reaction. When aromatic aldehydes are treated with aliphatic ketones in the presence of base, three reactions might be expected a Cannizzaro reaction of the aromatic aldehyde an aldol-type reaction of the ketone or a crossed aldol reaction between the ketone and the aromatic aldehyde. In either of the last two possibilities dehydration might also occur. Undoubtedly all these reactions will take place in strong base, but by employing about 10 per cent aqueous sodium hydroxide, good yields are often obtained of j3-unsaturated carbonyl conipounds derived from a crossed aldol reaction between the aldehyde and the ketone. This reaction, generally called a Claisen-Schmidt reaction, can be illustrated by the synthesis of benzalacetophenone.16... 

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]. 

The indium-mediated allylation reaction is an aldol-type reaction where the nucleophile is an allylindium species usually generated from allylic halide and indium. By far the greatest number of indium-mediated organic reactions involves the allylation of unsaturated compounds, and the list of indium-mediated allylations is formidable. In principle, there are five types of indium-mediated allylation reactions depending on the unsaturated functional groups (Scheme 9). 

Diastereo-Controlled Aldol-Type Reactions between C4-CHIRAL 3-Acetyl-1,3-TH1AZOLIDINE-2-THIONES (ATT) AND a, -UNSATURATED ALDEHYDES... 

There was no problem with selectivity in the second aldol reaction because the aldehyde is not enolizable. The Reformatsky reaction in this sequence illustrates the fact that, as you saw in Chapter 26, aldol-type reactions happen at the ester oxidation level as well, and you should equally look to disconnect P-hydroxy or a,P-unsaturated esters, acids, or nitriles in this way. Just remember to look for 1,3-relationships, convert the functional groups to oxygen-based ones, and disconnect them to d plus a synthons. 

Vinylogous aldol-type reaction of aromatic and heteroaromatic aldehydes with silyl dienol ethers 21.115, derived from a,p-unsaturated esters, also proceeded smoothly, furnishing exclusively the y-addition products 21.116 (>99 1) with high enantioselectivity in the range of 82-98%... 

Tables 1 and 2 show some examples of self- or cross-aldol condensation reactions followed by dehydration to obtain a,/3-unsaturated carbonyl compounds. Also in Table 1, a review of methyl isobutyl ketone (a saturated ketone) synthesis in the presence of hydrogen is included (10). In Table 2, some examples of fine chemicals obtained by aldol-type reactions are shown.

The classic Perkin reaction is the base-catal) ed condensation of an aromatic aldehyde with a carboxylic acid anhydride to yield and an a,p-unsaturated carboxylic acid. The initial stages of the condensation can be viewed as an aldol-type reaction (see Experiments [20], [SAadv], [3Badv], and [A3aj. 

Alternatively, Li et al. reported a RUCI2 (PPhs) 3 -catalyzed reshuffling of functional groups of homoallylic alcohols in water (Eq. 4.61). The reaction led to an aldol-type reaction by reacting allyl alcohols with aldehyde (Scheme 4.23). The presence of In(OAc)3 promoted the aldol reaction with a -vinylbenzyl alcohol and aldehyde. An indium hydride-promoted reductive aldol reaction of unsaturated ketones in aqueous media was developed. The use of water/methanol as a solvent dramatically reverses stereochemistry from anti to syn. Boron enolates have been used for aldol reactions in water using catalytic amounts of boron reagents. 

The aldol reaction has long been recognized as one of the most useful synthetic tools. Under classical aldol reaction conditions, in vhich basic media are usually employed, dimers, polymers, self-condensation products, or a,j5-unsaturated carbonyl compounds are invariably formed as byproducts. The lithium enolate-mediated aldol reaction is regarded as one useful synthetic means of solving these problems. Besides the vell-studied aldol reaction based on lithium enolates, very versatile regio- and stereoselective carbon-carbon bond forming aldol-type reactions have been established in our laboratory by use of boron enolates (1971), silicon enolates-Le vis acids (1973), and tin(II) enolates (1982). Here we describe the first t vo topics, boron and silicon enolate-mediated crossed aldol reactions, in sequence. 

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