Acetaldehyde, Michael reactions

The yield of the cyclization step under the influence of a metal template can be increased when the corresponding dialdehyde 19 of the tetrapyrrole 16 is used. The reaction sequence is initiated by insertion of palladium(II) or nickel(II) into the tetrapyrrole to give 20 followed by Michael addition of one acrylaldehyde side chain to the other yielding the macrotetracycle 21 from which in a retro-Michael reaction acetaldehyde is eliminated to give 22. 

The 0-TBS-hydro>y-diphenylprolinol silyl ethers 14, analogues of the Jorgensen-Hayashi catalyst 3a, were tested in 2008 by List and coworkers for the challenging catalytic asymmetric Michael reactions of acetaldehyde with nitroalkenes. While 4-hydroxy-proline derivative 14a displayed diminished activity, but slightly better enantioselectivity with respect to 3a, the 3-hydroxy-proline derivative 14b gave in this case very poor results (Scheme 11.12). 

A catalytic triple domino Michael-aldol-oxa-Michael reaction of acetaldehyde with ( -2-(2-nitrovinyl)phenols catalyzed by (R)-2- diphenyl [(trimethylsilyl)oxy] methyl pyrrolidine followed by a sequential one-pot Wittig, Michael/Wittig-Horner reactions with PPh3=CHC02Et was applied to the asymmetric synthesis of polyfunctionalized chromans (14EJO3076). 

Scheme 2.19 Michael reaction of acetaldehyde and synthetic applications...

In particular, as a more challenging nucleophile, acetaldehyde was also suitable for the Michael addition with nitroalkenes. Using diarylprolinol silyl ether 7 as catalyst. List and co-workers [8] and Hayashi et al. [9] independently developed the first organocatalytic Michael reaction of acetaldehyde to afford a-unsubstituted y-nitro aldehydes in moderate to good yields and with excellent enantioselectivities (Scheme 5.3). The synthetic utility of this reaction was illustrated by List and... 

Garcia-Garcia P, Ladepeche A, Haider R, List B. Asymmetric Michael reaction of acetaldehyde catalyzed by diphenylproli-nol silyl ether. Angew. Chem. Int. Ed. 2008 47(25) 4719-4721. 

The forward scheme for this strategy is shown below. One equivalent of ethanol is oxidized with PCC to give acetaldehyde, which is then heated with aqueous sodium hydroxide to give an a,P-unsaturated aldehyde (via an aldol condensation reaction). Another equivalent of ethanol is oxidized with chromic acid to give a carboxyhc acid, which is then treated with ethanol under acidic conditions to give an ester (via Fischer esterification). The ester is then converted into a P-ketoester (via a Claisen condensation). The P-ketoester is then deprotonated with ethoxide to give a doubly stabilized enolate which then attacks the a,P-unsaturated aldehyde to give a Michael reaction ... 

Adolph Baeyer is credited with the first recognition of the general nature of the reaction between phenols and aldehydes in 1872 ([2,5-7] [18], Table 5.1). He reported formation of colorless resins when acidic solutions of pyrogallic acid or resorcinol were mixed with oil of bitter almonds, which consists primarily benzaldehyde. Baeyer also saw resin formation with acidic and basic solutions of phenol and acetaldehyde or chloral. Michael and Comey furthered Baeyer s work with additional studies on the behavior of benzaldehyde and phenols [2,19]. They studied a variety of acidic and basic catalysts and noted that reaction vigor followed the acid or base strength of the catalyst. Michael et al. also reported rapid oxidation and darkening of phenolic resins when catalyzed by alkaline materials. 

The stereoselective intramolecular Henry reactions have been reported by Seebach. The Michael addition of doubly deprotonated acetyl acetaldehyde to l-methylenedioxyphenyl-2-nitroethene followed by subsequent intramolecular nitro-aldol cyclization leads to the diastereomerically pure cyclohexanone derivative, where the nitro and OH groups are cis as shown in Eq. 3.73.114 This reaction is applied to the synthesis of l-desoxy-2-lycorinone as shown in Eq. 3.74.115... 

An accessory proposal was Arthur Michael s hypothesis that many reactions proceed by addition, for example, a polymerization of acetaldehyde (CH3CH = O) in the presence of bases (OH) to an aldol (CH3CHOHCH2CHO), with subsequent loss of water to form crotonaldehyde (CH3CH = CHCHO). Michael, educated in America, Germany, and France, made use of Kekule s idea that two molecules may form a "polymolecule" or molecular compound, which, in turn breaks up to yield the final products.33 Lachman expressed fairly standard misgivings about this proposal of an intermediary and transition form "If we are going to explain reactions by means of addition products which we do not or cannot isolate, our explanation loses its definiteness. It becomes simply a possible explanation, and its conclusions are by no means binding."34... 

The pentane-1,5-dione is usually formed in situ by aldol- or Michael-type reactions (203 — 204 — 200). Thus, acetaldehyde (203 R = H, R = Me) and ammonia give 4-picoline and 3-ethyl-4-methylpyridine by formation of the intermediate (205), condensation with another molecule of MeCHO, and subsequent dehydrogenation. The same reaction also yields 2-picoline and 5-ethyl-2-methylpyridine via the intermediate (206). Such reactions are used industrially. 

Michael addition to a complexed styrene. A key step in a synthesis of 11-deoxy-anthracyclinone (3) involves the regioselective reaction of 1 with the carbanion of a protected acetaldehyde cyanohydrin to give 2 by stereospecific earo-addition. 

Thiamine anions add to aldehydes and ketones (e.g., acetaldehyde, carbohydrates, and pyruvic acid). Pyruvic acid adducts decarboxylate with a half-life of 24 hours in water and 3.2 minutes in ethanol, since ethanol cannot stabilize the intermediate zwitterion as well as water. After acidification, acetaldehyde is split off. In the adduct between acetaldehyde and thiamine, the electrophilic carbon atom of the aldehyde undergoes an Umpolung " to a resonance-stabilized enolate carbon atom. The thiazole-bound acetaldehyde then functions as carban-ion in Michael additions under mildly basic conditions. Retro-aldo reactions are observed, when 1,3-thiazolium ions react with the carbonyl groups of carbohy-... 

Detailed mechanistic studies of this reaction have been undertaken hy several teams. Michael addition of the simplest enolisahle aldehyde, acetaldehyde, poses a significant challenge due to high auto-aldol reactivity of acetaldehyde. List and coworkers used prolinol silyl ether eatalysts to promote enantioselective Michael addition of acetaldehyde to nitroalkenes.The key to successful accomplishment of this transformation was slow addition of acetaldehyde via a syringe pump. 

Using a similar strategy, Hayashi described synthesis of dipeptidyl peptidase IV inhibitor ABT-421. The key reaction was Michael addition of acetaldehyde to a nitroalkene, followed by another Michael addition to unsaturated phosphonate and then HWE annulation. Lu and coworkers applied a different approach to the same molecule. They used ot,p-unsaturated aldehyde and a premade nitrophosphonate. ... 

Prolinol silyl ether catalysts were also able to control the Mannich reaction of acetaldehyde. Xu and coworkers utilised Michael adducts of aldehydes with nitroalkenes in the subsequent Mannich-type reaction with imines followed by cyclisation. Highly substituted chiral piperidines were formed. Suitable imines for organocatalytic Mannich reactions can also be generated in situ from amido sulfones (Scheme 8.34). ... 

Despite of the fact that Baylis and Hillman reported the synthesis of a-hydr-oxyethylated nitroethylene through the reaction between nitroethylene and acetaldehyde in the presence of DABCO, nitroalkenes employed as activated olefins in MBH reaction have not received much attention until recently. Prompted by the fact that nitroalkenes have shown superior Michael acceptor abilities, and that the first step in the MBH reaction is the Michael-type addition of the catalyst to substrate, Namboothiri et al. have published a series of papers on nitroalkenes involved the MBH reaction. The MBH reactions between nitroalkenes and various electrophiles such as formaldehyde, activated carbonyl compounds, imines, alkenes and azodicarboxylates " in the presence... 

An interesting variant of these Michael-type additions is the 1,6-addition of the anion of type (29) to a dienyl sulfone as a route to tagetones and 1,4-addition to nitrostyrene to form 3-nitro ketones. A key step in a synthesis of 11-deoxyanthracyclinone involves die regioselective reaction of complexed stjmne with lithiated protected acetaldehyde cyanohydrin. ... 

An NHC catalyst gives yields up to 86% in Stetter reactions of acetaldehyde with a variety of Michael acceptors, and a chiral version gives fair ees ... 

In 2012, a comparable combination of catalysts was employed by Jorgensen et al. to induce a Michael-initiated cascade reaction of atyloTgr-acetaldehydes to give the corresponding chiral 3,4-dihydrocoumarins. As shown in Scheme 2.33, these important products were produced in good yields and moderate to high enantioselectivities of up to 96% ee. 

The original method for the preparation of 2-perfluoroalkyl benzothiazoles by reaction of a-perfluoroalkyl aldehydes with 2-aminobenzenethiole includes dehydrofluoii-nation, Michael addition-cyclization followed by elimination of acetaldehyde [102]. 

Prior to the work on prostaglandins, Hayashi and coworkers found a new route to effectively produce the dipeptidyl peptidase IV-selective inhibitor ABT-341 (Scheme 14.6) [14]. The strategy also comprised a Michael addition and HWE reaction, but these were in this case used to generate disubstituted cyclohexene carboxylates instead. After a diphenylprolinol silyl ether (10 mol%)-promoted asymmetric Michael addition of acetaldehyde (2.0 equiv) to nitroalkene 38 (97% ee) in 1,4-dioxane in 5 h, another Michael addition was initiated by addition of vinyl phosphonate 40 (1.2 equiv) under basic conditions (CS2CO3, 2.0 equiv) at 0 °C in dichloromethane. The subsequent intramolecular HWE reaction in ethanol at room temperature afforded the cyclohexene in 15 min., which was isomerized in situ by the addition of DiPEA (10 equiv) to yield trans-43. 

The simplest enoUzable aldehyde, acetaldehyde, was until recently not examined in organocatalytic reactions due to its high reactivity as electrophile or as nucleophile leading to intractable mixture of products resulting from side reactions. The groups of List [63] and Hayashi [64] reported independently the use of acetaldehyde as donor in Michael addition to nitroalkenes (Scheme 34.24). They both selected diphenylprolinol silyl ether (6) as the best catalyst but employed different solvents (acetonitrile or DMF/Pr OH for LisL and 1,4-dioxane for Hayashi) at room temperature. Similar selectivities were observed under both conditions but higher yields were obtained with Hayashi s conditions. 

A similar organocatalytic quadruple domino Friedel-Crafts/Michael/Michael/ aldol condensation reaction initiated by Friedel-Crafts reaction of indole to acrolein was also developed by Enders et al. [48], as well as a microwave-assisted qnadruple cascade organocatalytic Michael/Henry condensation/Michael/aldol condensation anploying acetaldehyde and nitroalkenes as substrates [49]. 

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