Michael addition-aldol reaction

Recently, the Texier-Boullet group [26] has prepared nitrocyclohexanols 10-77 by a twofold Michael addition/aldol reaction sequence (Scheme 10.19). Simply mixing chalcone 10-75 with nitromethane in the presence of a mixture of KF and A1203 under microwave irradiation gave 10-79 via the proposed intermediates 10-76, 10-77 and 10-78 as a single diastereomer in 65 % yield. One possible explanation for the stereoselectivity of the transformation is fixation of the reactive species onto the solid KF/A1203, as depicted in 10-79. 

An efficient and selective procedure for the synthesis of spiro-fused isoxazolinopyrazol-3-ones 23 from 2-(spiro-isoxazolino) jS-keto esters 21, starting from methyl acrylate 14, has been developed by Kurth and co-workers (02JOC876) (Scheme 5). The process consists of utilizing the Baylis-Hillman reaction, or a quicker stepwise Michael addition, Aldol reaction and Cope elimination (MAC) procedure, 1,3-dipolar... 

This methodology furnished also an efficient access into the furofuran skeleton, Scheme (19). A tandem Michael addition-aldol reaction was used to provide lactone 107 in 62% yield as a mixture of diastereomers in a ratio of 60 40. Dithiane 107 was converted into ketone 108 using HgO in combination with BF3 Et20. Subsequent reduction using an excess of LiAlH4 afforded tetraol 109 in 67% yield. The synthesis of (-)-eudesmin (110) was completed in 16% overall yield by dehydratation of 109 with BF3 Et20. 

Ohnemuller UK, (nee Schmid), Nising CF, Nieger M, Erase S (2006) The Domino Oxa-Michael-addition Aldol Reaction - an Access to Variably Substituted Tetrahydroxanthenones. Eur J Org Chem 29 1535... 

Formally, the MBH reaction involves a sequence of Michael addition, aldol reaction and P-elimination. The commonly proposed mechanism consists in a reversible conjugate addition of the nncleophile to the starting enone 237, generating an intermediate enolate 238. This enolate reacts with the electrophilic aldehyde in an aldol-type process, in which two stereogenic centers are formed, to give 239, which suffers an intramolecnlar acid-base eqnilibrinm to give another enolate 240. From this intermediate, the p-elimination of the nncleophile provides the MBH product... 

Since this pioneering study, a breathtaking number of naturally occurring alkaloid derivatives have emerged, finding application in a wide range of processes such as alkylations, Michael additions, aldol reactions, Darzens... 

Scheme 1.40 Silylated biphenylprolinol-catalysed triple cascade Michael addition-Michael addition aldol reactions.

Shibasaki also disclosed an application that incorporates an asymmetric tandem Michael addition-aldol reaction sequence with this family of bimetallic catalysts [117], as shown for the synthesis of the prostaglandin 11-deoxy-PGF (132, Scheme 12.16) [119]. In this route, the first two stereo-genic centers in the cyclopentane ring are installed in the course of an asymmetric Michael addition of malonate 128, followed by trapping of the resulting enolate 129 with aldehyde 130. The sequence provided the trans-cyclo-pentanone 131 in 92% ee. The stereoinduction at Cy was observed to range from dr 6 1 to dr 17 1, although this was inconsequential, as the secondary alcohol at C7 was later excised. 

When the cnolate of an enone is brought into reaction with an enone, usually a carbocyclic system is prepared by two consecutive Michael additions (M1MIRC reactions). Due to the lower temperatures employed and the absence of diene polymerization these reactions are useful alternatives for Diels-Alder reactions and proceed in general with high diastereoselectivities. When neither enolate nor enone is cyclic a monocyclic system is formed 338 which can be converted into a bicyclic system when the Michael addition is followed by an aldol reaction339. When, however, the enolate is cyclic a bicyclic or a tricyclic system is formed340 341. 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

A SN reaction-based domino route to clerodane diterpenoid tanabalin (2-488) [258] has been described by Watanabe s group (Scheme 2.111) [259]. This natural product is interesting as it exhibits potent insect antifeedant activity against the pink bollworm, Pectinophora gossypiella, a severe pest of the cotton plant The domino sequence towards the substituted trans-decalin 2-487 as the key scaffold is induced by an intermolecular alkylation of the (5-ke toes ter 2-484 with the iodoalkane 2-483 followed by an intramolecular Michael addition/aldol condensation (Robin-... 

Enantioselective organocatalytic conjugate additions such as Michael and aldol reactions have been intensely studied under new catalysts. However, only a few organocatalyzed Michael reactions have been developed. The reaction involves construction of a new C-N bond that is very attractive for syntheses of molecules with biological properties. 

Application of this work to a domino process using 51 involves Michael addition of P-ketoesters [91], p-diketones or P-ketosulfones [92] to a,P-unsaturated ketones followed by an intramolecular aldol reaction provides highly functionalised cyclohexanone building blocks with up to four contiguous chiral centres. Gryko has also reported examples of this domino Michael/intramolecular aldol reaction in the coupling of 1,3-diketones and methyl vinyl ketone using L-proUne as catalyst [93],... 

In another study Feringa et al. [20] reported a catalytic enantioselective three-component tandem conjugate addition-aldol reaction of dialkyl zincs. Here, zinc enolates were generated in situ via catalytic enantioselective Michael addition of dialkylzinc compounds to cydohexenone in the presence of a chiral Cu catalyst. Their diastereoselective reaction with an aldehyde then gave trans-2,3-disubstituted cyclohexanones in up to 92% yields and up to >99% ees (Scheme 9.11). 

Lewis acid-catalyzed tandem Michael imino-aldol reactions enable the one-pot synthesis of 7-acyl-(5-lactams from a, j6-unsaturated thio-esters, silyl enolates and imines [15]. For the initial Michael addition, the combination of SbClj with Sn(OTf>3 (5 mol %) proved to be efficient. However, after the addition of the imino compound the iminoaldol product was isolated in moderate yield. For the enhancement of turnover and yield, Sc(OTf)3, once again proved to be the Lewis acid of choice (Scheme 4, 15 16 = 81 19, 94%). 

Among the fluoride ion promoted reactions which occur in dipolar non-HBD solvents are alkylations of alcohols and ketones, esterifications, Michael additions, aldol and Knoevenagel condensations as well as eliminations for a review, see reference [600]. In particular, ionic fluorides are useful in the dehydrohalogenation of haloalkanes and haloalkenes to give alkenes and alkynes (order of reactivity R4N F > K ([18]crown-6) F > Cs F K F ). For example, tetra-n-butylammonium fluoride in AjA-dimethylformamide is an effective base for the dehydrohalogenation of 2-bromo-and 2-iodobutane under mild conditions [641] cf Eq. (5-123). 

The isoquinuclidine ring system is readily accessible through various synthetic routes. The most widely used approach to the construction of the ISQ ring system is through Diels-Alder or 4+2 cycloaddition reactions. Dihydropyridines (DHPs) or 1,3-cyclohexadienes are most commonly employed as diene components and various dienophiles have been employed based on the substitution pattern of the final desired product. Intramolecular cyclizations, tandem-Michael addition/aldolizations or cyclization via tricyclic aziridines or perhydro / -aminobenzoic acid derivatives have also been reported. Several synthetic routes employing asymmetric or chiral synthetic approaches have also been reported. Most recently, solution-phase parallel synthesis of ISQ derivatives using several of these approaches has been reported [49,50,51]. 

The Diels-Alder addition of 69 to methyl acrylate [76] gave the cycloadduct 70 in only 23% yield while addition to acryloyl chloride [77] followed by esterification afforded 71 in higher yield (57%) (Scheme 6). Removal of the bulky silyl group of 69 facilitated the DA reaction and allowed for the production of 71 by a tandem Michael addition/aldolization, which has proven useful in the construction of ISQs. Desilylation of 70 with BU4NF on silica gel, followed by... 

An alternative tandem Michael addition/aldol condensation for the synthesis of 3,5-diaryl-substituted phenols 121 employs, instead of 1-(2-oxopropyl)pyridinium chloride (112), l-(benzotriazol-l-yl)propan-2-one (119) in the presence of excess of NaOH in refluxing ethanol (equation 106) ". Under these conditions, several types of 3,5-diaryl-substituted phenols 121 have been obtained in 52-94% yield. The reaction proceeds by Michael addition of the enolate of 119 to the a,/3-unsaturated ketone 118 to afford intermediate 120, which then undergoes an intramolecular aldol condensation with elimination of benzotriazole. 

Synthesis of fused cyclohexenones by reaction of cyclanones with vinyl ketones (base or acid catalyzed), a tandem Michael addition-aldol condensation (see 1st edition). 

---