Tandem Michael/intramolecular

Tandem Michael-intramolecular Wittig reactions of cyclic-ylide (81) with... 

Fujimoto and co-workers ° have reported a tandem Michael-intramolecular Corey haykovsky reaction of the five-membered cyclic oxosulfonium ylide 247 with acetates of the MBH adducts in the presence of base, producing cyclo-heptene oxide derivatives 248 as a single stereoisomer. However, in the case of the six-membered oxosulfonium ylide 247, the cyclooctane oxide derivatives 249 were obtained as a mixture of stereoisomers in moderate yields (Scheme 3.95). 

Scheme 2.43 Tandem Michael/intramolecular alkylation sequence between bro-momalonate and nitroalkenes catalysed by a preformed diamine nickel catalyst.

Other types of multicomponent reactions have also been successfully developed, such as the first practical three-component imino-Reformatsky reaction, and a pseudo-three-component reaction between allenes and isocyanates, providing excellent levels of enantioselectivity. Finally, excellent results were described for several novel enantioselective tandem sequences. For example, very high enantioselectivities were reached in tandem Michael/ intramolecular cyclisation sequences, as well as in a remarkable multicat-alytic Michael sequence occurring between enones, alkynes, and DIBAL, which stereoselectively afforded a range of chiral p-alkenyl ketones bearing an all-carbon-substituted quaternary stereogenic centre in excellent enantioselectivities. 

The first tandem Michael-intramolecular Horner-Wittig olefination of 3-(dietho qqjhosphoiyl)coumarins (428) with 2,5-hexanedione (429) has been reported by Krawczyk et al. In a simple and fully diastereoselective process, corresponding functionalised cyclopentene[c]chromanones... 

Unfortunately, much of Fiesselmann s work was documented only in patents and doctoral theses, allowing for the rediscovery of this classic reaction in recent years. In fact, as late as 1997, the Fiesselmann reaction of 5 with methylthioglycolate was rediscovered as a novel, tandem Michael addition/intramolecular Knoevenagel approach to thiophenes such as 6 ... 

The enolate of the 1,4-adduct, obtained after the stereoselective Michael addition step, as discussed in the previous sections, may be quenched in situ with various electrophiles. The fact that additional stereogenic centers may be formed via such tandem Michael addition/quench-ing procedures, giving products with high diastereoselectivity in many cases, extends the scope of these methods substantially. Furthermore these procedures occasionally offer the possibility of reversing the syn/anti diastereoselection. In the next sections pertinent examples of diastereoselective inter- and intramolecular quenching reactions will be discussed. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

NHCs have also been shown to promote the reaction of benzoins and methyl acrylate to produce y-butyrolactones (Scheme 44) [143], In the absence of dimeth-ylimidazolium iodide, the reaction does not proceed. The mechanism is still under investigation, although the authors propose that the transformation may proceed via a tandem transesterification/intramolecular Michael addition LXVin or Michael... 

An interesting alternative intramolecular cyclisation was discovered by Jprgensen and co-workers [187]. Although not strictly exploiting an enamine intermediate, the transformation represents a secondary amine catalysed Morita-Baylis-Hillman reaction leading to a series of highly functionalised cyclohexene products. Reaction of the Nazarov reagent 137 with a,P-unsaturated aldehydes in the presence of the diarylprolinol ether 30 led to the cyclohexene products 138 (49-68% yield 86-96% ee) via a tandem Michael/Morita-Baylis-Hillman reaction (Scheme 54). 

Very recently examples of tandem Michael-azomethine ylide cyclization reactions have been presented.626 Thus, divinyl sulfone reacted with imine (124) in the presence of lithium bromide and tri-ethylamine to give (126) in 40% yield (Scheme 38). Presumably formation of Michael adduct (125), tau-tomerization to an azomethine ylide and ensuing intramolecular [3 + 2] cycloaddition afforded (126). Indeed, (125) could be independently synthesized and converted to (126) under the reaction conditions. The preference for initial Michael addition, rather than cycloaddition, was variable. When (124) and divinyl sulfone were treated with silver acetate and triethylamine in DMSO, intermolecular azomethine cycloaddition occurred giving (127) in 27% yield. 

Carbocyclization of m-alkcnyl-z-methoxybcnzy I lithiums to form five- or six-membered rings has been studied 101 the five-membered ring is formed with a cis-stereochemical relationship between the methoxy substituent and the adjacent methyl group. Intramolecular carbolithiation of vinyl sulfides at — 105°C in THF has been found to occur non-stereospecifically with regard to the newly formed C—Li centre.102. The stereochemistry of selective tandem Michael addition alkylation reactions of vinylphosphonates has been explored.103... 

Intramolecular tandem Michael reaction.1 Angular triquinane sesquiterpenes such as pentalenene (5) have been synthesized from the bis(enone) 1 by an ntramolecular tandem Michael reaction as the key step for conversion to the rncvclic system. Lithium amides, even bulky ones, are not useful for this step, nor > dimethyl-t-butylsilyl triflate. Annelation can be achieved by reaction of 1 with c lSi(CH3)3, zinc chloride, and N(C2H5), at 160° in either toluene or CH2C12. Use... 

An intramolecular tandem Michael aldol reaction was described for esters that have an enolizable aldehyde in the molecule. The lithium ester enolate generated through the Michael reaction undergoes an intramolecular aldol reaction. Thus, the reaction of unsaturated esters 153 with lithium benzylthiolate provided the expected cyclization products 156 and 157 via (w-formylenolate 154 in an excellent cis stereoselectivity (Scheme 49)no. 

Polyfluoroalk-2-ynoic acids such as 20 readily undergo tandem interniolecular-intramolecular Michael addition with ethane-1,2-dithiol to provide the 2-pol)dluoroalkylated 1,3-dithiolanes 22 m good to excellent yields. The method can be extended to other binucleophiles including propane-1,3-dithiol.2-sulfanylethanol, and 2-aminoethanethiol. ... 

The synthesis of both enantiomers of the antitumor-antibiotic fredericamycin A was achieved in the laboratory of D.L. Boger. The DE ring system of the natural product was assembled via a tandem Michael addition-Dieckmann condensation. The highly substituted 4-methylpyridine precursor was treated with excess LDA followed by the addition of the Michaei acceptor cyciopentenone. The Michael adduct underwent an intramolecular acylation with the ester functionaiity in situ to afford the desired DEF tricycie. 

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]. 

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. 

Functionalised nucleophiles normally need to be protected, as in the synthesis of the bicyclic enone 67 which requires the addition of a d3 reagent to cycloheptenone 69. The Me2S complex of the Cu(I) derivative of 70 fills this role deprotection and cyclisation being accomplished in acid solution.28 This synthesis also illustrates that tandem Michael-aldol sequences of this kind with an intramolecular aldol are perfectly satisfactory. 

The 1,4-Michael addition on solid phase was studied using various nucleophiles. Intramolecular and tandem Michael additions have also been investigated. Several representative examples are given. Until now, only one example has been reported where the nucleophile has been attached to the resin. 

As enolates of type 14 are formed as intermediates in intramolecular allylsilane Michael additions (e.g., 18), a tandem Michael addition-Cope rearrangement can be used as a method for the construction of fused cyclooctenones, e.g., formation of 19926. 

Intramolecular tandem Michael addition-amide formation in the intermediate (291) afforded an epilupinine precursor (Scheme 60) <89H(29)1209>. Another quinolizidine synthesis forming two a bonds in its key step is the reductive double alkylation of azido epoxides with an (o leaving group (292). This strategy has been applied to the synthesis of ring-expanded analogues of indolizidine alkaloids (e.g. (293)) from D-arabinose (Scheme 61) <93TL822l>. 

Treatment of acetylenic ketones 2 with methyl thioglycolate gave in a tandem Michael-ad aon intramolecular A"noevenage/-condensation highly substituted thiophenes 18 in high yields (entry e). 

Since the mechanism of chalcogenide-MBH reaction involved the Michael addition of chalcogenide to electron-deficient olefins and the intramolecular Michael addition reaction of a sulfide group to an enone moiety in an acidic medium is known, Kataoka et al. envisaged that the tandem Michael aldol... 

---