Michael-type reactions tandem

Murata, K., Kitazume, T. Study of the effect of fluorine atom(s)on fluoromethylated imines in the tandem Mannich-Michael-type reaction. 

Via tandem Michael-type addition followed by an aza-Wittig reaction, 2,3,6,7-tetrahydro- and 2,3,4,5,6,7-hexahydro-lH-l,4-diazepines have... 

Novel aldol-type reactions under Cinchona-deriwed chiral thiourea catalysis was reported by Wang et al. [78]. In their report, a novel cascade Michael-aldol reaction was presented. The reaction involves a tandem reaction catalyzed via hydrogen-bonding with as little as 1 mol% catalyst loading to generate a product with three stereogenic centers (Scheme 28). hi the reaction of 2-mercaptobenzaldehyde 128 and a,P-unsatnrated oxazolidinone 129, the desired benzothiopyran 130 was formed smoothly in high yield and excellent stereoselectivity. 

From the retrosynthetic perspective (Fig. 2), the tetracyclic structure is expected to be accessible by tandem Michael-Dieckmann type reaction of 59 with 60. The suitably substituted chiral intermediate 59 would be synthesized by Diels-Alder reaction of the cyclohexenone 57 and the silyloxybutadiene 58. The regio- and stereoselectivities are established as a consequence of the dienophile geometry according to Gleiter s theory (29). Compound 57 could be obtained from 51 through Ferrier reaction of 54. 

Dommo-type reactions involve careful design of a multistep reaction in a one-pot sequence in which the first step creates the functionality to trigger the second reaction and so on, making this approach economical and environmentally friendly. A classical example of a tandem reaction is the Robinson annulation (a Michael reaction followed by aldol condensation and dehydration). 

Increasing importance has to be attributed to modem tandem (or cascade ) techniques—reaction sequences that can be performed as a one-pot procedure because the first reaction step creates the arrangement of functional groups needed for the second to occur. Schemes 5-7 present some in situ preparations for iminium species, which can then react further with appropriate nucleophiles that are already present (preferably in the same molecule). Most elegantly, in situ generation of iminium ions for tandem processes was performed by a 3,3-sigmatropic (aza-Cope-type) rearrangement (Scheme 5), but also by initial Michael-type addition reactions to vinyl-substituted Atio... 

Chen and coworkers have reported a new domino Michael-Michael addition reaction between a,a-dicyanoalkene [26] derived from cyclohexanone and benzyli-deneacetone, resulting in a stepwise [4 + 2]-type cycloaddition to afford almost enantiopure bicyclic adduct 15. In contrast to the completely inert function of secondary ammonium salt, a primary amine, 9-amino-9-deoxyepiquinine lo [27], in combination with trifluoroacetic acid, was found to be highly efficient in the activation of the a, 3-unsaturated ketone by tandem iminium-enamine catalysis (Scheme 10.21) [28],... 

An important type of tandem reaction arises when both steps are conjugate additions (Michael reactions, chapter 9). The most widely used case is the conjugate addition 38 of a kinetic a eno-late from an enone 37 (chapter 11) to a second enone. The resulting enolate than adds back 39 to the first compound in a second conjugate addition. The product 41 contains a six-membered ring formed in the tandem process. 

DBU (1) catalyses the formation of 2//-l-benzopyran from salicylic aldehydes and aUenic carbonyl compounds [82]. This reaction could be categorized as a tandem reaction composed of Michael and aldol-type reactions. Wide substrate tolerance on the aldehyde unit is observed. The introduction of a large phenyl group on and use of aUenyl ester diminishes the yield of benzopyrans (Table 3.6). 

Most recently, Xu et al. have demonstrated the first example of a diastereo-and enantioselective aza-MBH-type reaction by the asymmetric synthesis of p-nitro-y-enamines via a (li ,2i )-diaminocyclohexane thiourea derivative (182) mediated tandem Michael addition and aza-Henry reaction in good yields (up to 95%) with high enantioselectivities (up to 91% ee) and diastereoselectivities (up to 1 99 dr) (Scheme 2.90) easily prepared A -tosylimines and nitroalkene are employed as the starting materials. ... 

Sonogashira/nucleophilic addition (Scheme 7.34) [70], The reaction started by the Ugi-4CR, giving the intermediate 82, which was transformed into the enyne 83 by a Heck-Sonogashira tandem reaction. Finally, the activated enyne evolved an aza-Michael-type addition to give the final six-component product 84. 

The aldol-type reaction occurs in some processes (i.e. Weiss-Cook and Hantzsch reactions), in tandem with the Michael reaction. Therefore, some significant applications of this last reaction in aqueous media will be illustrated. 

Dihydrothiazolo[3,2-a]pyrimidin-5-ones 127 (Scheme 57) were prepared in a one-step reaction based on a Michael-type tandem reaction, by heating 2-thiobarbituric acid with ethyl 4-bromocrotonate in ethanol at 60 for 2 h, a 2,3-dihydrothiazolo[3,2-a]pyrimidin-5-one was obtained in 73% yield [83],... 

An unexpected result from the same series of work as above by Perumal et al was obtained when cycloalkenones were used as dienophiles [187]. Instead of the imino Diels-Alder product, azabicyclic ketones were obtained (Figure 8.79). The authors proposed a novel Diels-Alder reaction between In-dienolate ions as dienes, and the imines as dienophiles. Another possibility brought up by the authors was that the products were the result of a tandem aldol reaction on the imine, followed by a Michael-type cyclization reaction. 

Lee et al found that the reaction of cyclic 1,3-dicarbonyl compounds with a,P-unsaturated aldehydes did not give the Michael-type addition products observed for enones (see Section 8.4, Figure 8.26), but products from tandem Knoevenagel condensation and cyclization [210] (Figure 8.95). 

The successful achievement of the (/ )-LSB catalyst in asymmetric Michael addition suggested that the metal centers other than rare earths might lead to a novel heterobime-talhc asymmetric catalyst with unique properties. With this foundation, the same group further developed a new heterobimetallic chiral catalyst (/ )-ALB consisting of aluminum, lithium, and (/ )-BINOL in 1996 (Table 9.3). They reported that this type of catalyst could be more efficiently prepared from LiAlH with two equivalents of (/ )-BINOL. When this AlLibis(binaphthoxide) complex (/ )-ALB was employed as catalyst, up to 99% ee and 88% yield of products could be obtained in the reaction of dibenzyl malonate to 2-cyclohexen-l-one. Notably, both dimethyl and diethyl malonates furnished the 1,4-adducts with more than 90% of enantioselectivities. In particular, the catalytic asymmetric tandem Michael-aldol reactions were also achieved in the presence of (/ )-ALB. This protocol provides a usefid method for the catalytic asymmetric synthesis of complex molecules. 

Hetero substituted 2-cyclopropylideneacetates are ring-strain activated acrylates, highly reactive dienophiles in Diels-Alder reactions, but also powerful Michael acceptors. The reactivity of these compounds is enhanced by the same strain release in the Diels-Alder cycloadditions as well as in the 1,4-additions, and indeed the borderline between tandem Michael-cyclization and Diels-Alder-type cycloaddition is not well defined in many cases. 

---