Michael-initiated cascade

More recently, following the same strategy, Vicario and co-workers [60] described the first example of the use of hydrazone derivatives as nucleophiles in aza-Michael initiated cascades under iminium activation, opening an efficient enantioselective entry to functionalized dihydropyridazines (Scheme 16.30). 

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. 

Scheme 59 Oxa-Michael initiated cascade approaches toward spiroacetals...

Coquerel Y, Eilippini MH, Bensa D, Rodriguez J (2008) The MARDi cascade a Michael-initiated domino-multicomponent approach for the stereoselective synthesis of seven-membered rings. Chem Eur J 14 3078-3092... 

Abstract Cascade reactions involving a transition metal-promoted step and a Michael-type addition process have emerged as a powerful tool to construct cyclic and polycyclic structures. In this review, recent advances in this field are presented. The first part is related to cycloaddition reactions based on zwitterionic jr-allylPd complexes. The second part deals with Michael initiated metal-catalyzed cyclofunctionalization reactions of unactivated C C jt-bonds. Parts three and four feature reactions where an initial Michael addition reaction is followed by either a coupling reaction or an electrophilic trapping. Part five is devoted to Michael terminated reactions. 

Conversely, when the reaction was carried out by using Amberlyst A15 (200%) in the presence or absence of liquid BEMP (10%), the only observed reaction product was substituted pyrrole 135, which was isolated in 68% yield product 134 was not present at all in the reaction mixture. However, when the reaction was repeated by using a combination of PS-BEMP (10%) and Amberlyst A15 (200%), the sole reaction product was the desired tetracyclic product 136 -obtained in 83% yield as a 1 1 mixture of diastereoisomers. By using sub-stoichiometric quantities of PS-BEMP (10%) and Amberlyst A15 (50%), an 85% conversion into 136 after 5 days was produced. These results demonstrate that PS-BEMP and Amberlyst A15 can operate as mutually compatible strongly basic and strongly acidic reagents, respectively, in the same vessel to facilitate the Michael-initiated N-acyl iminium ion cyclization cascade. 

Table 3.12 Polycyclic products obtained by Michael-initiated A-acyl iminium ion cyclization cascade between p-ketoamides and a,p-unsaturated carbonyl compounds catalysed by PS-BEMP and Amberlyst A-15 mixture.

The Mannich reaction is a very common process that occurs in many tandem reaction sequences. For example, the Overman Aza-Cope cascade sequence is terminated by a Mannich reaction (cf. Scheme 35). Several groups have used variants of the Mannich reaction to initiate cascades that lead to the formation of heterocyclic molecules. For example, the Lewis acid-catalyzed intermolecular vinylogous Mannich reaction (01T3221) of silyloxy furan 281 with nitrone 282 produced a diastereomeric mixture (49 3 42 6) of azabicycles 284a-d in 97% combined yield (Scheme 52) (96TA1059). These products arose from an intramolecular Michael addition of the initially formed oxonium ion 283. 

Very recently, Pilling et al. explored a new methodology using a combination of PS-BEMP (10%) and Amberlyst A15 (200%) to facilitate the Michael-initiated V-acyl iminium ion cyclization cascade starting from p-ketoamide substrates, thus providing a unique entry to a variety of complex heterocyclic molecules [40] (Scheme 6.8). 

Pilling, A.W., Boehmer, J. and Dixon, D.J. (2007) Site-isolated base- and acid-mediated Michael-initiated cyclization cascades. Angewandte Chemie - International Edition, 46, 5428-5430. 

With a similar strategy of combined diarylprolinol silyl ether and N-heterocyclic carbene catalysts, j0rgensen and coworkers [21] examined the cascade reaction of easily accessible i-keto heteroaryl-sulfones as nucleophiles with a,P-unsaturated aldehydes (Scheme 43.11). In this cascade reaction, following the initial iminium ion-catalyzed Michael reaction of nucleophiles to a,(i-unsaturated aldehydes, the subsequent step was then promoted by carbene catalyst 57 to afford 2,4-disubstituted cyclopentenones 55 via an intramolecular benzoin condensation initiated Smiles rearrangement. The superiority of combinational use of two catalysts in the similar Michael/benzoin cascade reaction was also independently demonstrated by Enders et al. (Scheme 43.12) [22]. 

In addition to imininm-initiated cascade reactions, two of the steps in enamine-activated cascade reactions can also be enforced by cycle-specific catalysis. It is well known that diphenylprolinol silyl ether catalyst 34 is optimal for diverse enamine-mediated transformations to fnmish prodncts with high enantioselectivities. However, similar to imidazolidinone catalysts, it proved to be less effective or ineffective for bifunctional enamine catalysis. Cycle-specific catalysis via an aza-Michael/Mannich sequence by combining 34 and either enantiomer of proline was thus developed to generate 206 in about 60% yields with excellent diastereo- and enantioselectivities (Scheme 1.89) [139]. 

Cascade sequences involving Michael additions have also been reported recently for the synthesis of spiroacetals. An oxa-Michael initiated spirocyclization cascade sequence has been used in the synthesis of berkelic acid by both Fiirsmer et al. [128] and Brimble et al. [129] (Scheme 59). 

The history of dendrimer chemistry can be traced to the foundations laid down by Flory [34] over fifty years ago, particularly his studies concerning macro-molecular networks and branched polymers. More than two decades after Flory s initial groundwork (1978) Vogtle et al. [28] reported the synthesis and characterization of the first example of a cascade molecule. Michael-type addition of a primary amine to acrylonitrile (the linear monomer) afforded a tertiary amine with two arms. Subsequent reduction of the nitriles afforded a new diamine, which, upon repetition of this simple synthetic sequence, provided the desired tetraamine (1, Fig. 2) thus the advent of the iterative synthetic process and the construction of branched macromolecular architectures was at hand. Further growth of Vogtle s original dendrimer was impeded due to difficulties associated with nitrile reduction, which was later circumvented [35, 36]. This procedure eventually led to DSM s commercially available polypropylene imine) dendrimers. 

The solid-state interaction of enamines (428, 333a) with trans-l,2-diben-zoylethene (87) provides quantitative yields of the pyrrole derivatives 445 or 446 [140]. These remarkable 5-cascades consist of initial vinylogous Michael addition, enol/keto tautomerism, imine/enamine tautomerism, cyclization, and elimination, all within the crystal without melting. A waste-free extraordinary atom economy is achieved that cannot nearly be obtained in solution. The milling times are unusually long here (3 h) but it s certainly worth the effort... 

Poly(amidoamine)-(PAMAM-Starburst)-Monodendrons Among the first Starburst (Cascade) syntheses we performed in the early 1980s [83] involved partially masked (differentiated) initiator cores. For example dodecyl-amine, hydroxyalkyl amines or partially protected alkylene diamines were used as initiator cores and submitted to sequential (a) Michael addition with methyl acrylate followed by (b) reaction with an excess of ethylene diamine to give in situ branch cell construction in a divergent manner. The resulting products were core functionalized monodendrons as shown below ... 

Another type of metal-catalyzed cascade reaction using a Michael addition step was the use of this latter in the terminating step of the reaction in order to trap an initial intermediate created by a metal-catalyzed step. This particularly useful strategy was developed by several groups allowing the creation of polyfunctionalized structures. 

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... 

Repetitive strategy is a fundamental principle for the synthesis of dendrimers, that was first coined, to the best of our knowledge in our seminal cascade paper.1 It implies a repetitious sequence of the same reaction steps, as initially demonstrated in the synthesis of linear polyamines,1 by sequential Michael addition, followed by a facile nitrile reduction (Scheme 1). The preparation of Newkome s arborols5 is an-... 

It was suggested that this reaction proceeds via the DKR-mediated Michael-retro-Michael-Michael-Michael cascade reaction pathway the initially formed Michael adduct undergoes a DKR process in the presence of catalyst 81b, where the deprotonation of the highly acidic proton of 109 by the quinuclidine base of the catalyst leads to a reversible and stereoselective retro-Michael-Michael-Michael process. This proposal was supported by the observation that the reaction of racemic 109 with nitrostyrene under identical conditions depicted in Scheme 9.36... 

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