Michael pyrroles with ketones

The pivotal step associated with our approach to compounds 31-34 was an organocatalysed, enantioselective and intramolecular Michael addition reaction of the nucleophilic C-2 carbon of a pyrrole to an iV-tethered a,p-unsaturated aldehyde residue and thereby estabhshing the required CD-ring system. Full details of the reaction sequence are shown in Scheme 4 and this involves initial reaction of the potassium salt, 35, of pyrrole with butyrolactone (36) to give, after acidic workup, compound 37 (60-90%). Conversion of this last species into the corresponding Weinreb amide 38 (87%) followed by its reaction with ethylmagnesium bromide then afforded the ethyl ketone 39 (95%) that was subjected to standard Homer-Wadsworth-Emmons (HWE) conditions and thereby generating the... 

It was also possible to perform the pyrrole 5 Michael addition with a variety of a,p-unsaturated ketones 2 catalyzed by MSSA in the same fashion, affording 2-substituted pyrroles 6 in good yields (Scheme 1.3b). Furthermore, MSSA was used as a solid acid heterogeneous catalyst to synthesize 1,1,3-triindolyl compounds through the tandem Michael addition and Friedel-Craft reaction of a, P-unsaturated aldehydes or ketones and indole (3) (Scheme 1.4). The authors found two protocols of general applicability employing 1 mmol of a,P-unsaturated compound and 4 mmol... 

The Michael dclclidon of nitro ilkdnes to a,fi-unsdnirdted ketones gives Y-nitroketones, which re convetted into pyrroles by reduction of the nitro group with and PhSSPh fEq. 10.2. ... 

Several iodine-catalyzed organic transformations have been reported. Iodine-catalyzed reactions are acid-induced processes. Molecular iodine has received considerable attention because it is an inexpensive, nontoxic and readily available catalyst for various organic transformations under mild and convenient conditions. Michael additions of indoles with unsaturated ketones were achieved in the presence of catalytic amounts of iodine under both solvent-free conditions and in anhydrous EtOH (Scheme 19) [85,86]. l2-catalyzed Michael addition of indole and pyrrole to nitroolefins was also reported (Scheme 20) [87]. 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

It has also been demonstrated that ketimines may participate in reactions with nitrostyrenes providing fused pyrroles, as shown by the preparation of the system 311. The series of events leading to this outcome were suggested to involve a Michael-type addition of the enamine tautomer of the substrate 312 to the olefin, followed by annulation with concomitant elimination of the nitro functionality (Equation 92) <1999TL4177>. In addition, solid-state reactions of enamine esters or ketones with ( )-l,2-dibenzoylethene induced by milling gave excellent yields of pyrroles <1999AGE2896>. 

When the p-ketoamide 133, containing an acidic methine group and pendant nucleophilic pyrrole substituent, was dissolved with methyl vinyl ketone (53) in dichloromethane and treated at room temperature with PS-BEMP (10%), the Michael adduct 134 was formed as the sole reaction product in 100% yield. 

The stabilised anion of tosylmethyl isocyanide (TosMIC) (or of benzotriazol-l-ylmethyl isocyanide -BetMlC ") adds in Michael fashion to unsaturated ketones and esters, with subsequent closure onto isocyanide carbon, generating the ring. Proton transfer, then elimination of toluenesulfinate generates a 3//-pyrrole that tautomerises to an aromatic pyrrole that is unsubstituted at both a-positions. Addition of the TosMIC anion to unsaturated nitro-compounds gives rise to 2,5-unsubstituted-3-nitropyrroles. ... 

Recent examples, for instance, of the catalytic application of the commercially available macroporous Amberlyst-15 include the Michael addition of pyrroles to a,P-unsaturated ketones (Scheme 10.4) [48]. In this process, the acid ion exchange resin (dry, 10% w/w) allows on to obtain mono and dialkylated pyrroles 5 and 6 in reasonable yields. Similarly, this catalyst (dry, 30% w/w) can catalyze the aza-Michael reaction of amines with a,P-unsaturated ketones, esters and nitriles to afford 7 in 75-95% yields under solvent-free conditions. Interestingly, yields were significantly lower using typical solvents such as DCM (dichloromethane), CH3CN, THF, DMF or EtOH [49], Recycling the catalyst is possible in both cases, but a smooth decrease in the yield is observed for each new run. 

Full details are also available of the structure elucidation of elaeokanines A-E, and elaeokanidines A-C, the leaf alkaloids of E. kaniensis Schltr. further, the structures of elaeokanines A-C have been confirmed by synthesis. The reaction of the diazoketone prepared from butyroyl chloride and diazomethane with pyrrole in the presence of copper powder gave the ketone (9), which was hydrogenated to the basic pyrrolidine ketone (10). Michael addition of ethyl acrylate... 

Both pyrrole and indole anions are sufficiently nucleophilic to react with Michael acceptors such as unsaturated esters, ketones and nitriles. When the reaction is done under alkaline conditions the alkylation usually occurs at nitrogen. Pyrrole and indole are also reactive Michael acceptors under... 

Application of solid-state chemistry for quantitative multistep cascades in a ball mill is also demonstrated by reaction of enamine ketone 291 with 1,2-dibenzoylethene 292 (Scheme 3.78). Pyrrole derivative 293 was obtained by Kaupp et al. in quantitative yield through four reaction steps (vinylogous Michael addition, imine/enamine rearrangement, cyclization, and elimination), without the use of add catalysts [18]. 

Thus, the asymmetric catalysis of cyanoethoxycarbonylation, cyanophosphoryla-tion, epoxidation of electron-deficient olefins, Michael reactions of malonates and (3-keto-esters, Strecker reaction of keto-imines, conjugate addition of cyanide to a, (3-unsaturated pyrrole amides, ring opening of meso aziridines with TMSCN and cyanosilylation of ketones (example shown below) have been successfully carried out using these complexes as asymmetric catalysts. 

Reported examples of the second reaction occur at the j8-position in an a,a -disubstituted pyrrole. Whilst for the second reaction there is no evidence to indicate the intermediate formation of ethyl methylenemalonate, followed by Michael addition, pyrroles can participate in such additions. Examples are the ready reaction with ethynyl ketones , with quinones" and with acrylic esters (in the presence of boron trifluoride etherate)" ... 

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