Intramolecular Michael

Alkenones were used by Rao and coworkers [40] to prepare cyclohexane derivatives which, for example, can be transformed into substituted arenes in a single step. Another interesting intermolecular Michael/intramolecular aldol reaction sequence for the construction of the highly substituted 2-hydroxybicy-clo[3.2.1]octan-8-one framework has been described by Rodriguez group [41]. This process can be extended to a three- and even a fourfold domino reaction [41a, 42, 43],... 

The following example completes the section of threefold anionic domino processes initiated by a SN-type reaction. As discussed earlier in Section 2.2, the reaction of a five-membered cyclic phosphonium ylide with enones, a, 3-unsaturated esters, and a, 3-unsaturated thioesters provides cycloheptene or hydroazulene derivatives in a domino Michael/intramolecular Wittig reaction. This sequence... 

This sequence involves a Henry reaction of 41 with nitromethane followed by a dehydration of the resulting acyclic D-heptitol derivative 42 and a Michael intramolecular addition of the resulting nitroolefin 43. 

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],... 

Fig. 10 Catalytic cycle for the organocatalytic domino Michael/intramolecular aldol condensation...

Michael intramolecular alkylation. The reaction of f-butyl lithioacetate (1) with ethyl 6-iodo-2-hexenoate 2 in the presence of potassium t-butoxide in THF at - 78° results in a single trans-1,2-disubstituted cyclopentane (3). Reaction of 2 with f-butyl lithiopropionate (4) under the same conditions results mainly in syn-5, but when HMPT is also present anti-5 is mainly formed. Similar stereoselectivity is observed in reaction of 1 and 4 with ethyl 6-iodo-2-heptenoate in formation of... 

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

Scheme 7.12 One-pot Michael/intramolecular [3 + 2] cycloadditions for the synthesis of complex bicyclic isoxazolidines.

In a related work, a useful procedure for the synthesis of cyclohexenones was also developed by means of the reaction of ethyl benzoylacetate with methyl alkenyl ketones, using primary amine 129 as catalyst in this case. This reaction also consisted of a Michael/intramolecular aldol reaction sequence starting... 

Scheme 7.23 Cascade Michael/intramolecular condensation for the synthesis of cyclohexenes.

In a completely different context, a cascade Michael/intramolecular addition process involving nitroalkenes and isocyanoesters has been developed, which results in a formal [3 -I- 2] cycloaddition reaction and therefore consisting of a direct and very efficient methodology for the asymmetric synthesis of 2,3-dihydropyrroles (Scheme 7.70). ° The reaction was catalyzed by cinchona... 

Scheme 7.74 Epoxidation of enones by cascade oxa-Michael/intramolecular nucleophilic displacement.

There are a couple of examples of cascade processes starting by a Michael-type addition of a carbon nucleophile proceeding under phase-transfer eatalysis conditions which deserve to be mentioned at this point. The first one eonsists of an enantioselective cyclopropanation of 2-bromocyclopentenone by a cascade Michael/intramolecular nucleophilic displacement in which a variety of C-H acidic carbon pro-nucleophiles such as nitromethane, cyanomethylsulfone and benzyl cyanoacetate reacted with this Michael acceptor in the presence of a quinidinium salt of type 67 (Scheme 7.79). In addition, the conditions needed to be optimized for each Michael donor employed, requiring a different catalyst and inorganic base for each case. Under the best conditions, the final cyclopropanes were obtained in moderate yields and enantioselectivities, albeit as single diastereoisomers. 

Related cyclopropanations have also been reported using sulfonium and telluronium ylides as intermediates. In particular, the cyclopropanation of enones has been carried out employing an allyl bromide as the cyclopropa-nating reagent and sulfonium and telluronium salts 134 and 135 as pre-catalysts (Scheme 7.84). These species, in the presence of a base, generated the corresponding ylide which underwent the cascade Michael/intramolecular nucleophilic substitution and it is in this second step that the real catalytically active species is released, able to interact with another molecule of the allyl bromide and thus regenerating the sulfonium or telluronium salts pre-catalysts, which can afterwards continue in the catalytic cycle. The substitution at the... 

Recently, the Biju group demonstrated a highly enantioselective NHC-eatalyzed synthesis of functionalized cyclopentenes via o,p-unsaturated acyl azolium intermediates. This organo cascade reaetion of modified enals with malonic ester derivatives having a y-benzoyl group involves the Michael/ intramolecular aldol/p-lactonization/decarboxylation sequence to deliver functionalized cyclopentenes in good yields and excellent ee values (up to 85% yield and >99% ee) (Scheme 7.105). 

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). 

A large number of enantioselective domino Michael/intramolecular heterocyclization reactions have been successfully developed in the last years, using three... 

Scheme 11.5 Cu-catalyzed Michael/intramolecular alkylation reaction of 20 [12).

SCHEME 16.19. Enantioselective domino Michael/intramolecular cylization reaction. 

In a related transformation, the same group described a three-component domino reaction of 2-hydroxy-l,4-naphthoquinone, acting as a P-dicarbonyl surrogate, aromatic aldehydes and 1-(2-oxo-2-phenylethyl)pyridinium bromides in the presence of ammonium acetate, in water under microwave irradiation, that affords naphtho[2,3-Z)]furan-4,9-diones 31 [22]. Mechanistically, this domino reaction probably follows the same Knoevenagel-Michael intramolecular S 2 pathway described for the preparation of compounds 28, with ammonium acetate acting in this case as the base, to give intermediates 33. These compounds, which can be considered as tautomers of a hydroquinone species, would be finally transformed into the observed quinones by air-promoted oxidation, yielding the final products 31 (Scheme 1.16). 

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

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