Michael reactions sequence

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

This domino6 Michael-Michael reaction sequence is one of the key steps in this synthesis and proceeds with complete asymmetric induction, which could be confirmed by X-ray crystallographic analysis. The two five-membered rings in the target molecule are thereby generated in a single step. 

This methodology opens up an efficient stereoselective access to chiral piperidi-none derivatives 60 which have opposite configuration compared to compounds 46 obtained by the tandem Mannich-Michael reaction sequence described in Section 4.3.2. The high diasteroselectivity and regioselectivity in these reactions once again illustrate the stereodifferentiating potential of carbohydrates in the synthesis of chiral heterocyclic systems. 

A Mannich/Michael reaction sequence was used by Waldman for the formation of several piperidone derivatives. The reaction of 285 with 286 in the presence of a... 

Using diene 288 and imine 289, the tandem Mannich/Michael reaction sequence afforded the vinylogous amide 290 in 66% yield (97TL2829). Imines derived from other aldehydes were also studied, providing derivatives of 290 in moderate yields... 

The next series of syntheses is based on conjugate additions. A 2-arylcyclo-hexanone was regio- and stereoselectively added to nitroethylene to access the octahydroindole core present in the alkaloids. This has enabled the total synthesis of (+j-y-lycorane and (+)-crinane (280). Tomioka described a chemoselective conjugate addition - nitro Michael reaction sequence to prepare a- and -lycoranes in their racemic form (281). The addition of an arylcuprate to a D-mannitol-derived... 

Enamine catalysis provided the synthetic platform for a second example of asymmetric MCR. In 2001, Barbas and colleagues described a Knoevenagel/Michael reaction sequence between acetone, benzaldehyde (14), and diethyl malonate (15) catalyzed by the chiral secondary amine 16 (Scheme 42.4). Despite the moderate level of enantioselectivity, this reaction was engineered upon rather sophisticated catalytic machinery [21]. The catalyst promoted both individual steps of the MCR, although only the second enamine-catalyzed process was stereo-determining. The... 

Figure 6.91 Use of alkyl C C]acetoacetates in a tandem Knoevenagel-Michael reaction sequence...

The Michael reaction plays a part in some more extended synthetic sequences of great importance. Analyse TM 116 as an a,p-unsaturated carbonyl compound and continue your analysis by the Michael reaction. 

This sequence of Michael reaction and cyclisation is known as tile Robinson annelation since it makes a ring. 

Another procedure relies on a domino Michael-O-alkylation reaction sequence to yield a variety of dihydrofurans. Combination of cyclohexanedione (30) with vinyl bromide 50 in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) provides dihydrofuran 51 in 83% yield. Numerous 1,3-dicarbonyls and vinyl bromides are amenable to this methodology, and thus a wide range of products like 51 are available via this strategy. 

Once formed, 7 and 8 undergo a Michael reaction that gives rise to ketoenamine 9. Ring closure, to form 10, and loss of water then afforded 1,4-dihydropyridine 11. The presence of 9 and 10 could not be detected thus ring closure and dehydration were deduced to proceed faster than the Michael addition. This has the result of making the Michael addition the rate-determining step in this sequence. Conversely, if the reaction is run in the presence of a small amount of diethylamine, compounds related to 10 could be isolated. Diol 20 has been isolated in an unique case (R = CFb). Attempts to dehydrate this compound under a variety of conditions were unsuccessful. Stereoelectronic effects related to the dehydration may be the cause. In related heterocyclic ring formations, it has been determined that dehydration (20 —> 10) is about 10 times slower than diol formation (19 —> 20). Therefore, one would expect 20 to... 

Another important feature of the Nef reaction is the possible use of a CH-NO2 function as an umpoled carbonyl function. A proton at a carbon a to a nitro group is acidic, and can be abstracted by base. The resulting anionic species has a nucleophilic carbon, and can react at that position with electrophiles. In contrast the carbon center of a carbonyl group is electrophilic, and thus reactive towards nucleophiles. 1,4-Diketones 4 can for example be prepared from a-acidic nitro compounds by a Michael additionfNef reaction sequence " ... 

An elegant example of sequence of reactions involving the Henry reaction, the Michael reaction, and elimination of HNO is demonstrated in a short synthesis of anthracyclmones. Nitromethane is used to introduce the ClO-gronp simultaneously v/irh the C9-hydroxy group fEq. 7,136. ... 

The yield of the cyclization step under the influence of a metal template can be increased when the corresponding dialdehyde 19 of the tetrapyrrole 16 is used. The reaction sequence is initiated by insertion of palladium(II) or nickel(II) into the tetrapyrrole to give 20 followed by Michael addition of one acrylaldehyde side chain to the other yielding the macrotetracycle 21 from which in a retro-Michael reaction acetaldehyde is eliminated to give 22. 

A common reaction sequence is shown in the schemes printed above. The sulfosuccinate monoesters are produced by a two-step reaction. In the first step 1 mol of maleic anhydride is reacted with a hydroxyl group-bearing component. In the second step the monoester is reacted with sodium sulfite (or sodium bisulfite) to form the disodium alkyl sulfosuccinate. At the so-called halfester stage, there are two possibilities for an electrophilic attack [61] (Michael-type reaction) at the double bond (Scheme 6). Reactivity differences between the two vinylic carbons should be very small, so that probably an exclusive formation of one single regioisomer can be excluded. 

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

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],... 

A novel cyclopropanation method based on a domino l,4-addition/SN sequence has recently been described by Florio and coworkers [95]. A diastereoselective Michael reaction of lithiated aryloxiranes 2-174, obtained from 2-173, onto an a,(3-un-... 

Coupling of the aminomethylindole 2-558 with acrolein in a Michael manner followed by a HWE reaction with phosphonates 2-560 afforded 2-561 which cyclized under basic conditions to give the desired product 2-566 via the intermediates 2-562-2-565 in 55 % yield (Scheme 2.127). The reaction sequence was also conducted in a stepwise manner, resulting in a greatly reduced yield this clearly demonstrates again the advantage of domino strategies over conventional methods. 

Recently, the Texier-Boullet group [26] has prepared nitrocyclohexanols 10-77 by a twofold Michael addition/aldol reaction sequence (Scheme 10.19). Simply mixing chalcone 10-75 with nitromethane in the presence of a mixture of KF and A1203 under microwave irradiation gave 10-79 via the proposed intermediates 10-76, 10-77 and 10-78 as a single diastereomer in 65 % yield. One possible explanation for the stereoselectivity of the transformation is fixation of the reactive species onto the solid KF/A1203, as depicted in 10-79. 

Another method that yields quinolizidine derivatives by creation of two ct-bonds from acyclic precursors is based on a domino process involving a sequence of a double N-deprotection and a double intramolecular Michael addition sequence of reactions, as summarized in Scheme 75 <2002TL6505>. 

The nonsymmetrical quinolizidine 373 was obtained from the acyclic symmetrical precursor 372 by means of a reaction sequence comprising azide formation, intramolecular 1,3-dipolar cycloaddition, thermal triazoline fragmentation to a diazoalkane, and Michael addition individual steps, as shown in Scheme 85 <2005CC4661>. 

A Michael addition-Nef reaction sequence was used in a synthesis of disaccharides. Addition of the sodium salt of 1-thio-D-glucose to sugar nitroolefin 112 gave a mixture of isomers 113. The subsequent deacetylation, followed by a Nef reaction, afforded the S -disaccharides 114 and 115 (Scheme 35).82... 

Recently, a synthesis of tetrodotoxin from D-glucose was described (Scheme 36). After a Michael addition of the lithium salt of bis(phenylthio)-methane to the nitroolefin 116, the major component (117b) of the resulting epimeric mixture 117a + 117b was subjected to a reaction sequence that involved an intramolecular nitroaldol reaction, to give the complex nitro cyclohexane derivative 118. 

---