Michael addition amides

The monoamide 5-oxo-cyclam (43) is prepared from 2,3,2-tet by a Michael addition/amide condensation reaction with (m)ethylacrylate, or by reaction with the bifunctional nucleophile chloroacetyl chloride. 

Intramolecular tandem Michael addition-amide formation in the intermediate (291) afforded an epilupinine precursor (Scheme 60) <89H(29)1209>. Another quinolizidine synthesis forming two a bonds in its key step is the reductive double alkylation of azido epoxides with an (o leaving group (292). This strategy has been applied to the synthesis of ring-expanded analogues of indolizidine alkaloids (e.g. (293)) from D-arabinose (Scheme 61) <93TL822l>. 

Oxidative dimerization of various 2-benzyloxy-2-thiazoline-5-ones (222) catalyzed by iodine and triethylamine is another example of the nucleophilic reactivity of the C-4 atom (469) (Scheme 112). Treatment of 212 with pyrrolidinocyclohexene yields the amide (223) (Scheme 113). The mechanism given for the formation of 223 is proposed by analogy with the reactivitx of oxazolones with enamines (4701. 4-Substituted 2-phenylthiazol-5(4Hi-ones react with A -morphoiino-l-cyclohexene in a similar manner (562j. Recently. Barret and Walker have studied the Michael addition products... 

Aqueous ammonia and acryUc esters give tertiary amino esters, which form the corresponding amide upon ammonolysis (34). Modem methods of molecular quantum modelling have been appHed to the reaction pathway and energetics for several nucleophiles in these Michael additions (35,36). 

Another approach to processible bismaleimide resins via a Michael addition chain extension, is the reaction of bismaleimide, or alow melting mixture of bismaleimides, with aminobenzoic hydrazide to provide a resin that is soluble in various solvents, such as acetone [67-64-1methylene chloride [75-09-2] and dimethylform amide [68-12-2] (33). The idealized chemical stmcture for a 2 1 BMI—aminobenzoic hydrazide resin is as follows ... 

When the enamine is in conjugation with a carbonyl function, as in a-aminomethylene aldehydes (528,529), ketones (530), or esters (531), a Michael addition is found in vinylogous analogy to the reactions of amides. An application to syntheses in the vitamin A series employed a vinyl lithium compound (532). 

Vinylogous amides undergo reduction with lithium aluminum hydride, by Michael addition of hydride and formation of an enolate, which can resist further reduction. Thus -aminoketones are usually produced (309, 563,564). However, the alternative selective reduction of the carbonyl group has also been claimed (555). 

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

For amide enolates (X = NR2), with Z geometry, model transition state D is intrinsically favored, but, again, large X substituents favor the formation of nt/-adducts via C. Factors that influence the diastereoselectivity include the solvent, the enolate counterion and the substituent pattern of enolate and enonc. In some cases either syn- or unh-products are obtained preferentially by varying the nature of the solvent, donor atom (enolate versus thioeno-late), or counterion. Most Michael additions listed in this section have not been examined systematically in terms of diastereoselectivity and coherent transition stale models are currently not available. Similar models to those shown in A-D can be used, however all the previously mentioned factors (among others) may be critical to the stereochemical outcome of the reaction. 

A limited number of examples only exist for the Michael addition of lithium enolates to a,)3-unsaturated amides high stereocontrol was observed in only a few cases62-67,379. 

The Michael addition of lithium enolates of amides, which have preferentially the Z geometry, under kinetically controlled conditions to a,/i-unsaturated esters provides a highly... 

In general, the Michael addition of a-substituted amide dienolates to a,/j-unsaturated esters is a method with great future potential for the diastereoselective construction of adjacent tertiary and quaternary stereogenic centers80. 

The published synthesis does the Michael addition first to give (19) which is not isolated but combined immediately with symmetrical (18). Amide formation to give (17) and condensation to give (16) occur under the same conditions and decarboxylation is carried out in the usual way,... 

Amide disconnection reveals (18) and FGl (amino to nitro) gives (19) which could be made by Michael addition of nitro compound (16) to an acrylate ester.. lalys-ts... 

A thio-substituted, quaternary ammonium salt can be synthesized by the Michael addition of an alkyl thiol to acrylamide in the presence of benzyl trimethyl ammonium hydroxide as a catalyst [793-795]. The reaction leads to the crystallization of the adducts in essentially quantitative yield. Reduction of the amides by lithium aluminum hydride in tetrahydrofuran solution produces the desired amines, which are converted to desired halide by reaction of the methyl iodide with the amines. The inhibitor is useful in controlling corrosion such as that caused by CO2 and H2S. 

The scheme used to prepare the direct 8-aza-analogue 21 of estrone bears at least formal similarity to the Torgov-Smith steroid total synthesis sequence. Acylation of the phenethylamine 9 with acryloyl chloride gives amide 16. Michael addition of dimethylamine followed by Bischler-Napieralski cyclodehydration gives the dihydroisoquinoline, 17. 

Since mild activation conditions appear to be important, a number of solution activation conditions were tested. PAMAM dendrimers are comprised of amide bonds, so the favorable conditions for refro-Michael addition reactions, (low pH, high temperature and the presence of water) may be able to cleave these bonds. Table 1 shows a series of reaction tests using various acid/solvent combinations to activate the dendrimer amide bonds. Characterization of the solution-activated catalysts with Atomic Absorption spectroscopy, FTIR spectroscopy and FTIR spectroscopy of adsorbed CO indicated that the solution activation generally resulted in Pt loss. Appropriate choice of solvent and acid, particularly EtOH/HOAc, minimized the leaching. FTIR spectra of these samples indicate that a substantial portion of the dendrimer amide bonds was removed by solution activation (note the small y-axis value in Figure 4 relative... 

Michael addition by hydrazine, cyclization, and subsequent amide formation led to the synthesis of the tricyclic 5 6 5 ring system 273 from the cinnamoyl-substituted amine 272 (Equation 74) <2003HAC530>. 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

A series of 2-(thiazol-5-yl)acetamides and acetates 35a/b has been prepared in one pot from the reactions of benzotriazolylthione derivatives 32 with A,A-dimethyl-4-A ,A -bis(trimethylsilyl)aminobut-2-yne amide 31a and ethyl 4-A,A-bis(trimethylsilyl)aminobut-2-ynoate 31b, respectively <06TL8661>. Presumably, the initial adducts 33a/b undergo intramolecular thia-Michael addition to give 34a/b, which isomerize to thiazoles 35a/b. 

In 2002, Leadbeater and Torenius reported the base-catalyzed Michael addition of methyl acrylate to imidazole using ionic liquid-doped toluene as a reaction medium (Scheme 6.133 a) [190], A 75% product yield was obtained after 5 min of microwave irradiation at 200 °C employing equimolar amounts of Michael acceptor/donor and triethylamine base. As for the Diels-Alder reaction studied by the same group (see Scheme 6.91), l-(2-propyl)-3-methylimidazolium hexafluorophosphate (pmimPF6) was the ionic liquid utilized (see Table 4.3). Related microwave-promoted Michael additions studied by Jennings and coworkers involving indoles as heterocyclic amines are shown in Schemes 6.133 b [230] and 6.133 c [268], Here, either lithium bis(trimethylsilyl)amide (LiHMDS) or potassium tert-butoxide (KOtBu) was em-... 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

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