Michael addition, nucleophilic additions

From the beginning one of the critical points in the chemistry of addition polyimides was to adjust the formulations in order to prevent brittleness of the final curing material. The first approach for improving the mechanical behaviour of poly(bismaleimides) was the incorporation of moieties which provide a separation of the two active maleimide groups. Diamines and dithiols have worked as very suitable spacers, capable to react with the double bonds of bismaleimides [301-304]. The reaction takes place by nucleophilic addition (Michael addition) on the electron-deficient double bond, which is activated by the two adjacent carbonyl groups (Scheme 56). The reaction is usually carried out in acidic solvents (m-cresol or DMF/acetic acid mixtures) to avoid cross-linking that occurs by reaction of the anionic intermediate with maleimide double bonds [305,306]. The mechanism for the reaction of thiols and maleimides is depicted in Scheme (56). 

The retrosynthesis involves the following transformations i) isomerisation of the endocyclic doble bond to the exo position ii) substitution of the terminal methylene group by a more stable carbonyl group (retro-Wittig reaction) iii) nucleophilic retro-Michael addition iv) reductive allylic rearrangement v) dealkylation of tertiary alcohol vi) homolytic cleavage and functionalisation vii) dehydroiodination viii) conversion of ethynyl ketone to carboxylic acid derivative ix) homolytic cleavage and functionalisation x) 3-bromo-debutylation xi) conversion of vinyl trimethylstannane to methyl 2-oxocyclopentanecarboxylate (67). 

Reaction of the ambidentate complex 1 with carbon nucleophiles results in exclusive 1,4-addition (Michael addition) to the enone-like acyl ligand no products of 1,2-addition of the nucleophile are observed (see also Houben-Weyl, Volume 13/9 a, p 416)38 39. 

Friedel-Crafts reactions are almost unknown in pyridine and azine chemistry. Direct electrophilic alkylation in the pyrimidine 5-position can be carried out on pyrimidines with at least two strongly donating groups, and more readily with three such groups. Thus, a-haloketones and a-bromocarboxylic esters can be used for direct alkylation of 6-aminouracils (118), for example in the formation of (119). The 5-position can also act as the nucleophile for Michael additions (e.g. 118 — 120, where a subsequent elimination occurs) (92AHC(55)129). For similar reactions in barbituric acids see (85AHC(38)229). 

Lactam 45 (R = H) was used, in base as a nucleophile in Michael addition, to yield iV-alkyl derivatives in good to high yields (73-90%), <1995TL829, 1995JME5045, 2000BMC1111> however, when ethylenediamine was reacted with artemisinin, dimer 46 was isolated in low yield (Equation 6) <2003MOL901>. 

Palladium chemistry has been used in the synthesis of tetrahydroisoquinolines. Different combinations of iodoaryl-amine-alkene can be used in these multicomponent reactions. For example, the metal-mediated o-alkylated/alkenyl-ation and intramolecular aza-Michael reaction (Scheme 109) give moderate yields of heterocycle <2004TL6903>, whereas the palladium-catalyzed allene insertion-nucleophilic incorporation-Michael addition cascade (Equation 172) produces good yields of tetrahydroisoquinolines in 15 examples <2003TL7445> with further examples producing tetrahydroquinolines (Scheme 110) <2000TL7125>. 

TABLE 12.4. Glutathione 5-Transferase-Mediated Conjugations Involving Nucleophilic Displacement, Michael Addition, and Nucleophilic Attack on Strained Oxirange Rings... 

Primary amines reacted via a palladium-catalysed allene insertion-nucleophilic incorporation-Michael addition cascade to give isoquinoline derivatives. The yields were good and fifteen examples are reported <03TL7445>. 

Various chelated lithium imide enolates have also served as nucleophiles in Michael additions to 3-trifluoromethyl acrylate, favoring the anti isomer (eq 22). ... 

Using tryptamine as the nucleophile, the Michael addition-cyclization strategy was extended to the enantioselective synthesis of the /J-carboline alkaloid system. Michael addition of tryptamine to the chiral acetylenic sulfoxides took place smoothly at room temperature. Either trifluoroacetic acid or p-toluene-sulfonic acid was effective as a catalyst for the cyclization step (Scheme 7). The results of the Michael addition-cyclization reaction sequence are summarized in Table 3. In general, we found that the indole moiety is more reactive than the dimethoxyaryl ring used in the tetrahydroisoquinoline synthesis. Therefore, the cyclization step could take place at a temperature as low as -60 °C. Also, p-tolu-enesulfonic acid resulted in a better diastereoselectivity. However, the diastereo-selectivity of the system is much less sensitive to the aryl substituents of the acetylenic sulfoxides compared to that of the tetrahydroisoquinoline system. Also, to our surprise, the steric factor on the chiral acetylenic sulfoxide has little effect on the diastereoselectivity. Even with the bulky 2-methoxy-naphthyl acetylenic sulfoxide lc [11], the diastereoselectivity still remained roughly the same as for 1 a and 1 b (Scheme 7) (Table 3). 

Alkyl phosphonates are prepared smoothly by TMG (1) catalysed aldol-type addition of dialkyl phosphites to ketones and imines under mild conditions [28] (Scheme 4.9). Dialkyl phosphites can also serve as good nucleophiles for Michael addition (phospha-Michael Reaction). 

In alkenyl- and alkynylcarbene complexes the addition of nucleophiles to the carbene carbon competes with the addition to the 3-carbon of the conjugated C-C multiple bond. [17] The regioselectivity of the addition of amines to alkynylcarbene complexes is temperature dependent 1,2-addition is favoured by lower temperatures. [17c] Enolates turned out to be efficient C-nucleophiles for Michael addition reactions to unsaturated metal carbenes. The product distribution may depend on steric factors as shown in Scheme 7 for the addition of different enolates to alkenylcarbene complex 10. The less bulky acetone enolate 11 adds to the carbene carbon protonation of the primary addition product results in demetalation and in the formation of a mixture of isomeric enones 12. In contrast, the more bulky cyclopentanone enolate 13 adds to the less shielded vinylic position. 

Also known as conjugate addition, Michael addition is the 1,4-addition of a nucleophile to an a,P-unsaturated system. 

Enantioselective organocatalytic synthesis of 3,4-dihydro-2H-pyran-2-ones can be accomplished through a nucleophile-catalyzed Michael addition-proton transfer—enol lactonization of a,P-unsaturated acyl chlorides and 1,3-dicarbonyl compounds (Scheme 47) (13AGE13688). 

The strategy used for the formation of methylenecyclopentanes was applied to the one-pot synthesis of various 3-methylenetetrahydrofurans. The methodology was based on an oxygen nucleophile initiated Michael addition of propargyl alcohols to alkylidene or arylidenemalonates followed in situ by a Pd-mediated cyclization. ° ... 

The oxidative transfonnation of 2-trifluoromethylfuran 69 into butenolide 265 was perfonned using m-nitrobenzenesulfonyl peroxide (m-NBSP) followed by hydrolysis under basic conditions. Deprotonated butenolide was shown to be good nucleophile in Michael addition to various substrates [155],... 

Scheme 5 One-pot thiolactone-based ctmjugation aminolysis of a thiolactone, followed by thiol-click conjugation. The in situ generated thiol can react according to three distinct reaction pathways (a) radical (UV-initiated) or (b) nucleophilic (thiol-Michael) addition of a thiol to a double bond (thiol-ene), and (c) thiol-disulfide exchange...

Phosphorus nucleophiles Asymmetric Michael addition of diaryl phosphine oxides to a,/ -unsaturated A-acylated oxazolidinones (299) has been reported to proceed with excellent enantioselectivities (<99% ee) in the presence of a catalyst generated from Et2Zn and the polydentate ligand (301). °... 

Carbon nucleophiles enamines Michael addition of cyclohexanone and other cyclic ketones to chalcones Ar CH=CHCOAr, catalysed by the pyrrolidine-based phthalimide and/or 1,8-naphthalimide (316) (30mol%) in the presence of PhC02H (10mol%), neat at 20 C, has been found to exhibit good stereoselectivity (<99 1 dr, <96% ee) Similar results were obtained with the C2-sytnmetric tetraamine (317) as 0 catalyst (20 mol%) with <99 1 dr and 93% ee in the presence of 4-Me0-C6H4C02H (20 mol%) (neat, r.t.). Here, a mechanism has been proposed, based on the ESI-MS study of the intermediates. ... 

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... 

A synthetically useful reaction known as the Michael reaction, or Michael addition, involves nucleophilic addition of carbanions to a p unsaturated ketones The most common types of carbanions used are enolate 10ns derived from p diketones These enolates are weak bases (Section 18 6) and react with a p unsaturated ketones by conjugate addition... 

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). 

In the absence of a base, the ayiridine ring can be quaterni2ed and opened by the nucleophile. A pyrroli2idine synthesis, in which such a reaction proceeds intramoleculady followed by a Michael addition (159), is shown as follows ... 

Primary cycloaUphatic amines react with phosgene to form isocyanates. Reaction of isocyanates with primary and secondary amines forms ureas. Dehydration of ureas or dehydrosulfuri2ation of thioureas results in carhodiimides. The nucleophilicity that deterrnines rapid amine reactivity with acid chlorides and isocyanates also promotes epoxide ring opening to form hydroxyalkyl- and dihydroxyalkylaniines. Michael addition to acrylonitrile yields stable cyanoethylcycloalkylarnines. 

Nucleophilic Substitution Reactions. Many of the transformations reali2ed through Michael additions to quiaones can also be achieved usiag nucleophilic substitution chemistry. In some iastances the stereoselectivity can be markedly improved ia this fashion (100), eg, ia the reaction of ben2enethiol with esters (R = CH C O) and ethers (R = 3) 1,4-naphthoquiaones. 2-Bromo-5-acetyloxy-l,4-naphthoquiQone [77189-69-6J, R = Br, yields 75% of 2-thiophenyl-5-acetyloxy-l,4-naphthoquinone [71700-93-1], R = SC H. 3-Bromo-5-methoxy-1,4-naphthoquinone [69833-10-9], R = Br, yields 82% of 3-thiophenyl-5-methoxy-l,4-naphthoquinone [112740-62-2] R = SC H. ... 

Micha.elAdditions. The reaction of a bismaleimide with a functional nucleophile (diamine, bisthiol, etc) via the Michael addition reaction converts a BMI building block into a polymer. The non stoichiometric reaction of an aromatic diamine with a bismaleimide was used by Rhc )ne Poulenc to synthesize polyaminobismaleimides as shown in Figure 6 (31). 

The Michael addition of nucleophiles to the carbon—carbon double bond of maleimide has been exploited ia the synthesis of a variety of linear polymers through reaction of bismaleimide with bisthiols (39). This method has been used to synthesize ethynyl-terminated imidothioether from the reaction of 4,4 -dimercaptodiphenyl ether [17527-79-6] and A/-(3-ethynylphenyl)maleimide (40). The chemical stmcture of this Michael addition imide thermoset is as follows ... 

The use of carbon nucleophiles in Michael-type addition reactions with pteridine and its derivatives leads to a quite complicated and divergent pattern. These reactions are strongly dependent on the nature of the carbon nucleophile and can be divided into various categories. 

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