A Michael addition with

The Bsmoc derivative is formed from the chloroformate or the A -hydroxy-succinimide ester. It is cleaved rapidly by a Michael addition with tris(2-aminoethyl)amine at a rate that leaves Fmoc derivatives intact. More hindered bases, such as A -methylcyclohexylamine or diisopropylamine, do not react with the Bsmoc group, but do cleave the Fmoc group, illustrating the importance of steric effects in additions to Michael acceptors. 

Krohnke observed that phenacylpyridinium betaines could be compared to 3-diketones based on their structure and reactivity, in particular, their ability to undergo Michael additions. Since 3-dicarbonyls are important components in the Hantzsch pyridine synthesis, application of these 3-dicarbonyl surrogates in a synthetic route to pyridine was investigated. Krohnke found that glacial acetic acid and ammonium acetate were the ideal conditions to promote the desired Michael addition. For example, N-phenacylpyridinium bromide 50 cleanly participates in a Michael addition with benzalacetophenone 51 to afford 2,4,6-triphenylpyridine 52 in 90% yield. 

The group ofWalborsky probably has described one of the first true anionic/radi-cal domino process in their synthesis of the spirocyclopropyl ether 2-733 starting from the tertiary allylic bromide 2-730 (Scheme 2.161) [369]. The first step is a Michael addition with methoxide which led to the malonate anion 2-731. It follows a displacement of the tertiary bromide and a subsequent ring closure which is thought to involve a SET from the anionic center to the carbon-bromine anti bonding orbital to produce the diradical 2-732 and a bromide anion. An obvious alternative Sn2 halide displacement was excluded due to steric reasons and the ease with which the reaction proceeded. 

A typical second step after the insertion of CO into aryl or alkenyl-Pd(II) compounds is the addition to alkenes [148]. However, allenes can also be used (as shown in the following examples) where a it-allyl-r 3-Pd-complex is formed as an intermediate which undergoes a nucleophilic substitution. Thus, Alper and coworkers [148], as well as Grigg and coworkers [149], described a Pd-catalyzed transformation of o-iodophenols and o-iodoanilines with allenes in the presence of CO. Reaction of 6/1-310 or 6/1-311 with 6/1-312 in the presence of Pd° under a CO atmosphere (1 atm) led to the chromanones 6/1-314 and quinolones 6/1-315, respectively, via the Jt-allyl-r 3-Pd-complex 6/1-313 (Scheme 6/1.82). The enones obtained can be transformed by a Michael addition with amines, followed by reduction to give y-amino alcohols. Quinolones and chromanones are of interest due to their pronounced biological activity as antibacterials [150], antifungals [151] and neurotrophic factors [152]. 

The electroreduction of oxazolinium salts gives acylanion equivalents that react in a Michael addition with activated olefins as shown for methylacrylate in Scheme 145 [263]. 

Aromatic aldehydes react very easily with tetramic acid under acidic conditions to give 3-benzylidene compounds (41). The yields are moderate, because often there are subsequent reactions. As a,/3-unsaturated carbonyl compounds, (41) react in a Michael addition with excess tetramic acid to form (67), but it can also react with other acyclic and cyclic 1,3-dicarbonyl compounds. In these reactions the aryl substituents may vary over a wide range. Thus, (67) and (68) can be cyclized with ammonium acetate to afford pharmacologically interesting compounds (70) and (71) (90TH1). The latter are dihydropyridines. Curiously, (69) does not cyclize under these conditions. (See Fig. 32.)... 

Recently Martin and Narayanan [104] reported that the a-aminonitrile 2(JV,iV-diethylamino)-2-phenylacetonitrile undergoes a Michael addition with acrylonitrile in the absence of solvent but in the presence of benzyltrimethyl-ammonium hydroxide. The residue, obtained by ether extraction, is rapidly dehydrocyanated during distillation to give the enamine 4-(jV,jV-diethyl-amino)-4-phenyl-3-butenenitrile in 58 % yield (Eq. 44). Whether this reaction... 

As is to be expected, an alkynic ketone undergoes a Michael addition with a carbanion, leading eventually to a pyranone (50JA1022). Using malonic esters, a 3-alkoxycarbonyl derivative results, which is hydrolyzed to the 2-oxopyran-3-carboxylic acid under alkaline conditions, but to the pyranone by sulfuric acid. Rapid ester exchange is observed with the initial products, the alcohol used as solvent determining the nature of the alkyl group in the 3-carboxylic esters (Scheme 90). 

Ring closure can be considered to involve participation of the anion (511) in a Michael addition with the neighbouring ring, with subsequent loss of methoxide (Scheme 187). 

The scope of the chemistry outlined in Figure 16.21 can be further expanded by including other acids susceptible to irreversible reaction with a primary amine. These can be other halocarboxylic acids, such as (chloromethyl)benzoic acids, or acrylic acid, which reacts with amines to yield N-substituted (1-alanines. N-Substituted oligo((5-ala-nines) have been successfully prepared by sequentially acylating support-bound amines with acrylic acid and then performing a Michael addition with primary amines [239]. 

An asymmetric version of a Michael addition with nitrogen nucleophiles can be also realized with simple short-chain peptides as catalysts. This has been demonstrated by Miller et al. for the addition of an azide to a,/(-unsaturated carbonyl compounds [16]. In the presence of the tripeptide 9 as a catalyst (2.5 mol-%) the products 10 have been formed in excellent yields and with up to 85% ee (Scheme 7). In addition, this reaction represents an attractive access to /(-amino acids. 

Poly(amidoamine)-(PAMAM-Starburst)-Monodendrons Among the first Starburst (Cascade) syntheses we performed in the early 1980s [83] involved partially masked (differentiated) initiator cores. For example dodecyl-amine, hydroxyalkyl amines or partially protected alkylene diamines were used as initiator cores and submitted to sequential (a) Michael addition with methyl acrylate followed by (b) reaction with an excess of ethylene diamine to give in situ branch cell construction in a divergent manner. The resulting products were core functionalized monodendrons as shown below ... 

Other saccharide electrophiles utilized have been an a, 8-unsaturated keto derivative and ethylated thiolevoglucosan. The former yielded in a Michael addition with tetra-O-acetyl-l-thio-/3-D-glucop)Tanose the (1— 4)-linked disaccharide in an excellent yield (O Scheme 59) [183,184]. The latter, when reacted with the sodium salt of the above glucose thiol, gave the (1 6)-linked disaccharide as its thioethyl glycoside (O Scheme 60) [185]. 

The Knoevenagel condensation is a base-catalyzed aldol-type reaction, and the exact mechanism depends on the substrates and the type of catalyst used. The first proposal for the mechanism was set forth by A.C.O. Hann and A. Lapworth Hann-Lapworth mechanism) In 1904." When tertiary amines are used as catalysts, the formation of a p-hydroxydlcarbonyl Intermediate is expected, which undergoes dehydration to afford the product. On the other hand, when secondary or primary amines are used as catalyst, the aldehyde and the amine condense to form an Imlnlum salt that then reacts with the enolate. Finally, a 1,2-ellmlnatlon gives rise to the desired a,p-unsaturated dicarbonyl or related compounds. The final product may undergo a Michael addition with the excess enolate to give a bis adduct. 

Dicarbonyl compound 52 being strongly acidic undergoes a Michael addition with methyl vinylketone (MVK) and the intermediate products can be cyclized to s/wVo-cyclohexenone 68 (Scheme 64, ref. 65). 

A number of 5-aryl- and 5-hetarylmethylenebarbituric acids have been found to react with diethyl malonatc or ethyl cyanoacetate in the presence of excess ammonium hydroxide or acetate via a Michael addition with subsequent ring closure to give ethyl 7-amino-5-aryl-2,4-dioxo-1,2,3.4-tetrahydropyrido[2,3-[Pg.114]

Carbanions 26 are derived from azlactones by the action of bases. They undergo a Michael addition with alkenes possessing electron-withdrawing substituents such as acrylonitrile. On hydrolysis, the adducts 27 yield keto nitriles 28 [80] ... 

Wang and coworkers achieved p-functionalisation of simple aldehydes. This concept was realised by oxidation of an enamine formed from the catalyst and aldehydes with suitable oxidant, such as IBX. The thus-formed unsaturated iminium ion underwent a Michael addition with various nucleophiles. Similarly, Hayashi s laboratory described oxidation of enamines with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) and then Michael addition using nitromethane as nucleophile. ... 

Interestingly, the retained alkynone moiety 56 can be reacted in a Michael addition with several secondary amines 57 to give 1,2,3-triazolyl-methyl aminoacrylates 58 with exclusive -configuration. Again, high yields were obtained considering the formation of five new bonds and a bond-forming efficiency of 87—91%. 

Knoevenagel condensation between the aldehyde (1) and malononitrile (16) to form cyanoolefins (40), followed by a Michael addition with amidine (38), cycloaddition, isomerization, and aromatization to afford the 4-amino-5-pyrimidinecarbonitriles (39) (Figure 9.2). 

Each of the respective research groups effected the transformation of the endocyclic enamine 62 to ( )-mesembrine by means of a Michael addition with methyl vinyl ketone (Scheme 16). The yields for this reaction reported... 

Just as ammonia undergoes a Michael addition with a,P-unsaturated carbonyl derivatives, amines also add to conjugated acids such as acrylic acid to give -amino... 

This transformation presumably involves the initial formation of pyrazolamine 57 and its L-proline-promoted conversion to azadiene 58. This intermediate gives a Michael addition with 2-hydroxy-1,4-naphthoqttinone affording a naphthotrione... 

In a different approach to the synthesis of chromane derivatives, Penunal developed a three-component reaction between salicylaldehyde, malononitiile and indole in water using L-proline as the catalyst (Scheme 1.39). In the meehanism of this transformation, indole reacts readily via a Michael addition with a 2-imino-3-chromene-3-caibonitrile intermediate 73, generated from salicylaldehyde and malononitiile in water, to furnish compounds 74 [61],... 

Lithiated bis(methylthio)(trimethylsilyl)methane undergoes a Michael addition with cyclohept-2-enone to give (309) after hydrolysis. 4-Chloro-2,6-bis(methylthio) thiopyrylium perchlorate condenses with P-diketones in the presence of triethylamine to give thiopyranylidene derivatives, e.g. cycloheptane-1,3-dione gave (310). ... 

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