Imines Michael-type addition

The history of dendrimer chemistry can be traced to the foundations laid down by Flory [34] over fifty years ago, particularly his studies concerning macro-molecular networks and branched polymers. More than two decades after Flory s initial groundwork (1978) Vogtle et al. [28] reported the synthesis and characterization of the first example of a cascade molecule. Michael-type addition of a primary amine to acrylonitrile (the linear monomer) afforded a tertiary amine with two arms. Subsequent reduction of the nitriles afforded a new diamine, which, upon repetition of this simple synthetic sequence, provided the desired tetraamine (1, Fig. 2) thus the advent of the iterative synthetic process and the construction of branched macromolecular architectures was at hand. Further growth of Vogtle s original dendrimer was impeded due to difficulties associated with nitrile reduction, which was later circumvented [35, 36]. This procedure eventually led to DSM s commercially available polypropylene imine) dendrimers. 

All of these reactions proceed in a similar pathway which involves the Michael type additions of enamines to nitroalkenes or addition of nitroalkanes to imines and cyclization. This process has been achieved by solid-phase variation (Scheme 10.2).14... 

Michael-type addition of activated methylene compounds to imines (Table 6.17)... 

The most common preparations of amines on insoluble supports include nucleophilic aliphatic and aromatic substitutions, Michael-type additions, and the reduction of imines, amides, nitro groups, and azides (Figure 10.1). Further methods include the addition of carbon nucleophiles to imines (e.g. the Mannich reaction) and oxidative degradation of carboxylic acids or amides. Linkers for primary, secondary, and tertiary amines are discussed in Sections 3.6, 3.7, and 3.8. 

In a more recent approach, 6-aminouracil or its 6-iminophosphorane is reacted with A -phenylbenzimidoyl chloride to give, in a Michael-type addition, a tautomeric pair of imines, A and B. The equilibrium is shifted in different solvents. Tautomer B is intercepted by an acetylenic ester to form a l,4-dihydropyrido[2,3-c/]-pyrimidine. The iminophosphorane of A and isocyanate results in an aza-Wittig reaction and polar 67r-electron cyclization reaction to give pyrimido[4,5-[Pg.159]

The first prominent catalytic asymmetric Michael-type addition reaction of an organolithium reagent was shown by the reaction of 1-naphthy[lithium with 1-fluoro-2-naphthylaldehyde imine in the presence of 6 to afford the binaphthyls in high ee. Only catalytic amounts of 6 (0.05 mol%) effects the reaction to give 82% ee, in which an enantioselective Michael-type addition-elimination mechanism is operative (Eq. (12.12)) [31],... 

A chromium complex of benzaldehyde imine is also a good substrate for the Michael-type addition of organolithium reagents mediated by a stoichiometric amount of the chiral diether 6 in toluene to give the corresponding product in up to93%ee(Eq. (12.13)) [32]. 

Despite of the fact that Baylis and Hillman reported the synthesis of a-hydr-oxyethylated nitroethylene through the reaction between nitroethylene and acetaldehyde in the presence of DABCO, nitroalkenes employed as activated olefins in MBH reaction have not received much attention until recently. Prompted by the fact that nitroalkenes have shown superior Michael acceptor abilities, and that the first step in the MBH reaction is the Michael-type addition of the catalyst to substrate, Namboothiri et al. have published a series of papers on nitroalkenes involved the MBH reaction. The MBH reactions between nitroalkenes and various electrophiles such as formaldehyde, activated carbonyl compounds, imines, alkenes and azodicarboxylates " in the presence... 

A diastereoselective 6-exo-tng cyclization of (318), producing the trans-disubstituted tetralone (319) upon treatment with BF3-Me2S at low temperature, has been reported. This cyclization can be regarded as an intramolecular Michael-type addition with umpolung at the imine carbon. The mechanism includes an internal... 

Similar observations have been made with 6-a-halopenicillanic acids but in this case the thiol anion in the analogous enamine [71] displaces the halide at C(6) via the imine tautomer [72] (Gensmantel et aL, 1981). If the enamine [71] is produced in the transpeptidase-cataiysed reaction with penicillins, then inactivation of the enzyme could occur by a nucleophilic group on the enzyme attacking C(5) in a Michael-type addition reaction. 

In terms of relay and sequential metal-organo multicatalytic systems, these catalysts are most commonly used for 1,2 (aldol type) or 1,4 (Michael type) additions to suitable electrophiles. The most pervasive approach takes advantage of some metal-catalyzed process to generate a substrate for the organocatalyst. The examples illustrated in Scheme 26.16 show how chemical [94] or photochemical [95] metal-catalyzed oxidation of amines generates imine species that then undergo organocatalyzed 1,2 addition. 

The Michael-type addition of cyclohexanone imines (210 = H, Me), reacting as... 

The Michael type of addition, in the presence of acids, has been extended successfully to cyclopropyl ketones347 (reaction 86). Of course, the functional group can also undergo subsequently a transformation202,346,347,349, compatible with the phosphonium structure (acetalization, thioacetalization, imination, etc.). 

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). 

Various electron-withdrawing groups, such as aldehyde, nitrile, esters, ketones, sulfones, etc. have been utilized to activate the vinyl moiety. The generally accepted mechanism (1) shown in Scheme 2 involves the Michael addition of Ae amine catalyst to the alkene, followed by an aldol type addition to the carbonyl or imine com und. Subsequent elimination releases the catalyst, and the cycle continues. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

An analogous cyclization to eventually form five-membered rings has also been observed for l-metalla-l,3,5-hexatrienes with an additional heteroatom within the chain, such as in the complexes 157. These are obtained by Michael additions of imines to alkynylcarbene complexes in good to excellent yields (reaction type F in Scheme 4), and their configurations were determined to be Z (>91%) in all cases. Upon warming in THF solution, complexes 157 underwent cyclization with reductive elimination to furnish 2Ff-pyrroles 158 in up to 97% yield (Scheme 34). With two cyclopropyl substituents at the terminus in... 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

The analogy between imines and carbonyls was introduced earlier, and just as 1,3-dike-tonate complexes undergo electrophilic substitution reactions at the 2-position, so do their nitrogen analogues. Reactions of this type are commonly observed in macrocyclic ligands, and many examples are known. Electrophilic reactions ranging from nitration and Friedel-Crafts acylation to Michael addition have been described. Reactions of 1,3-diimi-nes and of 3-iminoketones are well known. The reactions are useful for the synthesis of derivatised macrocyclic complexes, as in the preparation of the nickel(n) complex of a nitro-substituted ligand depicted in Fig. 5-12. 

Aliphatic amines can be readily oxidized by Pd(II) to imines or iminium salts and hydrido complexes. The latter can transfer hydrogen to alkenes, leading to the formation of alkanes as byproducts of the Heck reaction (last example, Scheme 8.18). Such reactions can be avoided by using alkali carbonates as base instead of aliphatic amines [148]. Treatment of stannanes or organoboron derivatives with electron-deficient alkenes under acidic reaction conditions can also lead to formal products of Michael addition instead of the products of a Heck-type reaction [149, 150] (Scheme8.19). 

The od.p unsaturated carbonyl compounds and imines formed in this manner react by a type of Michael addition with nucleophilic groups (Nu), such as the OH of serine residues, the SH of cysteine residues and the w-NH2 of lysine residues, frequently found at the active sites of enzymes. 

Further extension of the reaction pool of Schilf bases 138 was achieved by their reaction with tran -l-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky s diene) to give 2-substituted 5,6-didehydro-piperidin-4-ones 164 [135,136] (Scheme 10.54). The reaction is considered to be a sequence of an initial Mannich reaction between the imine and the silyl enol ether, followed by an intramolecular Michael addition and subsequent elimination of methanol. If the reaction was terminated by dilute ammonium chloride solution, then the Mannich bases 163 could be isolated and further transformed to the dehydropiperidinones 164 by treatment with dilute hydrochloric acid. This result proved that the reaction pathway is not a concerted hetero Diels-Alder type process between the electron-rich diene and the activated imine. The use of hydrogen chloride as a terminating agent resulted in exclusive isolation of the piperidine derivatives 164 formed with... 

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