Three-component reductive alkylation

Ramachary and Reddy developed one of these sequences using an amino acid-catalyzed three-component reductive alkylation (TCRA) as the first reaction of their MCC. This multicomponent reaction involved an aldehyde 21, a malonate 22, and the Hantzsch ester 24 under amino acid catalysis starting with a Knoevenagel condensation, which was followed by hydrogenation of the formed olefin 23 to form... 

Scheme 1J.5 Three-component reductive alkylation (TCRA) as first cascade of the multicatalysis domino reaction.

D. B. Ramachary, M. Kishor, Org. Biomol. Chem. 2010, 8, 2859-2867. Direct catalytic asymmetric synthesis of highly functionalized tetronic acids/tetrahydro-isobenzofuran-1, 5-diones via combination of cascade three-component reductive alkylations and Michael-aldol reactions. 

NHC N-heterocyclic carbene TCRA three-component reductive alkylation... 

In 2010, Enders et al. reported on an organocatalytic, one-pot, three-component reductive amination/aza-Michael sequence. They used bis(2,4,6-triisopropyl-phenyl)-l,l -binaphthyl-2,2 -diyl hydrogenphosphate (TRIP) 319 as the organocatalyst and 2-binaphthyl substituted benzathioazole derivatives 320 as the reducing agent and t-BuOH was used as the base. After alkylative cyclization, substituted tetrahydroisoquinoline derivatives 318 were formed in high yields with excellent stereoselectivity (Scheme 40.69). 

Two essentially different mechanisms, (i) oxidative cyclization of two 7T-components (formation of metallacycle) and (ii) oxidative addition of reducing or alkylating agents followed by insertion of 7t-components, can operate in these three-component reactions.426 However, the aforementioned phenomena such as the reversal of regiochemistry and the crossover from reductive to alkylative manifolds remain unsolved. 

Two examples of three-components coupling reaction are shown in Reactions (7.77) and (7.78) [27,87]. These radical chain reactions proceeded by the addition of an alkyl or vinyl radical onto carbon monoxide, generating an acyl radical intermediate, which, in turn, can further react with electron-deficient olefins to lead, after reduction, to a formal double alkylation of carbon monoxide. These three-components coupling reactions require the generation of four highly disciplined radical species, which have specific functions during the chain reaction. 

Following Ellman s pioneering work on benzodiazepines,2 another study from the same laboratory illustrated the vast potential of combining a variety of chemical reactions on drug-like heterocycles. In this case a preformed heterocycle was grafted as a whole onto the solid phase to be subsequently derivatized via a three-component palladium-mediated coupling reaction followed by a reductive alkylation or an acylation (Fig. 12).34... 

An enantioselective one-pot, three-component imino-Reformatsky reaction has been reported.20 Combining a benzaldehyde, an aniline, and an alkyl bromoacetate ester, (g) ees of up to 92% have been achieved in the /i-amino ester product, using a recyclable A-methylcphedrinc as auxiliary. A nickel(II) salt and dimethylzinc are employed the latter serves as dehydrating agent, reductant, and coordinating metal. 

Scheme 6.33 illustrates an example of some zinc-induced three-component coupling reactions of alkyl iodides, electron-deficient alkenes, and carbonyl compounds [51]. In this instance, the isopropyl radical is generated by a one-electron reduction of isopropyl iodide followed by elimination of iodide ion. The resulting radical then adds to acrylonitrile to form an a-cyano alkyl radical, which is con-... 

List and coworkers reported an excellent approach to the enantioselective synthesis of P branched a amino phosphonates, which involved the extension of the dynamic kinetic resolution strategy (Scheme 3.53) [110] that was previously applied to the enantioselective reductive amination of a branched aldehydes by his research group (see Scheme 3.45). The method combines dynamic kinetic resolution with the parallel creation of an additional stereogenic center. They successfully accomplished the direct three component Kabachnik Fields reaction of 1 equiv each of the racemic aldehyde, p anisidine, and di(3 pentyl)phosphite in the presence of newly developed chiral phosphoric acid It. The corresponding p branched a amino phosphonates were obtained in high diastereo and enantioselectivities, especially for the aldehydes bearing a secondary alkyl group at the a position. 

Three-component formation was observed for pyrene- and naphtha-lene-/9-CD complexes in the presence of surfactants such as n-alkyl sulfates (chain length C4-C12), n-alkylammonium chlorides (Cj-Cg), and n-al-kyltrimethylammonium bromides (CiQ-Cig) [118]. The two complexes exhibit different behavior in the presence of surfactants. With respect to the value of the two-component system, increased association constants were found for pyrene (short-chain surfactants gave higher constants than long-chain). Lower association constants were found for / -CD-naph-thalene in the presence of surfactants. By following the time course of T-T absorption of the two aromatics in the presence of nitrite, it was found that their different behaviors were due to surfactant influence on the rate constants of formation (k+) and dissociation (k ) of the inclusion compound. For naphthalene, a reduction of k+ was observed in the presence of surfactants while k was unaffected. For pyrene, short-alkyl-... 

The [l,4,2]-oxazaphosphinane naphthoquinones 51 were obtained from a short synthesis based on transformation of 2,3-dichloro-l,4-naphthoqui-none into 2-amino-3-hydroxy-1,4-naphthoquinone 50 by a double Michael addition of water and of nitrite, followed by the reduction of the nitro group into an amino group using sodium dithionite (Scheme 11). Then, a three component reaction, mixing various ketones, alkyl dichloro-phosphate, and quinone 50 furnished fused the quinonic systems 51 in yields ranging from 60% to 95%. The monoester derivative 52 is readily obtained by treatment of the ester 51 ((R = Et, = R = Me) with TMSBr in chloroform, followed by methanolysis of the sdyl ester intermediate. 

When 1,3-diene is the radical acceptor, a three-component coupling reaction of alkyl halide, 1,3-diene, and trimethylsilylmethyl-magnesium chloride takes place to afford homoallylsilane The final step of the three-component coupling is reductive elimination from allyl(trimethylsilylmethyl)cobalt that predominates over conceivable /3-hydride elimination. 

Romo and coworkers were able to expand on their tetrahydrofuran synthesis by finding conditions for a three-component cascade sequence that resulted in 2,5-cis-tetrahydrofurans from keto-aldehydes, ketene acetals, and EtaSiH (Scheme 8) [11]. Optimal conditions required an excess of ZnCh and Et3SiH to give tetrahydrofurans in high diastereoselectivity. The two-step yields, with alkyl ketones, were in the 42-54 % range with the lowest yield of 13 % coming from the use of a benzylic ketone (R = Ph). The authors found it easier to isolate the products after reduction of the crude reaction mixture. 

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