Cascade reactions amine-catalyzed

Scheme 5.14 One-pot cascade involving acid-catalyzed acetal hydrolysis followed by the addition of methyl vinyl ketone (MVK) in an amine-catalyzed Baylis-Hillman reaction. The acid and base used were synthesized as in Scheme 5.13 [30],...

In the second case, Melchiorre and co-workers [59] used a Michael—Michael cascade reaction between an unsaturated spirocycle and an enone. This reaction is efficiently catalyzed by a primary amine derived (XIII) in a single step from the cinchona alkaloid hydroquinine. The reaction afforded the final spirooxindoles in... 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

In a convenient one-pot process, easily accessed propargyl vinyl ethers and aromatic amines are effectively converted into tetra- and pentasubstituted 5-methylpyrroles, which can fnrther be transformed into 5-formylpyrroles via 2-iodoxybenzoic acid (IBX)-mediated oxidation (Binder and Kirsch 2006). The cascade reaction proceeds through a silver(l)-catalyzed propargyl Claisen rearrangement, an amine condensation, and a gold(l)-catalyzed 5-exo-dig heterocyclization, as shown in Schane 11.4. 

The insertion of CO into Pd-carbon bonds has also been employed in several tandem/cascade reactions that afford five-membered nitrogen heterocycles [97]. A representative example of this approach to the construction of heterocydes involves synthesis of isoindolinones via the Pd-catalyzed coupling of 2-bromobenzaldehyde with two equivalents of a primary amine under an atmosphere of CO [97bj. As shown below (Eq. (1.57)), this method was used for the preparation of 144 in 64% yield. The mechanism of this reaction is likely via initial, reversible condensation of 2-bromobenzaldehyde with 2 equiv of the amine to form an aminal 145. Oxidative addition of the aryl bromide to Pd° followed by CO insertion provides the acylpalladium spedes 146, which is then captured by the pendant aminal to afford the observed product. An alternative mechanism involving intramolecular imine insertion into the Pd—C bond of a related acylpalladium species, followed by formation of a paUadium-amido complex and C—N bond-forming reductive elimination has also been proposed [97b],... 

Synthesis of 1,2-disubstituted indole frameworks 257 via a formal 4 - - 1 cydoaddition between a 4-carbon unit and a primary amine was recently developed by Ackermann (Scheme 9.90) [242]. Reactive intermediates, 2-(o-haloaryl)enam-ines 256 were generated via the Cu(I)-catalyzed hydroamination of the orfHo-halo-substituted phenylacetylenes 254 with primary amines 255. A subsequent Cu(I)-catalyzed intramolecular enamine arylation reaction gave the corresponding indoles 257 in good yields. The authors demonstrated that alkynyl chlorides 254 could also participate in this cascade double amination process, albeit with a substantially diminished efHdency. 

In a cascade reaction, Wang and coworkers showed that Pd(0) in the presence of PPh3 could be used to access 1,2,5-substituted pyrroles at modest temperatures in short reaction times (Scheme 15.100). First, allyHc amination via a Pd-catalyzed... 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

In 2013, Buchwald and Jui developed a novel approach to palladium-catalyzed regioselective Al-aiylbenzimidazole synthesis. This methodology involves cascade intermolecular amination and amidation reactions of 2-chloroaiyl sulfonates (or halides) the desired benzimidazoles were isolated in good yields in general (Scheme 2.19). In their procedure, a single catalyst based on tBuBrettPhos was able to selectively perform both catalytic... 

This type of cyclization reaction was applied in the synthesis of p-carbo-linones and total synthesis of dipyrrolobenzoquinone ( )-terreusinone as well. In 2005, Barluenga and co-workers reported a novel approach for the synthesis of indoles from o-bromoanilines and alkenyl halides via a palladium-catalyzed cascade process (Scheme 2.112). The reaction involves an alkenyl amination followed by an intramolecular Heck reaction. As the authors demonstrated, this process represents the first example of the participation of alkenyl amination reactions in Pd-catalyzed cascade reactions. Initially, the relative reactivity of aiyl and alkenyl bromides and chlorides towards Pd-catalyzed amination was investigated. Competition... 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

In order to establish the two-step strategy, both en2ymatic steps were evaluated separately this included the engineering of the TK to accept the non-natural substrate propanal, and use of a bioinformatic-based strategy to identify a suitable co-TA with the ability to accept the ligation product. The final reaction was performed in two sequential steps, because preliminary experiments indicated that the co-TA also aminates the TK substrates in the presence of an amine donor. Notably, for the reductive amination (second step), cheap and achiral 2-PrNH2 could be used successfully as an alternative amine source. The final product was isolated after the two enzymatic steps, with a calculated overall isolated yield of 18% under nonoptimized conditions. However, while the TK-catalyzed C-C bond formation already displayed suitable conversions (23%), the cb-TA was identified to be the bottleneck of the cascade reaction further optimization, especially with respect to the reductive amination, should facilitate a more efficient process. 

Palladium and chiral amine co-catalyzed enantioselective dynamic cascade reaction of simple starting materials leads to the synthesis of polysubstituted carbocycles with a quaternary carbon stereocenter (Scheme 6.14) [16]. 

Ma, G., Afewerki, S., Deiana, L., Palo-Nieto, C., Liu, L., Sun, J., Ibrahem, I., Cordova, A. (2013). A palladium/chiral amine co-catalyzed enantioselective dynamic cascade reaction synthesis of polysubstituted carbocycles with a quaternary carbon stereocenter. Ange-wandte Chemie International Edition, 52, 6050-6054. 

In the second reaction, a Michael-Michael cascade between an unsaturated oxin-doles 17 and enones 22 was shown to be catalyzed by a primary amine-derived catalyst (II) (Scheme 10.3). The reaction afforded the spirooxindoles 23 in excellent yields and diastereo and enantioselectivities. Wang used a similar approach in the reaction of isatylidene malononitriles and enones [12]. The reaction was catalyzed by the dual combination of cinchona-based chiral primary amine and BINOL phosphoric acids to afford the spirocycles in excellent yields (88-99%), diastereo (up to 99 1 dr), and enantioselectivities (95-99% ee). 

Wang and coworkers made a similar approach using isocyanoesters [25]. The reaction was catalyzed by bifunctional tertiary amine-thiourea catalysts and afforded the pyrrolidinyl spirooxindoles in good yields and excellent enantioselectivities but low diastereoselectivities. Later, Yan and coworkers developed a similar reaction involving the three-component cascade reaction of isatin, isocyanoesters, and malononitrile [26]. First, the Knoevenagel reaction between isatin and malononitrile afforded the... 

Finally, Han, Huang, and Peng reported a multicomponent cascade reaction for the synthesis of the spirooxindole pyranone scaffold [38]. The reaction started with the addition of aliphatic aldehydes 15 to nitrostyrenes 64 catalyzed by chiral secondary amine catalyst I. Next, the resulting adduct reacted with A-benzyl isatin (54b) by a Henry-hemiacetal formation cascade followed by pyridinium chlorochromate (PCC) oxidation to afford the corresponding spirooxindoles 70 in good yields and stereoselectivities (Scheme 10.24). 

In 2011, Moreau, Greek and coworkers reported a multicatalytic process [6] merging two consecutive enamine catalytic cycles based on a Michael addition/a-amination cascade reaction [7]. The Michael addition of aldehydes to p-nitrostyrene followed by the electrophilic amination were catalyzed, respectively, by the diphenylprolinol silylether 5 and the 9-amino-(9-deoxy)-cpf-cinchonine 6 (Scheme 12.4), both previously described by Hayashi and coworkers [8] and Melchiorre and coworkers [9]. One interesting feature of this reaction is that diphenylprolinol silylether 5 can specifically catalyze the Michael addition, while 9-amino-(9-deoxy)-ep/-cinchonine 6 is required to promote the electrophilic amination. The Michael addition of propionaldehyde to p-nitrostyrene was achieved by using only 5 mol% of catalyst 5 in chloroform at 0 C. After completion of the reaction, dibenzyl azodicarboxylate (DEAD, 1.5 equiv), trifluoroacetic acid (15 mol%) and the second catalyst 6 (5 mol%) were added. The expected product 7 was obtained as a single diastereomer in good yield (80%) and with excellent enantioselectivity (ee 96%). Various nitroalkenes bearing electron-rich and electron-deficient aryl... 

Conceptually similar palladium-catalyzed cascade reactions have been developed, involving molecular-queuing cycloaddition, cyclocondensation and Diels-Alder reactions [71], cydization-anion-capture-olefin metathesis [72], carbonylation-allene insertion [73], carbonylation/amination/Michael addition [74], sequential Petasis reaction/palladium-catalyzed process [75], supported allenes as substrates [76], and palladium-ruthenium catalysts [77]. 

Scheme 11.13 Deracemization of racemic amino acids by cascade reactions, including DAAOs-catalyzed reactions and reductive amination reactions catalyzed either by amino acid dehydrogenases (a) or transaminases (b).

Continuing their investigation of tandem cascade reactions toward indole synthesis, Barluenga et al. reported a process combining palladium-catalyzed aza-enolate a-arylation followed by intramolecular N-arylation (Scheme 24.1, disconnection D-7) [51]. The process is outlined in Scheme 24.9 initial palladium-catalyzed aza-enolate arylation generates intermediate imine 23 and then palladium-catalyzed intramolecular amination, presumably via intermediate enamine 24, results in the product indole in excellent 86% yield. An XPhos-derived catalyst facilitated both steps of the cascade, and a wide range of imines could be incorporated. 

These findings were extended to a set of very useful cascade reactions by the MacMiUan group [111]. In a first series 1,4-hydride additions were combined with aminations, oxidations, or Mannich reactions (Scheme 4.30). The hydride transfer was catalyzed by imidazoHdinone 9, whereas subsequent functionalization was realized by enamine catalysis through the deployment of proline. Depending on the chirality of proline used, optically pure anti- or syu-configured products 84-86 were isolated. 

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